Key Mechanistic Features of Enantioselective C–H Bond Activation Reactions Catalyzed by [(Chiral Mono-N-Protected Amino Acid)–Pd(II)] Complexes

Monoprotected chiral amino acids have recently been established as a class of ligand scaffolds for effecting Pd-catalyzed enantioselective C–H bond activation reactions. However, to elucidate the mechanistic details and controlling factors of these reactions, more comprehensive studies are needed. In this work we report computational investigations into the key mechanistic features of enantioselective C–H bond activation reactions catalyzed by a [chiral (mono-N-protected amino acid)–Pd­(II)] complex. Structural analysis points to a C–H insertion intermediate in which the nitrogen atom of the ligand is bound as a neutral σ-donor. The formation of this C–H insertion intermediate could, in principle, proceed via a “direct C–H cleavage” or via “initial N–H bond cleavage followed by C–H cleavage”. The computational studies presented herein show that the pathway initiated by N–H bond cleavage is more kinetically favorable. It is shown that the first step of the reaction is the N–H bond cleavage by the coordinated acetate group (OAc). In the next stage, the weakly coordinated OAc^– (the second acetate group) activates the ortho-C–H bond of the substrate and transfers the H-atom from the C-atom to the bound N-atom of the ligand. As a result, a new Pd–C bond is formed and the carbamate is converted from X-type to L-type ligand. The absolute configuration of the products that are predicted on the basis of the calculated energies of the transition states matches the experimental data. The calculated enantioselectivity is also comparable with the experimental result. On the basis of these data, the origin of the enantioselectivity can be largely attributed to steric repulsions in the transition states.