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A series of new methyl 4-aryl-6-oxo-5-cyano-1,6-dihydropyridine-2-carboxylates and 4-aryl-6-oxo-5-cyano-1,6-dihydropyridine-2-carboxylic acids were synthesized by reacting methyl esters of acylpyruvic acids with malononitrile and cyanoacetamide, respectively.

The antiproliferative activity of previously obtained 3-R-6-imino-2,7-dioxabicyclo[3.2.1.]octane-4,4,5-tricarbonitriles was tested on 59 cell lines obtained from human lung, colon, brain, ovary, kidney, prostate, and breast tumors and leukemia and melanoma. The most pronounced effect was observed against blood cancer cell lines of leukemia. The strength of the activity and specificity of the compounds on certain types of cells were related directly to the nature of the 3-substituent on the 2,7-dioxabicyclo[3.2.1]octane core. Compounds with multiple bonds and alkyl radicals exhibited more pronounced cytotoxic activity. A compound with a coumarin moiety showed high activity exceeding those of reference drugs (dacarbazine, cisplatin) with respect to kidney cancer cell lines.

A shot cut method for the determination of isoniazid in a solid dosage formulation (DF) has been developed. The method is based on isoniazid titration with a solution of photogenerated iodine obtained as a result of irradiation of an auxiliary solution containing potassium iodide, a mixture of sensitizers (sodium eosinate, fluorescein, auramine taken in a molar ratio of 1:1:1) and phosphate buffer solution (pH 7.5). Since the titrant content in the cell was controlled using the voltammetric method (amperometric titration with two polarized electrodes), the interaction of a physiologically active compound with the latter was accompanied by a decrease in the amount of titrant in the cell and, hence, in the current in amperometric circuit. Stabilization of the current in the circuit of the amperometric setup indicated the completeness of the reaction, and, therefore, provided estimation of the content of a physiologically active compound in the dosage formulation. Further irradiation of the solution and measurement of the generation time required to replenish the loss of titrant in the cell also made it possible to regulate the content of isoniazid in the preparation. The technique was tested on the samples of solid dosed formulations. It was shown that the components of the tablet mass (calcium stearate monohydrate, polysorbate, crospovidone and potato starch) do not affect the results of the determination of physiologically active compound provided that the analyzed form is obtained at room temperature. The determined content of isoniazid in a solid dosage formulation varies in the range of 286.0 – 296.0 mg and falls within the range recommended by the General Pharmacopoeia Monograph 1.4.2.0009.15 (285 – 315 mg), which indicates that the quality of the drug meets the GMP standards. The linear dependence of the analytical signal on the concentration of physiologically active compound is observed in the range of 161 – 1610 mg for the drug «Isoniazid. Tablets, 300 mg». The calculated detection limits and quantitative determination are 13.5 and 41.0 mg (both in terms of change in the current strength and in the time of titrant generation), respectively. The developed photochemical method for the determination of isoniazid in solid dosed formulation is easy to use, meets the requirements set out in the guidelines for validation of bioanalytical methods, and does not require expensive equipment. The method can be recommended for routine control of the DF quality indicators in any analytical laboratory.

The reactions of arylidenemalononitriles with malononitrile, methyl cyanoacetate and cyanoacetamide yielded aminophenyldi- and tricarbonitriles. Formation of these compounds occurs through the dehydrocyanation step of the corresponding aminohexenepolycarbonitriles.

Aseries of cyclobutane-1,1,2,2-tetracarbonitriles contained a compound with significant activity against various cancer cell lines. The compound featured a thiosemicarbazide and the α,β-unsaturated aldehyde myrtenal in its structure and showed the highest activity against leukemia cells, the average growth inhibition against which was 88%. The proposed mechanism of action was associated with alkylation of the nucleophilic regions of tumor-cell DNA. The results showed that compounds with an ethyl-1,1,2,2-tetracarbonitrile fragment inhibited proliferation of malignant cells.

The possibility of using water soluble pyrogallol red (PRWS) as a photometric reagent for the quantitative determination of antimony (III) in real objects has been studied. Formation of a colored product is observed in acidic solutions (pH 3.8 - 4.5) with a weak oxidizing agent (iodine) present for preliminary oxidation of SbHg to salts of Sb (III). The excess iodine is eliminated through introduction of sodium thiosulfate solution after obtaining the photometric form. The maximum analytical signal of the colored form is observed at 378 nm (e = 5.936 x 103). A decrease in the acidity of the solution (pH > 7) is accompanied by the formation of sodium salts of the reagent which prevents further complexation, whereas the only one maximum in the absorbance within the recommended pH range directly indicates to the formation of the the only one ionic associate (AI). The ionic associate thus formed appeared low stability in time. Unfortunately, change in the dielectric constant of the solution failed to give a positive effect and measurements of the absorbance of the colored compound were limited to 3 minutes. Determination of the composition and possible mechanism of the ionic associate formation was carried out on using the methods of molar ratios and isomolar series. After stripping of stibine into the absorption system, an ionic associate of the composition M:R = 1:1 is formed with a calculated stability constant of 4.01 x 105. The obtained results are used to develop a spectrophotometric (SP) method for antimony determination with the limits of detection and quantitative determination of the element 1.30 and 4.32 pg/ml, respectively. The developed method is valid in terms of the specificity, linearity, precision and accuracy, and, therefore, can be recommended for determination of the antimony content in any control and analytical laboratory.

Recently, reactions of allylidenhydrazones with tetracyanoethylene were found to lead to cyclobutanes-products of usually unfavorable (2 + 2) cycloaddition. Herein we computationally demonstrate that the (4 + 2) product of this reaction is severely destabilized by incomplete C-N bond formation, arising from a complex interplay of substituent electronic effects. We show how destabilization of a single bond in the front-runner product averts its formation and redirects chemical reaction toward an uncharacteristic pathway.

Two approaches to the synthesis of 2-(2-oxo-5-aryl-1,2-dihydro-3H-pyrrol-3-ylidene)malononitriles (DCAA-pyrroles 1) were implemented. The first one was based on the transformation of 4-oxobutane-1,1,2,2-tetracarbonitriles 2 by the action of morpholine. The second approach was based on the reaction between protected form of 4-oxobutane-1,1,2,2-tetracarbonitriles 2 namely 2,7-dioxabicyclo[3.2.1]octane-4,4,5-tricarbonitriles 3 and morpholine. This approach involving sequential furan and pyran ring-opening of the 2,7-dioxabicyclo[3.2.1]octane moiety with further pyrrole ring-closure, resulted in a smoother formation of DCAA-pyrroles 1. The optical absorption properties of DCAA-pyrroles 1 were studied for the first time. The absorption maxima were observed in the range of 506–545 nm showing positive solvatochromism and dependence on the substituent in aryl moiety.

We discovered a new method to methylate tertiary amines such as urotropine, triethylamine, pyridine, 2-methylpyridine, 4-acetylpyridine, and isonicotinamide, up to quaternary ammonium compounds, with 1,1-dicyano-2-methoxy-2-oxoethane-1-ide being the counterion. Methyl-1,3,5,7-tetraazaadamantan-1-ium 1,1-dicyano-2-methoxy-2-oxoethane-1-ide, N,N-diethyl-N-methylethanaminium 1,1-dicyano-2-methoxy-2-oxoethane-1-ide, and substituted-methylpyridinium 1,1-dicyano-2-methoxy-2-oxoethane-1-ides were synthesized. Quaternary ammonium compounds of 1,1-dicyano-2-methoxy-2-oxothane-1-ide were synthesized within a single stage by stirring methanol solutions of tertiary amines with ethene-1,1,2,2-tetracarbonitrile (ETCN) at room temperature. In the reaction of ETCN with tertiary amines in methanol, processes occur that form the 1,1-dicyano-2-methoxy-2-oxoethane-1-ide fragment with simultaneous N-methylation. Crystal structures based on X-ray diffraction analysis of the obtained compounds were studied.

Base-catalyzed nucleophilic addition of carbon nucleophiles to the exocyclic double bond of 2-(5-aryl-4-methyl-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)malononitriles afforded spiro-fused pyrrole derivatives, 7-amino-3-aryl-4-methyl-1-oxo-8-oxa-2-azaspiro[4.5]deca-3,6,9-triene-6-carbonitriles. The products can be regarded as rare structural analogs of biologically active spirans based on isatin.

A library of 29 2-amino-6-sulfanylpyridine-3,5-dicarbonitriles functionalized with a pyridoxine moiety was synthesized using a three-component one-pot reaction of aldehyde derivative of pyridoxine,...

An environmentally friendly method has been developed for the preparation of 5H-chromeno[2,3-b]pyridine derivatives in an aqueous medium under ultrasound irradiation.

Successive treatment of 3-acylcyclopropane-1,1,2,2-tetracarbonitriles with sodium hydrogen carbonate and alkylmercaptan in water environment results in the formation of 2-(5-amino-2-aryl-2-alkyl-sulfanyl-4-cyano-2,3-dihydrofuran-3-ylidene)propanedinitriles.

Reaction of methyl 2,4-dioxobutanoates with tetracyanoethylene yielded methyl 3-acyl-4-cyano-5-(dicyanomethylene)-2-hydroxy-2,5-dihydro-1H-pyrrole-2-carboxylates. X-Ray diffraction data showed that 3-acyl-4-cyano-5-(dicyanomethylene)-2-hydroxy-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl esters can form supramolecular structures with one-dimensional channels which make possible inclusion of large organic and bioorganic molecules.

A procedure has been developed for the synthesis of polyfunctional pyrano[3,4-c]pyrrole derivatives via intramolecular cyclization involving vicinal cyano and carboxamide groups on a pyran ring. 3-Amino-1-oxo-1,3a,4,7a-tetrahydropyrano[3,4-c]pyrrole-3a,7a-dicarbonitrile thus obtained react with organic amines to give stable ammonium salts and undergo hydrolysis to 1,3-dioxo-1,2,3,3a,4,7a-hexahydropyrano[3,4-c]pyrrole-3a,7a-dicarbonitriles in the presence of sulfuric acid.

The reaction of 2-acyl(aroyl)-1,1,3,3-tetracyanopropenides with gaseous hydrogen halides was used to obtain 2-amino-3-aroyl(acyl)-6-halopyridine-3,5-dicarbonitriles, which were subsequently converted to the respective 4-amino-1-aryl-6-halo-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles by treatment with concentrated sulfuric acid, followed by aqueous workup.

Reaction of 2-chloropyridine-3,4-dicarbonitriles with primary amines in the presence of potassium carbonate in ethanol results in the fusion of pyrrole cycle and the formation of N 1-substituted 4-halo-1H-pyrrolo-[3,4-c]pyridine-1,3(2H)-diimines.

2-Acyl-1,1,3,3-tetracyanopropenides undergo cascade heterocyclization under the action of mercaptoacetic esters, leading to the formation of new 3,6-diamino-4-aroyl-5-cyanothieno[2,3-b]pyridine-2-carboxylates. The fast and convenient synthetic way to highly substituted thieno[2,3-b]pyridine scaffold is described.

In reaction of tetracyanoethylene with ketones and HCl in 1,4-dioxane at 30–40°? 6-hydroxy-2-chloro-1,4,5,6-tetrahydropyridine-3,4,4-tricarbonitriles are formed.

N-Aryl- and N,N-diethyl-3-oxobutanamides reacted with salicylaldehyde and N-phenylthiourea in ethanol in the presence of sodium hydrogen sulfate as catalyst to give the corresponding N-substituted 2-methyl-3-phenyl-4-sulfanylidene-3,4,5,6-tetrahydro-2H-2,6-methano-1,3,5-benzoxadiazocine-11-carboxamides.

1-[2-(1H-indol-3-yl)ethyl]-4-acetyl-3-hydroxy-5-phenyl-1H-pyrrole-2(5H)-ones were synthesized by the short heating of a mixture of tryptamine, aromatic aldehyde, and methyl acetylpyruvate followed by stirring at room temperature for one day.

The reaction of potassium 2-(2,2-dimethylpropanoyl)-1,1,3,3-tetracyanopropenide with an equimolar amount of 2-sulfanylethanol afforded 2-{5-amino-2-(tert-butyl)-4-cyano-2-[(2-hydroxyethyl)sulfanyl]- 2,3-dihydrofuran-3-ylidene}propanedinitrile, whereas 4-amino-1-(tert-butyl)-1,6-bis[(2-hydroxyethyl)- sulfanyl]-3-imino-1,3-dihydrofuro[3,4-c]pyridine-7-carbonitrile was obtained in the reaction with excess 2-sulfanylethanol.

The reaction of potassium 2-aroyl-1,3-dicyano-1,3-bis-methoxycarbonylpropenides with hydrogen peroxide is unusual for compounds of this type and results in formation of highly substituted 5-amino-3-aroylfuran derivatives. In contrast to few related literature methods leading to formation of this moiety, the advantages of this synthesis includes a readily available and inexpensive precursors, non-usage of any toxic reagents or solvents and short process time. The structure of one of the obtained compounds was determined by X-ray diffraction.

Annulation of 2-chloropyridine-3,4-dicarbonitriles with hydrazine hydrate and N,N-dimethylhydrazine afforded 3-aminopyrazolo[3,4-b]pyridine-4-carbonitriles and 3-amino-1-methylpyrazolo[3,4-b]pyridine- 4-carbonitriles, respectively.

A series of methyl 3-acyl-6-amino-4-aryl-5-cyano-4H-pyran-2-carboxylates were synthesized using the reaction of methyl 2,4-dioxobutanoates with arylidenemalononitriles in EtOAc in the presence of catalytic amounts of morpholine or piperidine. The structures of the compounds were elucidated using IR, PMR, 13C NMR, and mass spectral data. The antimicrobial, analgesic, and antipyretic activities of the synthesized compounds and their influence on antibody response were studied.

An efficient diastereoselective approach for the synthesis of functionalized 3,4-dihydro-2H-pyran-4-carboxamides with variable frame was developed based on the reaction of available 4-oxoalkane-1,1,2,2-tetracarbonitriles (adducts of TCNE and ketones) with aldehydes in an acidic media. An unusual process of quasi hydrolysis of the cyano group was observed in the course of the described regio- and diastereoselective transformation.

A novel route for synthesis of 2-acyl-1,1,3,3-tetracyanopropenides (ATCN) salts in high yields and excellent purities starting from readily available methyl ketones, malononitrile, bromine, and alkali metal acetates is reported. The starting aryl(heteroaryl) methyl ketones were oxidized to the corresponding α-ketoaldehydes by new a DMSO-NaBr-H2SO4 oxidation system in yields up to 90% within a short reaction time of 8-10 min. The subsequent stages of ATCN preparation are realized in aqueous media without use of any toxic solvents, in accordance with principle 5 of "green chemistry". Lithium, sodium, potassium, rubidium, and cesium 2-benzoyl-1,1,3,3-tetracyanopropenides were characterized by X-ray diffraction analysis. These salts show a good potential for synthesis of five- and six-membered heterocycles and may serve as potentially useful ligands in coordination and supramolecular chemistry.

A procedure has been developed for the synthesis of methyl 6-alkyl-3-cyano-2-halopyridine-4-carboxylate by three-component reaction of 4-oxoalkane-1,1,2,2-tetracarbonitriles with hydrogen halides in methanol.

A novel fast, convenient and inexpensive synthesis of 1',3'-dioxo-1',3'-dihydrospiro[cyclopropane-1,2'-indene]-2,2,3,3-tetracarbonitrile and dimethyl 2,3-dicyano-1',3'-dioxo-1',3'-dihydrospiro[cyclopropane-1,2'-indene]-2,3-dicarboxylate is reported. These compounds undergo double carbanion cleavage under the action of alcohols resulting in the formation of stable salts, containing new allylic-type anions with potential application in organic electronics and as ionic liquid components.

Reactions of acetoacetanilide with aromatic aldehydes in ethanol at room temperature in the presence of molecular iodine and arylamine afford to 6-aryl-2-methyl-4-oxo-N,N’-diphenyl-2-cyclohexene-1,3-dicarboxamides. The structure of obtained compounds was confirmed by mass spectrometry, IR and NMR spectroscopy data.

A method for rapid determination of sodium thiosulfate in solution for injection that is based on titration of the active ingredient by photogenerated iodine is proposed. The titrant was produced by 1-2-min irradiation of an absorbing solution containing KI, acetate buffer, and eosin. The limits of detection (with errors of

A fast and convenient synthesis and solid-state luminescence properties of new highly-substituted 6-amino-2H-pyran-2-one derivatives is described. These compounds were obtained from inexpensive and available 2-acyl(aroyl)-1,3-dicyano-1,3-bis-methoxycarbonylpropenides via regioselective heterocyclization under the action of sulfuric and hydroiodic acid. Compounds containing 6-amino-2H-pyran-2-one moiety are nearly unstudied, but are of interest for obtaining condensed biologically active compounds based on this scaffold.

A series of novel N,N-dialkyl-2-amino-3-cyanoisonicotinamides were synthesized in good to high yields (61–84%) via the reaction of 2-(5-aryl-2-oxo-1H-pyrrol-3(2H)-ylidene)malononitriles and amines according to the ANRORC process. The developed approach represents a novel method for the synthesis of functionalized nicotinonitriles.

A new method of the synthesis of 3-(2,2-dimethylhydrazono)-5-R-1,1,2,2-tetracarbonitriles via oxidation of 3-(2,2-dimethylhydrazino)-5-R-1,1,2,2- tetracarbonitriles with diluted nitric acid was developed. High reactivity of 3-(2,2-dimethylhydrazono)-5-R-1,1,2,2-tetracarbonitriles caused by the presence of ethyl-1,1,2,2-tetracarbonitrile and N,N-dimethylhydrazone moieties allowed obtaining 2-methyl-5-R-3,4-dihydro-2Н-cyclopenta[e]1,2,4triazine-6,6,7,7-tetracarbonitriles, 3-amino-4-(2,2-dimethylhydrazono)-6-methyl-1,3а,4,5,6,6а- hexahydrocyclopenta[c]pyrrole-3а,6а-dicarbonitriles, and 3-(2,2-dimethylhydrazino)-5-methylcyclopent-2-ene-1,1,2-tricarbonitrile.

A simple method for the synthesis of inaccessible gem-dinitro derivatives of pyridine is described. A wide range of 2-halogencycloalka[b]pyridine-3,4-dicarbonitriles are produced by the three-component reaction (ketone, TCNE, hydrohalic acid), side-chain nitration of latter with 60% nitric acid in a solvent-free conditions leads to the formation of gem-dinitro derivatives with high selectivity and without disturbing of other reaction centers.

2-Acyl-1,1,3,3-tetracyanopropenides undergo intermolecular reductive heterocyclization under the action of mercaptoethanol or sodium borohydride, resulting in the formation of 2-[5-amino-4-cyano-2-alkyl(aryl)furan-3(2 H ]-ylidene)malononitriles in high yields and excellent purities, These are of interest as potential precursors to organic nonlinear optical (NLO) materials and prospective antibiofilm antimicrobial agents.

5-Oxoalkane-2,2,3,3-tetracarbonitriles have been synthesized by reaction of 4-oxoalkane-1,1,2,2-tetracarbonitriles with methyl iodide in dimethyl sulfoxide.

4-Aryl-2-aminobuta-1,3-diene-1,1,3-tricarbonitriles (benzylidene derivatives of malononitrile dimer) reacted with bromo(cyano)acetic acid amide and esters to give the corresponding 2-amino-6-aryl-5-cyano-4-(dicyanomethylidene)-3-azabicyclo[3.1.0]hex-2-ene-1-carboxylic acid amides and esters.

A novel universal method for the preparative synthesis of 6-imino-2,7-dioxabicyclo[3.2.1]octane-4,4,5-tricarbonitriles was developed, previously unknown 1- and 8-aryl-substituted derivatives were synthesized, stereochemical characteristics of this transformation were studied, and the reasons for its diastereoselectivity were identified.

The first example of glycine-catalyzed direct domino synthesis of 6-imino-2,7-dioxabicyclo[3.2.1]octane-4,4,5-tricarbonitriles in aqueous medium is described, giving products in excellent yields and moderate to excellent diastereoselectivities. This approach provides a highly efficient and environmentally benign access to cyano-substituted 2,7-dioxabicyclo[3.2.1]octane.

Methyl aroylpyruvates reacted with 4-amino-N-carbamimidoylbenzene-1-sulfonamide in acetic acid–ethanol (1: 1) to give methyl 4-aryl-2-{[4-(carbamimidoylsulfamoyl)phenyl]amino}-4-oxobut-2-enoates which were found to exist in solution as mixtures of Z and E isomers.

9-Aryl-12-imino-10,11-dioxatricyclo[5.3.2.01,6]dodecane-7,8,8-tricarbonitriles were synthesized via the reaction of 1-(2-oxocyclohexyl)ethane-1,1,2,2-tetracarbonitrile with aromatic aldehydes. The corresponding 3-aryl-1,1,2,2-tetracyanocyclopropanes were prepared from bromomalononitrile and aromatic aldehydes. The structures of the synthesized compounds were elucidated using IR, PMR, 13C NMR, and mass spectra. The analgesic activity of the synthesized compounds was investigated.

2-Oxocycloalka[b]pyridine-3,4-dicarbonitriles reacted with nitric acid in the presence of potassium nitrate to give α-gem-dinitro derivatives of cycloalka[b]pyridines.

Antiproliferative and antimicrobial activity of methyl-6-amino-3-acyl-4-aryl-5-cyano-4H-pyran-2-carboxylates and their analogs that were synthesized from methyl-2,4-dioxobutanoates was studied. Studies of their antiproliferative activity at the USA National Cancer Institute under the program NCI 60 Cell One-Dose Screen found that methyl-6-amino-5-cyano-4-(furan-2-yl)-3-(3-methoxybenzoyl)-4H-pyran-2-carboxylate had the highest activity, greater than those of busulfan and cisplatin. Methyl-6-amino-3-acetyl-4-phenyl-5-cyano-4H-pyran-2-carboxylate had antimicrobial activity that was comparable with that of chloramine.

Reactions of 2-aroyl-1,1,3,3-tetracyanopropenides with hydrogen halides in solvents of low dielectric permittivity result in the formation of 6-amino-2-aroyl-2-halopyridine-3,5-dicarbonitriles. 2-Acyl-1,1,3,3-tetracyanopropenides under similar conditions afford 2-(2-alkylidene-5-amino-4-cyano-2,3-dihydrofuran-3-ylidene)propanedinitriles. In solvents of high dielectric permittivity the result of the reaction depends on the nature of the hydrogen halide and the acyl(aroyl) substituent: With HCl and HBr 2-aroyl-1,1,3,3-tetracyanopropenides form 2-(5-amino-2-aryl-2-halo-4-cyano-2,3-dihydrofuran-3-ylidene)-propanedinitriles, and 2-acyl-1,1,3,3-tetracyanopropenides give 2-(2-alkylidene-5-amino-4-cyano-2,3-dihydrofuran-3-ylidene)propanedinitriles; with HI depending on the reaction conditions and the structure of the acyl substituent 2-(5-amino-2-aryl-4-cyano-2,3-dihydrofuran-3-ylidene)propanedinitriles, 2-(5-amino-4-cyano-2,3-dihydrofuran-3-ylidene) propane-dinitrile, 2-amino-4-(dimethoxybenzyl)-6-iodo-5-cyanonicotinamide, 4-amino-6-iodo-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitrile, or 4-amino-6-iodo-3-oxo-1-ethylidene-1,3-dihydrofuro[3,4-c]pyridine-7-carbonitrile are obtained.

The synthesis of 2-(dicyanomethylene)-1,2-dihydropyridine derivatives from the reactions of arylmethylidene derivatives of malononitrile dimers with 1,3-dicarbonyl compounds is described.

Reaction of arylmethylidene derivatives of malononitrile dimer with 1,3-cyclohexanediones in anhydrous methanol in the presence of sodium methylate as catalyst affords 4-amino-5-aryl-2-methoxy-6-oxo-5,6,7,8,9,10-hexahydrobenzo[b][1,8]naphthyridine-3-carbonitrile. In the presence of strong electron-donor substituents in the benzene ring the reaction takes another route resulting in 4-amino-2-aryl-6-methoxypyridine-3,5-dicarbonitriles.