Ligand-promoted site-selective regiodivergent lactamization of activated δ- versus inert γ-methylene C(sp³)–H bonds via open-shell copper(II) nitrenoid catalysis

Abstract

Significant advances have been achieved in developing transition metal catalysts capable of regioselectively functionalizing benzylic or tertiary C–H bonds, leveraging their bond dissociation energies and steric properties. However, catalytic transformations effectively differentiating methylene C–H bonds within the same hydrocarbon skeleton, especially selecting the stronger C–H bond over the weaker one, remains a significant challenge. Here, we present a copper-catalyzed regiodivergent lactamization of activated δ-benzylic, -allylic, -tertiary, and inert γ-C(sp³)–H bonds mediated by ligand-promoted 1,6- versus 1,5-hydrogen atom transfer (HAT). Using 1,4,2-dioxazol-5-ones derived from 5-arylpentanoic acids as nitrene precursors, combined experimental and computational studies reveal that the lactamization proceeds through open-shell Cu(II)–iminyl diradical intermediates, which undergo intramolecular HAT at the γ- and δ-methylene C–H bonds to form carboradical intermediates. When 2-bromophenanthroline (L9) is used as the ligand, the Cu(II)–iminyl diradical complex reacts via 1,6-HAT, thereby targeting the δ-benzylic C–H bonds to afford the δ-lactams with > 18:1 rr. However, with 2,9-diphenyl phenanthroline (L7) as ligand, lactamization of the γ-methylene C–H occurred preferentially (>10:1 rr) through 1,5-HAT. A linear free-energy relationship study and computational analysis suggest that the selectivity between γ- and δ-C–H lactamization is governed by the steric properties of the ligands.