Polyethylene glycol as an environmentally friendly and recyclable reaction medium for enantioselective hydrogenation

Article abstract of DOI:10.1002/adsc.200606215

Polyethylene glycol (PEG) was found to be an inexpensive, non-toxic and recyclable reaction medium for ruthenium- and rhodium-catalyzed asymmetric hydrogenation of 2-arylacrylic acids (Ru-catalyzed C=C bond reduction), enamides (Rh-catalyzed C=C bond reduction), β-keto esters and simple aromatic ketones (Ru-catalyzed C=O bond reduction). In all cases, high catalytic activities and enantioselectivities have been achieved, which are comparable to those obtained in conventional organic solvent systems. The Ru and Rh catalysts prepared with commercially available chiral diphosphine ligands could be readily recycled by simple extraction, as in the case of ionic liquids, and reused up to nine times without obvious loss of catalytic activity and enantioselectivity. The reduced products were obtained from the extracts in high isolated yields. These results indicate that PEGs as new reaction media are attractive alternatives to room temperature ionic liquids.

Full text of DOI:10.1002/adsc.200606215

FULL PAPERS
DOI: 10.1002/adsc.200606215
Polyethylene Glycol as an Environmentally Friendly and Recycla-
ble Reaction Medium for Enantioselective Hydrogenation
a,b
b,
c
c
b
Hai-Feng Zhou, Qing-Hua Fan, * Wei-Jun Tang, Li-Jin Xu, Yan-Mei He,
b
a,b
a,
c,
Guo-Jun Deng, Li-Wen Zhao, Lian-Quan Gu, * and Albert S. C. Chan *
a
School of Chemistry and Chemical Engineering, and School of Pharmaceutical Science, Sun Yat-Sen University,
Guangzhou 510275, Peopleꢀs Republic of China
Fax : +(86)-20-8411-0272; e-mail: cedc42@zsulink.zsu.edu.cn
National Laboratory of Molecular Sciences, Center for Chemical Biology, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100080, Peopleꢀs Republic of China
b
Fax : +(86)-10-6255-4449; e-mail: fanqh@iccas.ac.cn
Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong,
Peopleꢀs Republic of China
c
Fax : +(852)-2364-9932; e-mail: bcachan@polyu.edu.hk
Received: May 9, 2006; Accepted: August 8, 2006
Abstract: Polyethylene glycol (PEG) was found to could be readily recycled by simple extraction, as in
be an inexpensive, non-toxic and recyclable reaction the case of ionic liquids, and reused up to nine times
medium for ruthenium- and rhodium-catalyzed without obvious loss of catalytic activity and enantio-
asymmetric hydrogenation of 2-arylacrylic acids (Ru- selectivity. The reduced products were obtained from
catalyzed C=C bond reduction), enamides (Rh-cata- the extracts in high isolated yields. These results indi-
lyzed C=C bond reduction), b-keto esters and simple cate that PEGs as new reaction media are attractive
aromatic ketones (Ru-catalyzed C=O bond reduc- alternatives to room temperature ionic liquids.
tion). In all cases, high catalytic activities and enan-
tioselectivities have been achieved, which are compa-
rable to those obtained in conventional organic sol- Keywords: asymmetric hydrogenation; diphosphine
vent systems. The Ru and Rh catalysts prepared with ligands; immobilized catalyst; polyethylene glycol;
commercially available chiral diphosphine ligands reaction medium; recycling
Introduction
catalysts have suffered from reduced catalytic activity
and/or enantioselectivity due to mass transfer limita-
Transition metal-catalyzed asymmetric hydrogenation tions and/or degradation of the support. Alternatively,
has been established as one of the most versatile and room temperature ionic liquids can be used to immo-
powerful tools for the preparation of a wide range of bilize the transition metal catalysts and to facilitate
enantiomerically pure compounds in organic synthe- catalyst recycling, and have consequently attracted a
[
6]
sis. High activity and enantioselectivity have been ob- great deal of interest. A series of prochiral olefins,
served using Rh, Ru, and Ir complexes with chiral ketones, and imines has been successfully hydrogenat-
[
1,2]
phosphine, phosphite, or phosphoramidite ligands.
ed in ionic liquids, and the results were comparable to
However, the high cost of both these chiral ligands or even better than those obtained in common organ-
[
7]
and the noble metals as well as the toxicity of trace ic solvents. In most cases, ionic liquids are miscible
metal contaminants in the organic products have re- with the organic co-solvent, and the catalytic reac-
stricted their use in industry. Immobilization of these tions were thus carried out under homogeneous con-
catalysts offers an attractive solution to these prob- ditions. Upon the completion of the reaction, the or-
[
3–5]
lems.
Homogeneous chiral catalysts can be anch- ganic products could be easily separated via extrac-
[5a–c] [5d–g]
ored onto insoluble
drimers,
or soluble
and inorganic materials
polymers, den- tion with less polar solvents, and the ionic liquid
[
5h–l]
[4b,5m–p]
via cova- phase containing the active catalyst could be readily
lent or non-covalent attachment. However, all of reused several times without significant loss of cata-
these approaches often require additional ligand or lytic activity and/or enantioselectivity. However, ionic
catalyst modifications, which are tedious and time- liquids as solvents still suffer from the disadvantages
consuming. Furthermore, most of these immobilized of tedious preparation, high price, as well as limited
2172
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2172 – 2182

Polyethylene Glycol as an Environmentally Friendly and Recyclable Reaction Medium
FULL PAPERS
knowledge of their toxicity. We have demonstrated immobilized in DMPEG could be reused for eight
and report here that poly(ethylene glycol) (PEG) is times without significant loss of reactivity and enan-
an attractive alternative to room temperature ionic tioselectivity. In contrast, ionic liquids have proven to
liquids as a reaction medium for catalytic asymmetric be ineffective in this reaction, giving both poor con-
hydrogenation reactions.
versions and low enantioselectivities. Similarly, alco-
Recently, liquid PEGs have been attracting increas- holic PEG (molecular weight=400) also gave unsatis-
ing interest as novel solvents for organic reactions factory enantioselectivity due to the detrimental
[
8]
due to their benign characteristics. Like ionic liq- effect of the OH groups on PEG. Based on these ob-
uids, PEGs are non-volatile, recyclable, and stable to servations and as a part of our continuing efforts in
acid, base and high temperature. On the other hand, the immobilization and recycling of chiral catalysts in
[
4a,5d,i,7n,11b,c,16,17]
PEGs have the following advantages over ionic liq- asymmetric hydrogenation,
we report
uids: (1) much lower cost; (2) completely non-halo- here a practical protocol for Ru- and Rh-catalyzed
genated, and (3) well known low toxicity. Several re- asymmetric hydrogenations of prochiral olefins and
views have covered the chemistry of PEGs and their ketones in PEG using commercially available chiral
[
9]
applications in biotechnology and medicine. PEGs diphosphine ligands (Figure 1). The catalysts immobi-
have previously been used as phase-transfer catalysts lized in PEG could be recycled (up to 9 times) with-
[
10]
for catalytic reactions, and as soluble supports for out obvious loss of enantioselectivity, and the results
[
5f,g,11]
the immobilization of homogeneous catalysts.
are comparable to or better than those obtained in
Recently, liquid PEGs have been adopted as a new ionic liquid.
approach for catalyst recycling, in a broad range of
catalytic organic reactions including polymerization
[
12–14]
and biotransformation.
However, reports on the Results and Discussion
utilization of PEG as solvent or co-solvent for asym-
metric catalytic reactions and recycling of the homo- Asymmetric Hydrogenation of 2-Arylacrylic Acids in
[
14–16]
geneous chiral catalysts are rather limited.
Very PEG
recently, we reported an air-stable Ir-(P-Phos) com-
plex for highly enantioselective hydrogenation of qui- The asymmetric catalytic hydrogenation of 2-aryl-
nolines in a biphasic poly(ethylene glycol) dimethyl acrylic acids provides a convenient way to prepare
[
16]
ether (DMPEG) and hexane system. The Ir catalyst chiral 2-arylpropionic acid products, which constitute
Figure 1. Structures of the ligands used in this study.
Adv. Synth. Catal. 2006, 348, 2172 – 2182
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2173

Hai-Feng Zhou et al.
FULL PAPERS
an important class of anti-inflammatory drugs and an- were comparable to those obtained in methanol.
[18]
algesics.
have been achieved in alcoholic organic solvents.
High enantioselectivities and conversions Lower reaction temperature and higher hydrogen
[11c,19]
pressure afforded better enantioselectivity (entries 8–
Such asymmetric hydrogenations performed in ionic 11). The hydrogenation was extended to 2-phenyl-
liquids also have been reported, but significantly acrylic acid (8b) and 2-(6’-methoxy-2’-naphthyl)acrylic
lower enantioselectivities than the best results ob- acid (8c). Similarly, high enantioselectivities were ob-
[
7b–d]
tained in alcoholic solvents were observed.
termine whether the catalytic reactions could proceed MeOH (entries 12, 13). It was notable that the enan-
smoothly in PEG as solvent, the Ru(BINAP)-cata- tioselectivities achieved in this study were higher than
lyzed asymmetric hydrogenation of 2-[p-(2-methylpro- those reported for the same reactions in ionic liquids
pyl)phenyl]acrylic acid (8a) was chosen as a model re- using Ru(tolBINAP) as catalyst (for 8a: 85% ee in
action. As shown in Table 1, much lower catalytic [bimim]PF /MeOH under 100 bar of H ; for 8b: 54%
To de- served, which were comparable to those obtained in
AHCTREUNG
AHCTREUNG
[20]
6
2
[
7c,d]
activity and enantioselectivity were observed in pure ee in [bimim]PF /MeOH under 50 bar of H ).
6
2
PEG or dimethyl PEG (DM-PEG) as solvents as
The recyclability of the Ru catalysts in PEG was in-
compared with those obtained in methanol (entry 1 vestigated using 8a as a model substrate. Upon com-
vs. entries 2–4). This might be partially due to the pletion of the reaction, the methanol was removed
higher viscosity of PEG than that of methanol. In under reduced pressure, and the reduced products
view of the significant co-solvent effect of alcohol in were extracted with a less polar solvent. After being
asymmetric hydrogenations in ionic liquids, and in cooled to 08C, the solidified PEG phase could be
order to lower the viscosity of PEG, we used metha- easily separated via decantation of the extract, and
nol as a co-solvent for this reaction. To our delight, was recharged with 8a, NEt and MeOH and then
3
high enantioselectivities and conversions could be ob- subjected to hydrogenation again under the same con-
tained with Ru
A
C
H
T
R
E
U
N
G
(BINAP) catalyst in both PEG/MeOH ditions. Firstly, Ru(1a) was chosen as the catalyst and
and DM-PEG/MeOH (entries 5–7), and the results degassed anhydrous ethyl ether as the extracting sol-
[a]
Table 1. Asymmetric hydrogenation of 2-arylacrylic acids catalyzed by Ru(BINAP) in different solvent systems.
A
H
R
U
G
[b]
[b]
Entry
Substrate
Solvent system (v/v)
H [atm]
2
Temp. [8C]
ee [%]
Conv. [%]
1
2
3
4
5
6
7
8
9
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8c
MeOH
PEG-300
PEG-600
DM-PEG-500
PEG-600/MeOH=1/1
PEG-600/MeOH=1/2
DM-PEG-500/MeOH=1/2
PEG-600/MeOH=1/2
PEG-600/MeOH=1/2
PEG-600/MeOH=1/2
PEG-600/MeOH=1/2
PEG-600/MeOH=1/2
PEG-600/MeOH=1/2
50
50
50
50
50
50
50
20
80
80
50
50
50
20
20
20
20
20
20
20
20
20
0
87.6
58.3
39.2
31.0
83.0
87.7
88.0
78.2
90.2
92.0
79.2
>99
86
61
60
>99
>99
>99
>99
>99
>99
>99
10
11
12
13
50
20
20
[
c]
[c]
92.4 (90.6)
90.2 (89.7)
>99 (>99)
99 (99)
[
d]
[c]
[c]
[
a]
The hydrogenations were carried out using 0.04M of substrate (25 mg) under the following conditions: substrate/cata-
lyst=100 (M/M), Et N/catalyst=3/2 (M/M), reaction time=6 h except for entry 10 (12 h).
3
[
b]
The ee values and conversions were determined by GC with a Chrompack Chirasil-DEX CB column (25 m”0.25 mm)
after the reduced acids had been transformed to their corresponding methyl esters. All products were in the R-configura-
tion.
Data in brackets were obtained by using MeOH as solvent under otherwise identical conditions.
The ee values were determined by HPLC with a Sumichiral OA-2500 column after the reduced acids had been trans-
formed to their corresponding methyl esters. The product was in the R-configuration.
[
[
c]
d]
2174
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2172 – 2182

Polyethylene Glycol as an Environmentally Friendly and Recyclable Reaction Medium
FULL PAPERS
vent. It was found that 4.2 wt% of PEG leached into pled plasma (ICP) spectroscopy was used to deter-
the extracted products. In contrast, when hexane was mine the leaching of Ru, and the results are summar-
used to extract the products from PEG, a very low ized in Table 2. The level of Ru leached into the prod-
degree of leaching (<0.1 wt%) was observed. How- uct depended on the polarity of the ligand. Incorpora-
ever, owing to the high polarity of the hydrogenated tion of polar groups such as amino groups in 2, hy-
[
24]
acid, a very low extracting yield (<27%) was ob- droxy groups in 5, and polar polymer chains in 7
served by using hexane alone for extraction. For the significantly reduced the leaching of catalyst.
balance of keeping the PEG and sustaining high prod-
uct-extraction efficiency, a mixture of ethyl ether and
hexane (1:1, v/v) was finally chosen as the solvent for Asymmetric Hydrogenation of Enamides in PEG
extraction. The mass recovery of the products (after
column chromatography) was found to be 65% in the Chiral amino acids are attractive targets for enantio-
first cycle, and the degree of leaching of PEG was no selective synthesis on account of their vital role in the
more than 0.3 wt%. As shown in Table 2, high mass pharmaceutical industry both as nutritional supple-
recovery of the product was obtained in the second ments and as synthetic intermediates. Asymmetric
run, and quantitative recovery of the product has catalytic hydrogenation of prochiral amidoacrylic
been achieved from the third catalytic run (data acids and their esters represents a convenient method
[
25]
shown in brakets in the second column). The Ru(1a) for the synthesis of such compounds.
Among the
catalyst could be recycled at least four times. Interest- variety of chiral rhodium phosphane catalysts report-
ingly, the level of enantioselectivity increased slightly ed to date, Rh-DuPHOShas been found to be partic-
and the highest ee (89.6%) was achieved in the third ularly efficient as a homogeneous catalyst in the
[
26]
run. Similar phenomena have been observed in a asymmetric hydrogenation of enamides.
study of recycling of Ru catalysts in ionic liquids.
However,
[
7m]
as good as its performance is, the rather expensive
In contrast, a significant drop in activity was observed Rh-DuPHOSis very sensitive to oxidation. The suc-
in the fifth run. To further demonstrate the recyclabil- cessful separation and recycling of this rhodium cata-
[
7e]
ity of this system, we chose some other ligands lyst is still a challenge. We thus chose the commer-
(
Figure 1) for this study. Unexpectedly, when diphos- cially available Rh-DuPHOScatalyst for further
[21] [11b]
[22]
phines 2,
4
and 7
were used, much lower study. A mixture of PEG and methanol was chosen as
enantioselectivities were observed in PEG/MeOH in the solvent and the results are summarized in Table 3.
the first run than those in pure MeOH (Table 2). All In the asymmetric hydrogenation of methyl a-acet-
catalysts could be recycled and reused in the PEG amidocinnamate (10a), it was found that the amount
system, and a similar trend of increase in enantiose- of methanol as co-solvent could significantly influence
lectivity was observed except in the case of using the enantioselectivity (entries 1–4). High enantiose-
[23]
Ru(3a) catalyst. Good activities for most catalysts lectivity (up to 98.1% ee) was achieved in a mixture
were retained in the first four runs. Inductively cou- of 1:4 PEG/MeOH, which was comparable to that ob-
Table 2. Reuse of catalysts using different chiral diphosphine ligands for asymmetric hydrogenation of 8a in PEG/MeOH as
[a]
reaction medium.
[b,c]
[b]
[b]
[b]
[b]
[b]
Run
1a [%]
2 [%]
3a [%]
4 [%]
5 [%]
7 [%]
Conv.
ee
Conv.
ee
Conv.
ee
Conv.
ee
Conv.
ee
Conv.
ee
[
d]
1
1
2
3
4
5
>99
87.6
85.8
86.8
89.6
88.8
88.2
>99
>99
>99
>99
>99
58
88.0
79.8
87.6
88.6
90.0
89.6
>99
>99
>99
98
64
40
86.2
85.5
79.0
78.4
78.4
75.6
>99
>99
>99
>99
>99
67
85.6
79.2
80.0
85.4
88.0
88.6
>99
>99
>99
92
75
30
83.2
82.6
83.6
83.5
84.0
80.0
>99
>99
>99
>99
>99
63
85.8
81.8
88.2
87.8
88.4
88.0
>99 (65)
>99 (89)
>99 (99)
>99 (99)
76.0 (72)
1.99 (0.4)
[e]
Ru (%)
0.28 (0.06)
3.09 (0.67)
3.86 (0.83)
0.83 (0.18)
0.24 (0.05)
[
a]
The hydrogenations were carried out using 0.02M of 8a in 6 mL of PEG-600/MeOH (1:2, v/v) under the following condi-
tions: substrate/catalyst=100 (M/M), Et N/catalyst=3/2 (M/M), P(H )=50 atm, reaction time=6–14 h, room tempera-
3
2
ture.
[
b]
The ee values and conversions were determined by GC with a Chrompack Chirasil-DEX CB column (25 m”0.25 mm)
after the reduced acids had been transformed to their corresponding methyl esters.
Data in brackets were isolated yields after column chromatography.
Hydrogenations were carried out using MeOH as solvent under otherwise identical conditions.
Percentage of Ru leached to the product in the second run determined by ICP. Data in brackets are Ru concentration
[
[
[
c]
d]
e]
(
ppm) in the extract.
Adv. Synth. Catal. 2006, 348, 2172 – 2182
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2175

Hai-Feng Zhou et al.
FULL PAPERS
+
À
[a]
Table 3. Asymmetric hydrogenation of enamides catalyzed by [Rh-(S,S)-Et-DuPHOS] BF in different solvent systems.
4
[b,c]
Entry
Substrate (R)
Solvent system (v/v)
ee [%]
1
2
3
4
5
6
7
8
9
10a (C H )
PEG600/MeOH (1/1)
PEG600/MeOH (1/2)
PEG600/MeOH (1/3)
PEG600/MeOH (1/4)
PEG600/MeOH (1/3)
PEG600/MeOH (1/3)
PEG600/MeOH (1/3)
PEG600/MeOH (1/3)
PEG600/MeOH (1/3)
PEG600/MeOH (1/3)
93.0
93.0
97.6
98.1 (98.6)
94.2 (97.2)
97.0 (98.6)
97.1 (98.8)
93.4 (95.0)
98.6 (99.0)
98.2 (99.6)
6
5
10a (C H )
6
5
10a (C H )
6
5
10a (C H )
6
5
10b (2-Cl-C H )
10c (3-Cl-C H )
10d (4-Cl-C H )
6
4
6
4
6
4
10e (4-NO -C H )
2
6
4
10f (4-CH O-C H )
3
6
4
10
10g (H)
[
[
[
a]
The hydrogenations were carried out using 20–50 mg substrate under the following conditions: substrate/catalyst=200
M/M), P(H )=10 atm, temperature=15–208C, reaction time=3 h. Complete conversion was observed in all cases.
The ee values and conversions were determined by GC with a Chrompack Chirasil-L-Val column (25 m”0.25 mm). All
products were in the S-configuration.
(
2
b]
c]
Data in brackets were obtained by using MeOH as solvent under otherwise identical conditions.
tained in pure methanol (entry 4). The hydrogenation high efficiency upon 10 successive cycles, without sig-
was then extended to other substrates and high enan- nificant loss of enantioselectivity and catalytic activity.
tioselectivities (93.4–98.6%) were observed in all In contrast, the enantioselectivity of the catalyst de-
cases, which were slightly lower than those in metha- creased significantly after the first cycle in ionic liquid
[
7e]
nol.
(from 93% to 80% ee). Furthermore, the Rh cata-
To examine the recyclability of the Rh-DuPHOS lyst leaching was determined by ICP analysis. As ex-
catalyst in the PEG/MeOH system, we chose the pected, no appreciable leaching (<0.13%, 0.02 ppm)
asymmetric hydrogenation of methyl a-acetamidocin- of Rh occurred during the extraction of organic prod-
namate (10a) and methyl acetamidoacrylate (10g) as ucts because of the ionic behavior of the catalyst.
the standard reactions. As shown in Table 4, in the
first three runs (entries 1–3), the high enantioselectivi-
ties obtained for the two substrates in PEG were re- Asymmetric Hydrogenation of b-Keto Esters in PEG
tained, the values being slightly lower than those in
pure methanol. In the case of the asymmetric hydro- Optically active b-hydroxy carboxylic acids and their
genation of 10a, the catalyst could be reused at least esters have various applications in the synthesis of
four times with high conversions and isolated yields. enantiomerically pure pharmaceuticals, pesticides, fla-
Notably, when methyl acetamidoacrylate was used as vors, and as monomers for biodegradable polymers.
the substrate, the rhodium catalyst showed extremely The enantioselective reduction of b-keto esters to b-
+
À
Table 4. Reuse of catalyst for the asymmetric hydrogenation of enamides 10a and 10g using [Rh-(S,S)-Et-DuPHOS] BF as
4
[a]
catalyst in PEG-600/MeOH as solvent.
Substrate
Run 1
Run 2
Run 3
Run 4
Run 5
Run 6 Run 7 Run 8 Run 9 Run 10
[
[
b,c]
b]
1
0a conv. [%]
>99 (92)
97.0
>99
>99 (95)
95.2
>99 (99) 99 (98) 99 (98)
[b]
ee [%]
93.6
>99
98.0
91.1
98
95.5
87.6
99
93.5
1
0g conv. [%]
>99
98
94.2
99
94.2
99
93.1
99
93.4
70
92.0
[b]
[d]
ee [%]
98.2
98.4
[
[
a]
The hydrogenations were carried out using 20–50 mg substrate in 6 mL PEG-600/MeOH (1:3, v/v) under the following
conditions: substrate/catalyst=200 (M/M), P(H )=10 atm, temperature=15–208C, reaction time=3–10 h.
2
b]
The ee values and conversions were determined by GC with a Chrompack Chirasil-L-Val column (25 m”0.25 mm). All
products were in the S-configuration.
Data in brackets are isolated yields after column chromatography.
[
[
c]
d]
Percentage of Rh leached to the product in the second run was no more than 0.13% (0.02 ppm) by ICP analysis.
2176
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2172 – 2182

Polyethylene Glycol as an Environmentally Friendly and Recyclable Reaction Medium
FULL PAPERS
hydroxy esters was successfully achieved with several
The recovery and reuse of the catalyst and PEG
types of Ru-BINAP complexes in pure alcoholic or- have also been demonstrated in the asymmetric hy-
[27]
ganic solvents under mild reaction conditions. Such drogenation of methyl acetoacetate (12a) and 3-oxo-
asymmetric hydrogenations performed in a mixture of 3-(4’-chlorophenyl)propanoate (12c) (Table 6). At the
[
7l,m]
ionic liquid and MeOH also have been reported.
In most cases, however, modification of the catalyst were extracted with degassed hexane, and the PEG
was required. Furthermore, the modified Ru(BINAP) phase was reused directly in the next cycle. We have
end of each hydrogenation run, the reduced products
AHCTREUNG
catalysts sometimes suffered from lower enantioselec- successfully reused the catalyst in both cases. Notably,
tivities in ionic liquids than those obtained with the the enantioselectivity was retained for all five runs al-
[
7m]
parent homogeneous catalyst.
To determine wheth- though the activity of the catalyst slightly decreased
er the catalytic reduction of prochiral ketones could after the third cycle. These results were better than
[
7l,m]
proceed smoothly in PEG as solvent, we chose the di- those obtained in ionic liquid.
The inductively
nuclear complex [NEt H ][{RuCl(R-BINAP)} (m-Cl) ] coupled plasma (ICP) spectroscopy further showed
A
H
R
U
G
A
H
R
U
G
ACHTREUNG
2
2
2
3
[
28]
as the catalyst for our study. The effect of solvents that no appreciable leaching of Ru occurred during
on the enantioselectivity was firstly studied and the the extraction of organic products because of the
results are summarized in Table 5. We attempted to ionic behavior of the catalyst. We estimated from ICP
hydrogenate methyl acetoacetate (12a) with 0.2 experiments that less than 0.34% (0.14 ppm) of the
mol% Ru(BINAP) in pure PEG. After 20 h of reac- Ru catalyst has leached into the hexane extracts from
A
C
H
T
R
E
U
N
G
tion at 10 atm of H pressure, complicated products the PEG phase.
2
were obtained. When methanol was used as co-sol-
vent, the hydrogenation reaction proceeded smoothly
and cleanly with high enantioselectivity, which was Asymmetric Hydrogenation of Simple Aromatic
comparable to that obtained in pure methanol Ketones in PEG
(
98.8% vs. 99.0% ee). The use of increased amounts
of MeOH did not influence the enantioselectivity but Enantiomerically pure alcohols are important inter-
improved the catalytic activity. For the best catalyst mediates in the pharmaceutical industry and are usu-
activity and enantioselectivity, an equal volume mix- ally available from the reduction of ketones either by
ture of PEG and MeOH was chosen as the solvent chemical means or biotransformation. Among the
for all the subsequent hydrogenations. As shown in many protocols available for the transformation of
Table 5, a variety of b-alkyl keto esters and b-aryl prochiral ketones to chiral alcohols, the catalytic
keto esters were hydrogenated in the homogeneous asymmetric hydrogenation of ketones is one of the
[1a]
PEG/MeOH system to afford high enantioselectivi- most efficient and cost-effective methods.
ties, which were similar to those obtained in pure number of efficient catalysts has been developed for
MeOH. the asymmetric hydrogenation of functionalized keto-
A
[
2b,20]
nes.
In contrast, only a few catalysts have been re-
Table 5. Asymmetric hydrogenation of b-keto esters catalyzed by [NEt H ]
systems.
A
H
R
U
G
A
H
R
U
G
A
H
R
U
G
2
2
[a]
1
2
[b,c]
[b,c]
Entry
Substrate (R /R )
Solvent system
Conv. [%]
ee [%]
1
2
3
4
5
6
7
8
12a (CH /CH )
PEG600/MeOH=3/1
PEG600/MeOH=1/1
PEG600/MeOH=1/3
PEG600/MeOH=1/1
PEG600/MeOH=1/1
PEG600/MeOH=1/1
PEG600/MeOH=1/1
PEG600/MeOH=1/1
95
99
>99
>99 (>99)
>99 (>99)
96 (>99)
>99 (>99)
96 (99)
98.8 (99.0)
98.8
99.2
93.4 (94.3)
90.0 (92.0)
85.8 (83.0)
85.0 (86.0)
85.3 (87.4)
3
3
12a (CH /CH )
3
3
12a (CH /CH )
3
3
12b (CH /t-Bu)
3
12c (C H /CH )
6
5
3
12d (C H /C H )
6
5
2
5
12e (4-Cl-C H /CH )
6
5
3
12f (4-F-C H /CH )
6
5
3
[
[
[
a]
b]
c]
The hydrogenations were carried out using 60–80 mg substrate under the following conditions: substate/catalyst/HCl=
00/1/0.5 (M/M/M), P(H )=10 atm, temperature=608C, reaction time=20 h.
The ee values and conversions were determined by GC with a Chrompack Chirasil-DEX CB column (25 m”0.25 mm).
All products were in the R-configuration.
5
2
Data in brackets were obtained by using MeOH as solvent under otherwise identical conditions.
Adv. Synth. Catal. 2006, 348, 2172 – 2182
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Hai-Feng Zhou et al.
FULL PAPERS
Table 6. Reuse of catalyst for the asymmetric hydrogenation of b-keto esters 12a and 12c using [NEt H ]
A
H
R
U
G
A
H
R
U
G
2
2
2
[a]
A
C
H
T
R
E
U
N
G
(m-Cl) ] as catalyst in PEG-600/MeOH as solvent.
3
Run
12a
Conv. [%]
12e
Conv. [%]
[b]
[b]
[b,c]
[b]
ee [%]
ee [%]
1
2
3
4
>99
>99
99
80
93
98.6
99.0
98.2
97.8
97.6
>99 (94)
>99 (98)
>99 (99)
86 (83)
85.0[
d]
84.6
84.4
85.2
85.6
[
e]
5
77 (75)
[
a]
The hydrogenations were carried out using 60–80 mg substrate in 6 mL PEG-600/MeOH (1:1, v/v) under the following
conditions: substrate/catalyst/HCl=500/1/0.5 (M/M/M), P(H )=10 atm, temperature=608C, reaction time=20 h.
The ee values and conversions were determined by GC with a Chrompack Chirasil-DEX CB column (25 m”0.25 mm).
All products were in the R-configuration.
Data in brackets are isolated yields after column chromatography.
Percentage of Ru leached to the product in the second run was no more than 0.34% (0.14 ppm) by ICP analysis.
Reaction time=30 h.
2
[
b]
[
[
[
c]
d]
e]
[
7p]
ported in the asymmetric hydrogenation of simple ke- BINAP ligand. Both Ru catalysts and ionic liquid
[29]
tones. Recently, a significant breakthrough was ach- could be recycled by simple extraction and reused for
ieved by Noyori and co-workers by using chiral four times. For our study, the commercially available
RuCl (diphosphine)(diamine) complexes as catalysts diphosphine ligands xyl-P-Phos, xyl-BINAP and
A
H
R
U
G
2
[
30]
in the hydrogenation of a variety of simple ketones.
BINAP were chosen for the asymmetric hydrogena-
For the best economic effect, it is still highly desirable tion of aromatic ketones. Firstly, we investigated the
to make this catalyst system recyclable. Although im- effect of isopropyl alcohol as a co-solvent on the cata-
mobilization of the homogeneous catalyst offers an lytic activity and enantioselectivity, and the results are
attractive solution to this problem, so far, only a few summarized in Table 7. To our delight, in the presence
[
5b,r,17d]
successes have been achieved.
Most recently, of 0.2 mol% of RuCl [(S)-xyl-P-Phos][(S,S)-DPEN]
A
H
R
U
G
2
Lin and co-workers reported the successful asymmet- as catalyst, the hydrogenation of acetophenone (14a)
ric hydrogenation of aromatic ketones in a mixture of proceeded smoothly in a mixture of PEG/isopropyl
ionic liquid and isopropyl alcohol by using a modified alcohol with almost the same enantioselectivity as
Table 7. Asymmetric hydrogenation of simple ketones 14 catalyzed by Ru(1b, 1c or 3b)(DPEN) in different solvent
A
H
R
N
[a]
systems.
[b,c]
[b,c]
Entry
Substrate (R)
Solvent system (v/v)
Conv. [%]
ee [%]
1
2
3
4
5
6
14a (C H )
PEG600/i-PrOH (3/1)
PEG600/i-PrOH (1/1)
PEG600/i-PrOH (1/3)
PEG600/i-PrOH (1/1)
PEG600/i-PrOH (1/1)
PEG600/i-PrOH (1/1)
PEG600/i-PrOH (1/1)
PEG600/i-PrOH (1/1)
73 (>99)
99
>99
>99 (>99)
>99 (>99)
98 (>99)
99 (>99)
98 (>99)
97.0 (97.0)
98.2
98.0
98.2 (98.2)
97.8 (96.4)
97.4 (97.0)
94.8 (95.0)
97.4 (98.0)
6
5
14a (C H )
6
5
14a (C H )
6
5
14b (2-CH -C H )
3
6
4
14c (4-CH O-C H )
3
6
4
14d (1-naphthyl)
14d (1-naphthyl)
14a (C H )
[
[
d]
e]
7
8
6
5
[
a]
The hydrogenations were carried out using 50–70 mg substrate under the following conditions: (S)-xyl-P-Phos as ligand
otherwise specified, substate:ligand:Ru:diamine:t-C H OK=500:1.1:1 :1:6 (mol ratio), P(H )=20 atm, reaction time=
4
9
2
2
0 h, room temperature.
[
b]
The ee values and conversions were determined by GC with a Chrompack Chirasil-DEX CB column (25 m”0.25 mm).
All products were in the R-configuration.
Data in brackets were obtained by using i-PrOH as solvent under otherwise identical conditions.
[
[
[
c]
d]
e]
(
(
S)-BINAP was used as ligand, temperature=808C, P(H )=40 atm, reaction time=4 h.
2
R)-xyl-BINAP was used as ligand, room temperature, P(H )=20 atm, reactiom time=20 h. The product was in the S-
2
configuration.
2178
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Adv. Synth. Catal. 2006, 348, 2172 – 2182

Polyethylene Glycol as an Environmentally Friendly and Recyclable Reaction Medium
FULL PAPERS
that in isopropyl alcohol alone (entry 1). The use of nificantly only in the fifth run. Furthermore, the
an increased amount of isopropyl alcohol improved leaching of Ru to the hexane extracts was measured
both the catalytic activities and enantioselectivities by ICP and was found to be no more than 3.54%
(
entries 2 and 3). The asymmetric hydrogenation was (0.85 ppm).
extended to other simple ketones 14b, 14c and 14d.
Similarly, high enantioselectivities were observed,
which were comparable to those obtained in pure iso- Conclusions
propyl alcohol (entries 4–6). To further demonstrate
the efficacy of the PEG/isopropyl alcohol system, A practical protocol for the effective asymmetric hy-
other two chiral ruthenium catalysts RuCl [(R)-xyl- drogenation of prochiral olefins and ketones and the
2
BINAP]
A
C
H
T
R
E
U
N
G
[(R,R)-DPEN] and RuCl [(S)-BINAP][(S,S)- recycling of catalsyt in PEG has been developed. Ru
A
H
R
U
G
2
DPEN] were also employed to the asymmetric hydro- and Rh catalysts obtained with commercially avail-
genation of simple ketones. Comparable enantioselec- able chiral diphosphine ligands were employed for
tivities and conversions to those obtained in isopropyl the asymmetric hydrogenation of 2-arylacrylic acids,
alcohol were observed (entries 7 and 8).
enamides, b-keto esters and simple aromatic ketones
Having established the efficacy of this catalytic in PEG and an organic co-solvent, affording compara-
system, we then investigated the recovery and reuse ble enantioselectivities and catalytic activities to those
of the catalysts. All three catalysts were studied and obtained in conventional organic solvent systems.
the results are presented in Table 8. At the end of Both the catalysts and PEG could be readily recycled
each hydrogenation experiment, the reduced chiral al- by simple extraction with immiscible organic solvents
cohol was extracted with degassed hexane. The PEG such as diethyl ether and hexane, as in the case of
phase was washed once more with degassed hexane ionic liquids, and reused up to nine times without sub-
and was reused in the next run. All three catalysts stantial loss of catalytic activity and enantioselectivity.
could be recycled and afforded high enantioselectivi- No severe leaching of metal catalysts (<3% in most
ties. In particular, the catalyst RuCl [(S)-xyl-P-Phos]- cases) was observed during the extraction of the or-
2
A
C
H
T
R
E
U
N
G
[(S,S)-DPEN] gave almost the same enantioselectivi- ganic products. All these results indicated that PEGs
ties in all the five catalytic runs. The conversions were as green and recyclable reaction media are attractive
also retained in the first four cycles and decreased sig- alternatives to room temperature ionic liquids.
Table 8. Reuse of catalysts using different chiral diphosphine
Experimental Section
ligands for asymmetric hydrogenation of simple ketones in
[a]
PEG/i-PrOH as reaction medium.
General Remarks
[
b]
[c]
[d]
Run 14a
Conv.
14b
14d
All experiments were carried out under a nitrogen atmos-
phere by using standard Schlenk-type techniques, or were
performed in a glove-box. All solvents were dried by using
standard, published methods and were distilled under a ni-
trogen atmosphere before use. PEG was dried under re-
duced pressure using the toluene azeotrope before use. The
b-keto esters and simple ketones were distilled under re-
duced pressure before use. All other chemicals were used as
received from Aldrich, Acros, or Strem without further pu-
rification. (S)-5,5’-Diamino-BINAP (2) and (S)-6,6’-dihy-
droxy-BIPHEP (5) were synthesized according to the pub-
ee
[%]
Conv.
ee
[%]
Conv.
ee
[%]
[
e,f]
[e]
[e]
[e]
[e]
[e]
[
%]
[%]
[%]
1
2
3
4
5
>99 (91) 97.4
>99 (95) 97.3
>99 (98) 96.8
>99 (97) 96.0
>99
>99
>99
>99
56
98.2
98.0
97.7
98.0
97.6
99
99
99
76
94.8[
93.6
94.3
90.2
g]
88 (82)
95.2
[
a]
The hydrogenations were carried out using 50–70 mg
substrate in 6 mL PEG-600/i-PrOH (1:1, v/v) under the
following conditions: substrate:ligand:Ru:diamine:t-
C H OK=500:1.1:1:1:6 (mol ratio), P(H )=20 atm, reac-
tion time=20 h, room temperature.
R)-xyl-BINAP was used as ligand.
S)-xyl-P-Phos was used as ligand.
S)-BINAP was used as ligand, temperature=808C,
[21,24]
lished methods.
PEG-supported (R)-BINAP (7) was
[11b]
4
9
2
synthesized as previously reported.
The set-up of the
high-pressure reactor was carried out in a glove-box. GC
chromatography was performed on a Varian-6000 with FID
detector.
[
[
[
b]
c]
d]
(
(
(
P(H )=40 atm, reaction time=4 h.
The ee values and conversions were determined by chiral
2
[
e]
General Procedure for the [RuCl(diphosphine)
A
C
H
T
R
E
U
N
G
(h-
GC with a Chrompack Chirasil-DEX CB column (25 m”
C H )]Cl-Catalyzed Asymmetric Hydrogenation of 2-
6
6
0.25 mm).
Arylacrylic Acids with Catalyst Recycling
[
[
f]
Data in brackets are isolated yields after column chroma-
tography.
Percentage of Ru leached to the product in the second
run of 14d was no more than 3.54% (0.85 ppm) by ICP
analysis.
The catalyst [RuCl(diphosphine)
in situ according to the method reported in the literature.
A mixture of [RuCl (C H )] (12 mg) and chiral diphosphine
A
H
E
N
g]
AHCTREUNG
2
6
6
2
ligand (2.2 equivs.) in dry and degassed DMF (2 mL) was
Adv. Synth. Catal. 2006, 348, 2172 – 2182
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www.asc.wiley-vch.de
2179

Hai-Feng Zhou et al.
FULL PAPERS
stirred under N at 1008C for 30 min. After the mixture was
ed using a 1:4 mixture of anhydrous ether and hexane
(10 mL”2). The recovered catalyst in PEG media was
reused in the next batch of the catalytic reaction under iden-
tical conditions. The conversion and the ee value of the
product were determined by GC analysis with a Chrompack
Chirasil-DEX CB column.
2
cooled to room temperature, the solvent was removed under
reduced pressure and the catalyst (0.0012 mmol) was trans-
ferred to a 20-mL glass-lined stainless steel reactor contain-
ing PEG/MeOH (6 mL), NEt3 and substate (0.12 mmol).
The autoclave was closed and pressurized with H to 50 atm.
2
The mixture was stirred with a magnetic stirrer under H2
pressure at room temperature for a predetermined period of
time. After releasing the hydrogen, the methanol was re-
moved under reduced pressure. Anhydrous ether (5 mL)
and hexane (5 mL) were added to extract the organic prod-
uct. The resultant two layers were mixed thoroughly by vig-
orous stirring for 5 min and then cooled to solidify the cata-
lyst-containing PEG layer. The upper solution layer was sep-
arated by decantation. This manipulation was repeated one
more time. The combined extracts containing the product
was purified by flash chromatography on silica gel. The con-
version and the ee value of the product were determined by
GC with a Chrompack Chirasil-DEX CB column after the
reduced acid had been transformed to its corresponding
methyl ester. The recovered PEG and catalyst were reused
in the next batch of the catalytic reaction under identical
conditions.
General Procedure for the RuCl (diphosphine)-
DPEN-Catalyzed Asymmetric Hydrogenation of
Simple Aromatic Ketones and the Catalyst Recycling
2
The catalysts RuCl
situ according to the same procedures reported in the litera-
(diphosphine)-DPEN were prepared in
2
[17d,30c]
ture.
diphosphine ligand (2.2 equivs.) in dry and degassed DMF
(2 mL) was stirred under N at 100 8C for 30 min to form a
A mixture of [RuCl
A
H
R
U
G
2
2
reddish brown solution. After the solution was cooled to
room temperature, the R- or S-form of DPEN (2.2 equivs.)
was added and the mixture was stirred for further 10 h.
After the solvent had been removed under reduced pres-
sure, the catalyst (0.001 mmol) was transferred to the auto-
clave in which PEG/i-PrOH (6 mL), t-C H OK and sub-
4 9
strate (0.5 mmol) were charged. The hydrogenation reaction
was performed under 20 atm H pressure at room temper-
2
ture for 20 h. The reduced product was extracted using a 1:4
mixture of anhydrous ether and hexane (10 mL”2). The re-
covered catalyst in PEG media was reused in the next batch
of catalytic reaction under identical conditions. The conver-
sion and the ee value of the product were determined by
GC analysis with a Chrompack Chirasil-DEX CB column.
General Procedure for the [Rh-(S,S)-Et-
+
À
DuPHOS] BF -Catalyzed Asymmetric
4
Hydrogenation of Enamides with Catalyst Recycling
In a glove-box under a nitrogen atmosphere, a 20-mL glass-
lined stainless steel reactor with a magnetic stirring bar was
charged with catalyst (0.0016 mmol), substrate (0.32 mmol),
and PEG/MeOH (6 mL). The autoclave was closed and
pressurized with H2 to 10 atm. The mixture was stirred
under H pressure at room temperature for a predetermined Acknowledgements
2
period of time. After the autoclave was depressurized, the
methanol was removed under reduced pressure. Hexane
10 mL”2) was added to extract the product. The extracts
We are grateful to the National Natural Science Foundation
(
of China,the Major State Basic Research Development Pro-
gram of China (2005CCA06600),the Chinese Academy of
Sciences,and the Hong Kong Research Grants Council (Proj-
ect N PolyU 506/04) for financial support of this study.
were used for the analysis of the conversion and the ee
value of the product on GC with a Chrompack Chirasil-L-
Val column. The recovered catalyst in PEG was reused in
the next batch of the catalytic reaction under identical con-
ditions.
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A
H
R
U
G
A
H
R
U
G
2
2
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A
C
H
T
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E
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2 3
Hydrogenation of b-Keto Esters and the Catalyst
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A
H
R
U
G
A
H
R
N
A
H
R
U
G
2
2
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A
H
R
U
G
(
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pressure at 608C for 20 h. The reduced product was extract-
2180
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Adv. Synth. Catal. 2006, 348, 2172 – 2182

Polyethylene Glycol as an Environmentally Friendly and Recyclable Reaction Medium
FULL PAPERS
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