Remote γ-C(sp3)–H Alkylation of Aliphatic Carboxamides via an Unexpected Regiodetermining Pd Migration Process: Reaction Development and Mechanistic Study

Abstract

In the presence of accessible β-C–H bonds, γ-C–H activation of saturated aliphatic carboxamides remains unresolved because β-C–H activation is kinetically favored. This is almost a dogma in the development of C–H activation reactions. Here we report a strategy to change this dogma, as we have found that a Pd-catalyzed, ligand-enabled remote γ-alkylation of saturated aliphatic carboxamides can be realized in the presence of more accessible β-C–H bonds by using strained bicyclic alkenes as the coupling partners. Density functional theory calculations and experiments suggested that the realization of the present reaction is due to a change in the regiodetermining step from commonly encountered irreversible C–H activations, which are reversible here, to an unexpected Pd migration process, which is regiodetermining. This is a new strategy to achieve γ-C–H activation, compared with the previous strategy, making γ-C–H activation both the turnover- and regiodetermining step.