Mechanistic Insights into Additive Loading-Controlled Chemoselectivity in Pd-Catalyzed Cyclization of Biphenylamines with Propargyl Alcohols

DFT calculations were employed to systematically investigate the Pd-catalyzed annulation of biphenylamines with propargyl alcohols: the catalytic Cu(OAc) 2 with stoichiometric H 2 O in an air atmosphere favored a dual C–H functionalization product, whereas the stoichiometric Cu(OAc) 2 with no-H 2 O promoted the formation of a dual oxidative cyclization product. For both reactions, following initial N–H deprotonation and C–N reductive elimination, a subsequent second N–H deprotonation step is requisite toward the two distinct products. Subsequently, the system employing a catalytic amount of Cu(OAc) 2 with stoichiometric H 2 O exhibits a distinct mechanistic profile: a unique Pd(II)–Pd(IV)–Pd(II) redox cycle is featured, over the conventional Pd(II)–Pd(II)–Pd(II) manifold commonly documented in analogous transformations. Notably, the oxidation from Pd(II) to Pd(IV) avoids breaking the strong C–C bond to facilitate a nucleophilic attack. Instead, a novel “π–σ–π isomerization-induced oxidative cyclization” mechanism is proposed for the stoichiometric Cu(OAc) 2 -mediated system. Specifically, the π–σ–π isomerization not only enhances the electrophilicity of the active C site but also promotes the substantial orbital overlap between this C center and the hydroxyl O atom, thereby facilitating the nucleophilic cyclization initiated by the hydroxyl O atom. Further analyses reveal that the chemoselectivity of the reaction is predominantly governed by the combined effects of Cu(OAc) 2 and H 2 O loading.