Grignard Reagents Unlock 3D Nitrogen Heterocycles via Single Carbon Ring Insertion

Nitrogen heterocycles are integral part of pharmaceuticals, catalysts, and materials, yet most accessible molecular scaffolds remain flat, aromatic rings with limited three-dimensionality. As medicinal chemistry increasingly seeks non-planar, sp3-rich architectures to improve molecular performance and to expand underexplored chemical space, methods that can remodel existing heterocycles into new 3D frameworks are urgently needed. Here we introduce a fundamentally new strategy for ring insertion that uses simple nucleophilic reagents - most notably, Grignard reagents - to introduce one-carbon into azolium rings. This unprecedented nucleophilic rearrangement converts planar triazolium salts, derived from alkenes, into a previously inaccessible family of saturated, three-dimensional 1,2,4-triazinanes. These underexplored compounds are 3D counterparts of planar 1,2,4-triazines well represented in pharmaceuticals and bioactive molecules. The method is operationally simple, broadly applicable to cyclic, acyclic, natural, and highly functionalized alkenes, and remarkably tolerant of sensitive groups including esters, amides, sulfonamides, acetals, phosphates, and alkynes. Mechanistic experiments and density functional theory computations reveal a unique nitrenium-centered pathway that enables this umpolung reactivity. By transforming readily available olefins into complex, non-planar nitrogen heterocycles in just two steps, this work provides a powerful entry into new heterocyclic space and opens opportunities for late-stage diversification relevant to drug discovery, catalysis, and molecular design.