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

-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.