Endgame Strategy of Metal-Free Reductive C–C Bond Coupling of Tosylhydrazones and Boronic Acids to Assemble a Series of Novel Thiazole Derivatives

A novel series of thiazol-2-ylacetamide derivatives was synthesized via a multi-step protocol featuring a metal-free reductive C–C bond coupling as the key late-stage transformation. The synthetic route commenced with acylation of 5-acetylthiazole-2-amine to afford N-(5-acetylthiazol-2-yl)acetamide, which was converted to N-[5-(1-(2-tosylhydrazono)ethyl)thiazole-2-yl)acetamide. In the final step, a Barluenga-type metal-free reductive coupling between the resulting tosylhydrazone and a diverse set of boronic acids resulted in the successful synthesis of 10 target compounds thiazole-2-yl acetamides. This strategy offers broad substrate scope, good functional group tolerance, and metal-free conditions. The representative product, N-(5-isopropylthiazol-2-yl)acetamide, was further transformed via hydrolysis and N-acylation to afford three additional novel thiazole derivatives. Additionally, a control experiment afforded a racemic alcohol―N-[5-(1-hydroxyethyl)thiazol-2-yl]acetamide―which was resolved into 2 enantiomers by chiral HPLC. In total, 16 novel thiazole-containing target compounds were synthesized following optimization of each step. Future work will focus on the pharmacological evaluation of these new compounds.