Ruthenium-catalyzed asymmetric transfer hydrogenation of ketones in ethanol

Article abstract of DOI:10.1016/j.tetlet.2011.03.098

A ruthenium catalyst formed in situ by combining [Ru(p-cymene)Cl ₂]₂ and an amino acid hydroxy-amide was found to catalyze efficiently the asymmetric reduction of aryl alkyl ketones under transfer hydrogenation conditions using ethanol as the hydrogen donor. The secondary alcohol products were obtained in moderate to good yields and with good to excellent enantioselectivity (up to 97% ee).

Full text of DOI:10.1016/j.tetlet.2011.03.098

Tetrahedron Letters 52 (2011) 2754–2758
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Tetrahedron Letters
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Ruthenium-catalyzed asymmetric transfer hydrogenation of ketones in ethanol
⇑
Helena Lundberg, Hans Adolfsson
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A ruthenium catalyst formed in situ by combining [Ru(p-cymene)Cl ] and an amino acid hydroxy-amide
2
2
Received 18 February 2011
Revised 9 March 2011
Accepted 18 March 2011
was found to catalyze efficiently the asymmetric reduction of aryl alkyl ketones under transfer hydroge-
nation conditions using ethanol as the hydrogen donor. The secondary alcohol products were obtained in
moderate to good yields and with good to excellent enantioselectivity (up to 97% ee).
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Amino acids
Ruthenium
Reduction
Enantioselective reductions of polarized organic compounds
such as ketones and imines are highly important transformations,
since the alcohols and amines formed are often employed as chiral
building blocks in the production of a variety of different fine-
chemicals. Methods employing non-hydride reagents as terminal
reductants are of particular interest, and an emerging number of
catalytic asymmetric protocols have been developed over the last
formed under thermodynamic conditions, and therefore reduc-
tions in 2-propanol can result in poor yields of the product due
to an unfavorable equilibrium. To circumvent the latter problem,
reductions are often performed with low substrate concentrations,
typically in the range of 0.1–0.2 M. However, in systems where for-
mic acid or its formate salt are employed as the hydride donor, the
reaction is practically irreversible due to the release of carbon
dioxide. On the other hand, the downside using formic acid as
the hydrogen donor is the limited compatibility with most of the
1
two decades. Most catalytic methods rely on the use of chiral
transition metal complexes in combination with either molecular
2
3c
hydrogen (hydrogenation) or organic hydrogen donors (transfer
catalysts used in ATH processes.
3
hydrogenation) as reducing agents. In particular, asymmetric
A highly interesting alternative to formic acid or 2-propanol as
the hydride source in asymmetric reductions is the use of primary
transfer hydrogenation (ATH) has emerged as one of the most pop-
ular methods for enantioselective ketone and imine reductions,
5
alcohols, and in particular ethanol. Ethanol is a renewable solvent
4
since the use of hazardous reaction conditions are avoided. Fre-
and energy source, and has attracted much attention for its poten-
tial as an alternative to fossil fuels. However, with the exception of
quently employed hydrogen donors in ATH of ketones are formic
acid and different formate salts, or secondary alcohols such as 2-
propanol. Transfer hydrogenation processes are reactions per-
5
a,b
the group of Grützmacher,
it has received little attention as a
hydrogen source in transfer hydrogenation. The reason for the rare
a
b
[
Ru(p-cymene)Cl2]2 (0.25 mol%)
O
O
OH
Ligand 1 (0.55 mol%)
H
OBut
CH3
Ru
N
Ar
i
Ar
NaOPr (5 mol%), LiCl (10 mol%)
2
H
Li
O
O
-PrOH : THF (1 : 1),
N
O
[ketone] = 0.2 M
H C
3
Scheme 1.
⇑
Corresponding author.
E-mail address: hansa@organ.su.se (H. Adolfsson).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.098

H. Lundberg, H. Adolfsson / Tetrahedron Letters 52 (2011) 2754–2758
2755
⁄
Table 1
[Ru(p-cymene)Cl
]
or [RhCp Cl
]
2
and the amino acid hydroxy-
2
2
2
Ruthenium-catalyzed asymmetric reduction of acetophenone with various alcohols as
hydrogen donors
7
amide ligand 1 as catalysts. A vast number of ligands based on
various amino acids were screened, and it was found that using a
combination of N-Boc alanine and amino-2-propanol resulted in
ruthenium catalysts with superior activity and enantioselectivity.
Furthermore, during optimization of the reaction conditions for
these ATH reductions, we found that the use of lithium 2-propox-
ide, or a combination of sodium 2-propoxide and lithium chloride,
gave significantly better enantioselectivities of the formed prod-
a
Entry
Alcohol
Time (h)
Conversionb (%)
Selectivityb (%)
eec (%)
1
2
3
4
MeOH
EtOH
1-PrOH
1-BuOH
6
2
6
6
3
100
90
66
>99
97
96
83
63
65
64
90
a
The reactions were carried out under an N
2
atmosphere under anhydrous
(0.5 mol %), ligand
conditions using acetophenone (0.8 mmol), [Ru(p-cymene)Cl
]
2 2
9
ucts (Scheme 1, a). The enhancing effect was traced to participa-
1
(1.1 mol %) and LiCl (10 mol %) at 40 °C in a 0.5 M solution with 1:1 alcohol/THF.
Conversion and selectivity were determined by GLC analysis.
Enantiomeric excess was determined using GLC (CP Chirasil DEX CB).
b
c
tion of the alkali cation in the transfer of the hydride from the
catalyst to the substrate. In ATH processes catalyzed by ruthe-
nium– or rhodium–arene complexes, the additional ligand (often
a vicinal aminoalcohol, or diamine) serves a dual purpose in (1)
controlling the stereochemical outcome of the process and (2)
use of ethanol in ATH reactions can be traced to its ability to form
stable carbonyl complexes with the catalysts used for the process.
In addition, there is an obvious risk of forming condensation prod-
ucts between acetaldehyde and the ketone substrate, when the
ATH reaction is performed under basic conditions. Nevertheless,
the catalyst compatibility of ethanol should be similar to that of
6
delivering a proton to the substrate oxygen in the reducing
3d,10
step.
The reaction path is normally referred to as an outer-
sphere type mechanism. However, when amino acid hydroxy-
amides are employed as ligands, the reaction mechanism is some-
what different. Instead of protonation of the substrate by the li-
gand, an alkali ion associated with the transition metal hydride
complex is transferred to the ketone oxygen simultaneously with
the hydride delivery. Hence the overall process can be described
2
-propanol, and the sometimes disfavored equilibria obtained with
the latter hydride donor could possibly be circumvented due to the
lower boiling point of acetaldehyde as compared to acetone. There-
fore, ATH reactions performed in ethanol would be expected to
reach higher conversions, since the formed acetaldehyde has a
chance of escaping the reaction vessel, and thereby help push the
equilibrium towards the product. Moreover, the initially formed
acetaldehyde can react further to generate ethyl acetate via dehy-
dration of the intermediate hemiacetal.5 From an environmental
perspective, it would be possible to perform the reactions with a
significantly higher substrate concentration and thereby reduce
effectively the amount of solvent used.
We have previously developed highly efficient and selective
ruthenium and rhodium catalysts for the asymmetric transfer
hydrogenation of ketones in 2-propanol.7 These half-sandwich
Ru- or Rh-complexes were chirally-modified using different N-car-
bamate protected a-amino acid derivatives as ligands, and depend-
ing on the choice of derivative, we were able to obtain both
9b
as a bimetallic outer-sphere type mechanism (Scheme 1, b). In
addition, we found that performing the ATH reactions in a mixture
of 2-propanol and THF resulted in better overall performance of the
catalyst.
Based on these findings, we anticipated that the optimized con-
ditions found for the 2-propanol system would also be applicable
in other alcohols. In an initial set of experiments, acetophenone
a,b
(
concentration: 0.5 M) was reduced in a 1:1 mixture of THF and
four different primary alcohols (Table 1). In order for the reaction
to proceed to high conversions, we had to increase the catalyst
loading to 1 mol % in comparison to the 2-propanol system. As seen
in Table 1, the use of methanol resulted in poor conversion of the
substrate (entry 1), whereas in solvent mixtures containing etha-
nol, 1-propanol, and 1-butanol, respectively, 1-phenylethanol
was obtained in moderate to high yields. Most gratifyingly, the
reaction performed using ethanol as the hydride donor gave the
overall best conversion and the highest enantioselectivity (entry
isomers of the alcohol products in high yields and enantioselectiv-
8
ity. The above catalyst system proved to be incompatible with for-
mic acid or formate as hydride donors, and we were therefore
interested to investigate if the scope could be expanded towards
other alcohols. Herein we report on an efficient and enantioselec-
tive method for the asymmetric transfer hydrogenation of aryl al-
kyl ketones in ethanol.
2
), and 1-phenylethanol was formed in 97% ee in favor of the S-iso-
mer. In addition to the desired secondary alcohol, we observed the
formation of small amounts of side products which lowered the
chemoselectivity to 90%. These additional compounds were found
to be condensation products from the reaction between acetophe-
none and the formed acetaldehyde. Furthermore, monitoring the
ATH reaction using NMR, we observed that ethyl acetate was
We have previously demonstrated that aryl alkyl ketones can be
reduced enantioselectively in 2-propanol using a combination of
O
O
O
N
H
N
H
N
H
NH
OH
NH
OH
NH
OH
Boc
1
Boc
2
Boc
3
S
O
O
OH
N
N
H
N
H
H
NH
NH
OH
NH
Boc
4
Boc
5
Boc
6
Figure 1. Amino acid based ligands for asymmetric transfer hydrogenation with ruthenium and/or rhodium.

2
756
H. Lundberg, H. Adolfsson / Tetrahedron Letters 52 (2011) 2754–2758
Table 2
Ruthenium-catalyzed asymmetric reduction of acetophenone with various ligands
Table 3
a
Ruthenium-catalyzed asymmetric reduction of acetophenone with various substrate
concentrations
a
Entry
Metal
Ligand
Conversionb (%)
Selectivityb (%)
eec (%)
Entry Acetophenone
M)
Time
(h)
Conversionb
(%)
Selectivity
(%)
eec
(%)
1
2
3
4
5
6
7
8
Ru
Ru
Ru
Ru
Ru
Rh
Rh
Ru
1
2
2
3
3
4
5
6
83
46
93
77
98
82
90
98
90
78
90
68
95
96
96
80
97 (S)
93 (S)
92 (S)
92 (S)
88 (S)
77 (R)
90 (S)
80 (R)
b
(
d
1
2
3
0.5
1
2
2
3
2
83
82
69
90
85
81
97
96
95
d
d
a
d
The reactions were carried out under an N
conditions using acetophenone (0.8 mmol), [Ru(p-cymene)Cl
(1.1 mol %) and LiCl (10 mol %) at 40 °C in a 0.5 M solution with 1:1 EtOH (99%)/
THF.
2
atmosphere under anhydrous
d
2 2
]
(0.5 mol %), ligand
1
a
The reactions were carried out under an N
conditions using acetophenone (0.8 mmol), [Ru(p-cymene)Cl
0.5 mol %), the corresponding ligand (1.1 mol %) and LiCl (10 mol %) at 40 °C over
h in a 0.5 M solution with 1:1 EtOH (99%)/THF.
2
atmosphere under anhydrous
b
2
]
2
or [Rh(Cp*)Cl
2
]
2
Conversion and selectivity were determined by GLC analysis.
Enantiomeric excess was determined using GLC (CP Chirasil DEX CB).
c
(
2
b
Conversion and selectivity were determined by GLC analysis.
Enantiomeric excess was determined using GLC (CP Chirasil DEX CB).
c
d
1
mol % metal precursor and 2.2 mol % ligand.
[
2 2
Ru(p-cymene)Cl ] proved to be superior to all other combinations
evaluated (Table 2, entry 1).
One particular benefit from performing the reactions in ethanol
is the theoretical possibility of using higher substrate concentra-
tions. As seen in Table 3, the increase of [acetophenone] to 1 M
gave similar results with respect to conversion and enantioselec-
tivity as those obtained with a 0.5 M substrate concentration
(Table 3, entry 2). However, we observed a larger amount of
byproducts formed in addition to the desired alcohol, which favor
the use of the lower concentration. Further increase of the concen-
generated in the reaction mixture. This observation is in agreement
with the studies presented by Grützmacher.5
a,b
Having established that the ATH process could be efficiently
performed in ethanol, we screened a number of previously devel-
oped and successfully employed amino acid based ligands
7
,8
(
(
Fig. 1) in the Ru- and Rh-catalyzed reduction of acetophenone
Table 2). The catalyst based on ligand 1 in combination with
Table 4
Ruthenium-catalyzed asymmetric reduction of various aryl alkyl ketonesa
Entry
Substrate
Time (h)
Conversionb (%)
83
Selectivityb (%)
90
eec (%)
O
O
O
1
2
97 (S)
2
3
4
23
4
40
15
74
100
97
95 (S)
94 (S)
97 (S)
O
4
87
O
5
6
7
8
4
4
1
3
53
100
94
94 (S)
96 (S)
93 (S)
89 (S)
MeO
MeO
O
86
O
>99
98
94
F3C
F3C
O
77

H. Lundberg, H. Adolfsson / Tetrahedron Letters 52 (2011) 2754–2758
2757
Table 4 (continued)
Entry
Substrate
Time (h)
Conversionb (%)
Selectivityb (%)
eec (%)
O
9
3
89
88
94 (S)
91 (S)
O
O
O
1
0
3
95
90
Br
O
O
1
1
1
2
6
3
35
86
63
88
96 (S)
93 (S)
O
O
MeO
MeO
1
1
3d
22
89
59
88
92
94 (R)
95 (R)
OMe
OMe
MeO
MeO
4d
5
a
2 2 2
The reactions were carried out under an N atmosphere under anhydrous conditions using acetophenone (0.8 mmol), [Ru(p-cymene)Cl ] (0.5 mol %), ligand 1 (1.1 mol %)
and LiCl (10 mol %) at 40 °C in a 0.5 M solution with 1:1 EtOH (99%)/THF.
b
Conversion and selectivity were determined by GLC analysis.
Enantiomeric excess was determined using GLC (CP Chirasil DEX CB).
Ligand ent-1 (1.1 mol %) was employed.
c
d
tration resulted in lower conversion, selectivity and ee. The lower
conversion obtained at higher substrate concentration is some-
what contradictory, and can possibly be explained by lower cata-
lyst solubility in the reaction medium.
ing agent (hydride donor). A series of differently substituted
ketones were subjected to the optimized reaction conditions, and
the corresponding secondary alcohols were formed in moderate
to good yields and in enantioselectivities ranging from 89% to
97%. The successful switch from 2-propanol to ethanol should
allow for further use of this renewable hydride source in other
reduction reactions.
General procedure for the ATH of aryl alkyl ketones. To a 10 ml vial
2 2
equipped with a septum and stirring bar, [Ru(p-cymene)Cl )
(0.0024 g, 0.004 mmol), ligand 1 (0.0028 g, 0.0088 mmol), and LiCl
From the above optimizations we concluded that the overall
best reaction conditions for the ATH of acetophenone in ethanol
were: 40 °C using 1 mol % catalyst in a 1:1 mixture of ethanol
and THF, at a substrate concentration of 0.5 M.1 Employing these
reaction conditions, we evaluated a series of other aryl alkyl ke-
tones and the results are presented in Table 4.
1
In most of the reactions the secondary alcohol products were
formed in moderate to good yields, and with good to excellent
enantioselectivity. The chemoselectivity was in most cases >87%
(0.0034 g, 0.08 mmol) were added. The vial was sealed and the
2
atmosphere exchanged via 3 ꢀ vacuum/N cycles. The vial was
placed in an oil bath at 40 °C and dry THF (0.8 ml), 99% EtOH
(0.4 ml) and the substrate (0.8 mmol) were added. The mixture
was allowed to stir for 20 min, after which NaOtBu (0.0046 g,
0.048 mmol) dissolved in 99% EtOH (0.4 ml) was added. Aliquots
were removed and filtered through a small plug of silica before
analysis on chiral GC. Solid substrates were added to the vial at
the same time as the metal precursor and the ligand.
0
0
with 3 -trifluoromethylacetophenone and 4 -methylacetophenone
being the exceptions (Table 4, entries 8 and 11). We have previ-
ously observed that substrates possessing potential sterically hin-
dering groups on the alkyl chain of ketones, result in poor
conversions when the ATH reaction is performed in 2-propanol.
The same trend is valid for reactions carried out in ethanol as seen
by the poor conversion obtained in the reduction of 2-methylpro-
piophenone (Table 4, entry 3).
Acknowledgments
In conclusion, we have demonstrated that the combination of
[
Ru(p-cymene)Cl
2
]
2
and amino acid hydroxy-amide 1 efficiently
We are grateful for financial support from the Swedish Research
Council, the Carl Trygger Foundation, and the K & A Wallenberg
Foundation.
catalyzes the reduction of aryl alkyl ketones in a solvent mixture
of THF and ethanol, where the latter solvent also acts as the reduc-

2
758
H. Lundberg, H. Adolfsson / Tetrahedron Letters 52 (2011) 2754–2758
M.; Grützmacher, H. Eur. J. Inorg. Chem. 2009, 5561; (c) Maytum, H. C.;
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