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.
Zhou et al. (Fri,) studied this question.
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