Mechanism of Copper(I)-Catalyzed Allylic Alkylation of Phosphorothioate Esters: Influence of the Leaving Group on α Regioselectivity

The mechanism of CuI‐catalyzed allylic alkylation and the influence of the leaving groups (OPiv, SPiv, Cl, SPO(OiPr)2; Piv: pivavloyl) on the regioselectivity of the reaction have been explored by using density functional theory (DFT). A comprehensive comparison of many possible reaction pathways shows that [(iPr)2Cu]− prefers to bind first oxidatively to the double bond of the allylic substrate at the anti position with respect to the leaving group, and this is followed by dissociation of the leaving group. If the leaving group is not taken into account, the reaction then undergoes an isomerization and a reductive elimination process to give the α‐ or γ‐selective product. If OPiv, SPiv, Cl, or SPO(OiPr)2 groups are present, the optimal route for the formation of both α‐ and γ‐substituted products changes from the stepwise elimination to the direct process, in which the leaving group plays a stabilizing role for the reactant and destabilizes the transition state. The differences to the energy barrier for the α‐ and γ‐substituted products are 2.75 kcal mol−1 with SPO(OiPr)2, 2.44 kcal mol−1 with SPiv, 2.33 kcal mol−1 with OPiv, and 1.98 kcal mol−1 with Cl, respectively; these values show that α regioselectivity in the allylic alkylation follows a SPO(OiPr)2>SPiv>OPiv>Cl trend, which is in satisfactory agreement with the experimental findings. This trend mainly originates in the differences between the attractive electrostatic forces and the repelling steric interactions of the SPO(OiPr)2, SPiv, OPiv, and Cl groups on the Cu group. Making sense of selectivity: Why can the CuI‐catalyzed alkylation of an allylic substrate give an α/γ‐substituted product, and why can the leaving groups cause different degrees of α selectivity (SPO(OiPr)2>OPiv>Cl; Piv: pivaloyl)? This work provides a theoretical insight into the mechanism on the molecular level; the selectivity trend mainly originates in the interaction differences (the electrostatic effects and steric hindrance) of the leaving groups on the Cu group.