New synthesis of isothiazoles from primary enamines

Abstract

Methyl 3-aminocrotonate 7 reacts with 4,5-dichloro-1,2,3-dithiazolium chloride 1 at room temperature to give methyl 5-cyano-3-methylisothiazole-4-carboxylate 9 in high yield (78%) (Schemes 1 and 2). This reaction is formally related to Woodward’s synthesis of methyl 3-methylisothiazole-4-carboxylate 24 from the same enamine and thiophosgene (Scheme 7). 3-Aminocrotononitrile 10 is similarly converted into 4,5-dicyano-3-methylisothiazole 12 but the yield is much reduced (to 40%) since the reaction is more complex (Scheme 3) giving 2,3,5-tricyano-4,6-dimethylpyridine 14 (20%), in a new pyridine ring construction, and three other minor products. All the products can be accounted for by reasonable mechanisms (Schemes 4, 5 and 6). One of the minor products, ketone 13, has been synthesized from the enolate anion 21 and the reagent 1, and the analogous ketones 23 have been readily prepared in high yield from the active methylene compounds 22 and reagent 1.