Highly efficient asymmetric transfer hydrogenation of ketones in emulsions

Article abstract of DOI:10.1016/j.catcom.2009.12.002

Ru-TsDPEN (TsDPEN = N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine) catalyzed asymmetric transfer hydrogenation of ketones in emulsions is reported for the first time. The new protocol provides markedly enhanced activity and enantioselectivities (up to 99% ee) as compared with results when performed either in an aqueous medium or in common organic solvents.

Full text of DOI:10.1016/j.catcom.2009.12.002

Catalysis Communications 11 (2010) 480–483
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Highly efficient asymmetric transfer hydrogenation of ketones in emulsions
*
Weiwei Wang, Zhiming Li, Wenbo Mu, Ling Su, Quanrui Wang
Department of Chemistry, Fudan University, Shanghai 200433, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 October 2009
Received in revised form 30 November 2009
Accepted 2 December 2009
Available online 6 December 2009
Ru-TsDPEN (TsDPEN = N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine) catalyzed asymmetric transfer
hydrogenation of ketones in emulsions is reported for the first time. The new protocol provides markedly
enhanced activity and enantioselectivities (up to 99% ee) as compared with results when performed
either in an aqueous medium or in common organic solvents.
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Emulsion
Water
Asymmetric hydrogenation
Ketones
1. Introduction
(mp = 82 °C). To solve this problem, we initiated a program to
search for novel practical procedures. Herein we report that asym-
Since the first introduction by Noyori and co-workers in the
1990s, asymmetric transfer hydrogenation with (1S,2S)- or
metric transfer hydrogenations of ketones could be efficiently
accomplished in emulsions.
(1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine
(TsD-
PEN) in combination with [RuCl2(p-cymene)]2 (Ru-TsDPEN I or II)
as the catalyst has witnessed great success in enantioselective
reduction of prochiral ketones [1–4]. The protocol constitutes an
efficient and practical method for preparation of optically pure sec-
ondary alcohols that belongs to a large family of key intermediates
for the enantioselective synthesis of bioactive products. Recently,
the interest in developing asymmetric transfer hydrogenation in
aqueous medium has been significantly surged [5–13]. The cata-
lytic organic transformation using water as medium is particularly
desirable because of the environmental concerns.
Although asymmetric transfer hydrogenation in water has been
proved to work well for an array of ketones, there is still much
room for improvement both in substrate scope and enantioselec-
tivity that can match or outperform the original organic solvent
version [14–22]. In many cases, inferior results were always
achieved when performing the asymmetric transfer hydrogenation
on water-insoluble ketones. Representatively, (S)-3-hydroxy-3-
phenylpropanenitrile 3 has been employed as the key intermediate
for preparation of the antidepressant drug fluoxetine [23]. To the
best of our awareness, no literature precedents for asymmetric
reduction of 3-oxo-3-phenylpropanenitrile 1 via asymmetric trans-
fer hydrogenation in water are known [24–28]. This should be
attributed to its insolubility and relatively high melting point
2. Experimental
2.1. General procedure for the asymmetric transfer hydrogenation in
water [5]
Ligand (1S,2S)-TsDPEN (4.4 mg, 0.012 mmol) and [RuCl2(p-cym-
ene)]2 (3.1 mg, 0.005 mmol) were stirred in water (2 ml) at 40 °C
for 1 h. Ketone (1.0 mmol) and HCO2Na (5.0 mmol) were added,
and the mixture was stirred at 40 °C. After the reaction was com-
pleted (monitored by TLC), the reaction mixture was extracted
with ethyl acetate. The organic phase was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The product
was purified by flash chromatography on silica gel to afford pure
alcohol product.
2.2. General procedure for the asymmetric transfer hydrogenation in
water and dichloromethane
Ligand (1S,2S)-TsDPEN (4.4 mg, 0.012 mmol), [RuCl2(p-cym-
ene)]2 (3.1 mg, 0.005 mmol) and Et3N (4 lL, 0.025 mmol) were
stirred in dichloromethane (1 ml) at 40 °C for 1 h. Ketone
(1.0 mmol), HCO2Na (5.0 mmol) and water (1 ml) were added,
and the mixture was stirred at 40 °C. The reaction progress was
monitored by TLC. The resulting mixture was extracted with ethyl
acetate. The organic phase was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The product was purified
* Corresponding author. Tel.: +86 21 65643978; fax: +86 21 65641740.
E-mail address: qrwang@fudan.edu.cn (Q. Wang).
1566-7367/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2009.12.002

W. Wang et al. / Catalysis Communications 11 (2010) 480–483
481
by flash chromatography on silica gel to afford pure alcohol
product.
water
DCM
Cat*
ultrasound
surfactant
2.3. General procedure for the asymmetric transfer hydrogenation in
emulsions
HCO2Na
ketone
Ligand (1S,2S)-TsDPEN (4.4 mg, 0.012 mmol), [RuCl2(p-cym-
ene)]2 (3.1 mg, 0.005 mmol) and Et3N (4 lL, 0.025 mmol) were
emulsion
stirred in dichloromethane (1 ml) at 40 °C for 1 h. The mixture of
ketone (1.0 mmol) and TBAI (tetrabutylammonium iodide,
740 mg, 2.0 mmol) in 5 M liquor of HCO2Na (20 ml) were added.
The emulsions were formed rapidly by ultrasonic irradiation
(power 80 W, and frequency 40 kHz) for 5 min, and then the mix-
ture was stirred at 40 °C. After the reaction was completed (moni-
tored by TLC), the reaction mixture was extracted with ethyl
acetate. The organic phase was separated, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The product
was purified by flash chromatography on silica gel to afford pure
alcohol product.
Scheme 1.
this question, the emulsions as an excellent reaction system were
tested to accelerate the asymmetric transfer hydrogenation of ke-
tones in aqueous media (Scheme 1). In an emulsion system, we ex-
pect that the organic reagents are well suspended and surrounded
by the aqueous reducing agents, thus efficiently provides greater
surface area of contact for reagents. The emulsions were readily
prepared by initial addition of a surfactant into the reaction sys-
tem. The mixture was treated by ultrasonic irradiation whereupon
the organic phase was dispersed into the aqueous phase as vesicles
[29–31].
3. Results and discussion
The transfer hydrogenation reaction of 1 using Ru-TsDPEN as
catalyst in emulsions was thus investigated in detail. The catalytic
system was prepared by reaction of the enantiopure monotosylat-
ed trans-1,2-diaminocyclohexane (1S,2S)- or (1R,2R)-TsDPEN with
the dimeric arene ruthenium complex [RuCl2(p-cymene)]2 in
dichloromethane (1 ml) at 35 °C for 1 h with Et3N as a base. It is be-
lieved that complexes I and respectively II could be formed from
the catalytic mixture and were presumable the active species
(Fig. 1) [32]. Thus, the mixture, containing the complex I as the cat-
alyst, and ketone 1 (1.0 mmol) were added into 5 M liquor of HCO2-
Na (20 ml), and TBAI (tetrabutylammonium iodide, 2.0 mmol) was
added as a surfactant. The emulsions were readily formed by ultra-
sonic irradiation for 5 min, and then the whole was stirred at 40 °C.
To our delight, 1 was almost fully converted into 3 in 99% ee in
3.5 h (entry 3, Table 1). Similarly, the reaction with 2 afforded also
markedly improved enantioselectivity in high yield (entry 6,
Table 1).
To probe the potential applicability of our method, we then ex-
tended this system to solid ketones 5–9 (mp > 40 °C). As shown in
Table 2, the method was applicable to all of the tested solid ke-
tones. Much better conversion and higher stereoselectivity oc-
curred when performing the reactions in emulsions than in pure
water. For substrates 5 and 6, excellent activities and enantioselec-
tivities were achieved in shorter time (entries 2 and 4, Table 2).
Particularly noteworthy was that the reaction on b-keto amide 7
afforded 90% yield and 98% ee of the corresponding alcohol in only
one hour (entry 6, Table 2), whilst the same reaction gave inferior
results (93% yield and 86% ee) in 22 h with formic acid-triethyl-
amine (azeotrope) as the hydrogen source and solvent [25].
Subsequently, we extended this protocol to a set of liquid ke-
tones 10–18. As demonstrated in Table 3, all of the tested ketones
were successfully reduced with more than 90% conversion within a
couple of hours except 11 (51%) and 13 (20%) (entries 2 and 4,
Table 3). These results were quite comparable to or top those based
on the homogeneous transfer hydrogenation with pure water as
In our initial study, we found that ketone 1 exists as granule in
aqueous media, in which the transfer hydrogenation reaction by
sodium formate in water did not proceed even after 18 h (entry
1, Table 1). In addition, there was no evident improvement when
the reaction was performed in a two-phase system, consisting of
an aqueous phase to dissolve the reductant and an added dichloro-
methane organic solvent to dissolve 1 (entry 2, Table 1). Mean-
while, the liquid ketone 2 was selected to study the effect of
organic solvents on transfer hydrogenation reaction in water. The
reaction of 2 in water without any additives proceeded smoothly
and went to completion in only 3 h. In contrast, organic solvent
dichloromethane seemed to retard the reaction. Thus, when
dichloromethane was added, only 40% yield of 2 was obtained
within the same reaction time (entry 4 vs. 5, Table 1).
When dichloromethane was added, it formed a biphasic reac-
tion system, in which the Ru-TsDPEN catalyst and the ketone sub-
strate resided mostly in the upper organic phase and the hydrogen
donor remained in the aqueous phase. The interface area and the
diffusion of reactants over the organic-water interface may domi-
nate the kinetics of the transfer hydrogenation reaction. To address
Table 1
Comparison of the asymmetric transfer hydrogenation under different conditions.
O
OH
R
R
(S,S)-Ru-TsDPEN
HCO2Na, H2O
1: R = CN
2: R = H
3: R = CN
4: R= H
Entry
Ketone
Solvent
t/h(%)
Yield(%)d
e.e.(%)e
1
2
3
4
5
6
1
watera
water, CH2Cl2
emulsionsc
watera
18
18
3.5
3
3
3
<3
<3
>99
95
40
93
-
-
99
93
91
97
b
b
2
water, CH2Cl2
Ts
N
Ts
N
emulsionsc
a
The reactions were performed at 40 °C, using 1 mmol of ketone, 5 equiv.
Ru
Ru
HCO2Na in 2 ml of water, and S/C = 100.
b
N
The reactions were performed at 40 °C, using 1 mmol of ketone, 5 equiv.
N
Cl
Cl
H2
H2
HCO2Na in 1 ml of water and 1 ml of CH2Cl2 at S/C = 100.
c
The reactions were performed at 40 °C at S/C = 100.
Yield of isolated product after flash chromatography.
Determined by Chiral HPLC chromatography. The configuration of alcohol was
d
I: (
S,
S
)-Ru-TsDPEN
II: (R,R)-Ru-TsDPEN
e
S.
Fig. 1. Structure of the plausible active catalysts I and II.

482
W. Wang et al. / Catalysis Communications 11 (2010) 480–483
Table 2
Comparison of the asymmetric transfer hydrogenation of solid ketones with (S,S)-Ru–TsDPEN I in emulsions and water.
F
F
O
O
O
OCH3
OCH3
CN
NHCH3
O
O
O
O
BnO
F
R
8: mp = 58 °C
5: R = CH3 (mp = 104 °C)
6: R = Cl (mp = 130 °C)
7: mp = 81 °C
9: mp = 41 °C
Entry
Ketone
5
Solvent
t/h
Yield(%)c
e.e. (%)d
1
2
3
4
5
6
7
8
9
10
watera
18
6.5
18
4
18
1
18
1.5
18
0.9
<10
>99
<3
>99
86
90
22
93
72
-
94
-
95
94
98
43
53
71
72
emulsionsb
watera
6
7
8
9
emulsionsb
watera
emulsionsb,
watera
emulsionsb,
watera
emulsionsb
95
a
b
c
The reactions were performed at 40 °C, using 1 mmol of ketone, 5 equiv. HCO2Na in 2 ml of water, and S/C = 100.
The reactions were performed at 40 °C, and S/C = 100.
Yield of isolated product after flash chromatography.
d
Determined by chiral HPLC chromatography. The configuration of alcohol was S.
Table 3
Asymmetric transfer hydrogenation of liquid ketones with (S,S)-Ru-TsDPEN I in emulsionsa.
O
O
O
O
O
O
OMe
BnO
OMe
OEt
R
O
O
OBn
18
15
16
17
10: R = p-Cl
11: R = p-MeO
12: R = p-CH3
13: R = o-CH3
14: R = m-CH3
Entry
Ketone
t/h
Yield(%)b
e.e. (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1.5
4
4
>99
51
90
20
91
90
>99
98
92
97
95
90
98
96
97
97
48
6
4.5
5.5
0.9
1.5
1.5
98
a
b
c
The reactions were performed at 40 °C, and and S/C = 100.
Yield of isolated product after flash chromatography.
Determined by chiral HPLC chromatography. The configuration of alcohol was S.
solvent. In most cases, the chiral induction and reactivity were
good to excellent. For instance, the reduction of -acetylnaphtha-
significantly enhanced activity and high ee have been achieved
as compared with the identical catalyst system under other condi-
tions. The emulsions are apparently ‘‘greener” since water is
adopted as the main solvent. This new system is believed to have
potential serving as an alternative protocol for accessing a variety
of significant chiral secondary alcohols from ketones. Application
of this methodology to other substrates is under way in our
laboratory.
a
lene 15 in emulsions led to a 90% conversion in 96% ee in 5.5 h (en-
try 6, Table 3). In comparison, the same reaction performed in neat
water was sluggish with only 87% ee [5]. The most notable is the
reduction of the b-ketoester 16, which afforded >99% conversion
and 97% ee in 55 min (entry 7, Table 3).
4. Conclusion
In summary, we have demonstrated that the emulsion system is
an excellent system for carrying out the asymmetric transfer
hydrogenation by HCO2Na. The reduction of various ketones has
been successfully realized with high enantioselectivity up to 99%
ee. Especially, for the asymmetric hydrogenation of solid ketones,
Acknowledgments
We thank the National Natural Science Foundation of China
(No: J0730419) for partial financial support. Mr. Yue Zou is
acknowledged for helpful discussions and analysis.

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