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

In the presence of accessible beta-C-H bonds, gamma-C-H activation of saturated aliphatic carboxamides remains unresolved because beta-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 gamma-alkylation of saturated aliphatic carboxamides can be realized in the presence of more accessible beta-C-H bonds by using strained bicyclic alkenes as the coupling partners. Density functional theory calculations and experiments suggested that the realization of the 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 gamma-C-H activation, compared with the previous strategy, making gamma-C-H activation both the turnover- and regiodetermining step.