Rapid and Scalable Synthesis of Oxazoles Directly from Carboxylic Acids

A highly efficient and expedient method for the synthesis of 4,5-disubstituted oxazoles has been developed directly from carboxylic acids, employing a stoichiometric amount of the easy-to-access and stable triflylpyridinium reagent. The overall transformation proceeds through the formation of an in situ generated acylpyridinium salt followed by trapping with isocyanoacetates and tosylmethyl isocyanide. This transformation has a broad substrate scope with good functional group tolerance (including hindered and less reactive substrates or those containing sensitive functional groups). The versatility of this newly developed reaction is illustrated through its application in the gram-scale production of the FDA-approved prodrug 5-aminolevulinic acid (5-ALA) and the late-stage functionalization of bioactive molecules including estrone, lipoic acid, valproic acid, and probenecid. Additionally, this process features the advantageous recovery and reuse of the base DMAP, underscoring its practical benefits.