Selective N‑Formylation and N‑Methylation of Amines Using Methanol as a Sustainable C1 Source

Methanol was utilized for C1 functionalization of primary amines; N-formylation, N-methylation, and N,N-formylmethylation. The reactions were achieved via dehydrogenation of methanol with a ruthenium-based catalyst. Various amines were selectively functionalized in moderate to excellent yields (30% to 99%). Mechanistic studies revealed that control of the reversibility between dehydrogenation of the hemiaminal to formamide and hydrogenation of the formamide back to the hemiaminal promotes the selectivity. The hemiaminal intermediate is further dehydrated to an imine, followed by irreversible hydrogenation to generate the N-methyl secondary amine. The N-methyl secondary amine can then undergo formylation to produce N,N-formylmethylamine. It can be also reversibly hydrogenated to the corresponding hemiaminal intermediate. Further dehydration and subsequent hydrogenation can generate N,N-dimethylamine. The hydrogen pressure and reaction temperature are critical to controlling the equilibria and reaction pathways for selective functionalization, demonstrating that simple variation of the reaction conditions can tune the reaction selectivity of a catalytic system for selective C1 functionalization of amines using methanol.