Ligand-Promoted Site-Selective Regiodivergent Lactamization of Activated δ- versus Inert γ-Methylene C(sp³)-H Bonds...

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.