Simulated Mechanism for Palladium-Catalyzed, Directed γ‑Arylation of Piperidine

Quantum chemical reaction path finding methods are herein used to investigate the mechanism of Pd-catalyzed distal functionalization of piperidine, as reported by Sanford. These methods allowed navigation of a complex reaction landscape with multiple reactants interacting at all key steps of the proposed catalytic cycle. A multistep cycle is shown to conceptually begin with substrate ligation and Pd­(II)-catalyzed C–H activation, which occurs through concerted metalation–deprotonation. In subsequent steps, the kinetic and thermodynamic profiles for oxidative addition, reductive elimination, and catalyst regeneration show why excess Cs salts and ArI were required in the experiment. Specifically, excess ArI is necessary to thermodynamically overcome the high energy of the C–H activated intermediate and allow oxidative addition to be favorable, and excess Cs salt is needed to sequester reaction byproducts during oxidative addition and catalyst regeneration. The overall catalytic profile is consistent with rate-limiting C–H activation, explains the probable functions of all major experimental conditions, and gives atomistic detail to guide experiment to improve this challenging transformation even further.