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C-Methylation of organic substrates was accomplished with a number of methylating agents other than methane, methanol, and methyl metals. They include methyl halides (MeX, X = I, Br, Cl, F), methyl-containing halogenated reagents, methyl peroxides, dimethyl carbonate (DMC), dimethylsulfoxide (DMSO), N,N-dimethyl formamide (DMF), diazomethane, formate salts, trioxane, CO/H2, CO2/H2, and dimethyl ether (DME). Under particular conditions, some methyl-containing molecules such as polymethylbenzenes, methylhydrazine, tris(diethylamino)sulfonium difluorotrimethylsilicate, methyl tosylate, long-chain alkyl alcohols, and acetic acid unexpectedly C-methylated a variety of organic substrates. A few cases of C-methylation only were reported to occur in the absence of catalysts. Otherwise, transition metal complexes as catalysts in conjunction with specific ligands and bases were ubiquitously present in most C-methylation reactions. Of the reactions, Suzuki-Miyaura-type cross-coupling remained of paramount importance in making 11CH3-bearing positron emission tomography tracers (PETs), one of the best applications of such methylation. Methylation proceeded at C(aromatic)-X, C(sp3)-X C(sp2)-X, and C(sp)-X of substrates (X = H, halogen). Ortho-methylation was regioselectively observed with aromatic substrates when they bear moieties such as pyridyl, pyrimidyl, amide, and imine functionalities, which were accordingly coined ‘ortho-directing groups’.
