Synthesis,Structure, and Electrochemical Characteristics of 4-Aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic Acid Nitriles

We have obtained 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid nitriles by S-alkylation of the corresponding 2-thioxo-1,2,3,4-tetrahydropyridine-3-carboxylic acid nitrile by iodoacetamide or one-pot multicomponent synthesis methods: condensation of 2-arylidene-acetoacetic acid ethyl ester, 2-cyanothioacetamide, piperidine, and iodoacetamide; acetoacetic acid ethyl ester, 3-aryl-2-cyanothioacrylamide, piperidine, and iodoacetamide; acetoacetic acid ethyl ester, an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and iodoacetamide. We have carried out a comparative analysis of the capability of 2-alkylthio-4-aryl-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid nitriles for electrochemical oxidation as a function of the electronic properties of the aryl substituent in the 4 position of the heterocycle and the 2-alkylthio substituent. X-ray diffraction data indicate the existence of a hydrogen bond between the C=O of the 2-carbamoylmethylthio substituent and the NH of the hydrogenated heterocycle, which explains the more facile oxidation of the studied compounds compared with 2-methylthio-substituted 1,4-dihydropyridines.Dedicated to Academician V. Minkin to show our appreciation for his contribution to organic chemistry and his wonderful humanity, remembering his collaboration with his colleagues from Riga.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 416–428, March, 2005.     

Synthesis of 3-cyano-4-aryl-5-ethoxycarbonyl-6-methyl-3,4-dihydropyridine-2-thiones

The condensation of ethyl arylidenacetoacetate with cyanothioacetamide and of arylidenecyanothioacetamides with ethyl acetoacetate or of arylidenecyanothioacetamides with ethyl -aminocrotonate gave 3-cyano-4-aryl-5-ethoxycarbonyl-6-methyl-3,4-dihydropyridine-2-thiones. PMR spectroscopy showed that the 3-cyano-4-aryl-3,4-dihydropyridine-2-thiones are formed as a mixture of cis and trans isomers.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 95–102, January, 1985.     

Synthesis and Electrochemical Oxidation of Nitriles of 4-Aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic Acids

Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-6-hydroxy-1,4,5,6-tetrahydropyridine-3-carboxylic acids were obtained by the alkylation of 1,4,5,6-tetrahydropyridine-2-thiolate with iodoacetamide or by a three-component synthesis by condensing 2-arylmethylene-1,3-dicarbonyl compounds with 2-cyanothioacetamide in the presence of piperidine with subsequent reaction with iodoacetamide. Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic acids were obtained by the dehydration of 6-hydroxy-1,4,5,6-tetrahydropyridines or with a one-reactor three-component system from 2-cyano-3-(4-methoxyphenyl)thioacrylamide, 1,3-dicarbonyl compounds, and iodoacetamide. The electrochemical oxidation of the synthesized nitriles was investigated and it was established that derivatives of 1,4,5,6-tetrahydropyridine as a rule are oxidized readily to the corresponding 1,4-dihydropyridines. A comparative analysis has been carried out of the ability of hydrogenated pyridines to be oxidized electrochemically depending on the electron-withdrawing properties of the substituents in the heterocycle.     

Synthesis and Antiradical Activity of 5-Acetyl-2-alkylthio-4-aryl-6-methyl-1,4-dihydropyridine-3-carboxylic Acid Nitriles

The alkylation of 3-cyano-1,4-dihydropyridine-2(3H)-thiones or the condensation of an aromatic aldehyde, cyanothioacetamide, acetylacetone, and methyl iodide in the presence of piperidine has given a series of novel 5-acetyl-2-alkylthio-4-aryl-6-methyl-1,4-dihydropyridine-3-carboxylic acid nitriles. A compound was obtained from 3,5-di(tert-butyl)-4-hydroxybenzaldehyde in the molecule of which were combined the active part of the antioxidant ionol and a 1,4-dihydropyridine ring. It was found that, among the compounds synthesized, the highest antiradical activity occurred in a compound having two hydroxyl groups in the 4-phenyl substituent.     

Synthesis and properties of 3-cyano-4-(4-cyanophenyl)-1,4-dihydropyridine-2(3H)-thiones

Piperidinium 3-cyano-4-(4-cyanophenyl)-1,4-dihydropyridine-2(3H)-thiolates were obtained by the condensation of 1,3-dicarbonyl compounds, 4-cyanobenzaldehyde, and cyanothioacetamide in the presence of an equimolar amount of piperidine. The acidification of these thiolates gave the corresponding 1,4-dihydropyridine-2(3H)-thiones and pyridine-2(1H)-thione. Alkylation of 1,4-dihydropyridine-2-thiolates or the reaction mixture of the three-carbon condensation using iodacetamide gave 2-carbamoylmethylthio-1,4,5,6-tetrahydro- or 1,4-dihydropyridines, which were characterized by their conversion to 4,7-dihydrothieno[2,3-b]pyridines.Latvian Institute of Organic Synthesis, LV-1006, Riga, LatviaTranslated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 794–798, June, 2000.     

Synthesis of N-unsubstituted and N-methyl derivatives of 4-aryl-2,6-dimethyl-1,2-dihydropyridine-3,5-dicarbonitriles

In the reduction of 2,6-dimethyl-4-arylpyridine-3,5-dicarbonitriles or their N-oxides by sodium borohydride, a mixture of 1,2- and 1,4-dihydropyridine-3,5-dicarbonitriles is formed. 1,2,6-Trimethyl-4-aryl-1,2-dihydropyridine-3,5-dicarbonitriles were obtained by reducing the corresponding pyridinium perchlorates or by alkylating 4-aryl-2,6-dimethyl-1,2-dihydropyridine-3,5-dicarbonitrile derivatives by methyl iodide.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 81–85, January, 1987.     

Ethyl 1,4-dihydropyridinecarbodithioates and the electronic effects of sulfur-containing ester substituents

Methods have been developed for the synthesis of the ethyl esters of 2,6-dimethyl-1,4-dihydropyridine-3,5-bis(carbodithioic) and 4-ary1-2-methyl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridine-3-carbodithioic acids. From the physicochemical properties (acid dissociation constants and electrochemical oxidation potentials of the 1,4-dihydropyridines with sulfur-containing substituents in the -positions, the electronic effects of these groups in the 1,4-dihydropyridine system have been determined. The inductive and resonance constants of these substituents in aromatic compounds have been found by ¹³C and ¹⁹F NMR spectroscopy.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 491–500, April, 1986.     

New method for the synthesis of 6-amino-4-aryl-3,5-dicyano-3,4-dihydropyridine-2(1H)-thiones by recyclization of 4-aryl-2,6-diamino-4H-thiopyranes

Ammonium 6-amino-4-aryl-3,5-dicyano-1,4-dihydropyridine-2-thiolates were synthesized by recyclization of 4-aryl-2,6-diamino-3,5-dicyano-4H-thiopyranes in the presence of organic bases. On acidification of the products, the corresponding substituted 3,4-dihydropyridine-2(1H)-thiones were obtained which were used in the synthesis of 2-alkylthio-1,4-dihydropyridines, bis-(pyridyl-2)disulfides and thieno[2,3-b]pyridines.Deceased.T. G. Shevchenko Lugansk State Pedagogical Institute, Lugansk 348011. N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 909–914, July, 1997.     

New synthetic method for functionally substituted morpholinium 1,4-dihydropyridine-2-thiolates and their derivatives

By condensation of aromatic aldehydes with cyanothioacetamide and enamines of 1,3-dicarbonyl compounds functionally substituted morpholinium 1,4-dihydropyridine-2-thiolates were obtained applied to the synthesis of 2-alkylsulfanyl-1,4-dihydropyridines, 1,4-dihydrothieno[2,3-b]-pyridines, and 2,3,4,7-tetrahydrothiazolo[3,2-a]pyridine.     

Synthesis and alkylation of 4,6-diphenyl-3-thiocarbamoyl-3,4,5,6-tetrahydropyridine-2(1H)-one and 4,6-diphenyl-3-thiocarbamoyl-3,4-dihydropyridine-2(1H)-one

Alkylation of 3-thiocarbamoyl-3,4,5,6-tetrahydropyridine-2(1H)-one with methyl iodide has given 5-methylthio-2,6-diazabicyclo[2.2.2]oct-5-en-3-one and 3-methyl-thiocarbonyl-3,4-dihydropyridine-2(1H)-one. Alkylation of 3-thiocarbamoyl-3,4-dihydridine-2(1H)-one with iodoacetamide affords 3-(1-amino-1-carbamoyl-3,4-methyl-thiomethylene)-1,4-dihydropyridine-2-one, which in acidic media is converted into 3-(4-oxo-3,5-dihydro-1,3-thiazol-2-ylidene)-1,4-dihydropyridine-2-one.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 787–794, June, 1989.     

Synthesis of carbamate derivatives of coumarin and chromene

Condensation of methyl (3-hydroxyphenyl)carbamate with ethyl acetoacetate and ethyl benzoylacetate at room temperature, as well as with L-2-hydroxysuccinic acid on heating, in the presence of concentrated sulfuric acid gave the corresponding methyl (4-R-2-oxo-2H-chromen-7-yl)carbamates (R = Me, Ph, H). Condensation of methyl (3-hydroxyphenyl)carbamate with benzylidenemalononitrile or with aromatic aldehydes and malononitrile on heating in propan-2-ol in the presence of piperidine led to the formation of the corresponding methyl (4-aryl-2-amino-3-cyano-4H-chromen-7-yl)carbamates.     

Tertiary amines and quaternary salts derived from alpha-substituted stilbenes and heterocyclic nitrogen bases

N-bromosuccinimide and -methylstilbenes, p-methyl--chlorostilbene, and p-methyltolan give bromomethyl derivatives, which react with piperidine to give tertiary amines. The latter and methyl iodide give quaternary salts.With pyridine, -picoline, and quinoline, the p-bromomethyl-d-chlorostilbenes synthesized give quaternary bromides which are readily soluble in water and converted into perchlorates by KClO₄.     

Reaction of ethyl 4-aryl-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates with N-methylmorpholinium 3-cyano-1,4-dihydro- and 3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates

Alkylation of N-methylmorpholinium 4-Ar¹-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates using ethyl 4-Ar-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (10 % KOH, DMF) gives mixtures of diastereomers of ethyl 4-Ar-6-[(4-Ar¹-3-cyano-1,4,5,6-tetrahydropyridin-2-ylthio)methyl]-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in overall 30-58 % yield. Under these conditions the N-methylmorpholinium 4-Ar1-5-(N-Ar²-carbamoyl)-3-cyano-6-methyl-1,4-dihydropyridine-2-thiolates undergo aromatization of the dihydropyridine ring to give ethyl 4-Ar-6-[4-Ar¹-5-(N-Ar²-carbamoyl)-3-cyano-6-methylpyridin-2-ylthio)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (37-51 %). In the absence of KOH, only the substituted pyridine-2(1 H)-thione is formed as a product of oxidation of the dihydropyridine ring in the starting substrate. Some of the alkylation products obtained possess weak or moderate antibacterial activity towards the specific strains of Escherichia coli and Bacillus subtilis but are inactive towards Candida albicans and Staphylococcus aureus.     

Stereoselective Methods for the Synthesis of 4-Benzoyl-1-benzoylamino-3-(2-chlorophenyl)-2-cyano-1-methylthio-1-butene and Its Structure

Selective methods were developed for the synthesis of 4-benzoyl-1-benzoylamino-3-(2-chlorophenyl)-2-cyano-1-methylthio-1-butene on the basis of the reaction of N-methylmorpholinium and piperidinium 5-benzoyl-4-(2-chlorophenyl)-3-cyano-6-hydroxy-6-phenyl-1,4,5,6-tetrahydropyridine-2-thiolates with methyl iodide. The structure of the product was established by X-ray crystallographic analysis.     

An efficient synthesis of 4H,5H-pyrano[3,4-c]pyran-4,5-diones from a suitably functionalized 2H-pyran-2-one

An efficient synthesis of ethyl 7-aryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-dione-1-carboxylate 5, and ethyl 6-aryl-3-cyano-2H-pyran-2-one-4-acetate 6 has been delineated by reaction of suitably functionalized 2H-pyran-2-ones 1 with ethyl acetoacetate 2.     

β-oxoacids esters in the synthesis of benzo[<Emphasis Type="Italic">f</Emphasis>]quinoline derivatives

Condensation of ethyl acetoacetate and ethyl 3-oxo-3-(2-furyl-, 2-quinolyl-, 3-pyridyl)propanoates with azomethines of 2-naphthylamine series led to the formation of ethyl (3-arylbenzo[f]quinol-1-yl)acetates and of esters of the corresponding 3-aryl-1-heteryl-2-benzo[f]quinolylcarboxylic acids. The intermediate reaction products were isolated: ethyl 5-(2-naphthylamino)-3-oxo-5-phenylpentanoate, 2-[(aryl)(2-naphthylamino)methyl]-3-heteryl-3-oxopropanoates, dihydro and tetrahydro derivatives of benzoquinolylacetic and benzoquinolinecarboxylic acids.     

Methyl 3-cyclopropyl-3-oxopropanoate in the synthesis of heterocycles having a cyclopropyl substituent

Reactions of methyl 3-cyclopropyl-3-oxopropanoate with chloroacetone and ammonia, benzaldehyde and ammonia, and benzoquinone gave, respectively, methyl 2-cyclopropyl-5-methyl-1H-pyrrole-3-carboxylate, dimethyl 2,6-dicyclopropyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate, and methyl 2-cyclopropyl-5-hydroxy-1-benzofuran-3-carboxylate. Cyclization of methyl 3-cyclopropyl-3-oxopropanoate with ethyl chloro(arylhydrazono)ethanoates and other halohydrazones led to the formation of 3-substituted 1-aryl-5-cyclopropyl-1H-pyrazole-4-carboxylic acids, and 5-cyclopropyl-1-(quinolin-5-yl)-1H-1,2,3-triazole-4-carboxylic acid was obtained by reaction of the title compound with 5-azidoquinolines.     

Chlorinating properties of the trimethylchlorosilane-potassium bromate-DMF system

-Dicarbonyl compounds such as ethyl acetoacetate, dimedone, and Meldrum's acid derivatives undergo monochlorination by the action of a mixture of C1SiMe₃ and KBrO₃ in DMF at 20°C.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 2, pp. 448–450, February, 1992.     

Three-component condensation in the synthesis of 4-(2-chlorophenyl)-3-cyano-5-ethoxycarbonyl-6-propyl-3,4-dihydropyridine-2(1H)-thione

Condensation of 2-chlorobenzaldehyde with cyanothioacetamide and ethyl butyroylacetate results in 4-(2-chlorophenyl)-3-cyano-5-ethoxycarbonyl-6-propyl-3,4-dihydropyridine-2(1H)-thione, whose further transformation affords the corresponding substituted 2-methylthio-1,4-dihydropyridine. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 173–175, January, 2000.     

Three-component condensation in the synthesis of 4-(2-chlorophenyl)-3-cyano-5-ethoxycarbonyl-6-propyl-3,4-dihydropyridine-2(1H)-thione

Condensation of 2-chlorobenzaldehyde with cyanothioacetamide and ethyl butyroylacetate results in 4-(2-chlorophenyl)-3-cyano-5-ethoxycarbonyl-6-propyl-3,4-dihydropyridine-2(1H)-thione, whose further transformation affords the corresponding substituted 2-methylthio-1,4-dihydropyridine. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 173–175, January, 2000.