Rebound-S _N 2 versus S _H 2 Mechanism in Cu-Catalyzed Radical Alkylation of Nucleophiles

Copper-catalyzed enantioconvergent radical alkylation of oxygen and nitrogen nucleophiles represents an efficient strategy for asymmetric synthesis. An inner-sphere mechanism comprising of radical capture and reductive elimination as well as an outer-sphere mechanism through SH2 were generally proposed for this type of reaction. Herein, a rebound-SN2 mechanism is put forward for the transformation of radicals with an anchoring group (e.g., an α-amide radical). This mechanism features a dangling radical center chelated to copper(II), and the transformation proceeds from the intramolecular radical capture by copper(II), nucleophile dissociation, and a subsequent SN2 step to afford the stereoinversed product. It outcompetes the reductive elimination pathway by avoiding the energetic penalty associated with fused-ring strain. The computational study of the enantiocontrol suggested that the enantioselectivity is governed by competition between the classical SH2 and rebound-SN2 mechanisms. Quantitative steric-electronic effects dissection (QSED) has quantified the influence of various radical–catalyst interactions on mechanism competition. The in-depth mechanistic understanding inspired us to put forward the ligand–radical dihedral angle θ as the indicator for predicting the mechanism discrimination between SH2 and rebound-SN2. The smaller θ (≤64.0°) in the phenoxy copper(II) amide intermediate indicates that the rebound-SN2 mechanism is kinetically more favorable, as a larger θ imposes a greater steric demand for transition state formation, particularly for the radical capture transition state.