Divergent C2 Functionalization of N-Heteroarenes via Nonclassical Rearomatization: Retro-hetero-ene Reactions versus Sigmatropic Rearrangements

Abstract Divergent and site-selective functionalization of aromatic N-heterocycles remains a long-standing challenge owing to their intrinsic aromatic stabilization and multiple reactive sites. Here we present a unified strategy that redirects reactivity of N-alkenyloxy-pyridinium and N-alkenyloxy-quinolinium salts away from the terminal alkene and toward the heteroaromatic core, enabling controlled access to two distinct product classes. Under Grignard-reagent conditions, pyridinium substrates undergo ultrafast C2 functionalization via a concerted, six-electron retro-hetero-ene rearrangement — a novel transformation not previously described in this context — delivering ortho-substituted pyridines (alkyl, aryl, heteroaryl, alkynyl) in up to 93% yield across 56 examples. In contrast, quinolinium substrates enter a cascade initiated by C2 addition followed by a 3,3-sigmatropic rearrangement, cycloaddition and dehydration, furnishing N-bridged, tri-fused 4H-pyrrolo[3,2,1-ij]quinolines in high yields (68 examples). Substrate electronics and sterics (benzannulation, C8 substitution) dictate pathway selection. The protocol is scalable, enables site-selective deuterium incorporation and late-stage diversification of drug-like scaffolds. Mechanistic assignments are supported by kinetic isotope effects, isotopic labelling and DFT calculations. This work expands the toolbox for constructing complex N-heteroarenes via nonclassical rearomatization pathways.