HETEROCYCLES

Communication | Regular issue | Vol. 78, No. 3, 2009, pp. 617-622
Received, 29th September, 2008, Accepted, 4th November, 2008, Published online, 5th November, 2008.
DOI: 10.3987/COM-08-11563

■ A Chiral “Roofed” cis-Diamine-Ru(II) Complex: An Efficient Catalyst for Asymmetric Transfer Hydrogenation of Ketimines

Hirofumi Matsunaga, Kyoko Nakanishi, Makoto Nakajima, Takehisa Kunieda, and Tadao Ishizuka*

Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan

Abstract

Highly enantioselective transfer hydrogenation of ketimines to the corresponding chiral amines was achieved with the chiral Ru(II) complex, prepared from the conformationally rigid and sterically bulky “roofed” cis-1,2-diamine.

Optically active amines are very important building blocks for biologically active molecules, pharmaceuticals, and agrochemicals. Among the numerous methods currently available for the preparation of enantiomerically pure amines, catalytic enantioselective reduction of ketimines is one of the most important methods,1 as it is used to accomplish chiral ligand-transition metal complex-catalyzed high-pressure hydrogenations,2 hydrosilylations3 or transfer hydrogenations4, and chiral organic compound-catalyzed hydrosilylations.5 However, compared with the reduction of ketones using a similar procedure, the number of highly effective methods currently available for the reduction of ketimines is limited. Therefore, the study of versatile and/or highly enantioselective reduction of ketimines remains challenging.
We previously demonstrated that chiral “roofed” cis-1,2-diamine, which is conformationally rigid and sterically bulky, was easily derived from chiral “roofed” 2-imidazolidinone. Moreover, cis-1,2-diamine was an excellent ligand for the Ru(II)-catalyzed asymmetric transfer hydrogenation of a wide variety of arylketones, including sterically bulky ketones, resulting in high catalytic activity and enantioselectivity (Scheme 1).6 These positive results encouraged us to apply this system to the catalytic asymmetric reduction of ketimines.

In this paper, we describe a highly effective asymmetric transfer hydrogenation of ketimines catalyzed by the “roofed” cis-1,2-diamine-Ru(II) complex in the presence of 5HCO2H•2NEt3.
Five types of “roofed” cis-1,2-diamines 10a-e were readily prepared by N’-sulfonylation of the optically pure N-((1S)-2-exo-methoxy-1-apocamphanecarbonyl (abbreviated as MAC))-2-imidazolidinone (7, 8), obtained from the thermal [4+2] cycloaddition of 1,3-dihydro-2-imidazolone (4), with anthracene (3) and successive optical resolution, followed by removal of the MAC group and hydrolytic ring cleavage with Ba(OH)2 (Scheme 2).6,7

The “roofed” cis-1,2-diamine-ruthenium(II) complexes (11a-e) were easily prepared by mixing the 1,2-diamines (10a-e) with [RuCl2(benzene)]2 in situ, according to the method of Noyori.8,9
Initially, we examined the catalytic efficiency of the N-tosyl complex 11c toward α-tetralone-derived ketimine 13 in the presence of an azeotropic mixture of 5HCO2H•2NEt3 as a hydrogen source at 25 °C. This reaction was completed in 6 hours to give the corresponding chiral amine in 91% yield and 81% ee (Table 1, entry 1). We also tested the co-solvent effects with ketimine 13. Although the reaction times were longer and the chemical yields slightly diminished, enantioselectivity was enhanced in the presence of CH2Cl2.10 Similar reactions were performed in the presence of a typical 1,2-diphenylethylenediamine-Ru(II) (p-cymene) complex (12)4a,8 to give results inferior to those obtained using catalyst 11c (Table 1, entries 3, 4).
We also tested the substituent effect of a sulfonyl group on the “roofed” cis-1,2-diamine ligand for the asymmetric reduction of ketimine 13 (Table 1, entries 2, 5-8). Higher enantioselectivities resulted with catalysts 11b, 11c and 11d (entries 2, 6 and 7). Therefore, additional trials of the asymmetric reduction of ketimine 14a in the presence of catalysts 11b-d were performed and, intriguingly, the N-isopropylsulfonylated catalyst 11b showed superior catalytic activity and enantioselectivity (entries 9-11).

presence of catalyst 11b and the 5HCO2H•2NEt3 azeotrope in CH2Cl2. Para-substituted acetophenone-derived ketimines 14a-e showed good to excellent chemical yields and ee values of 74-77%. The electronic nature of the para-substituent did not affect the enantioselectivity. Propiophenone-derived ketimines 14f showed higher reactivity than acetophenone-derived ketimines with slightly lower ee values. The greater the bulky of the R2 group of the ketimines (entries 7 and 8), the lower the observed reactivities and enantioselectivities. Cyclic imine 14i gave inferior enantioselectivity, but a relatively short reaction time.
Apparently, the enantioselectivities were correlated with the E/Z ratios of the imines measured using 1H NMR. Thus, higher E-containing ketimines, such as 13 (E only), and acetophenone-derived ketimines 14a-e gave good to excellent enantioselectivities, but higher Z-containing ketimines such as 14g-i showed poor ee values.
Although the precise structure of the catalyst 11 and the corresponding hydride species are unknown, we speculate the most likely hydride catalyst 16, depicted in Figure 1. Thus, the re-face of ketimines easily approach from the less-hindered side, which is opposite the “roof” moiety, of the ruthenium hydride 16 to create the (S)-amine 17. The clear discrimination between “shielding” and “non-shielding” site by minimum steric hindrance make the chiral ruthenium complex 16 a highly reactive and selective catalyst. The “roofed” cis-1,2-diamine structure, which is both conformationally rigid and sterically bulky, creates an ideal space for asymmetric transfer hydrogenation.

In conclusion, we demonstrated that the “roofed” cis-1,2-diamine-Ru(II) complex, which is both conformationally rigid and sterically bulky, is an excellent catalyst for asymmetric transfer hydrogenation of ketimines. Additional studies are now in progress.

References

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9. General procedure for asymmetric transfer hydrogenation of ketimines catalyzed by 11: A mixture of benzeneruthenium (II) chloride dimer (1.25 mg, 0.0025 mmol, 0.25 mol%), N-sulfonylated-“roofed” diamine 10 (0.005 mmol, 0.5 mol%) and triethylamine (1.4 μL, 0.01 mmol, 1 mol%) in 2-propanol (1 mL) was refluxed for 1 h under an argon atmosphere (formation of catalyst 11). After removal of the solvent in vacuo, 5HCO2H•2NEt3 azeotrope (0.5 mL), CH2Cl2 (1.5 mL) and ketimine (1 mmol) were successively added and the mixture was stirred at 25 °C. The reaction was monitored by TLC until substantial completion. After the addition of satd. NaHCO3 aq. (5 mL), the product was extracted (EtOAc, 20 mL × 3), washed (brine, 10 mL × 3), dried (anhyd. Na2SO4) and evaporated in vacuo, followed by purification using flash column chromatography on silica gel to afford the corresponding amine. Enantiomeric excess values were determined by chiral HPLC.
10. Other type of co-solvents were also examined (toluene, THF, MeCN, DMF, DMSO and IPA) and CH2Cl2 gave the optimal result.
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