Mechanism of the Palladium-Catalyzed C(sp3)–H Arylation of Aliphatic Amines: Unraveling the Crucial Role of Silver(I) Additives

DFT calculations have been combined with experiments to study the mechanism of γ-C(sp3)–H arylation of aliphatic amines promoted by palladium–glyoxylic acid cooperative catalysis, with a focus on the role of silver(I) additives. Glyoxylic acid (the cocatalyst) uses its aldehyde functionality to react with the amine substrate to form an iminoacetic acid. This acid acts as a transient directing reagent and metathesizes with Pd(OAc)2 (the precatalyst) to give a Pd(II)–diiminoacetate five-membered chelate, which has been shown computationally as the catalyst resting state and which has been experimentally synthesized and characterized. C(sp3)–H activation from the Pd(II)–diiminoacetate complex or its mononuclear derivatives would face a high kinetic barrier (>30 kcal/mol) arising mainly from breaking a stable five-membered N,O-chelate ring. The crucial role of the silver(I) carboxylate additive is in reacting with the Pd(II)–diiminoacetate complex to provide a heterodimeric Pd(II)−Ag(I) complex supported by b...