JACS: ruthenium catalyzed asymmetric direct reduction amination of alkylarylketone and NH3 / H2

Chiral amines are the basic modules in organic synthesis and play an important role in drugs and pesticides One of the effective strategies to obtain asymmetric amines is the transition metal catalytic reaction with hydrogen as reducing agent In the past few decades, olefinic amination, imine hydrogenation and reductive amination (RA) reactions have been widely used due to the remarkable progress in the study of catalysts and ligands Among them, reductive amination is the most direct way to obtain abundant enantiomeric amines However, existing methods for the synthesis of enantiomerically pure primary amines require multi-step reactions, including in-situ generation of protected imines, asymmetric hydrogenation and deprotection of secondary amines (Fig 1a) In recent years, many biocatalytic methods have been reported, which can directly convert ketones to amines with enantiomeric purity Although biocatalysis develops rapidly and is widely used, the method of using H2 / NH3 as reductive amination reagent has not been developed Figure 1 Transition metal catalyzed asymmetric reduction amination source: another mature method for the enantioselective synthesis of primary amines by J am Chem SOC Is leukart Wallach reaction, i.e the chemical equivalent of ammonium formate is used for transfer hydrogenation, and ammonium formate is used as the source of ammonia and hydrogen at the same time Following this strategy, the enantioselective reductive amination of ketones with ruthenium catalyst and tol BINAP ligand was reported in 2003 Although this method can achieve good enantioselectivity, it has some shortcomings The reaction can only produce formamide products, which need additional hydrolysis steps, and will be accompanied by the formation of by-products As early as 1999, asymmetric reductive amination was first reported as a key step in the synthesis of (s) - metolachlor (a herbicide) However, there are not many ways to synthesize primary amines directly by reducing amination of transition metal catalyzed ketones The reasons for its slow development may be as follows: (I) carbonyl in raw materials may be reduced to corresponding alcohols by catalysts; (II) formation of imines is very slow unless water trapping agent is added; (III) NH 3 It is difficult to obtain enantiomers due to the presence of E / Z non enantiomers in imine intermediates; (V) over alkylation may occur to produce secondary and tertiary amines Therefore, it has not been reported that simple NH 3 / H 2 system can realize enantioselective reduction amination Recently, Thomas Schaub from the University of Heidelberg - BASF Catalysis Research Laboratory (Carrla) in Germany and researchers from several institutions of BASF and Heidelberg University developed a reduction amination method involving ruthenium catalysis NH 3 / H 2 By using this method, the enantiomer primary amine can be directly obtained The only by-product in the reaction is water (Fig 1b) Relevant papers were published on J am Chem SOC In the experiment of condition optimization, the author used acetylbenzene (1a) as the reaction substrate, Ru (CL) H (CO) (PPh3) 3) as the precursor of ruthenium catalyst, 6 bar ammonia and 40 bar hydrogen as the reaction solvent and temperature (120 ℃), and screened the reaction ligand and promoter (Fig 2) It can be seen that when the ligands and auxiliaries are L7 and NH4I respectively, the yield of reduction amination product 2A can reach 99%, and the enantioselectivity is 87% ee (entry 9) Fig 2 Source of condition screening: after J am Chem SOC Established the best reaction conditions, the author began to expand the scope of reaction substrate, focusing on the study of acetylbenzene compounds (Fig 3) It can be seen from the experimental results that acetylbenzene, acetylnaphthalene and other aromatic ketones containing various substituents can be compatible with the reaction conditions However, the reaction also has some limitations The activity of alkylketone and electron deficient acetylbenzene is poor, and diaryletone substrate does not react Figure 3 Source of substrate expansion: J am Chem SOC During the study, the author found that the promoters had a significant effect on the chemical and stereoselectivity of the reaction It can be seen from Fig 4 that with the increase of the volume of halogen atom contained in auxiliary nh4x, the proportion of reductive amination products and the percentage of enantiomeric excess increase, while the proportion of ketone reductive product alcohol decreases The reason may be that the large volume of halogen atom improves the σ - donation of catalyst metal center and has the advantage of halogen exchange Figure 4 Source of halide effect: J am Chem SOC In addition, the author analyzed and studied the catalyst, and calculated the reaction process theoretically Finally, the mechanism of the reaction is given, and the influence of halides on the enantioselectivity and chemical selectivity is described in detail Summary: Thomas Schaub team developed ruthenium catalyzed direct asymmetric amination of alkylarylketone with NH 3 / H 2, and obtained primary amines with good enantioselectivity and chemical selectivity In the study, the team characterized the structure of the catalyst, and calculated the reaction mechanism and the effect of halogenated compounds on the reaction selectivity Paper link: http://pubs.acs.org/doi/10.1021/jacs.7b10496 catalytic research laboratory link: http:// introduction to Thomas Schaub http://