Screening method for the evaluation of asymmetric catalysts for the reduction of aliphatic ketones

Article abstract of DOI:10.1016/j.tetlet.2011.01.112

ATH reductions of aliphatic ketones in water catalyzed by ruthenium coordinated by prolinamide ligands produce alcohols with moderate enantiomeric excesses in most cases. A set of seven aliphatic ketones is proposed for a rapid evaluation of the enantioselectivity of catalysts by one-pot multi-substrates reduction. The screening of a library of prolinamides shows that according to the structure of the ketones different ligands give the best asymmetric inductions.

Full text of DOI:10.1016/j.tetlet.2011.01.112

Tetrahedron Letters 52 (2011) 1485–1489
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Screening method for the evaluation of asymmetric catalysts for the
reduction of aliphatic ketones
Mourad Boukachabia b, Saoussen Zeror b, Jacqueline Collin a,c, , Jean-Claude Fiaud a,
⇑
Louisa Aribi Zouioueche b,
⇑
a Université Paris-Sud, Laboratoire de Catalyse Moléculaire, ICMMO, UMR 8182, Orsay F-91405, France
b Equipe de Synthèse Asymétrique et Biocatalyse, LCOA, Université Badji Mokhtar, 23000 Annaba, Algeria
c CNRS, Orsay F-91405, France
a r t i c l e i n f o
a b s t r a c t
Article history:
ATH reductions of aliphatic ketones in water catalyzed by ruthenium coordinated by prolinamide ligands
produce alcohols with moderate enantiomeric excesses in most cases. A set of seven aliphatic ketones is
proposed for a rapid evaluation of the enantioselectivity of catalysts by one-pot multi-substrates reduc-
tion. The screening of a library of prolinamides shows that according to the structure of the ketones dif-
ferent ligands give the best asymmetric inductions.
Received 16 December 2010
Revised 19 January 2011
Accepted 24 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Ruthenium
Hydride transfer
Multi-substrate screening
Aliphatic ketones
1. Introduction
range of aliphatic ketones with high enantiomeric excesses
remains nowadays a challenging goal.
New methodologies for preparing chiral compounds are
required to meet the criteria of green chemistry, such as the use
of safe reagents and solvents, the recyclability of catalysts and
the easy separation of reaction products.1 In such a concern asym-
metric transfer hydrogenation (ATH), which allows the easy prep-
aration of enantiomerically enriched alcohols avoiding the use of
hydrogen gas under high pressure has been the focus of numerous
work.2 ATH reactions in water were developed more recently.3 The
first system described by Chung involved ruthenium catalysts
coordinated by amides derived from (S)-proline.4 Rhodium, iridium
or ruthenium associated to different types of ligands such as biden-
date diamines,5 or aminoalcohol ligands6 proved to be highly enan-
tioselective for the reduction of aromatic ketones in water.
Performing reactions in water with the same ligand than in organic
solvents led to chiral alcohols with high enantiomeric excesses and
many times with higher reaction rates.3,5b–d,5l However although
the transformation of aromatic ketones into alcohols by asymmet-
ric catalysed reactions is well documented, catalytic reductions of
aliphatic ketones with comparable enantioselectivities are rare and
in most cases are efficient for only a few substrates. Thus the devel-
opment of new asymmetric catalysts for the reduction of a wide
In the course of our previous investigations we have studied
asymmetric transfer hydrogenation (ATH) of aromatic ketones in
water using a catalyst obtained by the addition of N-phenyl-(L)-
proline amide ligand 3a to [RuCl2(p-cymene)]2 in water under
nitrogen.8 This catalyst could be reused either for the reduction
of the same ketone (fifteen reuses) or using a different ketone for
each cycle. Seven ketones could thus be successively reduced with
the same enantiomeric excess than in individual reactions. Next for
improving the enantioselectivity of our catalytic system we stud-
ied a method affording a rapid selection of ligands by multi-sub-
strate screening.9 Such method first developed by Kagan,10 is
based on single-pot reactions with several substrates followed by
the measurement of enantiomeric excesses on the mixture of prod-
ucts.11 We studied water ruthenium-catalyzed reductions of a mix-
ture of six aromatic ketones with a library of ligands and selected
the proline amide prepared from (1R,2S)-cis-aminoindanol as the
best ligand. The latter afforded also high enantiomeric excesses
for the reduction of other aromatic ketones. We now report water
ATH reductions of aliphatic ketones and multi-substrate reduction
of several aliphatic ketones for a rapid evaluation of ligands.
2. Results
⇑
Corresponding authors. Tel.: +33 169154740.
E-mail addresses: jacqueline.collin@u-psud.fr (J. Collin), lzouioueche@yahoo.fr
The study of one-pot multi-substrate reductions requires
choosing several ketones and checking that enantiomeric excesses
(L.A. Zouioueche).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.112

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M. Boukachabia et al. / Tetrahedron Letters 52 (2011) 1485–1489
of the corresponding alcohols can be easily measured. A series of se-
ven methyl ketones 1a–g substituted by alkyl groups with different
steric demand was considered. Indeed we found conditions for the
evaluation of the enantiomeric excesses of all the corresponding
alcohols 2a–g by a single GC analysis on a chiral column. All pairs
of enantiomeric alcohols were separated without overlap of the
peaks. The chromatogram of an equimolecular mixture of the seven
racemic alcohols is represented in Figure 1. For the reduction of ke-
tones 1a–g we first investigated the catalyst that we had previously
used for the reduction of aromatic ketones or ketoesters,12 that is,
O
O
OH
2.5% [RuCl2(p-cymene)]2, 5% 3a
R
N Ph
H
H2O, HCOONa, 30°C
R
N
1a-g
2a-g
H
3a
1a : R = t-Bu
1b : R = n-C4H9
1c : R = 4-methyl-pent-3-enyl
1d : R = cyclohexyl
1e : R = benzyl
1f : R = 2-phenyl-ethyl
1g : R = 1-adamantyl
ruthenium coordinated to N-phenyl-(L)-prolinamide. The water
Scheme 1. Enantioselective reduction of ketones 1a–g catalyzed by [RuCl2(p-
cymene)]2 coordinated by N-phenyl prolinamide 3a.
ATH reduction of each of these ketones has been examined prior to
the one-pot reduction of the seven substrates. An aqueous solution
of N-phenylprolinamide 3a and ruthenium complex [RuCl2(p-cym-
ene)]2 was stirred for one hour at room temperature before the addi-
tion of sodium formate and ketone (Scheme 1). Reactions were
monitored by GC and enantiomeric excesses were determined by
GC using a chiral column. Results are indicated in Table 1.
Table 1
ATH reduction of ketones catalyzed by ruthenium complex coordinated by N-
phenylprolinamide 3a
Entry
Product
ta (h)
Yieldb (%)
eec (%)
Conf.d
The catalytic system showed satisfying activity for the reduc-
tion of ketones 1a–g since a total conversion in alcohol was ob-
served for all the substrates. Reaction times were dependent on
the bulkiness of ketones varying from 17 h for substrates with lin-
ear chains to 48 h for ketone 1g including the bulky adamantyl
group. Enantiomeric excesses varied similarly with the steric hin-
drance close to the ketone functionality. Good asymmetric induc-
tions have been observed for alcohols 2a and 2g bearing a
tertiary group (70% and 68%, respectively, Table 1, entries 1 and
7). Moderate enantiomeric excess was observed for alcohol 2d
including a cyclohexyl group (entry 4). As might be expected the
reduction of linear ketones was less enantioselective (entries 2
and 3). The presence of phenyl substituents (entries 5 and 6) did
not improve the asymmetric induction.
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
35
20
18
24
17
17
48
40
54
60
49
80
85
93
70
20
29
42
13
35
68
R
R
R
R
R
R
R
2g
a
Reactions were performed with 2.5% [RuCl2(p-cymene)]2 and 5% ligand 3a in
water at 30 °C for total conversion.13
b
Isolated yields.
c
Enantiomeric excesses (%) have been determined by GC using Chiraldex b-PM
column.
d
Configurations were determined by comparison with literature (see Experi-
mental part).
Chromatographic analysis on the chiral column of a mixture of
the seven racemic alcohols 2a–g indicated different retention
times for all enantiomers. This allowed the measurement of the
enantiomeric excesses of the seven alcohols by a single analysis.
One-pot reduction of the mixture of ketones 1a–g using the same
catalyst, N-phenylprolinamide ligand 3a and the ruthenium pre-
cursor [RuCl2(p-cymene)]2 was then examined. We checked that
enantiomeric excesses of all alcohols had similar values to those
obtained in the individual reductions (Table 2, entry 1) as previ-
ously observed for the reduction of aromatic ketones. A variety of
ligands was investigated for the one-pot reduction of this mixture
of ketones with ruthenium to try to improve asymmetric induc-
tions. The different ligands are indicated in Scheme 2.
The ligands which led to the more enantioselective catalysts for
the reduction of aromatic ketones in our former investigations, 3b,
3c, or 3d were first examined for the one-pot reduction of the mix-
ture of aliphatic ketones 1a–g. The comparison of N-aminoindanol
prolinamide 3b with ligand 3a indicated a decrease of the enantio-
meric excesses obtained from all substrates with the former (Table
2, entry 2). Ligand 2-hydroxyphenyl prolinamide 3c led to similar
values than 3a for enantiomeric excesses of all alcohols except
2a and 2g which were obtained with lower ee (entry 3). Reaction
was slower with aminoindanol 3d than with phenyl prolinamide
3a and all alcohols were obtained under racemic form except alco-
hols 2d and 2e (40% ee) (entry 4). Hydroxyl substituents on the
amido groups of ligands 3b, 3c, had no positive effect on enantio-
Figure 1. Analysis of the mixture of enantiomers of alcohols 2a–g by chiral GC (Chiraldex b-PM column (50 m  0.25 mm), hydrogen as the carrier gas (1.0 mL/min); oven
temperature : 50 °C during 30 min, heated to 100 °C (5 °C/min) and maintained at 100 °C during 65 min, heated to 120 °C (5 °C/min) and maintained at 120 °C during 100 min.

M. Boukachabia et al. / Tetrahedron Letters 52 (2011) 1485–1489
1487
Table 2
O
OH
2.5% [RuCl2(p-cymene)]2, 5% L*
One-pot enantioselective reduction of the mixture of ketones 1a–g catalyzed by
[RuCl2(p-cymene)]2 coordinated by various ligands in water
R1 R2
R1 R2
2h-m
H2O, HCOONa, 30°C
1h-m
Entrya Ligand tb
ee
ee
ee
ee
2d
ee
2e
ee
2f
ee
2ac
2bc
2cc
2gc
L*= 3a, 3e, 3f, 3g, 3h
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
65 66
46 27
36 40
22
13
26
0
14
24
22
4
30
25
32
0
22
33
33
8
46c
0
13c
11d
13d
40c
9
33c
27d
36d
0
64
25
47
0
75
74
69
82
61
55
50
O
O
O
O
O
O
48c
16d
21c
49d
46c
37d
7
Br
t-Bu
Et
C6H13
t-Bu
i-Pr
72
0
54 69
48 63
40 55
80 68
96 60
96 56
50 38
22c
32c
37c
9
1h
1i
1j
1k
1l
1m
0
11c
3
Scheme 3. ATH reduction of a variety of aliphatic ketones.
9
10
11
6
0
0
15
11
10
9
19d
6
3j
3k
20d
40d
8
Table 3
50d
17d
Enantioselective ruthenium-catalyzed reduction of aliphatic ketones using prolina-
mide ligands in water
a
Reductions are performed with 2.5% [RuCl2(p-cymene)]2 and 5% 3 on a mixture
of 0.5 mmol of ketones 1a–g in water at 30 °C.15
Entry
Producta
Ligand
tb
Yieldc
eed
b
Reaction time (h) for 100% conversion.
(R) Configuration.
(S) Configuration.
c
1
2
3
4
5
6
7
8
2h
2h
2i
2i
2j
2k
2k
2l
2l
2l
3a
3g
3a
3g
3h
3e
3h
3a
3f
2
2
3
39
41
70
87
70
78
80
50
58
60
78
75
28
28
26
28
68
22
41
57
60
57
14
30
d
3
24
72
72
3
4
2
selection. In order to vary steric and electronic properties of the li-
gand, we envisaged other phenyl prolinamides with methyl, or tri-
fluoromethyl substituents on the phenyl groups (3e, 3f, and 3g). All
prolinamides are prepared as described in the literature.14 o-Toly-
lprolinamide ligand 3e furnished similar or lower enantiomeric ex-
cesses than phenyl prolinamide 3a except for alcohol 2g that had a
slightly enhanced enantiomeric excess (entry 5). Prolinamides 3f
and 3g with para-substituted phenyl groups afforded similar
enantioselectivities than 3a except a slight increase for alcohol
2g (entries 6 and 7). Steric hindrance (3b, 3e), donor or acceptor
substituents (3f, 3g) on the phenyl group of prolinamide ligands
did not increase the enantioselectivity of the ruthenium-catalyzed
reduction of aliphatic ketones. With benzyl prolinamide 3h slower
reaction and low values for the enantiomeric excesses of several
alcohols were observed. Interestingly, ketones with tertiary
groups, 2a and 2g were reduced with good enantiomeric excesses,
respectively, 68 % and 82% (entry 8). The influence of another chi-
rality center was studied by using the diastereoisomeric ligands 3i
and 3j. Both afforded similar or lower enantiomeric excesses than
the parent benzyl amide 3h for any alcohol of the mixture (entries
9 and 10). A second chiral center on the amide group has no posi-
tive effect on the enantioselection in the ruthenium-catalyzed
reduction of aliphatic ketones. The last ligand of the series was pro-
linamide 3k prepared from tert-butyl amine. The reduction of most
of the ketones (1a–c, 1f–g) was realized with lower asymmetric
inductions than with the ligands described above. However ligand
3k allowed recording of the highest value for the enantiomeric ex-
cess of 2-phenyl ethanol 2e (50%) (entry 11). Alcohols 2d, 2e, or 2f
9
10
11
12
3g
3a
3g
2m
2m
48
72
a
Reductions are performed with 2.5% [RuCl2(p-cymene)]2 and 5% 3 and 0.5 mmol
of ketone 1 in water at 30 °C.13
b
Reaction time (h) for 100% conversion.
Isolated yield (%).
Enantiomeric excesses (%) have been determined by GC using Chiraldex b-PM
c
d
column.
can be prepared with R or S as the major configuration depending
on the ligand employed.
The study of the ruthenium-catalyzed multi-substrate reduc-
tion of aliphatic ketones reveals a different trend than multi-sub-
strate reduction of aromatic ketones. In the latter case using
ligands 3b, 3c, or 3d we found enhanced enantiomeric excesses
in comparison with ligand 3a for nearly all alcohols. Conversely
for aliphatic ketones changing the ligands have different effects
on enantioselection depending on the structure of substrate. For
the alcohols with the bulkiest groups 2a, and 2g the highest
enantiomeric excesses (respectively, 68% and 82%) were observed
with benzyl prolinamide ligand 3h while phenyl prolinamide type
ligands with or without a substituent on the phenyl group, 3a, 3e–
g afforded also good enantioselectivities. As usually observed with
most catalysts linear alcohols 2b and 2c were obtained with low
HO
HO
HO
O
O
O
H2N
N
H
N
H
N
H
N
H
N
H
N
H
(1R,2S) 3d
3a
3b
3c
3g
CF3
O
O
O
O
N
N
N
H
N
H
N
H
N
H
N
H
N
H
H
H
3f
3e
3h
O
O
O
N
N
N
N
N
N
H
H
H
H
H
H
3i
3j
3k
Scheme 2. Structures of ligands 3a–k.

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M. Boukachabia et al. / Tetrahedron Letters 52 (2011) 1485–1489
enantioselectivities (ee up to 33%) and the best ligands are 3a, 3c,
3f, and 3g. These ligands similarly gave the highest ee for alcohols
2d (46–49%) and 2f (32–37%). t-Butyl prolinamide 3k is the best li-
gand for the reduction of ketone 1e. These results show that for
these water ruthenium-catalyzed reductions of aliphatic ketones
enantioselectivity depends both on the nature of ligand and
substrate.
Previous studies on multi-substrate ATH reduction of aromatic
ketones led us not only to find a highly enantioselective ligand
for all substrates but also to demonstrate the interest of the meth-
od of optimisation of the catalyst. The ligand selected (3b) was fur-
ther employed for the reduction of other aromatic ketones with
high asymmetric inductions. Since we did not find an enantioselec-
tive ligand for all substrates in one-pot reduction of aliphatic ke-
tones we examined separately the different families of ketones
according to the steric hindrance of substituents. We thus chose
for each type of ketones the ligand affording the highest enantio-
meric excesses and tested it for the reduction of other substrates
with similar structures (Scheme 3). The results are gathered in Ta-
ble 3.
mides derived from aryl, benzyl, or alkyl amines has been achieved.
According to the structure of the ketones different ligands give the
best asymmetric inductions (26% ee for linear ketones, 49% ee for
ketones with secondary carbon in
a-position to the carbonyl and
82% ee for ketones with tertiary carbon in
a-position to the
carbonyl). Up till now, only very few catalytic systems have been re-
ported for the reduction of aliphatic ketones with high enantioselec-
tivity. Multi-substrate reductions with the set of ketones described
above allow a rapid screening of the efficiencies of ligands or cata-
lysts for aliphatic ketones with different steric hindrance close to
the prochiral functionality. We thus assume that this method should
bring a useful tool for the design of new catalysts for preparing chiral
alcohols from aliphatic ketones.
Acknowledgments
We acknowledge the Ministère Algérien de l’Enseignement
Supérieur et de la Recherche Scientifique (FNR grant) and the Min-
istère Français des Affaires Etrangères for a Tassili grant (06 MDU
674). We thank CNRS for financial support.
The ligands 3a and 3g which were found as the most enantiose-
lective for the reduction of linear aliphatic ketones have been used
for the reduction of butanone 1h and 2-octanone 1i. Alcohols 2h
and 2i have been obtained after short reaction times (2 h) and with
26–28% ee (Table 3, entries 1–4). These values although moderate
are similar to those obtained for 2-hexanol 2b with ligands 3a and
3g. The reduction of 1j was performed with ligand 3h that reduced
the parent ketone 1a with high enantioselectivity. Indeed, with li-
gand 3h good asymmetric induction was observed for the reduc-
tion of ketone 1j since 68% ee was measured for alcohol 2j, the
same value than for 2a using the same ligand (compare Table 2 en-
try 8 and Table 3 entry 5). The reductions of 2,2-dimethylcyclo-
pentanone 1k using ligands 3e or 3h were less enantioselective
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.112.
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We have shown that ruthenium coordinated with prolinamide
type ligands are efficient catalysts for the reduction in water of
aliphatic ketones. The one-pot reduction of a mixture of seven
ketones of various structures followed by a single analysis allows a
rapid evaluation of ligands. The screening of a variety of prolina-

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1489
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evaporated under reduced pressure and purified by thin layer chromatography
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15. General procedure for one-pot multi-substrate reactions: In a Schlenk tube
[RuCl2(p-cymene)]2 (54.25 mg, 0.0875 mmol) and ligand (0.175 mmol) were
dissolved in water (4 mL). After one hour stirring at 30 °C, sodium formate
(10 mmol) and 0.5 mmol of each ketone were added to the solution. The
reaction mixture was maintained at 30 °C until total reduction of all ketones
(monitored by GC). The mixture of alcohols was extracted with pentane
(3 Â 10 mL) and the solution dried over MgSO4 and analyzed by GC on chiral
column.
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13. General procedure for catalytic reductions: In a Schlenk tube, dichloro-p-
cymene ruthenium dimer (15.5 mg, 0.025 mmol) and ligand (0.05 mmol) were
dissolved in water (4 mL) at 30 °C and stirred during 1 h. Sodium formate
(0.68 mg, 10 mmol) and substrate (1 mmol) were then added. The reaction
mixture was maintained at 30 °C until total reduction of the ketone (monitored
by GC). Alcohol was extracted with pentane (3 Â 10 mL), dried over MgSO4 and