A computational mechanistic study on the Pd(ii)-catalyzed γ-C(sp³)-H lactamization and further rational design

γ-Lactams are present in numerous natural and synthetic bioactive compounds, exhibiting a wide range of biological activities. Compared to traditional multi-step synthesis, intramolecular amination of aliphatic amides can directly construct valuable γ-lactam motifs from abundant amino acid precursors. Recently, Yu and coworkers reported novel 2-pyridone ligand-facilitated Pd(ii)-catalyzed γ-C(sp³)-H lactamization of amino acid-derived natural amides. This protocol is notable for its use of practical and environmentally friendly tert-butyl hydroperoxide (TBHP) as the sole oxidant and its broad substrate scope. In this study, we present a comprehensive computational mechanistic study on the Pd(ii)-catalyzed γ-C(sp³)-H lactamization, elucidating the key roles of the oxidant TBHP and Pd oxidation state transformations. The entire catalytic process can be divided into three stages: (i) the formation of actual active species (OAc)Pd-L1 followed by γ-C(sp³)-H bond activation generating the six-membered-metallacycle Pd(ii) intermediate IM4; (ii) with the assistance of oxidant TBHP, the C-N bond annulation occurs to complete the γ-lactamization process; (iii) product formation and active species (OAc)Pd-L1 regeneration for the next catalytic cycle. Each stage is both kinetically and thermodynamically feasible. Intermediate 1/3Pd₃(OAc)₆ to the IM2 step, with a barrier of 25.4 kcal mol⁻¹, should be the rate-determining step (RDS) in the whole catalysis. Based on mechanistic study, new pyridone ligands (i.e., L3 and L4) affording lower free energy barriers were further rationally designed, which will help to improve current catalytic systems and facilitate the development of new Pd(ii)-catalyzed γ-C(sp³)-H lactamization reactions.