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

Abstract

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 (L 1a ) 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 β-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.

Oxygen Dependent Switchable Selectivity during Ruthenium Catalyzed Selective Synthesis of C3-Alkylated Indoles and Bis(indolyl)methanes

“…In our previous work we observed that catalyst 1a efficiently dehydrogenates alcohols to the corresponding carbonyls . The hydrogen removed during the dehydrogenation step remains stored in the azo-chromophore of ligand L 1a , which readily gets transferred to molecular oxygen under air to H 2 O 2 while it reduces a hydrogen acceptor under an inert atmosphere .…”

“… , This was further strengthened by the fact that the 1a -catalyzed dehydrogenation of alcohols remains unaffected in the presence of TEMPO (Scheme , entry 3). However, after repeated efforts, we failed to identify any Ru–H intermediate; instead, the reaction mixture obtained after the stoichiometric reaction of 1a with CH 3 OH showed characteristic −NH stretching frequencies at 2955 and 2915 cm –1 upon IR spectroscopic analysis. , The stoichiometric reaction of 1a with CD 3 OD showed characteristic −ND stretching at 2284 and 2210 cm –1 , indicating the formation of a hydrazo-type intermediate in the reaction mixture (see SI, Figure S1). , Similar formation of a hydrazo-type intermediate was observed during 1a -catalyzed N -alkylation of amines and synthesis of pyrroles .…”

“…Two well-characterized hexa-coordinated Ru­(II)-complexes [Ru­(L 1a )­(PPh 3 )­Cl 2 ] ( 1a ) and [Ru­(L 1b )­(PPh 3 )­Cl 2 ] ( 1b ) bearing 2-(arylazo)-1,10-phenanthroline ( L 1a = 2-((4-chlorophenyl)-diazenyl)-1,10-phenanthroline; L 1b = 2-(phenyldiazenyl)-1,10-phenanthroline) were used in this work. Complexes 1a and 1b were prepared by reacting [Ru II (PPh 3 ) 3 Cl 2 ] with L 1a and L 1b in a 1:1 molar ratio in ethanol under air at room temperature . The Ru­(II)-centers in catalysts 1a and 1b possess distorted octahedral geometry.…”

“…One tridentate pincer L 1a or L 1b is bound to the Ru­(II)-center in a tridentate NNN fashion; two chlorides and one PPh 3 ligand occupy the rest of the coordination sites. In both 1a and 1b , two chlorido ligands are in cis geometry …”

“…Instead, when we performed the IR experiment of the reaction mixture, we observed −NH stretching at 2958 and 2918 cm –1 , respectively (see SI, Figure S8). Under the O 2 environment, 1a converts 3a to 13 in 98% yield (Scheme , entry 1). The formation of cyclobutanone as the exclusive product upon 1a -catalyzed dehydrogenation of cyclobutanol confirms that the 1a -catalyzed dehydrogenation proceeds via a two-electron hydride transfer pathway forming a Ru-hydride type intermediate (Scheme , entry 2) (see SI, Figure S153).…”