Benzoxazole and Benzothiazole Synthesis from Carboxylic Acids in Solution and on Resin by Using Ethyl 2-Cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate and para-Toluenesulfonic Acid

A metal-free and catalytic method for the synthesis of 2-substituted benzoxazoles and benzothiazoles from N-protected amino acids and carboxylic acids is described. The synthesis of benzoxazole on a solid support is demonstrated by the synthesis of benzoxazole attached to a human islet amyloid polypeptide, hIAPP_22-27, fragment and benzoxazole derivatives of the side chain of aspartic acid on a modified fragment of Aβ_18-21 (amyloid β) peptide. The reactions proceeded through a two-step mechanism. The coupling step is realized with a relatively new reagent, ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate (ortho-NosylOXY), and the cyclization step takes place thanks to an inexpensive organocatalyst, para-toluenesulfonic acid, under microwave irradiation. To the best of our knowledge, this is the first report of the complete synthesis of benzoxazole derivatives of a polypeptide on a resin solid support.