N-Alkylation of Amines by C1-C10 Aliphatic Alcohols Using A Well- Defined Ru(II)-Catalyst. A Metal-Ligand Cooperative Approach

A Ru(II)-catalyzed efficient and selective N-alkylation of amines by C1-C10 aliphatic alcohols is reported. The catalyst [Ru(L1a)(PPh3)Cl2] (1a) bearing a tridentate redox-active azo-aromatic pincer, 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline (L1a) is air-stable, easy to prepare, and showed wide functional group tolerance requiring only 1.0 mol % (for N-methylation and N-ethylation) and 0.1 mol % of catalyst loading for N -alkylation with C3-C10 alcohols. A wide array of N-methylated, N-ethylated, and N-alkylated amines were prepared in moderate to good yields via direct coupling of amines and alcohols. 1a efficiently catalyzes the N-alkylation of diamines selectively. It is even suitable for synthesizing N-alkylated diamines using (aliphatic) diols producing the tumor-active drug molecule MSX-122 in moderate yield. 1a showed excellent chemo-selectivity during the N-alkylation using oleyl alcohol and monoterpenoid beta-citronellol. Control experiments and mechanistic investigations revealed that the 1a-catalyzed N-alkylation reactions proceed via a borrowing hydrogen transfer pathway where the hydrogen removed from the alcohol during the dehydrogenation step is stored in the ligand backbone of 1a, which in the subsequent steps transferred to the in situ formed imine intermediate to produce the N-alkylated amines.

Automated summary

A Ru(II)-catalyzed N-alkylation reaction of amines with C1-C10 aliphatic alcohols was described. The air-stable catalyst 1a exhibited wide functional group tolerance and high catalytic efficiency, requiring only low catalyst loading. Various N-methylated, N-ethylated, and N-alkylated amines were efficiently prepared. The reaction proceeded through a borrowing hydrogen transfer pathway and showed excellent chemo-selectivity.