Grignard Reagents Unlock Three-Dimensional Nitrogen Heterocycles via Single-Carbon-Atom Insertion

Abstract Nitrogen heterocycles are an 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 nonplanar, sp3-rich architectures to improve molecular performance and expand underexplored chemical space, methods that can remodel existing heterocycles into new 3D frameworks are of considerable interest. Here, we introduce a strategy for atom insertion that uses simple nucleophilic reagents─most notably, Grignard reagents─to insert a single carbon atom into azolium rings. This nucleophilic rearrangement converts planar triazolinium 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. By transforming readily available olefins into complex, nonplanar 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.