Synthesis of Substituted Pyridines from Cascade [1 + 5] Cycloaddition of Isonitriles to <i>N</i>‑Formylmethyl-Substituted Enamides, Aerobic Oxidative Aromatization, and Acyl Transfer Reaction

A novel strategy for de novo synthesis of pyridines featuring an unprecedented α-addition of aldehyde and enamide to isonitrile as a key step is described. Under mild conditions, a cascade reaction involving Zn­(OTf)2-promoted [1 + 5] cycloaddition of isonitrile with N-formylmethyl-substituted enamide, facile aerobic oxidative aromatization and intermolecular acyl transfer from the pyridinium nitrogen to the 5-hydroxy oxygen, and finally acylation of the 4-amino group by an external acyl chloride efficiently afforded 2-substituted 4-acylamino-5-acyloxypyridines in good to excellent yields.本研究报道了一种构建吡啶类化合物的全新从头合成策略，其关键步骤为醛与烯酰胺对异腈发生前所未有的α加成反应。该反应可在温和条件下通过级联过程高效完成：首先由三氟甲磺酸锌（Zn(OTf)₂）催化异腈与N-甲酰甲基取代烯酰胺发生[1+5]环加成，随后依次经历便捷的需氧氧化芳构化、吡啶鎓氮向5-羟基氧的分子间酰基转移，最终通过外部酰氯对4-氨基的酰化反应，以良好至优异的收率得到2-取代-4-酰氨基-5-酰氧基吡啶类产物。