Three-component synthesis of alkyl-substituted functionalized 4H-thiopyrans, 1,2- and 1,4-dihydropyridines, 2-alkylsulfanylpyridines, thieno[2,3-b]pyridines, and cyclohexa-1,3-diene

Abstract

Three-component condensation of aliphatic aldehydes with CH-acids has afforded functionalized alkylsubstituted 4H-thiopyrans, 1,2-and 1,4-dihydropyridines, 2-alkylsulfanylpyridines, thieno[2,3-b]pyridines, and cyclohexa-1,3-diene.Multicomponent synthesis of heterocyclic compounds has recently become increasingly important [1][2][3]. This method is particularly relevant to obtain scarcely studied alkyl-substituted carbo-and heterocyclic compounds starting from aliphatic aldehydes, since the latter are known for high toxicity, flammability, and ability to readily isomerize and dimerize [4] as compared with the aromatic analogs.Extending the earlier research on synthesis of alkylsubstituted carbo-and heterocyclic compounds via a multicomponent condensation [5-7], we investigated new possibilities of three-component interaction of aliphatic aldehydes Ia-Ij with a number of CH-acids and organic bases under conditions of the Knöevenagel reaction. It was found that condensation of aliphatic aldehydes Ia and Ib with cyanothioacetamide II and ethyl 3-amino-3-thioxopropanoate III in anhydrous ethanol at 20°C in the presence of sodium ethylate resulted in ethyl 2-amino-4-isopropyl-6-mercapto-5-cyano-3-carboxylate IV and diethyl 6,6'-disulfandiylbis(2-amino-4-isobutyl-5-cyanonicotinate V. Apparently, the reaction proceeded through formation of alkene A followed by addition of the CH-acid III to give the adduct B. The latter intermediate [Alk = (Me) 2 CH] underwent chemoselective intramolecular cyclization accompanied with hydrogen sulfide elimination to form the substituted 1,4-dihydropyridine IV. In the case of Alk = (Me) 2 CHCH 2 , the reaction stopped at the stage of formation of the corresponding 1,4-dihydropyridine IV due to oxidation of the hydrosulfide group with air oxygen into organic disulfide V. On top of that, the reaction was accompanied with aromatization of the dihydropyridine core (Scheme 1).In the case of the Knöevenagel condensation involving 2-phenylpropionaldehyde Ic and malononitrile VI in the presence of morpholine as a catalyst, the formed alkene C was capable of the Michael-type dimerization under the reaction conditions. The adduct D underwent intramolecular cyclization into the substituted 1,3-cyclohexadiene VII.Three-component condensation of aliphatic aldehydes I with cyanothioacetamide II and malononitrile VI in the presence of morpholine in anhydrous ethanol at 20°C resulted in the formation of 4-alkyl-2,6-diamino-3,5-dicyano-4H-thiopyrans VIIIc, VIIIh, VIIIi, and VIIIj. At the same time, the same reaction in ethanol medium under reflux allowed preparation of 4-substituted 6-amino-2-thioxo-3,5-dicyano-1,2-dihydropyridines IXd and IXg, similarly to the analogous condensation involving aromatic aldehydes [8][9][10]. Thiopyrans VIII, the kinetic control products, underwent ring-opening via formation of intermediates