Enantioselective transfer hydrogenation of ketones with planar chiral?ruthenocene-based phosphinooxazoline ligands

Article abstract of DOI:10.1016/j.tet.2008.01.108

1,2-Disubstituted planar chiral ruthenocene-based phosphinooxazoline ligands (Rc-PHOX, 3 and 4) were synthesized easily and applied in the transfer hydrogenation of ketones to chiral alcohols using 2-propanol as a source of hydrogen with excellent enantio

Full text of DOI:10.1016/j.tet.2008.01.108

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3561e3566
www.elsevier.com/locate/tet
Enantioselective transfer hydrogenation of ketones with planar
chiral ruthenocene-based phosphinooxazoline ligands
*
Delong Liu, Fang Xie, Xiaohu Zhao, Wanbin Zhang
School of Chemistry and Chemical Technology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
Received 20 September 2007; received in revised form 22 January 2008; accepted 29 January 2008
Available online 2 February 2008
Abstract
1,2-Disubstituted planar chiral ruthenocene-based phosphinooxazoline ligands (Rc-PHOX, 3 and 4) were synthesized easily and applied in
the transfer hydrogenation of ketones to chiral alcohols using 2-propanol as a source of hydrogen with excellent enantioselectivity and high
catalytic activity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Ruthenocene-based phosphinooxazoline ligands; Transfer hydrogenation; Planar chiral; Ketones
1. Introduction
catalysis, by comparing with their corresponding C2-symmetric
tetrasubstituted ruthenocene compounds 1.3a To the best of
our knowledge, only one precedent concerning 1,2-disubsti-
tuted ruthenocene-based chiral ligand was reported by Bolm.2c
Here, we report the synthesis of 1,2-disubstituted ruthenocene-
based phosphinooxazoline ligands 3 and 4 and their application
in the transfer hydrogenation of ketones to chiral alcohols.
Ferrocene-based chiral ligands designed for asymmetric
synthesis have attracted tremendous scientific interest over
the past decades.1 However, the ruthenocene-based chiral li-
gands have received much less attention and only few papers
appeared so far.2 Recently, we have developed the air-stable
C2-symmetric tetrasubstituted ruthenocene compounds 1
(Fig. 1) and applied them to palladium-catalyzed asymmetric
allylic substitution.3 Comparing with the corresponding ferro-
cene ligands,4 much higher catalytic activity and comparable
excellent enantioselectivity were observed. Then, the central
chirality was removed by the transformation of the oxazoline
moieties in the molecule to give ligands 2 (Fig. 1) with only
planar chirality, which also showed excellent effectiveness for
palladium-catalyzed asymmetric allylic substitution,5 compa-
rable with or better than their corresponding ferrocene analogs.6
In the course of developing new ruthenocene-based chiral
ligands, we want to examine whether the monometallic systems
would provide different reactivity patterns with bimetallic sys-
tems. So C1-symmetric ruthenocene-based phosphinooxazoline
ligands(Rc-PHOX,3and4, Fig. 1)weredesignedforasymmetric
2. Results and discussion
The compounds 3 can be easily prepared from ruthenocene
via six steps (Scheme 1). First, the FriedeleCrafts acylation of
ruthenocene was studied. Details are shown in Table 1.
The procedure according to literature7 did not give the sat-
isfactory result (Table 1, entry 1). Then, the molar ratios of the
aluminum trichloride and o-chlorobenzoyl chloride (OCBC)
for the acylation were studied carefully (Table 1, entries 2e
8), and the optimal ratio was ascertained (Table 1, entry 8).
Thus, ruthenocene treated with 1.5 equiv aluminum trichloride
and 10 equiv OCBC in dichloromethane overnight, followed
by hydrolysis to give 1-carboxylic ruthenocene 5 in 66% over-
all yield.
Then, this acid 5 reacted with 4 equiv oxalyl chloride in
dichloromethane to give 1-chlorocarbonyl ruthenocene 6.
Without any purification, 6 was used directly to react with
* Corresponding author. Tel./fax: þ86 21 54743265.
E-mail address: wanbin@sjtu.edu.cn (W. Zhang).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.108

3562
D. Liu et al. / Tetrahedron 64 (2008) 3561e3566
O
PPh2
O
CO2R
Ru
O
R
R
PPh2
PPh2
N
R
i-Pr
N
N
PPh2
PPh2
N
PPh2
Ru
Ru
Ru
O
CO2R
1 (a: R=i-Pr, b: R=t-Bu)
3 (a: R=i-Pr, b: R=t-Bu)
Figure 1.
4
2 (a: R=Me, b: R=Et)
Cl O
Cl
COOH
COCl
1)
, AlCl3 /CH2Cl2
(COCl)2
L-aminoalcohol
DIPEA
Ru
Ru
Ru
2) t-BuOK / DME / H2O
5
6
66%
HO
O
O
N
O
N
R
R
sec-BuLi / Me3SiCl
N
H
R
MsCl
DIPEA
SiMe3
Ru
Ru
Ru
7
8
9
68-79% from 5
n-BuLi / Ph2PCl
1) sec-BuLi / TMEDA
2) Ph2PCl
PPh2
O
PPh2
O
O
R
R
R
N
N
PPh2
N
TBAF
SiMe3
Ru
Ru
Ru
3
4
10
76-77%
74%
52% from 8 in "one pot"
(a: R=i-Pr, b: R=t-Bu)
Scheme 1.
1.1 equiv L-aminoalcohol and then treated with 1.5 equiv
methyl sulfonyl chloride in ‘one-pot’ to afford the 1-[(S)-4-
substituted-oxazolin-yl]-ruthenocene 8 in 68e79% overall
yield from 5.
Lithiation of 8 was initially investigated using n-BuLi in
THF followed by addition of chlorodiphenylphosphine
(Ph2PCl),8 but the reaction did not occur and only trace
amount of 3 was produced upon addition of TMEDA. This
reaction did not occur in Et2O under the above-mentioned con-
ditions. Finally, this reaction proceeded smoothly with sec-
BuLi and TMEDA in Et2O. Thus, 8 in Et2O was treated
with 1.3 equiv of sec-BuLi and 1.3 equiv of TMEDA for a pe-
riod of 2 h at ꢀ78 ꢁC and then 20 min at 0 ꢁC to ensure com-
plete dilithiation. The lithiated species of 8 was then quenched
with 1.3 equiv of Ph2PCl at 0 ꢁC. After stirred at 0 ꢁC for 3 h,
3 was obtained in 76e77% yield. To our delight, compounds 3
were obtained as the sole product and no 4 was observed.
In order to obtain 4, intermediate 10 should be prepared
first.8b,f,g Thus, the above lithiated species of 8 was quenched
with 1.3 equiv of trimethylchlorosilane at 0 ꢁC to give (S,Rp)-9
with the yield of 68%. Compound 10 was then obtained in
44% yield by treating 9 with 1.3 equiv of sec-BuLi in Et2O
at ꢀ78 ꢁC for a period of 2 h and then 20 min at 0 ꢁC, fol-
lowed by addition of Ph2PCl. The overall yield was 30%
from 8. Furthermore, without isolation, 9 could be directly
treated with Ph2PCl in ‘one-pot’ to give 10 with the overall
yield of 52% from 8. Compound 4 was then obtained in
Table 1
Effect of the amount of AlCl3 and OCBC on FriedeleCrafts acylation
Entry
AlCl3 (equiv)
OCBC (equiv)
Conversiona (%)
1b
2
3
4
5
6
7
8
a
1
1
3
13.9
21.5
66.3
65.4
29.2
28.4
77.5
85.5
1
1
10
15
1
1
1.5
3
1
1.5
1.5
5
10
Determined by 1H NMR.
According to Ref. 7.
b

D. Liu et al. / Tetrahedron 64 (2008) 3561e3566
3563
74% yield by treating 10 with TBAF (1 M in THF) under re-
flux for 20 h.
The effect of planar chirality was examined also.10 When
3a was replaced by 4, only 65.7% ee was obtained with the
same configuration of product (Table 2, entry 4). However,
high catalytic activity was also obtained since the reaction
almost completed within 5 min. This demonstrates that the
enantioselectivity in the reactions discussed above is mainly
determined by the central chirality of 1,2-disubstituted ruthe-
nocene-based ligands. To match planar and central chiralities
is essential for obtaining excellent asymmetric induction.
Meanwhile, the C2-symmetric tetrasubstituted P,N-chelate
1 was used in this H-transfer hydrogenation. High catalytic ac-
tivity and good enantioselectivity were also obtained (Table 2,
entry 5). But 1 gave somewhat lower enantioselectivity than
3a did.
Transfer hydrogenation using 2-propanol (IPA) as a source
of hydrogen is an attractive method for the reduction of ke-
tones to alcohols.9 The reaction utilizes inexpensive reagents,
is simple to perform, and does not require the use of reactive
metal hydrides or hydrogen. With the novel planar chiral li-
gands in hand, we tried to apply them in H-transfer hydroge-
nation of ketones (Scheme 2). The complexes of novel ligands
with Ru(II) showed excellent turnover and catalytic activity in
the reduction of acetophenone. Details are shown in Table 2.
OH
CH3
O
OH
CH3
+
+
(CH3)2CO
Ph
Ph
CH3
H3C
From aforementioned results, it was known that the ruthe-
nocene-based ligands also showed high catalytic activity and
much higher enantioselectivity for the H-transfer hydrogena-
tion of acetophenone, comparing with their corresponding fer-
rocene-based phosphinooxzoline ligands.12
In order to examine the steric and/or electric effect of the
substituent in the phenyl group of the substrate, several
substituted substrates were examined (Scheme 3). All reac-
tions showed high catalytic activity and the reactions com-
pleted within 5 min (Table 3).
Scheme 2.
Compound 3a was used as a chiral ligand in this hydroge-
nation, and high catalytic activity and good enantioselectivity
were obtained within 5 min (Table 2, entry 1). But the ee value
decreased with longer reaction time since this reaction is an
equilibration. The substituent R on the oxazolinyl ring had
much effect on the enantioselectivity and a bulkier group gave
a better ee value. When 3b with a tert-butyl group was used as
a chiral ligand, up to 96.8% ee was obtained (Table 2, entry
2). Temperature affected the enantioselectivity obviously, and
the ee value was enhanced to 99.9% if the temperature was
lowered from reflux to 40 ꢁC (Table 2, entry 3).
O
OH
CH3
OH
CH3
+
+
(CH3)2CO
Ar
CH3
H3C
Ar
o-ClC6H4COCH3, p-ClC6H4COCH3, p-MeC6H4COCH3
Ar=
Scheme 3.
Table 2
H-transfer reduction with IPA as hydrogen donora
Entry Ligand Temp (ꢁC) Time (min) Conversionb (%) eec,d (%)
It was shown that the steric hindrance played an important
1
3a
Reflux
5
10
20
30
45
60
5
98
99
99
99
99
99
93
99
99
98
98
38
99
99
99
99
98
99
99
99
99
88.5
81.2
76.2
74.8
67.7
66.8
96.8
95.8
94.8
93.8
93.5
99.9
65.7
58.5
33.5
30.2
83.3
80.6
77.4
70.3
68.7
role in determining the degree of the enantioselectivity of the
reaction: ortho-substituted acetophenone gave higher enantio-
meric excess than their para-substituted analogs (Table 3,
entries 1 and 2). On the other hand, electronic effects of the
aromatic ring substituents also seemed to have influence in
this case in the same way. When the substituent on the benzene
2
3b
Reflux
10
30
60
180
24 h
5
Table 3
H-transfer reduction with IPA as hydrogen donor using 3aa
3
4
3b
4
40
Reflux
Entry Substrate
Temp (ꢁC) Time (min) Conversionb (%) eec,d (%)
10
30
60
1
1
2
3
4
o-ClC6H4COCH3 Reflux
5
15
5
100
100
100
100
100
100
100
100
82.2
76.4
61.1
59.4
66.2
61.1
81.1
69.2
p-ClC6H4COCH3 Reflux
p-MeC6H4COCH3 Reflux
p-MeOC6H4COCH3 Reflux
5
1a
Reflux
15
5
5
10
30
60
15
5
15
a
a
Preparation of the catalyst: Ru(II)Cl2(PPh3)3 (1.0 mol %) and chiral ligand
(1.3 mol %) were dissolved in 2-propanol (5 mL) and the mixture was refluxed
under nitrogen atmosphere for 0.5 h before use.
Preparation of the catalyst: Ru(II)Cl2(PPh3)3 (1 mol %) and chiral ligand
(1.3 mol %) were dissolved in 2-propanol (5 mL) and the mixture was refluxed
under nitrogen atmosphere for 0.5 h before use.
b
b
Determined by 1H NMR.
Determined by GC with Varian Chiralsil-L-Val column.
Determined by 1H NMR.
Determined by GC with Varian Chiralsil-L-Val column.
c
c
d
d
Absolute configuration of product was assigned through comparison of the
sign of specific rotations with the literature data.11
Absolute configuration of product was assigned through comparison of the
sign of specific rotations with the literature data.12

3564
D. Liu et al. / Tetrahedron 64 (2008) 3561e3566
ring was changed to electron withdrawing group such as
chloro, the value of enantiomeric excess was decreased to
61.1% (Table 3, entry 2). However, better enantioselectivity
were obtained when strong electron donating substituted
groups such as methyl and methoxyl were located in the
para-position of the benzene ring (66.2 and 81.1% ee, respec-
tively, Table 3, entries 3 and 4).
d 4.64 (s, 5H), 4.83 (t, J¼2 Hz, 2H), 5.01 (t, J¼2 Hz, 2H),
7.28e7.55 (m, 3H), 7.99e8.05 (m, 1H).
To a 500 mL flask was added 2-chlorobenzoyl ruthenocene
(8.2 g, 22 mmol) and t-BuOK (9.9 g, 88 mmol) under N2
atmosphere. Dimethoxy ethane (DME, 220 mL) and water
(0.44 mL, 23 mmol) were added and the reaction mixture
was refluxed for 18 h. The mixture was diluted by water
(220 mL) and extracted with dichloromethane (200 mL) and
ethyl ether (200 mL). The aqueous phase was adjusted to
pH¼2 with hydrochloric acid followed by filtration to afford
gray solid 5 (4.65 g, 90%). 1H NMR (400 MHz, CDCl3):
d 4.63 (s, 5H), 4.76 (t, J¼2 Hz, 2H), 5.17 (t, J¼2 Hz, 2H).
3. Conclusion
In summary, we have developed the novel 1,2-disubstituted
ruthenocene-based phosphinooxazoline ligands 3 and 4 and
applied them in asymmetric H-transfer hydrogenation of ke-
tones. High catalytic activity and excellent enantioselectivity
have been observed. Based on the experimental results, the
enantioselectivity of this reaction is mainly determined by
the central chirality in the oxazoline ring. It is essential to
match planar and central chiralities to obtain excellent asym-
metric induction. Studies on the steric and/or electric effects
of the aromatic ring substituents show that they have nonne-
glectable effects on the enantioselectivity in this reaction.
4.2.2. 1-[(S)-4-Isopropyloxazolin-2-yl]-ruthenocene (8a)
1-Carboxylic ruthenocene (2.53 g, 10 mmol) was sus-
pended in dichloromethane (60 mL) followed by the addition
of oxalyl chloride (4.0 mL, 40 mmol) and pyridine (0.1 mL).
This mixture was refluxed for 2 h and then evaporated to dry-
ness. The residue was washed with ethyl ether and the organic
phase was evaporated to offer 1-chlorocarbonyl ruthenocene as
a yellow-green solid. The product was directly used in the next
step without any purification.
To a solution of (S)-(þ)-valinol (1.13 g, 11 mmol) and di-
isopropylethylamine (3.9 mL, 22 mmol) in 20 mL of dichloro-
methane was added dropwise the above 1-chlorocarbonyl
ruthenocence in 40 mL of dichloromethane under nitrogen at-
mosphere in ice-water bath. The reaction mixture was stirred
at room temperature overnight. To this solution was added
dropwise diisopropylethylamine (5.3 mL, 30 mmol) and meth-
ane sulfonyl chloride (1.2 mL, 15 mmol) for a period of
30 min at 0 ꢁC, and then the solution was stirred at room tem-
perature for 2 h. The resulting solution was washed with
chilled water (5 ꢁC) and then brine. The organic layer was
dried over Na2SO4 and then the solvent was evaporated in vac-
uum. The residue was purified on silica gel column chroma-
tography with ethyl acetate to afford pure product 8a (2.7 g,
79%) as a light yellow solid. [a]2D7 ꢀ79.26 (c 1.46, CHCl3);
1H NMR (400 MHz, CDCl3): d 0.88 (d, J¼6.4 Hz, 3H), 0.95
(d, J¼6.4 Hz, 3H), 1.79e1.91 (m, 1H), 3.92e4.02 (m, 2H),
4.20 (dd, J¼8.4, 9.2 Hz, 1H), 4.58 (s, 5H), 4.67 (br s, 2H),
5.09 (br s, 1H), 5.14 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d 18.17, 18.96, 32.39, 69.34, 71.04, 71.74 (5C),
72.08, 72.16, 74.79, 164.88; MS (MALDI): m/z 344 [Mþ1þ]
(100); HRMS calcd for C16H20NORu 344.0587, found
344.0583.
4. Experimental
4.1. General comments
All reactions were performed under a nitrogen atmosphere
and the workup was carried out in air. The reaction solvents
were distilled prior to use (tetrahydrofuran was distilled from
sodium-benzophenone ketyl, methanol and ethanol were dried
with magnesium, and dichloromethane was distilled from
CaH2). The commercially available reagents were used without
further purification. Melting points were measured on a XT-5
1
microscopic melting point apparatus and are uncorrected. H
NMR (400 MHz) spectra, 13C NMR (100 MHz) spectra, and
31P NMR (162 MHz) spectra were recorded on a Varian MER-
CURY plus-400 spectrometer. The ee values were determined
by GC using Varian Chiralsil-L-Val column.
4.2. Procedure for the preparation of ligands 3 and 4
4.2.1. 1-Carboxylic ruthenocene (5)
Ruthenocene (11.6 g, 50 mmol), 2-chlorobenzoyl chloride
(63 mL, 0.5 mol), and dichloromethane (100 mL) were added
to a 250 mL flask. The mixture was then cooled to 0e2 ꢁC,
followed by the addition of anhydrous aluminum trichloride
(8.7 g, 65 mmol) in three portions. The reaction mixture was
stirred at room temperature overnight. Water (20 mL) was
then added carefully and the mixture was stirred for another
2 h. Toluene (200 mL) was added to the flask and the mixture
was washed with 10% NaOH solution, water, and brine. The
organic phase was dried with anhydrous Na2SO4 and then
the solvent was evaporated in vacuum. The residue was puri-
fied on silica gel column chromatography with petrol ethere
ethyl acetate (20:1) to afford pure product 2-chlorobenzoyl
ruthenocene (13.5 g, 73%). 1H NMR (400 MHz, CDCl3):
4.2.3. 1-[(S)-4-tert-Butyloxazolin-2-yl]-ruthenocene (8b)
Following a procedure identical to what was described for
the preparation of 8a, compound 8b (68%) was afforded as
a light yellow solid. [a]2D7 ꢀ106.94 (c 1.02, CHCl3); 1H
NMR (400 MHz, CDCl3): d 0.90 (s, 9H), 3.83 (dd, J¼6.8,
10 Hz, 1H), 4.08e4.18 (m, 2H), 4.57 (s, 5H), 4.65 (br s,
2H), 5.05 (br s, 1H), 5.17 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d 26.03, 34.10, 68.48, 71.04, 71.08, 71.68, 72.03,
72.08, 74.86, 75.93, 164.81; MS (MALDI): m/z 358 [Mþ1þ]
(100); HRMS calcd for C17H22NORu 358.0736, found
358.0739.

D. Liu et al. / Tetrahedron 64 (2008) 3561e3566
3565
4.2.4. 2-[(S)-4-Isopropyloxazolin-2-yl]-(S)-1-diphenyl-
phosphino ruthenocene (3a)
NaHCO3 solution, water, and brine. The organic layer was dried
over Na2SO4 and then the solvent was evaporated in vacuum.
The residue was purified on silica gel column chromatography
with ethyl acetateepetrol ether (15:1) to afford pure product 9
(0.21 g, 68%) as a light yellow oil. [a]2D7 þ7.07 (c 0.36, CHCl3);
1H NMR (CDCl3, 400 Hz): d 0.22 (s, 9H), 0.86 (d, J¼6.4 Hz,
3H), 0.96 (d, J¼6.4 Hz, 3H), 1.72e1.81 (m, 1H), 3.85e3.95
(m, 2H), 4.17 (dd, J¼7.6, 8.8 Hz, 1H), 4.54e4.56 (m, 1H),
4.54 (s, 5H), 4.70 (t, J¼2.4 Hz, 1H), 5.17e5.18 (m, 1H); 13C
NMR (CDCl3, 100 Hz): d 0.8, 18.1, 19.2, 32.7, 69.4, 71.8
(5C), 72.8, 73.2, 74.7, 77.1, 78.6, 79.4, 165.1; MS (MALDI):
m/z 416 [Mþ1þ] (100); HRMS calcd for C31H37NOSiPRu
600.1415, found 600.1420.
To a solution of 8a (138 mg, 0.4 mmol) in ethyl ether (7 mL)
was added dropwise TMEDA (42 mL, 0.52 mmol)and asolution
of sec-BuLi (0.6 mL, 0.98 M in cyclohexane, 0.52 mmol) at
ꢀ78 ꢁC under nitrogen atmosphere. The reaction solution was
stirred at the temperature for 3 h and then at 0 ꢁC for 40 min.
Ph2PCl (0.10 mL, 0.52 mmol) was added dropwise at 0 ꢁC to
the solution containing dilithiated species generated from 8a,
and then the solution was stirred at room temperature for 3 h.
The reaction mixture was diluted with ethyl ether (20 mL)
and washed with saturated NaHCO3 solution, water, and brine.
The organic layer was dried over Na2SO4 and then the solvent
was evaporated in vacuum. The residue was purified on silica
gel column chromatography with ethyl acetateepetrol ether
(10:1) to afford pure product 3a (0.162 g, 77%) as a light yellow
solid. Mp 136e138 ꢁC; [a]D27 ꢀ97.51 (c 0.46, CHCl3); 1H NMR
(CDCl3, 400 Hz): d 0.67 (d, J¼6.8 Hz, 3H), 0.79 (d, J¼6.8 Hz,
3H), 1.64e1.68 (m, 1H), 3.67 (t, J¼7.6 Hz, 1H), 3.79e3.84 (m,
1H), 3.94 (br s, 1H), 4.16e4.20 (dd, J¼8, 10 Hz, 1H), 4.59 (s,
4.2.7. 1-[(S)-4-Isopropyloxazolin-2-yl]-2-(R)-diphenylphos-
phino)-5(S)-(trimethylsilyl)ruthenocene (10)
To a solution of 9 (87 mg, 0.23 mmol) in Et2O (10 mL) was
added sec-BuLi (0.3 mL, 0.98 M in cyclohexane, 0.3 mmol) at
ꢀ78 ꢁC under nitrogen atmosphere. The reaction solution was
stirred at the temperature for 2 h and then at 0 ꢁC for 30 min.
Ph2PCl (54 mL, 0.3 mmol) was added dropwise at 0 ꢁC to the so-
lutionandthenthesolutionwasstirredatroomtemperatureover-
night. The reaction mixture was diluted with ethyl ether (10 mL)
and washed with saturated NaHCO3 solution, water, and brine.
The organic layer was dried over Na2SO4 and then the solvent
was evaporated in vacuum. The residue was purified on silica
gel column chromatography with ethyl acetateepetrol ether
(15:1) to afford pure product 10 (60 mg, 44%) as a light yellow
solid. [a]2D7 þ51.77 (c 0.20, CHCl3); 1H NMR (CDCl3, 400 Hz):
d 0.22 (s, 9H), 0.58 (d, J¼6.4 Hz, 3H), 0.65 (d, J¼6.4 Hz, 3H),
1.42e1.50 (m, 1H), 3.79e3.89 (m, 2H), 3.96 (dd, J¼8.4,
10 Hz, 1H), 4.01 (d, J¼2.4 Hz), 4.54 (d, J¼2.4 Hz), 4.56 (s,
5H), 7.23e7.47 (m, 10H); 13C NMR (CDCl3, 100 Hz): d 1.1,
18.2, 18.4, 32.8, 69.5, 72.0, 72.6, 73.2 (5C), 74.0, 78.3, 78.4,
79.0, 81.0, 127.9, 128.0, 128.14, 128.15, 128.2, 128.3, 128.8,
132.5, 132.6, 135.0, 135.2, 139.0, 139.2, 140.0, 140.1, 164.3,
164.4; 31P NMR (CDCl3, 162 Hz, 85% H3PO4): d ꢀ15.26; MS
(MALDI): m/z 528 [Mþ1þ] (100); HRMS calcd for C28H29NO-
PRu 528.1025, found 528.1036.
5H), 4.67 (br s, 1H), 5.31 (br s, 1H), 7.27e7.40 (m, 10H); 13
C
NMR (CDCl3, 100 Hz): d 17.7, 18.7, 32.2, 69.7, 72.1, 72.8,
74.3, 73.1 (5C), 76.5, 76.6, 79.5 (d, J¼18 Hz), 81.7 (d,
J¼17.6 Hz), 128.0, 128.1, 128.2, 128.3, 128.4, 128.9, 132.6,
132.8, 134.6, 134.8, 138.3 (d, J¼13.6 Hz), 139.8 (d,
J¼14.5 Hz); 31P NMR (CDCl3, 162 Hz, 85% H3PO4):
d ꢀ14.94; MS (MALDI): m/z 528 [Mþ1þ] (100); HRMS calcd
for C28H29NOPRu 528.1025, found 528.1041.
4.2.5. 1-[(S)-4-tert-Butyloxazolin-2-yl]-(S)-1-diphenyl-
phosphino ruthenocene (3b)
Following a procedure identical to that described for the
preparation of 3a, compound 3b (76%) was afforded as a light
yellow solid. Mp 176e178 ꢁC; [a]D27 ꢀ142.98 (c 0.13, CHCl3);
1H NMR (CDCl3, 400 Hz): d 0.77 (s, 9H), 3.69 (dd, J¼7.2,
10 Hz, 1H), 3.85 (dd, J¼7.6, 8.4 Hz, 1H), 3.95 (br s, 1H),
4.10 (dd, J¼8.4, 10 Hz, 1H), 4.59 (s, 5H), 4.66 (br s, 1H),
5.28 (br s, 1H), 7.27e7.38 (m, 10H); 13C NMR (CDCl3,
100 Hz): d 25.86, 34.00, 68.55, 72.75, 73.15 (5C), 74.24,
74.25, 76.11, 76.61, 76.65, 128.06, 128.13, 128.22, 128.28,
128.80, 138.51, 138.63, 139.96, 140.08, 163.71, 163.72; 31P
NMR (CDCl3, 162 Hz, 85% H3PO4): d ꢀ15.42. MS
(MALDI): m/z 542 [Mþ1þ] (100); HRMS calcd for
C29H31NOPRu 542.1181, found 542.1165.
4.2.8. 1-[(S)-4-Isopropyloxazolin-2-yl]-2-(R)-diphenylphos-
phino)-5(S)-(trimethylsilyl)ruthenocene (10), preparation
in ‘one-pot’ from 8
To a solution of 8a (276 mg, 0.8 mmol) in ethyl ether
(10 mL) was added dropwise TMEDA (0.17 mL, 1.04 mmol)
and a solution of sec-BuLi (1.06 mL, 0.98 M in cyclohexane,
1.04 mmol) at ꢀ78 ꢁC under nitrogen atmosphere. The reaction
solution was stirred at the temperature for 3 h and then at 0 ꢁC
for 20 min. Chlorotrimethylsilane (0.13 mL, 1.04 mmol) was
added dropwise at 0 ꢁC to the solution containing dilithiated
species generated from 8a, and then the solution was stirred
at room temperature for 3 h.
To the above reaction mixture was added THF (10 mL) and
then cooled to ꢀ78 ꢁC again. n-BuLi (0.4 mL, 2.89 M in cyclo-
hexane, 1.04 mmol) was added carefully and the mixture was
stirred at the temperature for 2 h and then at 0 ꢁC for 2 h. Ph2PCl
(0.19 mL,1.04 mmol)wasaddeddropwiseat0 ꢁCtothesolution
4.2.6. 1-[(S)-4-Isopropyloxazolin-2-yl]-2-(S)-(trimethylsilyl)-
ruthenocene (9)
To a solution of 8a (276 mg, 0.8 mmol) in ethyl ether
(10 mL) was added dropwise TMEDA (0.17 mL, 1.04 mmol)
and a solution of sec-BuLi (1.06 mL, 0.98 M in cyclohexane,
1.04 mmol) at ꢀ78 ꢁC under nitrogen atmosphere. The reaction
solution was stirred at the temperature for 3 h and then at 0 ꢁC
for 20 min. Chlorotrimethylsilane (0.13 mL, 1.04 mmol) was
added dropwise at 0 ꢁC to the solution containing dilithiated
species generated from 8a, and then the solution was stirred
at room temperature overnight. The reaction mixture was di-
luted with ethyl ether (20 mL) and washed with saturated

3566
D. Liu et al. / Tetrahedron 64 (2008) 3561e3566
and then the solution was stirred at room temperature overnight.
The reaction mixture was diluted with ethyl ether (20 mL) and
washed with saturated NaHCO3 solution, water, and brine. The
organic layer was dried over Na2SO4 and then the solvent was
evaporated in vacuum. The residue was purified on silica gel
column chromatography with ethyl acetateepetrol ether (15:1)
to afford pure product 10 (0.22 g, 52%) as a light yellow solid.
References and notes
1. (a) Ferrocenes; Hayashi, T., Togni, A., Eds.; VCH: Weinheim, Germany,
1995; (b) Metallocenes; Togni, A., Haltermann, R. L., Eds.; VCH: Wein-
heim, Germany, 1998; (c) Dai, L. X.; Tu, T.; You, S. L.; Deng, W. P.; Hou,
X. L. Acc. Chem. Res. 2003, 36, 659e667; (d) Colacot, T. J. Chem. Rev.
2003, 103, 3101e3118; (e) Arrays, R. G.; Adrio, J.; Carretero, J. C.
Angew. Chem., Int. Ed. 2006, 45, 7674e7715.
2. (a) Hayashi, T.; Ohno, A.; Lu, S.-J.; Matsumoto, Y.; Fukuyo, E.; Yanagi,
K. J. Am. Chem. Soc. 1994, 116, 4221e4226; (b) Abbenhuis, H. C. L.;
Burckhardt, U.; Gramlich, V.; Martelletti, A.; Spencer, J.; Steiner, I.;
Togni, A. Organometallics 1996, 15, 1614e1621; (c) Bolm, C.; Her-
manns, N.; Kesselgruber, M.; Hildebrand, J. P. J. Organomet. Chem.
2001, 624, 157e161; (d) Herberich, G. E.; Englert, U.; Wirth, T. Eur.
J. Inorg. Chem. 2005, 4924e4935.
4.2.9. 2-[(S)-4-Isopropyloxazolin-2-yl]-(R)-1-diphenylphos-
phino ruthenocene (4)
To the silyl compound 10 (0.25 g, 0.42 mmol) in THF (5 mL)
was added tetrabutylammonium fluoride (1 M, 5 mL). Then the
resulting reaction mixture was heated to reflux for 20 h. The
mixture was extracted with ethyl ether (10 mLꢂ2) and washed
with water and brine. The organic layer was dried over Na2SO4
and then the solvent was evaporated in vacuum. The residue was
purified on silica gel column chromatography with ethyl ace-
tateepetrol ether (15:1) to afford pure product 4 (0.22 g, 74%)
as a light yellow solid, mp 169e171 ꢁC. [a]D27 þ130.47 (c
0.46, CHCl3); 1H NMR (CDCl3, 400 Hz): d 0.62 (d,
J¼6.8 Hz, 3H), 0.64 (d, J¼6.8 Hz, 3H), 1.51e1.57 (m, 1H),
3.86e4.00 (m, 3H), 4.60 (s, 5H), 4.67 (br s, 1H), 5.30 (br s,
1H), 7.26e7.42 (m, 10H); 13C NMR (CDCl3, 100 Hz): d 18.0,
18.1, 32.6, 69.7, 72.1, 72.5, 73.1 (5C), 74.4, 76.8, 76.9, 79.2
(d, J¼18.3 Hz), 81.5 (d, J¼16 Hz), 128.0, 128.1, 128.2, 128.3,
128.4, 128.8, 132.6, 132.9, 134.8, 135.0, 138.4 (d, J¼12 Hz),
139.6 (d, J¼11.5 Hz); 31P NMR (CDCl3, 162 Hz, 85%
H3PO4): d ꢀ15.74: MS (MALDI): m/z 528 [Mþ1þ] (100);
HRMS calcd for C28H29NOPRu 528.1025, found 528.1036.
3. (a) Liu, D. L.; Xie, F.; Zhang, W. Tetrahedron Lett. 2007, 48, 585e588;
(b) Liu, D. L.; Xie, F.; Zhang, W. Tetrahedron Lett. 2008, 49, 1012e1015.
4. (a) Zhang, W.; Adachi, Y.; Hirao, T.; Ikeda, I. Tetrahedron: Asymmetry
1996, 7, 451e460; (b) Zhang, W.; Hirao, T.; Ikeda, I. Tetrahedron Lett.
1996, 37, 4545e4548.
5. Liu, D. L.; Xie, F.; Zhang, W. J. Org. Chem. 2007, 72, 6992e6997.
6. (a) Zhang, W.; Kida, T.; Nakatsuji, Y.; Ikeda, I. Tetrahedron Lett. 1996,
37, 7995e7998; (b) Zhang, W.; Shimanuki, T.; Kida, T.; Nakatsuji, Y.;
Ikeda, I. J. Org. Chem. 1999, 64, 6247e6251.
7. Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen, H. Pure Appl. Chem.
1997, 69, 513e518.
8. (a) Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org. Chem. 1995, 60,
10e11; (b) Richards, C. J.; Damalidis, T.; Hibbs, D. E.; Hursthouse,
M. B. Synlett 1995, 74e76; (c) Nishibayashi, Y.; Uemura, S. Synlett
1995, 79e81; (d) Sammakia, T.; Latham, H. A. J. Org. Chem. 1995,
60, 6002e6003; (e) Sammakia, T.; Latham, H. A. J. Org. Chem. 1996,
61, 1629e1635; (f) Richards, C.; Mulvaney, A. W. Tetrahedron Lett.
1996, 7, 1419e1430; (g) Ahn, K. H.; Cho, C. W.; Baek, J.; Lee, S.
J. Org. Chem. 1996, 61, 4937e4943; (h) Nishibayashi, Y.; Segawa, K.;
Arikawa, Y.; Ohe, K.; Hidai, M.; Uemura, S. J. Organomet. Chem.
1997, 545, 381e389.
4.3. General procedure for asymmetric transfer
hydrogenation
9. Selected reviews, see: (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res.
1997, 30, 97e102; (b) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry
1999, 10, 2045e2061; (c) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000,
33, 336e345; (d) Clapham, S. E.; Hadzovic, A.; Morris, R. H. Coord.
Chem. Rev. 2004, 248, 2201e2237; (e) Gladial, S.; Alberico, E. Chem.
Soc. Rev. 2006, 35, 226e236. Selected papers, see: (f) Reetz, M. T.; Li,
X. J. Am. Chem. Soc. 2006, 128, 1044e1045; (g) Cortez, N. A.;
Rodrguez-Apodaca, R.;Aguirre,G.;Parra-Hake,M.;Coleb,T.;Somanathan,
R. Tetrahedron Lett. 2006, 47, 8515e8518; (h) Zaitsev, A. B.; Adolfs-
son, H. Org. Lett. 2006, 22, 5129e5132.
10. (a) You, S.-L.; Zhou, Y.-G.; Hou, X.-L.; Dai, L.-X. Chem. Commun. 1998,
2765e2766; (b) You, S.-L.; Hou, X.-L.; Dai, L.-X. Tetrahedron: Asym-
metry 2000, 11, 1495e1500; (c) You, S.-L.; Hou, X.-L.; Dai, L.-X.; Yu,
Y.-H.; Xia, W. J. Org. Chem. 2002, 67, 4684e4695; (d) Muniz, K.;
Bolm, C. Chem.dEur. J. 2000, 6, 2309e2316; (e) Bolm, C.; Muniz-
Fernandez, K.; Seger, A.; Raabe, G.; Guenther, K. J. Org. Chem. 1998,
63, 7860e7867.
Under an atmosphere of argon, 1 mol % of [RuCl2(PPh3)3]
and 1.3 mol % of chiral ligand were dissolved by heating to
reflux in degassed dry 2-propanol (5 mL) for 30 min. Then
a solution of the ketone (4 mmol) in degassed dry 2-propanol
(3 mL) was added and the mixture was refluxed for 15 min.
The reaction was started by addition of a solution of
t-BuOK in 2-propanol (0.2 M, 0.2 mL) and refluxed. The
above reaction mixture was concentrated under reduced pres-
sure. The residue was determined by 1H NMR directly to give
the percent conversion and purified on silica gel column chro-
matography with EtOAc to afford pure product for the deter-
mination of ee value by HPLC.
11. Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.; Murata, K.;
Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1998, 120, 13529e13530.
Acknowledgements
12. (a) Sammakia, T.; Stangeland, E. L. J. Org. Chem. 1997, 62, 6104e
6105; (b) Arikawa, Y.; Ueoka, M.; Matoba, K.; Nishibayashi, Y.;
Uemura, S. J. Organomet. Chem. 1999, 572, 163e168; (c) Nishibayashi,
Y.; Takei, I.; Uemura, S.; Hidai, M. Organometallics 1999, 18,
2291e2293.
This work was supported by the National Natural Science
Foundation of China (No. 20572070) and Nippon Chemical
Industrial Co., Ltd.