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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
Preparation of glutarimide 2h
-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
Reaction 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
-fluorophenyl)glutarimide bearing the
-(3,4-methylenedioxy)phenyl group (2a
) afforded the
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
-(3,4-methylenedioxy)phenyl glutarimides undergo the
enantioselective hydrogenation to give the corresponding chiral
Cp*Ru(PN) catalyst 1
, paroxetine, and imides 2a
H2 = 3 MPa, 80 °C, imide:1
-Bu = 10:1:1, [imide] = 0.10–0.20
M in 2-propanol unless otherwise noted. b
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.
: R = 4-FC6H4
: R = 3,4-Cl
Thus, the present enantioselective hydrogenation is widely
applicable to access chiral compounds through breaking the
: R = CH3
symmetry of a prochiral compound having two enantiotopic
groups, as commonly observed in an enzyme-catalyzed reaction.
Representative chiral Cp*Ru(PN) catalysts and imides.
Several new symmetrical N
glutarimides with one substituent at the 4 position (2b
those with cis
oriented two substituents at the 3 and 5 positions
) have been readily prepared by the condensation between
3,4-methylenedioxyaniline and the corresponding dicarboxylic
acid derivatives. Because of the limited accessibility of
-cycloheptane-1,3-dicarboxylic acid derivatives, we prepared
1 (a) M. Ito and T. Ikariya, Chem. Commun.
5134 (2007). (b) M.
novel symmetrical N
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,
-(3,4-methylenedioxy)phenyl glutarimide in 3 steps including
, 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.
, 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.
) consistently adopts almost perpendicular orientation
, 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).
) with the binary chiral catalyst system of 1
4 M. Ito, A. Osaku, C. Kobayashi, A. Shiibashi, T. Ikariya,
proceeded smoothly to give the corresponding multiply
, 390 (2009).
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