Synthesis of oxaprozin analogs from 2H-azirines and cyclic anhydrides

Abstract

We report a novel, transition-metal- and base-free cascade reaction between 2H-azirines and cyclic anhydrides, yielding oxaprozin analogs containing a trisubstituted oxazole core through a ring-opening and annulation sequence. The method exhibits broad functional group tolerance, high bond-forming efficiency, and excellent atom economy, providing the desired products in good to excellent yields. Interestingly, we found that a small amount of dicarboxylic acid, formed adventitiously through partial hydrolysis of the anhydride, acts as a catalyst for this transformation. DFT calculations support the proposed mechanism and confirm the catalytic role of the dicarboxylic acid. This protocol offers a practical and efficient strategy for accessing oxaprozin-type frameworks from readily available starting materials.