Asymmetric hydrogenation of aromatic ketones using new chiral-bridged diphosphine/diamine-Ru(II) complexes

Article abstract of DOI:10.1016/j.cclet.2010.05.027

A series of chiral secondary alcohols were easily prepared by means of asymmetric hydrogenation of prochiral aromatic ketones using a new ((R_ax)-BuP)/(R,R)-DPEN-Ru(II) complex catalyst system. The hydrogenation of 2-methylacetophenone in n-butanol (t-BuOK/Ru=45.6/1, S/C=500, 20atm. of H₂, 20°C, 48h) afforded (S)-1-(2′-methylphenyl)ethanol in 92% ee and >99% conversion.

Full text of DOI:10.1016/j.cclet.2010.05.027

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1403–1406
www.elsevier.com/locate/cclet
Asymmetric hydrogenation of aromatic ketones using new
chiral-bridged diphosphine/diamine–Ru(II) complexes
b,
a
Yu Ming Cui a,c, Lai Lai Wang a, , Fuk Yee Kwong , Wei Sun
*
*
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, China
b Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis
and Department of Applied Biology and Chemical technology, The Hong Kong Polytechnic University, Hong Kong, China
c Graduate University of Chinese Academy of Sciences, Beijing 100039, China
Received 30 March 2010
Dedicated to Professor Albert S. C. Chan on the occasion of his 60th birthday.
Abstract
A series of chiral secondary alcohols were easily prepared by means of asymmetric hydrogenation of prochiral aromatic ketones
using a new ((Rax)-BuP)/(R,R)-DPEN–Ru(II) complex catalyst system. The hydrogenation of 2-methylacetophenone in n-butanol
(t-BuOK/Ru = 45.6/1, S/C = 500, 20 atm. of H2, 20 8C, 48 h) afforded (S)-1-(20-methylphenyl)ethanol in 92% ee and >99%
conversion.
# 2010 Lai Lai Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Asymmetric hydrogenation; Chiral alcohols; Diphosphine ligand; Ruthenium complexes; Diamine
Chiral alcohols may be used in the industrial production of synthetic intermediates for some important antibiotics
[1]. Asymmetric hydrogenation of prochiral ketones has been exceedingly successful and proved to be one of the most
efficient protocols for accessing a variety of chiral secondary alcohols since Noyori and co-workers developed the
BINAP–ruthenium–diamine complexes as a highly effective catalyst for this type of enantioselective transformation
[2]. Inspired by the intrinsic advantages, such as operational simplicity and environmental friendliness, of this
methodology, a continuous searching of a higher efficiency of chiral ligands for better stereocommunication has been
made [3]. Recently, Zhang and our group independently reported a new and highly modular approach for preparing
axially chiral diphosphine ligand family [4]. In particular, the chiral-bridged atropisomeric biphenyl diphosphine
ligands, demonstrated by our group, have found numerous applications in transition metal-catalyzed asymmetric
transformation, including the catalytic enantioselective hydrogenations of N-substituted allyphthalimides, a-and b-
ketoesters, 2-(60-methoxy-20-naphthyl)-propenoic acid, alkyl-substituted b-dehydroamino acids, and N-heteroaro-
matic compounds [4b]. Besides, the C3*-Tunephos/diamine–Ru(II) complex afforded remarkable reactivity and
* Corresponding authors.
E-mail addresses: wll@licp.cas.cn (L.L. Wang), bcfyk@inet.polyu.edu.hk (F.Y. Kwong).
1001-8417/$ – see front matter # 2010 Lai Lai Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.05.027

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Y.M. Cui et al. / Chinese Chemical Letters 21 (2010) 1403–1406
Table 1
Asymmetric hydrogenation of acetophenone (1a, R = H).a
[TD$INLE]
Entry
S/Cb
Solvent
Temperature (8C)
Time (h)
Conv (%)c
ee% (config.)d
1
2
3
4
5
6
1000
1000
1000
1000
5000
3000
CH3OH
2-PrOH
2-PrOH
n-BuOH
n-BuOH
n-BuOH
20
20
28
20
20
20
20
23
18
22
21
21
46
>99
>99
>99
38
55 (S)
79 (S)
75 (S)
80 (S)
79 (S)
80 (S)
99
a
Reactions were performed with ꢀ1.2 mol/L solutions of 1a in solvent with t-BuOK/Ru = 45.6/1 at 20 atm initial hydrogen pressure.
Substrate-to-catalyst molar ratio.
b
c
d
Determined by capillary GC (HP-5MS).
The ee values were determined by chiral GC (Chrompack Chirasil-DEX CB columns). The absolute configuration was determined by
comparison of the retention time with literature data.
excellent enantioselectivities in reduction of ketones [5]. Although the effect on enantio-differentiation using 3,5-
dimethylphenyl moiety on phosphorus donor has not been explicitly established, empirical evidences showed that the
needs of xylyl moieties in a number of chiral diphosphines were beneficial [3e,3g,5]. Based on the fact that subtle
changes in geometric, steric, and/or electronic properties of chiral ligands can lead to dramatic variations of reactivity
and enantioselectivity, the conformationally rigid yet tunable chiral ligands offer a great advantage and opportunity in
optimizing the enantioselectivity of a reaction. Thus, we expect that changing the chain length of chiral bridge on
diphosphine ligand will cause major influence on the performance of catalyst system [6]. Herein, we report our
preliminary results on the asymmetric hydrogenation of aromatic ketones using C2*-Tunephos((Rax)-BuP)/diamine–
Ru(II) complex.
By employing the method reported by Doucet [7], the catalyst was prepared by reacting (Rax)-BuP with
[Ru(benzene)Cl2]2 in DMF at 100 8C, followed by the addition of (R,R)-DPEN (DPEN = 1,2-diphenyl-
ethylenediamine). After removing of solvent, the resulting diphosphine–ruthenium–diamine complex was used as
the precatalyst directly in the hydrogenation reactions without further purification. Indeed, the 31P NMR showed only
a single peak at 47.5 ppm in CDCl3 that represented essentially completed coordination of ligand to Ru center. The
hydrogenation of acetophenone 1a was taken as the model reaction to examine the reaction parameters and the results
were listed in Table 1. Notably, an obvious solvent effect was observed and under otherwise identical conditions.
Methanol gave poor results with only 46% conversion and 55% ee (Table 1, entry 1). In contrast, hydrogenation of
acetophenone proceeded completely in isopropanol with 79% ee at 20 8C. Moreover, the optical outcome of 75% ee
was obtained at 28 8C, indicating that the enantioselectivity of the hydrogenation reaction was slightly sensitive to
temperature (Table 1, entries 2 and 3). n-Butanol provided slight better ee values, when compared to isopropanol
which is normally used as a common solvent in asymmetric hydrogenation of ketones (Table 1, entries 2 and 4).
Increasing the ratio of substrate to catalyst from 3000 to 5000 led to only 38% conversion of acetophenone to
1-phenylethanol but the enantioselectivity of the product was almost not affected (Table 1, entries 5 and 6), which was
comparable to that obtained using C3*-Tunephos/DPEN–Ru(II) complex system under similar conditions [5].
In order to explore the potential utilities of the catalyst system, a variety of substituted aryl methyl ketones were
submitted to hydrogenation. As shown in Table 2, all selected substrates were hydrogenated smoothly with >99%
conversion and moderate to good enantioselectivity. It was noted that the position of substituents at the phenyl ring had
dramatic effects on reactions. Substrate possessing ortho-substituent showed lower reactivity in hydrogenation and
they could only be hydrogenated at a relatively higher catalyst loading or prolonged reaction time. Nevertheless, the
introduction of either methyl, or methoxy, or bromo group to para-position of aromatic ketones had almost no effect

Y.M. Cui et al. / Chinese Chemical Letters 21 (2010) 1403–1406
1405
Table 2
Asymmetric hydrogenation of ketones.a
Entry
Ketone
R
S/Cb
Time (h)
Conv (%)b
ee% (config.)b
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
p-CH3
p-Br
3000
3000
3000
2000
2000
2000
500
45
41
40
64
22
44
48
48
48
>99
>99
>99
>99
>99
>99
>99
>99
>99
81 (S)
68 (S)
83 (S)
84 (S)
75 (S)
83 (S)
92 (S)
89 (S)
58 (S)
p-OCH3
m-CH3
m-Br
1g
1h
1i
m-OCH3
o-CH3
o-Br
500
1j
o-OCH3
500
a
Reactions were performed with ꢀ1.2 mol/L solutions of ketones in n-butanol with t-BuOK/Ru = 45.6/1 at 20 8C and 20 atm initial hydrogen
pressure.
b
See Table 1.
on reaction activity. Among the selected substitutents, the electron-withdrawing group activated the substrate and the
prochiral ketone was hydrogenated within a shorter reaction time under the same catalyst loading (Table 2, entries 4–
6), which is in consistent with previous findings [3e]. On the other hand, these substitutents had different influence on
enantioselectivity. Changing the methyl and bromo group position from para- to meta- to ortho- led to consecutively
increased enantioselectivity. However, it was found that the ortho-methoxy substituted aromatic ketone gave the
lowest ee value, among the substrate containing methoxy group at different positions.
In conclusion, we presented a new and efficient catalyst system which was applicable in asymmetric hydrogenation
of aromatic ketones [8]. The substitutent effects on substrate affecting the reaction reactivity and enantioselectivity
were studied in detail. Moderate to good enantioselectivity were obtained for a variety of substrates under complete
conversion. Further modification of substitutents on phosphorus donor on the chiral supporting ligands and their
application in asymmetric hydrogenation of other prochiral substrates are currently underway.
Acknowledgment
We thank the National Natural Science Foundation of China (Nos. 20343005, 20473107, 20673130, and 20773147)
and the Hong Kong PolyU Joint Supervision Scheme (A-PH78) for financial support.
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[8] Typical procedure of asymmetric hydrogenation of 1a: The precatalyst (0.0025 mmol) and t-BuOK (0.114 mmol) was dissolved in degassed n-
butanol (2 mL) in a 25-mL schlenk flask, substrate (2.5 mmol) were added via syringe. The resulting mixture was stirred for 20 min before being
transferred into an autoclave, and the autoclave was purged with H2 (3ꢁ 10 atm) and charged with H2 (20 atm). After stirring at 20 8C for 22 h,
the H2 was carefully released. The reaction solution was purified by a silica gel column to give the corresponding hydrogenation product, which
was then directly analyzed by chiral GC to determine the enantiomeric excess. The hydrogenation product was also characterized by 1H NMR
(Table 1, entry 4, (R)-1-phenylethanol; 1H NMR (CDCl3, 400 MHz): d 1.49 (d, 3H, J = 6.4 Hz), 2.02 (br, 1H), 4.88 (q, 1H, J = 6.4 Hz), 7.25–7.29
(m, 1H), 7.29–7.39 (m, 4H)).