Polysubstituted Oxazole Synthesis Enabled by Synergistic Combination of Multiple Isocyanide Insertions and Amide Bond...

As common functional groups, amides have demonstrated significant stability due to the high resonance energy of the amide bond. Research on amide C-N bond cleavage and transformations is only focused on single C-C or C-heteroatom bond formation; however, the multicomponent reaction (MCR) involving C-N bond cleavage and difunctionalization of the acyl group remains challenging and unexplored. Although isocyanide-based multicomponent reactions have been broadly investigated, harnessing the reactivity of multiple isocyanide insertions in IMCRs is also still undeveloped and challenging. Herein, we develop a BF₃·OEt₂-triggered multicomponent reaction of isocyanide, aldehyde and amide, affording pharmacologically interesting oxazole-4-carboxamides through a synergistic strategy of multiple isocyanide insertions and amide C-N bond cleavage. The given protocol involves orderly cyclization and remodeling of four molecules with excellent chemo- and regioselectivities, where oxetane-2,3-diimine is verified as the key intermediate. The proposed mechanism could be well supported by detailed control experiments, the ESI-MS/MS technique, and DFT calculations as well. The method showcases the use of an amide group as a synthetic handle under metal-free conditions and may find further application in the synthesis of heterocycles.