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.