Simple RuCl₃‐catalyzed N‐Methylation of Amines and Transfer Hydrogenation of Nitroarenes using Methanol

Abstract

Methanol is a potential hydrogen source and C1 synthon, which finds interesting applications in both chemical synthesis and energy technologies. The effective utilization of this simple alcohol in organic synthesis is of central importance and attracts scientific interest. Herein, we report a clean and cost‐competitive method with the use of methanol as both C1 synthon and H2 source for selective N‐methylation of amines by employing relatively cheap RuCl3.xH2O as a ligand‐free catalyst. This readily available catalyst tolerates various amines comprising electron‐deficient and electron‐donating groups and allows them to transform into corresponding N‐methylated products in moderate to excellent yields. In addition, few marketed pharmaceutical agents (e. g., venlafaxine and imipramine) were also successfully synthesized via late‐stage functionalization from readily available feedstock chemicals, highlighting synthetic value of this advanced N‐methylation reaction. Using this platform, we also attempted tandem reactions with selected nitroarenes to convert them into corresponding N‐methylated amines using MeOH under H2‐free conditions including transfer hydrogenation of nitroarenes‐to‐anilines and prepared drug molecules (e. g., benzocaine and butamben) as well as key pharmaceutical intermediates. We further enable one‐shot selective and green syntheses of 1‐methylbenzimidazole using ortho‐phenylenediamine (OPDA) and methanol as coupling partners.

Investigation of NNN Pincer Ruthenium(II) Complexes with a Pendant Hydroxyl Group for N‐Monomethylation of amines and Nitroarenes by Methanol

“…Several complexes of transition metals such as ruthenium, [3] iridium, [4] manganese, [5] palladium [6] and iron [7] have been developed for this purpose. Very recently, Natte's group developed RuCl 3 ‐catalyzed (5 mol %) N‐methylation of Amines using methanol without the assistant of ligands at 130–160 °C [3g] . Nevertheless, these transformations suffer from high loading of transition‐metal catalysts and harsh reaction conditions.…”

Methanol as a Potential Hydrogen Source for Reduction Reactions Enabled by a Commercial Pt/C Catalyst

“…p-Tolylmethanol (49). 75 It is obtained as a colorless liquid (31.81 mg, 52%) after purification by column chromatography (n-hexane/ EtOAc: 90:10).…”

A bimetallic PdCu–Fe3O4catalyst with an optimal d-band centre for selectiveN-methylation of aromatic amines with methanol

“…However, reactive formaldehyde formation via methanol dehydrogenation is challenging because of its high dehydrogenation energy (Δ H = +84 kJ mol −1 ) compared to other alkyl alcohols. 12 For efficient catalytic N -methylation with methanol, many researchers have developed novel homogeneous catalysts (Mn, 13 Fe, 14 Co, 15 Ru, 16 Re, 17 and Ir (ref. 18)) and heterogeneous catalysts (Pd, 19 Ag, 20 and Pt (ref.…”