Recent advances in the catalytic N-methylation and N-trideuteromethylation reactions using methanol and deuterated methanol

Abstract

N-methylamine functionalities are valuable motifs, which play vital roles in the properties and activities of essential fine and bulk chemicals including molecules used in life science applications, and functional materials. Thus, N-methylations constitute an important class of reactions in organic synthesis and drug discovery, giving access to advanced compounds, pharmaceuticals, biomolecules, and agrochemicals. The diversity of these kinds of amine structures and their biological relevance stimulated researchers in academia and industry to develop more sustainable, atom-economical, and cost-effective methodologies for the synthesis of N-methylated molecules and pharmaceutical agents. For their preparation, N-methylation using methanol represents a convenient and resourceful methodology because methanol is an abundantly available bulk chemical and serves as an effectual methyl (–CH₃) source. Moreover, methanol is less hazardous and produces water as the only by-product in methylation reactions. In this regard, in recent years, several discoveries have been made on the catalytic valorization of methanol as a powerful methylation reagent. This review aims to provide the most recent progress made in catalytic N-methylation of nitrogen-containing molecules employing methanol as a key C1 source from 2017 to August 2022. In particular, the synthesis of N-methylamines and related bioactive compounds starting from different organo-nitrogen compounds such as amines, nitroarenes, amides, sulfonamides, aldoximes, nitriles, and acyl azides using both homogeneous and heterogeneous catalysts including photo(redox) systems are discussed in detail. In addition, N-trideuteromethylation of amines or nitroarenes using deuterated methanol is described as a versatile synthetic tool for synthesizing N-trideuteromethyl labelled molecules, which play significant roles in pharmacological and metabolic activities. We sincerely hope that this review will be interesting and beneficial to scientists working in both academic research and industries in the areas of organic synthesis, medicinal, and biological chemistry.