Investigation of the C-N Bond-Forming Step in a Photoinduced, Copper-Catalyzed Enantioconvergent N-Alkylation: Characterization and Application of a Stabilized Organic Radical as a Mechanistic Probe.

Whereas photoinduced, copper-catalyzed couplings of nitrogen nucleophiles with alkyl electrophiles have recently been shown to provide an attractive approach to achieving a variety of enantioselective C-N bond constructions, mechanistic studies of these transformations have lagged the advances in reaction development. Herein we provide mechanistic insight into a previously reported photoinduced, copper-catalyzed enantioconvergent C-N coupling of a carbazole nucleophile with a racemic tertiary α-haloamide electrophile. Building on the isolation of a copper(II) model complex whose EPR parameters serve as a guide, we independently synthesize two key intermediates in the proposed catalytic cycle, a copper(II) metalloradical (L*CuII(carb')2) (L* = a monodentate chiral phosphine ligand; carb' = a carbazolide ligand), as well as a tertiary α-amide organic radical (R·); the generation and characterization of R· was guided by DFT calculations, which suggested that it would be stable to homocoupling. Continuous-wave (CW) and pulse EPR studies, along with corresponding DFT calculations, are among the techniques used to characterize these reactive radicals. We establish that these two radicals do indeed combine to furnish the C-N coupling product in good yield and with significant enantiomeric excess (77% yield, 55% ee), thereby supporting the chemical competence of these proposed intermediates. DFT calculations are consistent with R· initially binding to copper(II) via a dative interaction from the closed-shell carbonyl oxygen atom of the radical, which positions the α-carbon for direct reaction with the copper(II)-bound carbazole N atom, to generate the C-N bond with enantioselectivity, without the formation of an alkylcopper(III) intermediate.