Csp3–N bond formation in aminothiophenes by 1,1-dibromo isocyanide: the unexpected 1,5-binucleophilicity of substrates

Abstract

The N-cyclohexylcarbonimidoyl dibromide in situ, generated by cyclohexylisocyanide and bromine in reaction with several deactivated 5-acetyl-4-amino-2-methylsulfanyl-3-carbonitrile, appears as a cyclohexyl transformer to the substrate via Csp3–N bond formation without using any base or catalyst at room temperature. The present transformation suggests three main innovations. First, regarding the selective monoalkylation of aromatic amines, the performed condition is unprecedented. Second, for the first time in the field of isocyanide-based reactions, isocyanide is applied as an alkyl transformer agent. Third, this is the first example of coupling aminothiophenes with a secondary alkyl group. Interestingly, high yield and selectivity, short reaction time, easy purification accompany this protocol. Through this study, we investigated the electronic effects of substituents linked to acetyl on the efficiency of the reaction. Also, the potential of isocyanide dibromide for the synthesis of cyclic guanidine is evaluated. An efficient, useful and general procedure for the synthesis of 5-aroyl-4-cyclohexylamino-2-methylsulfanyl-3-thienyl cyanide via one-pot three-component reaction of 5-acetyl-4-amino-2-methylsulfanyl-3-carbonitrile, cyclohexylisocyanide and bromine in acetonitrile at room temperature has been described. The major advantages of this protocol are high yield and selectivity, short reaction time, easy purification.