We have reported the synthesis of pharmacologically valuable tetrasubstituted 2-aminothiophenes through a multi-component reaction using ketene dithioacetals, secondary amines, and thioglycolates in the presence of a catalytic amount of triethylamine in aqueous conditions. Various substrates, including symmetrical and asymmetrical ketene dithioacetals, were explored, demonstrating versatility in product formation. Notably, reactions involving ethyl 2-cyano-3,3-bis(methylthio)acrylate selectively produced single products. The mechanistic proposal elucidates the steric effects of secondary amines on reaction pathways, which facilitate the unique selectivity of intermediates and hence the product selectivity. Additionally, the synthesis of piperidone-bearing thiophenes was successfully achieved, underscoring the methodology's potential for generating biologically relevant compounds. The synthesized compounds were characterized by spectroscopic techniques, and the structure of four compounds (3a, 5a, 5b, and 7c) has been confirmed by single-crystal X-ray. This research contributes to the development of efficient synthetic strategies for 2-aminothiophenes, offering pathways for future drug discovery and development.

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