Convenient iron-catalyzed reductive aminations without hydrogen for selective synthesis of N-methylamines

Abstract

N-Methylated amines play an important role in regulating the biological and pharmaceuticalproperties of all kinds of life science molecules. In general, this class of compounds is synthesized via reductive amination reactions using high pressure of molecular hydrogen. Thus, on laboratory scale especially in drug discovery, activated (toxic) methyl compounds such as methyl iodide and dimethyl sulfate are still employed, which also generate significant amounts of waste. Therefore, the development of more convenient and operationally simple processes for the synthesis of advanced N-methylamines is highly desired. Herein, we report the synthesis of functionalized and structurally diverse N-methylamines directly from nitroarenes and paraformaldehyde, in which the latter acts as both methylation and reducing agent in the presence of reusable iron oxide catalyst. The general applicability of this protocol is demonstrated by the synthesis of >50 important N-methylamines including highly selective reductive N-methylations of life science molecules and actual drugs, namely hordenine, venlafaxine, imipramine and amitriptyline.

Catalytic Reductive Amination of Aldehydes and Ketones With Nitro Compounds: New Light on an Old Reaction

“…Other selectivity issues arise from the hydrogenation of the aromatic ring (Cirujano et al, 2013) and the formation of tertiary amines by a double reductive amination (Emerson and Uraneck, 1941). In reactions with formaldehyde, double reductive methylation to give tertiary amines occurs very easily, while the controlled monomethylation is challenging (Natte et al, 2017).…”

Homogenous Meets Heterogenous and Electro‐Catalysis: Iron‐Nitrogen Molecular Complexes within Carbon Materials for Catalytic Applications

“…Authors also performed in situ alkylation of the resulting aniline in the presence of an aldehyde with yields in the 46–94 % range (28 examples) . Using paraformaldehyde, the authors extended their scope to tertiary amines, in the form of N,N‐dimethylanilines . Under reaction conditions, paraformaldehyde depolymerizes into formaldehyde, then decomposes to H 2 and CO thus providing in situ both C1 source and reducing agents.…”

Selective N‐Monomethylation of Anilines with Methanol Catalyzed by Commercial Pd/C as an Efficient and Reusable Catalyst

“…The development of sustainable feedstocks and reusable catalysts is of great importance for the synthesis of N ‐methyl anilines, as they are essential intermediates in the manufacture of numerous fine chemicals, drugs, natural products, and dyes . Recently, more environmentally benign reagents such as methanol, carbon dioxide, formic acid, and paraformaldehyde as the methylation reagent have been intensively studied to replace toxic and hazardous reagents such as methyl iodide, methyl triflate, and dimethyl sulfate. Methanol is an important biomass because it is a readily available and renewable C1 feedstock, and its utilization in the N ‐monomethylation of anilines has attracted much attention because it is highly atom‐efficient and generates water as the only by‐product.…”