Use of amino amides derived from proline as chiral ligands in the ruthenium(II)-catalyzed transfer hydrogenation reaction of ketones

Article abstract of DOI:10.1016/S0040-4039(01)00914-5

We developed an efficient, easily available, and easy to use proline amide-based ruthenium(II) catalysts for the asymmetric hydride transfer reduction of prochiral ketones and e.e.s up to 98.8% have been measured.

Full text of DOI:10.1016/S0040-4039(01)00914-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5045–5048
Use of amino amides derived from proline as chiral ligands in
the ruthenium(II)-catalyzed transfer hydrogenation
reaction of ketones
Hae Yoon Rhyoo, Young-Ae Yoon, Hee-Jung Park and Young Keun Chung*
School of Chemistry and Center for Molecular Catalysis, Seoul National University, Seoul 151-747, South Korea
Received 18 April 2001; revised 24 May 2001; accepted 25 May 2001
Abstract—We developed an efficient, easily available, and easy to use proline amide-based ruthenium(II) catalysts for the
asymmetric hydride transfer reduction of prochiral ketones and e.e.s up to 98.8% have been measured. © 2001 Elsevier Science
Ltd. All rights reserved.
The catalytic enantioselective reduction of ketones has
been extensively studied during the last decade.1 In view
of the low cost of the reducing agent and operational
simplicity, the transition-metal-catalyzed transfer
hydrogenation reaction using iso-propanol (iPrOH) or
a HCO2H/Et3N mixture as a hydride source2 appears to
be an attractive supplement to catalytic hydrogenation
with H2. In particular, a ruthenium catalyst bearing a
chiral ligand such as N-tosylated diphenylethylene-
diamine (DPEN-Ts, Noyori’s ligand) has been well
studied.3 Recently, the use of amino acids4 or their
derivatives5 as ligands in the ruthenium(II)-catalyzed
enantioselective transfer hydrogenation of prochiral
aromatic ketones has attracted attention because of
their easy accessibility. However, when amino acids or
mixture cannot be used as a hydride source. This limits
the use of amino acids or their derivatives as chiral
ligands and especially when imines are reduced, the use
of HCO2H/Et3N mixture is a prerequisite for obtaining
good results.6 It seems that for catalytic systems bearing
amino amides a HCO2H/Et3N mixture can be used as a
hydride source. Another feature of catalytic systems
bearing amino amide is their fine tuning capacity
afforded by changing the functional group on the
amide. Surprisingly, there have been no reports on the
use of amino amides as chiral ligands in the asymmetric
hydrogen transfer reaction.
Herein, we report efficient, easily obtainable, and easy
to use proline amide-based ruthenium(II) catalysts for
the asymmetric hydride transfer reduction of prochiral
ketones.
i
their derivatives are used as chiral ligands, only PrOH
can be used as a hydrogen source. A HCO2H/Et3N
Scheme 1. Synthesis of proline amide derivatives.
* Corresponding author. E-mail: ykchung@plaza.snu.ac.kr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00914-5

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H. Y. Rhyoo et al. / Tetrahedron Letters 42 (2001) 5045–5048
was the solvent of choice owing to its easy purification
and low boiling point. The enantioselectivities and con-
version yields were rather insensitive to the ratio of
chiral ligand to metal. Thus, a 1:1 ratio of ligand to
metal was used for all the experiments. The best result
was obtained when the ratio of HCOOH/Et3N was 5:2.
We have also examined the hydrogen transfer reaction
of other aromatic ketones (Fig. 1) with various chiral
ligands (Table 2).
Chiral proline amides were synthesized by Scheme 1.
Treatment of N-carbobenzyloxy- -proline with triethyl
L
amine and ethyl chloroformate followed by aryl amine
and subsequent deprotection by Pd/C and cyclohexene
afforded proline amides.7,† The overall yields were 41–
91%. We have screened ruthenium metal complexes
using acetophenone and chiral ligand 2a as the stand-
ard substrate and ligand, respectively (Table 1).†
The conversion and enantioselectivity were highly
dependent upon the ruthenium complex, especially
arene. The best conversion rate and enantioselectivity
(92% and 78% e.e.) were obtained when cymene was
used as an arene. The chiral Ru complexes were pre-
pared in situ by heating a mixture of ruthenium com-
plex ([Ru(cymene)Cl2]2) and a chiral ligand (1 equiv.
versus Ru) in dichloromethane. Attempts to character-
ize the catalyst precursor were unsuccessful. We
assumed that it would be a similar form as the Noyori’s
catalyst. Catalytic reactions were carried out by adding
the substrate and a mixture of HCOOH/Et3N to the
catalyst solution and allowed to react for the predeter-
mined reaction time. The solution was quenched with
excess water and diethyl ether or ethyl acetate. GC
analysis of a sample aliquot then determined the con-
version rate and enantioselectivity.
For the transfer hydrogenation reaction of acetophe-
none 3a, the conversion yields and enantioselectivities
were highly dependent upon the chiral ligand 2. When
2c was used as a chiral ligand, no reaction was
observed. Chiral ligand 2b is not effective. Comparing
the activities and enantioselectivities of 2d–f, 2f which is
more electronegative and less sterically hindered, gave
the best results. Thus, the reaction was highly depen-
dent upon the steric bulkiness of alkyl group and
electronegativities of aromatic groups in the amino
amide ligand. However, the most active and selective
ligand is 2a, which has no substituents on the phenyl
ring. When (1S,2S)-DPEN-Ts was used as a ligand to
compare with ligand 2a, it showed a much higher
enantioselectivity than 2a. For the hydrogenation trans-
fer reaction of 3b–d, the enantioselectivities decreased
as the steric bulkiness increased. For the hydrogen
transfer reaction of 4a, conversion rates and enantio-
selectivities were obtained independently of the chiral
ligand. When the S/C ratio was doubled, the reaction
time for complete conversion was also twice as long
without the loss of the e.e. value. For the transfer
hydrogenation reaction of 3c, the highest enantioselec-
tivity (98.8%) was obtained when the chiral ligand 2a
was used. Chiral ligands 2d and 2f were also quite
effective. For the hydrogen transfer reaction of 4c, a
poor conversion rate was observed and the enantio-
selectivities were ca. 89%. For the hydrogen transfer
reaction of 4d, the yield was quantitative and quite high
enantioselectivities (94.8%) were obtained. In this case,
the conversion rate and enantioselectivities were rather
insensitive to chiral ligands. However, when (1S,2S)-
DPEN-Ts was used as a ligand, quite low conversion
(30.3%) and poor enantioselectivity (72.1%) were
obtained. Thus, the proline amides can be used as a
complement to the Noyori’s ligand for the hydrogen
transfer reaction of the ortho-substituted aromatic
Next, we investigated the effect of solvent, the ratio of
chiral ligand to metal ([Ru(cymene)Cl2]2), and the ratio
of HCOOH/Et3N on the enantioselectivities and con-
version yields. Dichloromethane, DMF, and aceto-
nitrile were good solvents. However, dichloromethane
Table 1. Asymmetric reduction of acetophenone with vari-
ous Ru(II) complexesa
Entry
Metal sources
Conv. (%)b
e.e. (%)b
1
2
3
4
[RuCl2(benzene)]2
[RuCl2(p-cym)]2
[RuCl2(Me6C6)]2
RuCl2(PPh3)3
49
92
33
0
3.7
78
54
a Acetophenone 1 mmol, S/C=50, HCOOH/Et3N (5/2) azeotrope
(distilled, 0.5 ml), and CH2Cl2 (0.5 ml) at 30°C for 6 h. Absolute
configuration (R) was determined by the sign of optical rotation.
b Conv. (%) and e.e. (%) were determined by chiral GC using a
Chrompak Chirasil-Dex CB column.
Figure 1. Prochiral aromatic acetophenone derivatives.
† See the Supporting Information.

H. Y. Rhyoo et al. / Tetrahedron Letters 42 (2001) 5045–5048
Table 2. Asymmetric transfer hydrogenation of aromatic ketonesa
5047
Entry
Ligand
Substrate
Time (h)
Conv. (%)
E.e. (%)
1
2
3
4
2a
2b
2c
2d
2e
2f
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
4a
4a
4a
4a
4b
4b
4b
4c
4c
4d
4d
4d
4d
5a
5b
6
7
15
24
7
6
7
7
7
6
7
6
6
12
6
6
6
9
6
6
96.5
29
0
82
57
79
50.8
74.6
74.2
74.1
96.2
69.8
70.8
33.9
90.9
90.2
90
91.6
98.8
98.3
96.8
88.8
89
5
6
76
7b
8
(1S,2S)-DPEN-Ts
2a
2a
2a
2a
2d
2d
2f
2a
2d
2f
2a
2f
2a
2d
2f
90.5
93.4
100
11.6
99.4
100
99.5
95
75
84
97
20
9
10
11
12
13c
14
15
16
17
18
19
20
21
22
23b
24
25
26
13
6
6
6
6
7
7
24
98.4
100
96.3
30.3
99.3
89
94.8
94.6
94.8
72.1
74.6
74
(1S,2S)-DPEN-Ts
2a
2a
2a
92
77.3
a Absolute configuration (R) was determined by the sign of optical rotation or retetion time of GC peak. The same reaction condition as in Table
1 was used. Conv. (%) and e.e. (%) were determined by GC using a Chrompak Chirasil-Dex CB 25 m×0.32 mm column. Conv. (%) and e.e. (%)
of 4a and 4b were determined by GC using a Ultra2 50 m×0.32 mm column.
b The starting material of ligand was 98% e.e. and configuration was R.
c 1 mol% catalyst was used.
ketones. The order of enantioselectivities for acetophe-
none derivatives is 4b>4d>4a>4c. For the hydrogena-
tion transfer reaction of 5 and 6, high yields were
obtained for all the reactions, but the enantioselectivi-
ties were rather poor.
ethyl acetate, filtered off any solids, evaporated to
dryness, and chromatographed on a silica gel column
eluting with hexane and ethyl acetate (v/v, 2:1).
Removal of the solvent gave 1a (2.40 g, 92.5%).
A typical procedure for synthesis of 2
This work shows that proline amides are good ligands
for the asymmetric hydride transfer reduction of
prochiral ketones since e.e.s up to 98.8% have been
measured. So, we have developed efficient, easily
obtainable, and easy to use catalyst. The next challenge
is recovery of the catalyst through the development of a
heterogeneous version. This is currently under
investigation.
Synthesis of 2a: Compounds 1a (2.0 g), 5% Pd/C (0.1
g), cyclohexene (1.0 ml), and ethanol (30 ml) were put
in a 100 ml Schlenk flask. The solution was heated at
reflux until no reactant (1) was remained in the solu-
tion. The solution was cooled to rt, washed with etha-
nol, filtered on Celite to remove any solids, and
evaporated to dryness. The residue was chromato-
graphed on a silica gel column or recrystallized in
n-hexane/CH2Cl2 to obtain pure 2a. Compounds 2a–c
were known compounds.8
Supporting information
A typical procedure for synthesis of 1
Compound 2d: mp 66–67°C; [h]2D1=−70 (c 0.1, CH2Cl2);
1H NMR (CDCl3): l 9.74 (s, CONH), 7.55–7.59 (m, 2
H), 6.98–7.05 (m, 2 H), 3.86 (dd, 9.26, 5.16 Hz, 1 H),
2.96–3.11 (m, 2 H), 2.03–2.22 (m, 2 H), 1.74–1.79 (m, 2
H), 1.73–1.78 (br, NH) ppm; IR (KBr) wCO 1668 (s)
cm−1. Anal. calcd for C11H13FN2O: C, 63.45; H, 6.29;
N, 13.45. Found: C, 63.09; H, 6.32; N, 13.43.
Synthesis of 1a: N-Carbobenzyloxy-L-proline (2.0 g, 8.0
mmol) and TEA (0.81 g, 8.0 mmol) were dissolved in 30
ml of THF. The solution was cooled to 0°C. To the
solution was added dropwise ethylchloroformate (0.88
g, 8.0 mmol) for 15 min. After the solution was stirred
for 30 min, aniline (8.0 mmol) was added for 15 min.
The resulting solution was stirred at 0°C for 1 h and at
rt for 16 h, and heated at reflux for 3 h. After the
solution was cooled to rt, the solution was washed with
Compound 2e: mp 81–82°C; [h]1D7=−63 (c 0.1, CH2Cl2);
1H NMR (CDCl3): l 9.54 (s, NH), 7.44 (d, 12.24 Hz, 2
H), 6.78 (d, 12.26 Hz, 2 H), 3.78 (dd, 9.18, 5.23 Hz, 1

5048
H. Y. Rhyoo et al. / Tetrahedron Letters 42 (2001) 5045–5048
H), 3.72 (s, OCH3), 2.87–3.05 (m, 2 H), 1.91–2.18 (m, 2
H), 1.83 (s, NH), 1.65–1.73 (m, 2 H) ppm; IR (KBr)
wCO 1662 (s) cm−1. Anal. calcd for C12H16N2O2: C,
65.43; H, 7.32; N, 12.72. Found: C, 65.35; H, 7.40; N,
12.82.
References
1. (a) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001,
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Chem. Rev. 1992, 92, 1051.
1
Compound 2f: mp 48°C; [h]1D7=−54 (c 0.1, CH2Cl2); H
2. (a) Matsumura, K.; Hashiguch, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1997, 119, 8738; (b) Ohkuma, T.;
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NMR (CDCl3): l 10.08 (s, CONH), 8.40 (t, 10.23 Hz, 1
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3.01–3.11 (m, 2 H), 2.05–2.22 (m, 2 H), 1.80–2.05 (br,
NH), 1.24–1.80 (m, 2 H) ppm; IR (KBr) wCO 1672 (s)
cm−1. Anal. calcd for C11H13FN2O: C, 63.45; H, 6.29;
N, 13.45. Found: C, 63.24; H, 6.40; N, 13.51.
A typical procedure for catalytic reactions
Ruthenium metal complex (2 mol% [Ru]), chiral ligand
(2 mol%), and solvent were dissolved in a 20 ml
Schlenk flask. The solution was stirred for 30 min and
allowed to warm to the temperature at which a catalytic
reaction would be carried out. At the temperature,
substrate (1 mmol) was added to the solution. Subse-
quently, a mixture of HCOOH/Et3N was added and
allowed to react for the predetermined reaction time.
The solution was quenched with excess water and
diethyl ether or ethyl acetate. GC analysis of a sample
aliquot then determined the conversion rate and
enantioselectivity.
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This work was supported by Grant No. 2000-2-12200-
001-1 from the Basic Research Program of the Korea
Science and Engineering Foundation (KOSEF) and
KOSEF through the Center for Molecular Catalysis.
Y.A.Y. and H.J.P. acknowledge receipt of the BK21
fellowship.
.