Molecular Reprogramming of Pyridines Unlocked by Photocatalysis

The remodeling of arenes is a critical frontier in molecular design, with far-reaching implications for drug discovery, late-stage functionalization, and chemical space exploration. This holds particularly true for N-heteroarenes, which are key units of many bioactive molecules. However, their inherent stability severely limits the convenience and the generality of chemical remodeling methods. Here, we introduce Molecular Reprogramming as a general and divergent strategy for the one-pot conversion of pyridines into diverse N-heterocycles, either homopyrroles, pyrroles, pyrrolidines or tropanes. The key step of the sequence is a photocatalytic di-π-methane rearrangement, which was unlocked thanks to the rational installation of a π- handle onto 1,2-dihydropyridine intermediates. This original activation avoids the limitations of UV- and thermal protocols, which are incompatible with present reactivity, and provides multipotent chemical entities, namely syn-π-homopyrroles, that could easily undergo divergent core modification. The logic offers a versatile foundation for skeletal contraction/expansion strategies and suggests new opportunities for visible-light-driven molecular editing. Highly decorated products become readily accessible, and challenging species, including several organometallic reagents, are smoothly tolerated. The one-pot approach targets a broad chemical space, which includes the late- stage derivatization of FDA-approved drugs, minimizing time consumption and wastes. The sequential process affords privileged three-dimensional N-heterocycles, including many bioactive compounds, from a ubiquitous family of aromatic precursors.