Asymmetric transfer hydrogenation of ketones in 2-propanol catalyzed by arsinooxazoline-ruthenium(II) complex

Article abstract of DOI:10.1016/j.tetlet.2004.11.097

Chiral arsinooxazoline Ru(II) complex has been found to be an efficient catalyst for asymmetric transfer hydrogenation of aromatic ketones in 2-propanol. Secondary alcohols with up to 94% enantiomeric excess were obtained at a substrate/catalyst mole ratio of 1000:1. Asymmetric kinetic resolution has also been obtained with 1-arylalkanols at room temperature with 99% ee.

Full text of DOI:10.1016/j.tetlet.2004.11.097

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 503–505
Asymmetric transfer hydrogenation of ketones in 2-propanol
catalyzed by arsinooxazoline–ruthenium(II) complex
Duan-Ming Tan and Kin Shing Chan*
Department of Chemistry, Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug
Discovery and Synthesis, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
Received 6 September 2004; revised 4 November 2004; accepted 5 November 2004
Available online 7 December 2004
Abstract—Chiral arsinooxazoline Ru(II) complex has been found to be an efficient catalyst for asymmetric transfer hydrogena-
tion of aromatic ketones in 2-propanol. Secondary alcohols with up to 94% enantiomeric excess were obtained at a substrate/cat-
alyst mole ratio of 1000:1. Asymmetric kinetic resolution has also been obtained with 1-arylalkanols at room temperature with
9
9% ee.
Ó 2004 Elsevier Ltd. All rights reserved.
Enantioselective reduction of prochiral ketones to pro-
duce optically pure secondary alcohols via transfer
hydrogenation has achieved rapid progress during the
last decade by using organometallic complexes as cata-
The chiral 2-[2-(diphenylarsino)phenyl]-4-isopropylox-
6
azoline (1) (Fig. 1) is prepared by the ZnCl -catalyzed
2
reaction of (S)-2-amino-3-methyl-1-butanol and 2-
(diphenylarsino)-benzonitrile, which in turn is obtained
from Pd-mediated arsination of 2-cyanophenyl triflate.
Initial studies of the complex formed in situ from opti-
cally active 1 and RuCl (PPh ) in asymmetric transfer
1
–3
lysts.
2
The non-hazardous hydrogen donors such as
-propanol and formate can replace the dangerous dihy-
drogen in a more easily handled way. Catalytic chiral
Ru, Rh, and Ir complexes have shown high reactivity
and enantioselectivity for asymmetric transfer hydroge-
nation of prochiral ketones and imines. Most of the
effective chiral ligands provide P, N, or O atoms chelat-
ing to metal centers. Since only limited arsine ligands
2
3 3
hydrogenation of acetophenone with 2-propanol (Eq.
1) promoted by catalytic amounts of NaOH, revealed
slightly higher activity and enantioselectivity in giving
89% yield with 82% ee of (R)-1-phenylethanol than its
P,N analogue 2, which gives 83% yield and 73% ee in
4
,5
7
have been used for enantioselective catalytic reactions,
we would like to explore the use of chiral arsine com-
1 h.
6
plexes as catalysts for asymmetric transfer hydrogena-
tion and kinetic resolution via dehydrogenative
oxidation.
Various metal complexes with 1 were then screened to
search for optimal catalysis. At room temperature, ace-
tophenone was reduced slowly into 1-phenylethanol under
the catalysis of the complex of 1–RhCl Æ3H O in 2-
3
2
propanol. A lower yield of 27% was obtained after 115 h
with moderate enantioselectivity of 35% ee (Table 1,
entry 1). When [RhCl(cod)] , RhCl(PPh ) , IrCl Æ3H O,
2
3 3
3
2
and [IrCl(cod)] were used, no enantioselectivity was
found (Table 1, entries 2–5) at room or elevated temper-
ature. Complex 1–RuCl (PPh ) exhibited low activity
at room temperature with high ee of 83% (Table 1, entry
6). Reaction in refluxing 2-propanol (bp 82 °C) gave
faster rate without significant loss of enantioselectivity
2
O
As
N
2
3 3
Ph
Ph
1
Figure 1.
(82% ee, Table 1, entry 7) with a turnover number of
890. Longer reaction time led to a slightly higher yield
*
Corresponding author. Tel.: +852 2609 6376; fax: +852 2603 5057;
e-mail: ksc@cuhk.edu.hk
but diminished enantioselectivity of 92% yield and
58% ee, respectively (Table 1, entry 8).
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.097

504
D.-M. Tan, K. S. Chan / Tetrahedron Letters 46 (2005) 503–505
a
Table 1. Asymmetric transfer hydrogenation of acetophenone catalyzed by arsinooxazoline 1-metal complexes in 2-propanol (Eq. 1)
b
Yield /%
Entry
Metal salts (mol %)
RhCl Æ3H O (0.25)
[RhCl(cod)]
RhCl(PPh
IrCl Æ3H
[IrCl(cod)]
Lig 1/M
[PhCOCH
3
]/M
Temp/°C
Time/h
% Ee
1
2
3
4
5
6
7
8
9
3
2
1.5
1.5
1.4
1.5
1.4
1.4
1.4
1.4
1.4
1.4
1.5
1.4
0.5
Rt
82
Rt
Rt
Rt
Rt
82
82
82
82
82
82
115
19
19
18
20
89
2
27
40
16
49
29
17
89
92
35
0
2
(0.1)
0.33
0.4
3
)
3
(0.25)
0
3
2
O (0.25)
(0.25)
0.5
0.4
0
2
0
RuCl
RuCl
RuCl
RuCl
RuCl
RuCl
2
2
2
2
2
3
(PPh
3
3
3
3
3
)
)
)
)
)
3
3
3
3
3
(0.1)
(0.1)
(0.1)
(0.1)
(0.01)
0.33
0.33
0.33
0.33
0.33
0.33
0.33
83
82
58
(PPh
(PPh
(PPh
(PPh
16
2
c
c
78
87
10
11
12
11
4
38
29
51
18
8
Æ3H
(cod)]
2
O (0.1)
(1.0)
[RuCl
2
x
76
22
a
Complexes were formed in situ in 2-propanol by refluxing for 1 h unless otherwise noted.
Yields and % ee were determined by GC (Chiraldex B-PH). Absolute configurations determined by optical rotations of isolated alcohols were in R
b
forms.
equiv of water w.r.t. acetophenone were added.
c
2
Although the 1–RuCl (PPh ) catalyst was found to be
2
Table 2. Asymmetric transfer hydrogenation of ketones catalyzed by
a
3 3
1
–RuCl (PPh
2
3
)
3
in 2-propanol
readily poisoned in air, small amounts of water were
8
b
Time/h Yield /% % Ee
b
compatible. With the addition of 2 equiv of water, no
significant difference in reaction rate and enantioselec-
tivity were observed (Table 1, entry 9).
Entry Ar
R
1
2
3
4
5
6
7
8
9
Ph
Ph
CH
CH
3
1
88
26
68
86
97
86
90
68
65
82
94
90
84
79
80
85
82
78
2
CH
3
0.5
4
2-Cl–C
6
H
4
CH
3
0.5
1
ð1Þ
4-Cl–C
3-Cl–C
6
H
H
4
CH
CH
CH
CH
3
3
3
3
1
6
4
1
4-Br–C
4-F–C
6
H
4
2
0.5
6
H
4
a
Lower loading of 0.01 mol % equiv of 1–RuCl (PPh )
2
2 3 3
Substrate/ligand 1/RuCl (PPh ) /NaOH = 1000/1.4/1/25; [substrate] =
3 3
catalyst to substrate resulted in significant lower enantio-
selectivity of 18% ee (Table 1, entry 10). Longer reaction
time was required and likely caused the erosion of enan-
tiomeric excess due to competitive backward reaction.
0.4 M.
b
Yields and % ee were determined by GC (Chiraldex B-PH). Absolute
configurations determined by optical rotations of isolated alcohols
were all in R forms.
Other ruthenium salts such as RuCl3 or polymeric
[
lectivity than RuCl (PPh ) (Table 1, entries 11 and 12;
RuCl (cod)] gave much lower reactivity and enantiose-
2 x
Successful kinetic resolution via dehydrogenative oxida-
tion of 1-arylalkanols catalyzed by RuCl (PPh ) –1
2
3 3
2
3 3
8
% and 22% ee, respectively). Therefore, the presence of
PPh ligand is essential for high catalytic reactivity and
complex in alkaline acetone at room temperature was
10,11
3
achieved (Eq. 3).
Fast rates and high enantioselec-
9
enantioselectivity.
tivity of over 98% ee at over 50% conversion were ob-
tained with unhindered aryl alcohols (Table 3, entries
RuCl (PPh ) –1 complex in acetonitrile did not catalyze
3 3
2
1
–3). 1-(4-Chlorophenyl)ethanol (Table 3, entry 5) re-
any reduction of acetophenone when either HCOOH/
Et N or HCOONa was used as the hydrogen source.
acted more slowly than 1-phenylethanol. Presumably,
the electron withdrawing chlorine substituent decreases
3
ð2Þ
a
Table 3. Room temperature catalyzed kinetic resolution of alkanols
b
b
Entry
Ar
R
Time/h
% Conv.
% Ee
1
2
3
4
5
6
Ph
Ph
Ph
Ph
CH
CH
3
1
2
3
3
8
9
52
58
60
64
74
0
73
99
The results of catalytic transfer hydrogenation in 2-pro-
panol with RuCl (PPh ) –1 complex for a series of aro-
3
2
3 3
CH3
Et
>99.5
>99.5
98
matic ketones are listed in Table 2. The reaction of
phenyl ethyl ketone (Table 2, entries 2 and 3) showed
slower rate but higher enantioselectivity than that of
acetophenone (Table 2, entry 1). Up to 94% ee could
be achieved. Other ketones, including a more hindered
4-Cl–C H
6
4
4
CH3
CH
2-Cl–C
6
H
3
0
a
Substrate/ligand 1/RuCl
2
(PPh
3 3
) /NaOH = 500/1.0/1.4/1/12.5; [sub-
strate] = 0.25 M.
Conversion and % ee were absolute configuration (all R) were
determined by GC (Chiraldex B-PH).
b
2-chlorophenyl methyl ketone, gave similar yields and
ee as acetophenone (Table 2, entries 4–9).

D.-M. Tan, K. S. Chan / Tetrahedron Letters 46 (2005) 503–505
505
the rate of beta-hydride elimination step during the
catalysis. The sterically more hindered 1-(2-chlorophen-
yl)ethanol did not react even at elevated temperature.
Grants Committee of the Hong Kong Special Adminis-
trative Region, China, (Project no. [AoE/P-10/01]).
References and notes
ð3Þ
1
. For recent reviews: (a) Zassinovich, G.; Mestroni, G.;
Gladiali, S. Chem. Rev. 1992, 92, 1051–1069; (b) Noyori,
R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–102; (c)
Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999,
In summary, we have discovered that a new chiral N,As-
ligand–RuCl (PPh ) complex can catalyze the transfer
hydrogenation in alkaline 2-propanol and the kinetic
resolution of 1-phenylalkanols in alkaline acetone. Fur-
ther studies of asymmetric catalysis of chiral arsinooxazo-
line complexes are in progress.
2
3 3
1
0, 2045–2061.
. For mechanistic study: Sandoval, C. A.; Ohkuma, T.;
2
3
Muniz, K.; Noyori, R. J. Am. Chem. Soc. 2003, 125,
1
3490–13503.
. For recent reports: (a) Debono, N.; Besson, M.; Pinel, C.;
Djakovitck, L. Tetrahedron Lett. 2004, 45, 2235–2238; (b)
Hannedouche, J.; Clarkson, G. J.; Wills, M. J. Am. Chem.
Soc. 2004, 126, 986–987; (c) Wu, X.; Li, X.; Hems, W.;
King, F.; Xiao, J. Org. Biomol. Chem. 2004, 2, 1818–1821;
(d) Chen, Y. C.; Xue, D.; Deng, J.-G.; Cui, X.; Zhu, J.;
Jiang, Y.-Z. Tetrahedron Lett. 2004, 45, 1555–1558.
Typical procedure for the transfer hydrogenation:
RuCl (PPh ) (9.6 mg, 0.010 mmol) and As,N-ligand 1
2
3 3
(
5.9 mg, 0.014 mmol) (Caution: toxic) were mixed in
N -purged 2-propanol (10 mL) and heated to reflux
2
for 1 h. After cooled to rt, 1/10 of the resulting yellow
solution (1.0 mL) was transferred into a degassed solu-
tion of ketone (1 mmol) in 2-propanol (0.5 mL) and stir-
red for 30 min. Then degassed 2-propanol (1.0 mL)
containing of NaOH (1.0 mg, 0.025 mmol) was added
and the resulting solution was heated to reflux. Aliquots
were taken and pass through a small silica gel column
eluting with EtOAc before analysis by GC–MS using a
Chiraldex B-PH column. The absolute configuration
was determined by the sign of rotation of the isolated
product.
4
. (a) Nemoto, T.; Ohshima, T.; Shibasaki, M. Tetrahedron
2
003, 59, 6889–6897; (b) Dai, W.-M.; Wu, A.; Wu, H.
Tetrahedron: Asymmetry 2002, 13, 2187–2191.
. We are aware of one chiral As,N-ligand. Namyslo, J. C.;
Kaufmann, D. E. Synlett 1999, 114–116.
5
6
. Kwong, F. Y.; Lai, C. W.; Chan, K. S. J. Am. Chem. Soc.
001, 123, 8864–8865.
2
7. Langer, T.; Helmchen, G. Tetrahedron Lett. 1996, 37,
1381–1384.
8. Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org.
Lett. 2003, 5, 2103–2106.
9
. Sammakia, T.; Strangeland, E. L. J. Org. Chem. 1997, 62,
104–6105.
0. Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.;
6
1
Acknowledgements
Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 288–
290.
11. Caro, Y.; Toorrado, M.; Masaguer, C. F.; Ravi n˜ a, E.
Tetrahedron: Asymmetry 2003, 14, 3689–3696.
We would like to thank the support by the Area of
Excellence Scheme established under the University