Parallel solution phase synthesis of a library of amino acid derived 2-arylamino-[1,3,4]-oxadiazoles

A mild method for the synthesis of peptidomimetic 2-arylamino 5-substituted 1,3,4-oxadiazoles from Boc-protected alpha-amino acid derived hydrazides has been developed, and applied in a parallel solution-phase synthesis. The optimized reaction conditions involve a one-pot reaction of Boc-protected amino acid hydrazides with arylisothiocyanates in the presence of either Hg(II) chloride, Mukaiyama's reagent (2-chloro-N-methylpyridinium iodide) or polymer supported Mukaiyama's reagent, with triethylamine in dichloromethane at ambient temperature. The 1,3,4-oxadiazole products were obtained in good to excellent yields without any detectable epimerization. The reactions proceed via initial formation of thiosemicarbazides, followed by dehydrothiolative cyclization to the 1,3,4-oxadiazoles. (C) 2008 Elsevier Ltd. All rights reserved.