Ni-Catalyzed Cross-Coupling Reaction of Aryl Halides with O-Alkyl-Substituted Hydroxylamines to Obtain Aniline...

Hydroxylamine derivatives typically serve as electrophilic amine or nitrene precursors because of the lower electronegativity of nitrogen relative to oxygen, particularly upon activation of the hydroxyl group as a leaving group. In contrast, the utilization of hydroxylamine derivatives as nucleophilic nitrogen sources remains rarely explored. Herein, we report a nickel-catalyzed C-N coupling of aryl halides under mild conditions, wherein O-alkyl-substituted hydroxylamines are employed as nucleophilic nitrogen sources through an umpolung approach. This protocol features exceptional substrate generality, accommodating a broad array of aryl halides with remarkable functional group tolerance, particularly toward moieties sensitive to the strong bases inherent in conventional methods. Notably, we could extend synthetic applications to the late-stage functionalization of complex bioactive molecules. Combined mechanistic investigations and density functional theory calculations reveal that the reaction proceeds through a Ni(I)/Ni(III) catalytic cycle rather than a Ni(0)/Ni(II) pathway. The success of this transformation stems from the use of self-immolative hydroxylamine derivatives, which enable a crucial coordination shift on the nickel center from oxygen to nitrogen by forming a carboxylic acid chelate, thereby overcoming the longstanding challenge of inefficient amine transmetalation in traditional metal-catalyzed cross-coupling.