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Asymmetric Hydrogenation of Imides Catalyzed by Novel Cp*Ru(PN) Complex
Masato Ito, Akio Himizu, Chika Kobayashi, and Takao Ikariya Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo 152-8552 We have recently developed a highly tunable bifunctional functionalized chiral hydroxyamides 3b–h with excellent ees, as
molecular catalyst, Cp*Ru(PN), based on metal–ligand cooperation.1–3 It effects efficiently the hydrogenation of a range of carboxylic acid derivatives including imides,2c Scheme 1. Preparation of glutarimide 2h
N-acylcarbamates,2d N-acylsulfonamides,2d and esters,2d in addition to ketones2a or epoxides.2b Furthermore, the chiral modification of the PN ligand4 in the molecular structure of Cp*Ru(PN) catalysts allows the asymmetric hydrogenation of symmetrical imides to produce chiral hydroxyamides with high enantioselectivities.2c Notably, the strucuture of substituents on aReaction conditions: (a) LHDMS, CH2=CHCH2Br. (b) Grubbs 2nd generation cat, nitrogen in the cyclic imides plays an important factor for ClCH2CH2Cl, 65 °C. (c) Pd/C, H2 (1 atm), CH2Cl2–C2H5OH, 30 °C. determining the enantio-group discrimination by the chiral
Cp*Ru(PN) catalyst (1). In fact, the reaction of Table 1. Enantioselective hydrogenation of 2b–h.a
4-(p-fluorophenyl)glutarimide bearing the
N-(3,4-methylenedioxy)phenyl group (2a) afforded the
1 + KOt-Bu
corresponding chiral hydroxyamide with >99% ee, which serves as a useful synthetic intermediate for the preparation of antidepressant, paroxetine (Chart 1). Encouraged by these results, we have further examined the substrate scope in the present asymmetric hydrogenation using chiral version of Cp*Ru(PN) catalysts and found that a wide variety of N-(3,4-methylenedioxy)phenyl glutarimides undergo the enantioselective hydrogenation to give the corresponding chiral Chart 1. Cp*Ru(PN) catalyst 1, paroxetine, and imides 2ag
aConditions: PH2 = 3 MPa, 80 °C, imide:1: KOt-Bu = 10:1:1, [imide] = 0.10–0.20
M in 2-propanol unless otherwise noted. bHPLC analysis.
The other chiral Cp*Ru(PN) catalysts4 also worked well in the asymmetric hydrogenation of other symmetrical imides (Chart 2) to give the corresponding chiral hydroxyamides. 2a: R = 4-FC6H4
2b: R = 3,4-Cl
Thus, the present enantioselective hydrogenation is widely applicable to access chiral compounds through breaking the 2d: R = CH3
symmetry of a prochiral compound having two enantiotopic groups, as commonly observed in an enzyme-catalyzed reaction. Chart 2. Representative chiral Cp*Ru(PN) catalysts and imides.
Several new symmetrical N-(3,4-methylenedioxy)phenyl glutarimides with one substituent at the 4 position (2bd) or
those with cis oriented two substituents at the 3 and 5 positions (2eg) have been readily prepared by the condensation between
3,4-methylenedioxyaniline and the corresponding dicarboxylic acid derivatives. Because of the limited accessibility of References
cis-cycloheptane-1,3-dicarboxylic acid derivatives, we prepared 1 (a) M. Ito and T. Ikariya, Chem. Commun. 5134 (2007). (b) M. novel symmetrical N-(3,4-methylenedioxy)phenyl glutarimide Ito and T. Ikariya, J. Synth. Org. Chem. 66, 1047 (2008).
with a bicyclic [4.1.3] skeleton (2h) from the parent
2 (a) M. Ito, M. Hirakawa, K. Murata, and T. Ikariya, N-(3,4-methylenedioxy)phenyl glutarimide in 3 steps including Organometallics 20, 379 (2001). (b) M. Ito, M. Hirakawa, A.
two-fold allylation and ring-closing metathesis followed by Osaku, and T. Ikariya, Organometallics 22, 4190 (2003). (c) M.
Ito, A. Sakaguchi, C. Kobayashi, and T. Ikariya, J. Am. Chem. hydrogenation as illustrated in Scheme 1. Soc. 129, 291 (2007). (d) M. Ito, L.-W. Koo, A. Himizu, C.
Notably, the aryl ring of the newly synthesized glutarimides Kobayashi, A. Sakaguchi, and T. Ikariya, Angew. Chem. Int. (2e–g) consistently adopts almost perpendicular orientation
Ed. 48, 1324 (2009).
toward the imide group in the solid state, as revealed by X-ray 3 (a) M. Ito, A. Osaku, S. Kitahara, M. Hirakawa, and T. Ikariya, Tetrahedron Lett. 44, 7521 (2003). (b) M. Ito, S. Kitahara, and
diffraction study.2c We were very pleased to find that the T. Ikariya, J. Am. Chem. Soc. 127, 6172 (2005). (c) M. Ito, A.
enantioselective hydrogenation of these prochiral substrates Osaku, A. Shiibashi, and T. Ikariya, Org. Lett. 9, 1821 (2007).
(2b–h) with the binary chiral catalyst system of 1 and KOt-Bu
4 M. Ito, A. Osaku, C. Kobayashi, A. Shiibashi, T. Ikariya, proceeded smoothly to give the corresponding multiply Organometallics 28, 390 (2009).


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