Mechanistic Insights into Additive Loading-Controlled Chemoselectivity in Pd-Catalyzed Cyclization of Biphenylamines...

DFT calculations were employed to systematically investigate the Pd-catalyzed annulation of biphenylamines with propargyl alcohols: the catalytic Cu(OAc)2 with stoichiometric H2O in an air atmosphere favored a dual C-H functionalization product, whereas the stoichiometric Cu(OAc)2 with no-H2O 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 H2O 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 H2O loading.