C-Methylation of Organic Substrates: A Comprehensive Overview. Part II—Methyl Metals as Methylating Agents

Abstract

C-Methylation of organic substrates was achieved with a number of methyl metals, including trimethylaluminum (Me3Al), trimethylgallium (Me3Ga), trimethylindium (Me3In), dimethylzinc (Me2Zn), methyl zinc halide (MeZnX), methylboranes (MeBRR’), methylboronic acid (MeB(OH)2), methylboronates (MeB(OR)2), methylcopper (MeCu), methyllithium cuprate (Me2CuLi), methylmagnesium halides (MeMgX), tetramethyltin (Me4Sn), methyl lithium, and lead tetraacetate. Most of the related reactions required the presence of transition metal complexes as catalysts and phosphine ligands. Overall, the yields of the methylated products actually depended on the types of used catalyst and ligand. In some instances, additives were needed as specific promoters, such as p-benzoquinone in the methylation through coupling with methyl boron agents. Best of all, methylation of substrates with some of these methylating agents occurred with some features. For example, asymmetric reactions of carbonyl compounds could be accomplished using dimethyzinc along with a specific ligand, leading to moderate to excellent yields of the major enantiomer with high enantiomeric excess. Ortho-methylation regioselectively occurred on aromatic substrates when they bear moieties such as heteroarenes (pyridine), amide, azomethine, oxazoline, N-nitrosoamine, oxime, coined ‘ortho-directing groups’.