A. Krauze, Igors Sturms, J. Popelis
2005
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Journal
Heterocyclic Communications
Abstract
Methyl 4,6-diary]-2(3H)-thioxo-l,4-dihydropyridine-3-carboxylates (5) were obtained by Michael reaction of arylmethylideneacetophenones i with methyl 2-thiocarbamoylacetate (2) in the presence of piperidine with subsequent treatment with HCl / EtOH solution. Methyl 2-carbamoylmethylthio-l,4-dihydropyridine-3-carboxylates 7 were prepared by alkylation of thiones 5 with iodoacetamide, but methyl 3-ethoxycarbonylmethyl-4,7dihydrothiazolo[3,2-a]pyridine-8-carboxylate 8 by treatment of thione 5a with ethyl 4-chloroacetoacetate in the presence of equimolar amount of triethylamine. Introduction 2(3H)-Thioxo-l,4-dihydropyridine-3-carbonitriles are of interest due to their high reactivity [1] and revealed cardiovascular [2,3], hepatoprotective [4], antioxidant [5] and antiradical [6] activities. A shortcoming of 2(3H)-thioxo-l,4-dihydropyridine-3-carbonitriles is their instability in diluted solutions and insufficient solubility for detailed biological investigation. Introduction of 3COOMe group instead of 3-CN group in the l ,4-dihydropyridine-2(3H)-thione skeleton could increase the solubility and the lipophilicity of them. Results and discussion Methyl 2(3H)-thioxo-l,4-dihydropyridine-3-carboxylates 5 were obtained by Michael reaction of arylmethylideneacetophenones 1. with methyl 2-thiocarbamoylacetate (2) in the presence of stoichiometric amount of piperidine as a promotor with subsequent treatment of formed mixture with HCl / EtOH solution. Stirring of compounds 1., 2 and piperidine in ethanol at room temperature gave rise to the mixture of primary Michael adducts: methyl 3-benzoyl-lthiocarbamoylbutyrates 3 and the Vol. 11, No. 1, 2005 Synthesis and properties of 4,6-diaryl-3-methoxy-carbonyl-l ,4 Dihydro-p)Tidine-2(3H)-tliiones products of further heterocyclization methyl 6-hydroxy-2-thioxopiperidine-3-carboxylates 4. The 3 to 4 ratio according to 'H NMR data was approximately 1:1. Application of stronger bases: sodium methylate or potassium hydroxide and elevation of reaction temperature in the case of condensation of chalcones i with 2-cyanothioacetamide yielded 2(3H)-thioxo-l,4-dihydropyridine3-carbonitriles and the corresponding 2(lH)-thioxopyridine-3-carbonitriles [7,8], but by making use of methyl 2-thiocarbamoylacetate (2) as Michael donor gave rise to further hydrolysis and decarboxylation of ester group of thiones 5 and complicated reaction mixture was formed usually. Only in the case of condensation of 2-chlorophenylmethyleneacetophenone (Id) with 2 in the presence of KOH 3,4-dihydropyridine-2(lH)-thione 6 was isolated (yield 22 %) as the main product. Thione 6 with 45 % yield was obtained in case of making use piperidine.