Copper-Catalyzed C(sp3)–H Methylation via Radical Relay

The methyl moiety is a key functional group that can result in major improvements in the potency and selectivity of pharmaceutical agents. We present a radical relay C–H methylation methodology that employs a β-diketiminate copper catalyst capable of methylating unactivated C­(sp3)–H bonds. Taking advantage of the bench-stable DABAL-Me3, an amine-stabilized trimethylaluminum reagent, methylation of a range of substrates possessing both activated and unactivated C­(sp3)–H bonds proceeds with a minimal amount of overmethylation. Mechanistic studies supported by both experiment and computation suggest the intermediacy of a copper­(II) methyl intermediate reactive toward both the loss of the methyl radical as well capture of radicals R• to form R–Me bonds.