Mechanistic Insight into Palladium-Catalyzed γ-C(sp)-H Arylation of Alkylamines with 2-Iodobenzoic Acid: Role of the -Carboxylate Group.

Density functional theory calculations were performed to understand the distinctly different reactivities of carboxylate-substituted aryl halides and pristine aryl halides toward the Pd-catalyzed γ-C(sp)-H arylation of secondary alkylamines. It is found that, when 2-iodobenzoic acid (a representative of -carboxylate-substituted aryl halides) is used as an aryl transfer agent, the arylation reaction is energetically favorable, while when the pristine aryl halide iodobenzene is used as the aryl transfer reagent, the reaction is kinetically difficult. Our calculations showed an operative Pd/Pd/Pd redox cycle, which differs in the mechanistic details from the cycle proposed by the experimental authors. The improved mechanism emphasizes that (i) the intrinsic role of the -carboxylate group is facilitating the C(sp)C(sp) bond reductive elimination from Pd rather than facilitating the oxidative addition of the aryl iodide on Pd, (ii) the decarboxylation occurs at the Pd species instead of the Pd species, and (iii) the 1,2-arylpalladium migration proceeds via a stepwise mechanism where the reductive elimination occurs before decarboxylation, not via a concerted mechanism that merges the three processes decarboxylation, 1,2-arylpalladium migration, and C(sp)-C(sp) reductive elimination into one. The experimentally observed exclusive site selectivity of the reaction was also rationalized well.