An iridium catalyst enables the reductive amination of carbonyl groups with unprecedented substrate scope, selectivity, and activity using formic acid as the hydrogen source (see scheme). The catalyst system provides significant improvement over commonly used boron hydrides.
,4-Tetrahydroquinolines exist as key structural elements in many natural products and have found broad commercial application.[1] In particular, optically pure tetrahydroquinolines are commonly present in alkaloids and are required in pharmaceutical and agrochemical synthesis. Representative examples include the bioactive alkaloids (+)-galipinine [2] and (À)-augustureine, [2b, 3] and the antibacterial drug (S)-flumequine.[2b]The most convenient route to chiral tetrahydroquinolines is the asymmetric reduction of quinolines. Successful examples of their hydrogenation by H 2 with organometallic catalysts have been reported.[4] However, although enantioselectivities of up to 99 % ee have been demonstrated, these catalysts usually require a high hydrogen pressure. In recently reported organocatalytic asymmetric reduction reactions of quinolines with the Hantzsch ester as the hydrogen source, excellent enantioselectivities were observed for 2-aryl substituted quinolines.[5] Surprisingly, there have been no reports of the asymmetric transfer hydrogenation (ATH) of quinolines with metal catalysts, although economical and environmentally benign hydrogen sources, such as isopropanol or formate, are generally used for ATH reactions, and ATH is operationally simpler than hydrogenation. [6,7] Herein we describe the ATH of quinolines [8] in water. The reactions were carried out in air, and excellent enantioselectivities were observed for a wide range of substrates (Scheme 1). The use of water as a reaction medium has been under intense investigation.[9] Apart from potential economic and ecological gains, water can offer new reactivity and selectivity patterns. [9,10] In this context, we and other research groups have reported successful ATH reactions of ketones and imines in neat water. [6g, 11-13] In particular, a combination of the unmodified Noyori ligand Ts-dpen (Ts-dpen = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) [14] and [{RuCl 2 (pcymene)} 2 ] or [(Cp*MCl 2 ) 2 ] (M = Rh, Ir) led to the efficient reduction of aryl ketones with HCOONa in water. Among these catalysts, the Rh-Ts-dpen catalyst showed the highest activity and selectivity. [11c] We chose to use presynthesized Rh-Ts-dpen as the catalyst [15] and began our study of quinoline reduction by examining the ATH of a model substrate, 2-methylquinoline (1 a: R = H, R' = 2-CH 3 ), with HCOONa in water (Scheme 1). Disappointingly, only 17 % conversion was observed at 40 8C in 12 h with a substrate/catalyst (S/C) ratio of 100:1 (1 a: 0.5 mmol, HCOONa: 10 equiv, water: 5 mL). However, the enantioselectivity was excellent: the product was obtained with 96 % ee.In our previous study on the ATH of ketones in water, the pH value of the solution was found to have a critical effect on the reaction rate. [11b,c] In the present quinoline reduction, the initial pH value of the solution was approximately 8. However, recent studies on asymmetric hydrogenation suggest that quinoline is hydrogenated through an ionic mechanism in its protonated form (Scheme 1). [4g, 5a, ...
In the synthesis of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (voriconazole), the relative stereochemistry is set in the addition of a 4-(1-metalloethyl)-5-fluoropyrimidine derivative to 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone. The diastereocontrol of this reaction has been examined by variation of pyrimidine substitution pattern and by changes in the metalation and reaction conditions. Excellent diastereoselection (12:1) is obtained using an organozinc derivative of 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine. After removal of the chlorine from the pyrimidine ring, the absolute stereochemistry of voriconazole is established via a diastereomeric salt resolution process using (1R)-10-camphorsulfonic acid. Synthetic routes to the pyrimidine partner have also been evaluated. The initial six-step development route from 5-fluorouracil has been superseded by a four-step synthesis involving fluorination of methyl 3-oxopentanoate and cyclisation with formamidine acetate.
I can do it! Accelerated by simple iodide ions, rhodium‐catalysed transfer hydrogenation can be readily performed on quinolines, isoquinolines and quinoxalines, affording the tetrahydro products in high yields with low catalyst loading (see scheme).
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