Cmethylation

C-methylation, sometimes written Cmethylation, refers to the introduction of a methyl group onto a carbon atom within an organic substrate. It is distinct from methylation at heteroatoms such as nitrogen or oxygen and is important in both chemical synthesis and biological metabolism.

In chemical synthesis, C-methylation can proceed through several general strategies. Nucleophilic carbon centers, such as enolates or carbanions, can attack methyl electrophiles like methyl iodide or methyl triflate in SN2-type processes. Electrophilic methylation of activated carbon sites and radical or photoredox methods provide alternative routes to install methyl groups on sp2 or sp3 carbons. Modern approaches also include transition-metal-catalyzed methods and cross-electrophile couplings that enable selective installation of methyl groups from various methyl donors, including methylzinc or methyl boron reagents. The choice of method depends on substrate type, desired Regio- and stereochemistry, and functional-group tolerance.

In biochemistry, C-methylation is often mediated by C-methyltransferases, enzymes that transfer a methyl group from S-adenosylmethionine (SAM) to carbon atoms in substrates. This can affect aromatic rings, alkenes, or saturated carbon centers and frequently contributes to the diversity and activity of natural products such as polyketides and terpenoids. Enzymatic C-methylation is typically highly regiospecific and can be stereoselective, enabling precise construction of complex molecules.

Applications of C-methylation span pharmaceutical development, natural-product synthesis, and metabolic labeling. Challenges include achieving high site selectivity, controlling stereochemistry, and minimizing competing methylation at other sites. See also methylation, C-methyltransferase, and enolate alkylation.