A New Chiral Bis(oxazolinylmethyl)amine Ligand for Ru-Catalyzed Asymmetric Transfer Hydrogenation of Ketones

Asymmetric catalytic transfer hydrogenation using 2-propanol as a hydrogen source offers an attractive route for reducing simple unfunctionalized ketones to chiral alcohols.1 The reaction uses inexpensive reagents and is usually easy to perform. Notable among the recently developed efficient transition-metal-based chiral reduction catalysts2 is the Ru(II)-TsDPEN (TsDPEN ) N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine) system reported by Noyori3 et al., who suggested that an NH moiety in the ligand may promote a cyclic transition state through hydrogen bonding to a ketone substrate.1c It therefore appears that the formation of a metal-ligand bifunctional catalyst can greatly increase the substrate affinity to the catalyst active site and induce high enantioselectivity. Earlier results from Noyori and Lemaire with different ligands have also shown a similar “NH effect”.4,5 Chiral tridentate ligands generally form a deeper chiral concave pocket around the metal center than the corresponding chiral bidentate ligands. An example is the chiral bis(oxazolinyl)pyridine ligand (pybox), developed by Nishiyama, which has been successfully applied to numerous asymmetric reactions.6 The two substituents on the oxazoline rings of pybox form a highly enantioselective “chiral fence”, which can effectively differentiate the re and si faces of many substrates. In an ongoing effort to develop effective chiral tridentate ligands for asymmetric catalysis,2a,b,e we have designed a bis(oxazolinylmethyl)amine (ambox) ligand system. Thus, by replacing the pyridine backbone of pybox with a secondary amino group, we expected that the new ambox ligand would form a six-membered cyclic transition state similar to that suggested by Noyori and highly enantioselective transfer hydrogenation of simple ketones might be realized (Figure 1). Herein, we present the synthesis of bis[4-(R)-phenyloxazolin-2-yl-methyl]amine (1, (R)-ph-ambox) and initial results for asymmetric transfer hydrogenation of aromatic ketones. We have synthesized this ligand through the route7 shown in Scheme 1. The imidate ester hydrochloride 2 was obtained in 76% crude yield from the inexpensive starting material, iminodiacetonitrile, and was used in the following step without purification. Treatment of (R)-2-phenylglycinol with 2 in CH2Cl2 at 0 °C and then warming to room temperature for 12 h afforded 1 in 25% unoptimized yield. The low yield of the second step is due to the formation of a mono-oxazoline as a side product along with reaction products derived from impurities in 2.