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

Abstract

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.