Synthesis of novel 2-aminothiophene-3-carboxylates by variations of the Gewald reaction

The synthesis of the title compounds through variations of the Gewald reaction is presented. Knoevenagel condensation of methylketone derivatives with methyl cyanoacetate and subsequent treatment of the alpha,beta -unsaturated nitriles with sulfur and amine resulted in the corresponding 2-aminothiophenes 5 or isomers 9 and 10. Reaction of methylketone derivatives bearing a leaving group at the methyl group under modified Gewald conditions selectively led to the formation of 4-substituted 2-aminothiophenes 9a and 12. The introduction of the sulfur atom occurs through nucleophilic displacement with sodium sulfide.