Copper(II/III) Redox Couple Enables C─H Methylation via a Radical Mechanism Analogous to SAM Enzymes

ABSTRACT Biological methylation is a fundamental regulatory process in gene expression, biomolecule modification, and cell repair. Many enzymatic C–H methylation reactions proceed through sequential one‐electron steps mediated by distinct redox cofactors, such as Fe 4 S 4 clusters and methylcobalamin. However, structurally faithful model complexes of these cofactors have thus far been unable to replicate the characteristic C–H methylation reactivity. Herein, we report the first isolable copper(II/III)–methyl complexes that undergo C─H methylation via a radical mechanism analogous to SAM enzymes. The copper(II)–methyl complex undergoes reversible one‐electron oxidation to a formal copper(III)–methyl species, which serves as a methyl radical reservoir capable of both generating and capturing carbon radicals. The Cu III –CH 3 complex mediates C–H methylation through hydrogen atom transfer (HAT) and methyl radical transfer, affording methylated products from substrates similar to those targeted by radical SAM methyltransferases. By merging the characteristic HAT and radical rebound reactivity within a single organometallic center, this copper(II/III)–methyl species provides a synthetic platform that mirrors key mechanistic features of enzymatic C–H methylation.