Thienoisothiazoles. II. The synthesis of 5-alkylthioisothiazoles and the preparation of Thieno[3,2-d]isothiazole derivatives

Abstract

Alkylation of the reaction product of sodium 3-iminobutyronitrile and carbon disulfide produces alkyl 2-cyano-3-iminodithiobutyrates (1) in moderate yield, which on iodine oxidation afford 5-alkylthio-3-methylisothiazole-4-carbonitriles (2b-e). Ethyl 4-amino-3-methylthieno[3,2-dliso- thiazole-5-carboxylate (3a) which was obtained by cyclization of ethyl 2-(4-cyano-3-methylisothiazol- 5-ylthio)acetate (2c) yields 3-methylthieno[3,2-d]isothiazole (3f) on deamination, hydrolysis and decarboxylation. This compound forms a 5-nitro and 5-bromo derivative. The position of the substituents was verified by synthesis. On reduction with hypophosphorous acid, 3-methylthieno- [3,2-d]isothiazole and some of its derivatives readily ring-open, yielding stable 3-acetimidoylthio-phen-2-thiols (4d-g), which are useful intermediates for the preparation of 3-acetyl-2-mercaptothiophen derivatives. Ring-opening of the isothiazole ring in 3-methylthieno[3,2-d]isothiazole (3f) and its 5-bromo derivative (3m) occurs during lithiation reactions, resulting in the formation of 3-acetyl-2-butylthiothiophen, isolated as the thiosemicarbazone (4c), and 3-acetyl-2-butylthio-thiophen-5-carboxylic acid (4b) respectively.