The S_N2 nucleophilic substitution reaction is a vital organic transformation used for drug and natural product synthesis. Nucleophiles like cyanide, oxygen, nitrogen, sulfur, or phosphorous replace halogens or sulfonyl esters, forming new bonds. Isocyanides exhibit unique C-centered lone pair σ and π* orbitals, enabling diverse radical and multicomponent reactions. Despite this, their nucleophilic potential in S_N2 reactions remains unexplored. We have uncovered that isocyanides act as versatile nucleophiles in S_N2 reactions with alkyl halides. This yields highly substituted secondary amides through in situ nitrilium ion hydrolysis introducing an alternative bond break compared to classical amide synthesis. This novel 3-component process accommodates various isocyanide and electrophile structures, functional groups, scalability, late-stage drug modifications, and complex compound synthesis. This reaction greatly expands chemical diversity, nearly doubling the classical amid coupling’s chemical space. Notably, the isocyanide nucleophile presents an unconventional Umpolung amide carbanion synthon (R-NHC(-) = O), an alternative to classical amide couplings.

S _N 2 亲核取代反应是用于药物和天然产物合成的重要有机转化。氰化物、氧、氮、硫或磷等亲核试剂取代卤素或磺酰酯，形成新的键。异氰化物具有独特的以 C 为中心的孤对电子 σ 和 π* 轨道，可实现多种自由基反应和多组分反应。尽管如此，它们在 S _N 2 反应中的亲核潜力仍未被探索。我们发现异氰化物在与卤代烷的 S _N 2 反应中充当多功能亲核试剂。与经典酰胺合成相比，通过原位腈离子水解引入替代键断裂，产生高度取代的仲酰胺。这种新颖的三组分工艺可容纳各种异氰化物和亲电子结构、官能团、可扩展性、后期药物修饰和复杂化合物合成。该反应极大地扩展了化学多样性，几乎使经典中间偶合的化学空间增加了一倍。值得注意的是，异氰化物亲核试剂呈现出一种非常规的 Umpolung 酰胺碳负离子合成子 (R-NHC(-) = O)，这是经典酰胺偶联的替代方案。