Divergent photochemical ring-replacement of isoxazoles

Isoxazoles, oxazoles, and other five-membered heteroaromatics are prevalent motifs in core structure of pharmaceuticals and agrochemicals. In early-stage drug discovery, it is common practice to prepare libraries of analogues featuring different heterocyclic cores and this generally requires a de novo synthesis for each scaffold. A valuable but currently unavailable strategy would involve the possibility for direct heterocycle "ring-replacement". Here we report a photochemical platform for the selective conversion of isoxazoles into oxazoles, pyrazoles, pyrroles, and isothiazoles by exploiting excited-state reactivity. Starting from a successful isoxazole-to-oxazole transformation, we uncover position-sensitive reactivity that prompted computational investigation. These insights guide a systematic reactivity survey and reveal a solvent-controlled deconstruction-reconstruction pathway via α-ketonitrile intermediates. This approach enables scaffold diversification without de novo synthesis, affording access to five distinct azole classes under mild conditions. The method's selectivity, functional group tolerance, and late-stage applicability suggest broad utility in heterocyclic library design for pharmaceutical research.