Thienoisothiazoles. III. The Synthesis and Reactions of 3-Phenyl-5-alkylthioisothiazole-4-carbonitriles and 3-Phenylthieno[3,2-d]isothiazoles

Abstract

Oxidation of the alkyl 3-amino-4-cyano-3-phenylpropenedithioates (1), obtained by alkylation of the condensation product of 3-amino-3-phenylpropenenitrile and carbon disulfide, produced 3-phenyl-5-alkylthioisothiazole-4-carbonitriles (2a-d). The ease of nucleophilic displacement of the S-alkyl group in the isothiazole (2a) was utilized to synthesize the isothiazoles (2f-j). 3-Phenylthieno[3,2-d] isothiazole (3e) was prepared by deamination, hydrolysis and decarboxylation of the intermediate ethyl 4-amino-3-phenylthieno[3,2-d]isothiazole-5-carboxylate (3a), which was obtained by ring-closure of ethyl 2-(4-cyano-3-phenylisothiazol-5-ylthio)acetate (2d). 3-Phenylthieno[3,2-d] isothiazole was unreactive towards weaker electrophiles , but undergoes bromination and nitration in the α-position of the thiophen ring. The position of substituents in 5-bromo- (3w) and 5-nitro-3-phenylthieno[3,2-d] isothiazole (4a) was verified by alternative synthesis. The attempted deamination of 4-amino-5-bromo-3-phenylthieno[3,2-d] isothiazoe (30) and 4-amino-S-nitro-3-phenylthieno[3,2-d] isothiazole (3r) yielded 3-phenyl-S-nitrothieno[3,2-d]isothiazol-4-ol (3s) only, but the isomeric 4-bromo-3-phenyithieno[3,2-d] isothiazole (3v) was obtained by decarboxylation of 4-bromo-3-phenylthieno[3,2-d]isothiazole-5-carboxylic acid (3u). An alternative synthesis of the 5-nitro derivative was achieved by decarboxylation of 5-nitro-3-phenylthieno[3,2-d]isothiazole-4-carboxylic acid (32). Mild reduction of 3-phenylthieno[3,2-dlisothiazole derivatives, (3a,b) and (4c), with hydrogen sulfide or hypophosphorous acid afforded the substituted 3-(α-aminobenzylidene )-2,3-dihydrothiophen-2-thiones (5a-c), and the 3-benzoyl-2-alkylthiothiophen derivatives (6a,b) were obtained by a one-step synthesis, which avoided the isolation of the air-sensitive intermediates.