Reactions of selected 3-bromoisothiazole-5-carbonitriles with the secondary dialkylamines pyrrolidine and morpholine

Abstract

Readily available 3-bromoisothiazole-5-carbonitriles bearing various C-4 substituents [H, CO2R C[tbnd]N and halogen (Cl or Br)], react with either pyrrolidine or morpholine to give, in most cases, the 3-amino-substituted derivatives in high yields. The reaction of 3-bromoisothiazole-4,5-dicarbonitrile, however, varied with the nucleophilicity of the dialkylamine: pyrrolidine led to cleavage of the isothiazole ring to give 2-[di(pyrrolidin-1-yl)methylene]malononitrile while morpholine led to the expected 3-(morpholin-4-yl)isothiazole-4,5-dicarbonitrile. By comparison, 3-chloroisothiazole-4,5-dicarbonitrile reacted with pyrrolidine to give surprisingly, 3-chloro-5-(pyrrolidin-1-yl)isothiazole-4-carbonitrile as the major product, while with morpholine the major product was the expected 3-(morpholin-4-yl)isothiazole-4,5-dicarbonitrile. The mechanisms of the transformations are discussed, together with rationalization for the formation of side products. Furthermore, the hydrolytic decarboxylation of methyl and ethyl esters of 3-dialkylaminoisothiazoles using both conventional heating and microwave irradiation is reported. © 2014 Elsevier Ltd