N-Methylation of Nitrogen-Containing Organic Substrates: A Comprehensive Overview

The present account surveys the results of the plethora of works on N-methylation of nitrogen-containing substrates, mainly amines. The countless reports in the literature on this issue reveal the emergence of a set of methylating agents, which include: methanol, dimethyl carbonate, formaldehyde/formic acid, carbon dioxide/reductant, methyl iodide, dimethylsulfate, peroxides, dimethylsulfoxide, tetramethylammonium salts, and other unusual ones. Types of the methylating agents including, catalyst, solvent, base, ligand, reducing agent and other reaction conditions such as temperature and time would greatly affect the extent of selectivity of N-monomethylation vis-a-vis N,N-dimethylation. The degree of acidity or alkalinity of catalysts such as the solid catalysts (i.e. zeolites) showed a substantial impact on the selectivity and the course of methylation, leading to design adequate catalysts or to bring suitable modifications to the existing ones. Although this account takes into consideration all types of methylating agents, it is worthwhile to mention that the relatively recent works have been focused on the utilization of eco-friendly methylating agents, including carbon dioxide/reductant, methanol, and dimethylcarbonate. N-Methyl-containing drugs were successfully synthesized with some methylating agents under specified conditions. In some instances, unexpected products and events from the planned N-methylation of some nitrogen-containing molecules occurred. N-Formylation occurred as an intermediate or concomitant reaction when amines were subjected to catalyze methylation with methanol, formaldehyde/formic acid, and carbon dioxide/reductant. The occasionally depicted mechanisms would elucidate the carbon and hydrogen sources of the affixing methyl group on the nitrogen site. Peculiarly, methylation involving methanol as a methylating agent and transition metal catalysis called for borrowing hydrogen process as a new mechanistic approach.