Safe cyanation of alcohols enabled by synchronized photocatalytic nucleophile and electrophile generation

Aliphatic nitriles are frequently found in active pharmaceutical ingredients and serve as important synthetic intermediates. The synthesis of these structural motifs often relies on SN2 reactions that require highly toxic cyanide salts. To address this safety issue, we present a photocatalytic manifold for the cyanation of alcohols that recreates Mitsunobu-type reactivity without relying on hazardous reagents. The reaction design is based on the photocatalytic generation of labile phosphoranyl radicals that usually undergo rapid β-scission yielding carbon-centered radicals. We show that presence of cyanopyridines outcompetes this fragmentation pathway by a single electron transfer event that results in the formation of an oxyphosphonium cation and on-demand cyanide generation, which engage in an SN2 reaction. The mechanistic blueprint was successfully extended to Appel-type halogenations, illustrating how synchronized radical processes can be leveraged to redesign established polar substitution manifolds.