Tunable mono- and di-methylation of amines with methanol over bimetallic CuCo nanoparticle catalysts

Methylation of amines is increasingly being employed as a powerful structural modification tool in medicinal chemistry. However, selectively accessing the mono- or di-methylated amines with an integrated catalytic system remains a pivotal challenge. We here report the selective N-mono- and di-methylation of amines over heterogeneous bimetallic CuCo nanoparticle catalysts with tunable supports relying on a methanol-based methyl source. N-methylamines were selectively produced on Cu-Co/MgAl-LDO under a hydrogen atmosphere, while N,N-dimethylamines could be easily accessed on Cu-Co/Al2O3 under a nitrogen atmosphere. A panel of structurally and functionally diverse amines, including primary/secondary aromatic amines and aliphatic amines, were efficiently methylated in excellent yields. Alternative substrate nitroarenes and aliphatic alcohols could be transformed in a predictable manner. Further characterization of the catalysts and a mechanistic study revealed that the metal-support interaction and acid-base properties originated from the support of the two catalysts, resulting in their selective methylation performances. Further fabrication of methylated pharmaceuticals or candidates highlighted the broad applicability of the selective N-mono- and N,N-dimethylation strategy with which the properties of drugs can be significantly changed.