Cyanoacetamide MCR (III): Three-Component Gewald Reactions Revisited

Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR) scaffolds. Here we describe valuable general protocols for the synthesis of arrays of 2-aminothiophene-3-carboxamides from cyanoacetamides, aldehydes or ketones, and sulfur via a Gewald-3CR variation. In many cases the reactions involve a very convenient work up by simple precipitation in water and filtration. More than 40 new products are described. We foresee our protocol and the resulting derivatives to become very valuable to greatly expanding the MCR scaffold space of cyanoacetamide derivatives.