Direct α-C–H Heteroarylation of Unprotected Primary Amines

The innate reactivity of unprotected primary alkylamines is dominated by electrophilic N-functionalization, and only recently have catalytic strategies begun to access direct C–C bond formation at the α-position. Nucleophilic aromatic substitution (SNAr) remains the most widely used N-arylation manifold in pharmaceutical synthesis, reflecting this intrinsic bias toward attack at nitrogen. Here we demonstrate that this long-standing paradigm can be reversed: unprotected primary amines, when paired with SNAr-active azolyl chlorides, undergo selective α-C–H heteroarylation under dual photoredox–hydrogen atom transfer (HAT) catalysis. This protocol furnishes previously inaccessible N-unprotected α-azolyl amines, including sterically demanding α-tertiary motifs. Continuous-flow photochemistry further broadens the scope to highly SNAr-reactive azolyl chlo-rides by combining high photon flux with low-temperature operation to suppress rapid background N-arylation. Together, these studies reveal that dual photoredox–HAT catalysis can overturn the canonical SNAr reactivity of amines, unearthing a divergent α-C-functionalization pathway from the same substrate pairs that conventionally yield N-arylated products.