A novel D2-symmetrical chiral tetraoxazoline ligand for highly enantioselective hydrosilylation of aromatic ketones

Article abstract of DOI:10.1002/adsc.201000018

A novel D₂-symmetrical chiral tetraoxazoline ligand was synthesized from 1,2,4,5-benzenetetracarboxylic acid and L-valinol via a one-pot reaction, and the asymmetric hydrosilylation of aromatic ketones was carried out in dichloromethane in the presence of 1.0mol% of a bivalent copper ion catalyst with the tetraoxazoline to give optically active secondary alcohols. The chiral catalyst showed excellent activities and enantioselectivities in the hydrosilylation of aryl ketones with up to 99% ee.

Full text of DOI:10.1002/adsc.201000018

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DOI: 10.1002/adsc.201000018
A Novel D2-Symmetrical Chiral Tetraoxazoline Ligand for Highly
Enantioselective Hydrosilylation of Aromatic Ketones
Wei Jie Lia,* and Sheng Xiang Qiua
a
Program for Natural Product Chemical Biology & Drug Discovery, South China Botanical Garden, Chinese Academy of
Sciences, Guangzhou 510650, Peopleꢀs Republic of China
Fax : (+86)-20-37081190; phone: (+86)-20-37252958; e-mail: weijieli1688@yahoo.com.cn
Received: January 8, 2010; Revised: March 25, 2010; Published online: April 22, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000018.
Abstract: A novel D2-symmetrical chiral tetraoxa-
zoline ligand was synthesized from 1,2,4,5-benzene-
tetracarboxylic acid and l-valinol via a one-pot re-
action, and the asymmetric hydrosilylation of aro-
matic ketones was carried out in dichloromethane
in the presence of 1.0 mol% of a bivalent copper
ion catalyst with the tetraoxazoline to give optically
active secondary alcohols. The chiral catalyst
showed excellent activities and enantioselectivities
in the hydrosilylation of aryl ketones with up to
99% ee.
trast to the great success of mono- or bis-oxazolines,
the development and application of polyoxazolines
are rather limited due to synthetic difficulties.[6] In
our efforts to develop superior catalysts which are
cheap, easy to access, air-stable, and water-tolerant,
we considered the improvement of bisoxazoline 1 into
the D2-symmetrical tetraoxazoline 2 (Figure 1), for
Keywords: aromatic ketones; asymmetric catalysis;
copper; hydrosilylation; tetraoxazoline
Figure 1. Structures of chiral oxazolines.
Enantiomerically pure chiral alcohols are key inter-
mediates in the synthesis of numerous biologically the following reasons: (i) compared with C2-symmetri-
active molecules.[1] For this reason, much effort has cal bisoxazoline 1, selective coordination of four ni-
been made to develop efficient techniques for the trogen atoms of tetraoxazoline 2 to the two metallic
asymmetric reduction of prochiral ketones in the last centers induce a more tunable D2-symmetrical chiral
30 years. The catalytic asymmetric reduction of pro- space to shield reactive sites; (ii) tetradentate ligand 2
chiral ketones as a direct route to enantiomeric alco- has a benzene ring and four oxazoline rings to form
hols is among the most attractive, and various strat- four cavities, and its four nitrogen atoms may selec-
egies have been developed accordingly.[2] Although tively coordinate with two metal cations, it is expected
intensive studies have been focused on the asymmet- to increase the stability of active intermediates with
ric hydrogenation that shows excellent enantioselec- respect to ordinary bidentate bisoxazolines. Thus, the
tivities for a wide range of simple ketones,[3–5] asym- metal complex may be tolerant of moisture, and it is
metric hydrosilylation as a desirable alternative has possible to improve the catalytic activity. In this arti-
also attracted much attention, owing to the mild reac- cle, we report our preliminary results on this subject.
tion conditions used and technical simplicity.[4] Since
The tetraoxazoline 2 can be easily synthesized from
the early reports three decades ago, the asymmetric 3 and l-valinol via a one-pot reaction (Scheme 1).
hydrosilylation of prochiral simple ketones catalyzed Compound 3 was refluxed with l-valinol in DMF
by complexes with oxazoline-based ligands has been through water deprivation to afford the desired tet-
extensively explored.[5] But, up to now, most of these raoxazoline 2 as a white solid in 92% yield.
reactions were routinely conducted by complexes
Although Star et al. have synthesized bisoxazoline
with mono- or bis-oxazoline ligands.[5] In sharp con- 1,[7] the asymmetric hydrosilylation of ketones cata-
Adv. Synth. Catal. 2010, 352, 1119 – 1122
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Wei Jie Li and Sheng Xiang Qiu
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Scheme 1. Synthesis of 1,2,4,5-tetraACHTNUTRGNEUNG[(4’S)-isopropyloxazolin-2’-yl]benzene from 1,2,4,5-benzenetetracarboxylic acid.
lyzed by complexes with bisoxazoline 1 has been not was prolonged to 40 h (Table 1, entry 1). To our de-
reported in the literature. To examine if our design is light, we found that the reaction proved to be temper-
operative, we tried the asymmetric hydrosilylation of ature-dependent. When the reaction temperature was
aryl ketones using the newly designed tetraoxazoline decreased from 40 to À308C, the ee value of 1-phe-
2/CuF2 complex as the chiral catalyst. We were nylethanol 5a increased from 80 to 99% (Table 1, en-
pleased to find that the catalytic activity was compa- tries 1–4). As for solvent effects, the choice of the sol-
rable to that of bisoxazoline 1/CuF2 and the enantio- vent has a significant effect on both the enantioselec-
selectivity of the reaction of acetophenone 4a with di- tivity and the yield. Dichloromethane was found to
phenylsilane was enhanced greatly (Table 1, entry 2 give the best results (Table 1, entry 2 vs. entries 5–7).
vs. entry 11).
Slightly lower enantioselectivities were obtained in
The asymmetric hydrosilylation of acetophenone 4a chloroform and 1,2-dichloroethane, and the enantio-
with diphenylsilane proceeded slowly at À308C, and selectivity and yield decreased in THF (Table 1,
the yield was only 75%; even when the reaction time entry 5). Catalyst concentrations were generally em-
ployed at 1.0 mol%, relative to substrate acetophe-
none, although loadings as low as 0.1 mol% could be
Table 1. Enantioselective Cu(II)-catalyzed hydrosilylation of
acetophenone.[a]
used, whereby a longer reaction time was required
(Table 1, entry 8). A higher catalyst loading of
2.0 mol% works well but the ee value of 5a showed
no significant improvement (Table 1, entry 10).
It is noteworthy that the tetraoxazoline 2/CuF2
complex is an air- and water-stable compound. It en-
hanced the reaction rate without loss of enantioselec-
tivity even when the reaction was carried out under
an air atmosphere (Table 1, entry 12 vs. entry 2).
Entry Solvent
t
T
Loading
Yield
[%][e]
ee
[h] [8C] [mol%][c]
[%][g]
The high yield and excellent enantioselectivity en-
couraged us to further evaluate the generality of this
reaction by investigating a variety of structurally dif-
ferent ketones and diphenylsilane in air (Table 2). Ar-
omatic ketones with diphenylsilane worked well to
afford the desired products in excellent yields, and
enantiomeric excesses ranging from 86 to 99% were
obtained (entries 1–8). The reactions of ortho-substi-
tuted aromatic ketones with diphenylsilane resulted
in lower enantioselectivities (entries 3 and 4), and a
similar trend was observed for the substrate with a
bulkier alkyl group at the carbonyl unit (entry 1).
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
40 À30 1.0
10 À5 1.0
75
90
95
97
73
84
86
76
83
92
79
94[f]
99
99
89
80
83
91
89
82
90
99
76
98
5
3
r.t.
40
1.0
1.0
10 À5 1.0
[b]
C2H4Cl2 10 À5 1.0
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10 À5 1.0
48 À5 0.1
10 À5 0.5
10 À5 2.0
10 À5 1.0[d]
10 À5 1.0
9
10
11
12
[a]
The catalst was prepared in situ by refluxing CuF2 and para-Substituted aromatic ketones were reduced to
ligand 2 in 5 mL of solvent.
C2H4Cl2 is 1,2-dichloroethane.
Loading: catalyst/PhCOMe (molar ratio).
The ligand is bisoxazoline 1.
Conditions: PhCOMe (2.0 mmol), Ph2SiH2 (3.2 mmol),
solvent (8.0 mL). The reactions were carried out under
the protection of a nitrogen atmosphere.
Performed under an air atmosphere.
Enantiomeric excess was determined by HPLC. All abso-
lute configurations were determined as S by optical rota-
tion measurements.
secondary alcohols with high enantioselectivities in
most cases (entries 5–8).
[b]
[c]
[d]
[e]
The high ee values obtained with l-valinol-derived
tetraoxazoline 2 are rather intriguing. Although its
catalytic mechanism on the asymmetric hydrosilyla-
tion of aromatic ketones is not yet clear at this stage,
all the above experimental results provide obvious
proof of this catalyst. In sharp contrast to the bisoxa-
zoline 1/CuF2 complex, the catalytic system with the
tetraoxazoline 2 and CuF2 may adopt the proposed
[f]
[g]
1120
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Adv. Synth. Catal. 2010, 352, 1119 – 1122

A Novel D2-Symmetrical Chiral Tetraoxazoline Ligand for Highly Enantioselective Hydrosilylation
Table 2. Asymmetric hydrosilylation of aromatic ketones
catalyzed by ligand 2 and CuF2 in air.
Experimental Section
General Remarks
Melting points were determined on an X-6 precision melting
point apparatus equipped with a polarization microscope.
13
1H and
C NMR spectra were measured on a Bruker
DRX-400 NMR spectrometer or a Bruker Avance DPX300
NMR spectrometer, using TMS as internal standard. Mass
spectra were taken on an LCQ DECA XP LC/MS system.
Elemental analyses were carried out on a Perkin–Elmer
240C elemental analyzer. Optical rotation values were mea-
sured on a Polartronic HNQW 5 polarimeter. The enantio-
meric excess (ee) was determined by HPLC analysis with
chiral stationary phases on an Agilent HP-1100 HPLC in-
strument.
All solvents used for the synthesis were of analytical
grade and were dried and freshly distilled under a nitrogen
atmosphere prior to use. 1,2,4,5-Benzenetetracarboxylic acid
and l-valinol were purchased from Alfa Aesar Co. Other re-
agents were of all analytical grade.
Entry Ketone Ar
R
t
Yield ee
[h] [%][a] [%][b]
1
2
3
4
5
6
7
8
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
2’-naphthyl CH3
2-CH3C6H4 CH3
2-ClC6H4
4-CH3C6H4 CH3
4-ClC6H4
4-BrC6H4
C2H5 12
87
85
81
83
86
90
92
94
89
98
86
87
93
94
96
99
16
10
10
10
8
CH3
CH3
CH3
8
6
4-NO2C6H4 CH3
[a]
Conditions:
catalyst/ketone=1.0 mol%,
ketone
(2.0 mmol), Ph2SiH2 (3.2 mmol), CH2Cl2 (8.0 mL), À58C.
Enantiomeric excess was determined by HPLC. All abso-
lute configurations were determined as S by optical rota-
tion measurements.
[b]
Preparation of 1,2,4,5-TetraACTHNUTRGNEUGN[(4’S)-isopropyloxazolin-
2’-yl]benzene (2)
To a three-neck flask equipped with a water segregator, a
reflux condenser and a magnetic stirring bar were added
1.27 g (5.0 mmol) of 1,2,4,5-benzenetetracarboxylic acid,
2.06 g (20.0 mmol) of l-valinol and 40 mL of DMF. The mix-
ture was refluxed with continuous removal of water for 10 h.
After cooling to room temperature, DMF was removed
under reduced pressure and the residue was purified by
silica gel column chromatography with dichloromethane as
eluant to afford the pure desired compound as a white solid;
yield: 2.40 g (92%); mp 214.5–215.58C; [a]2D0: À83.5 (c 1.0,
Figure 2. Transition structures of asymmetric hydrosilylation
of aromatic ketones.
1
EtOH); H NMR (400 MHz, CDCl3): d=0.86 (d, J=6.4 Hz,
12H), 1.09 (d, J=6.4 Hz, 12H), 2.42–2.45 (m, 4H), 3.94–
3.97 (m, 4H), 4.04–4.08 (m, 4H), 4.17 (dd, J1 =8.4 Hz, J2 =
18.8 Hz, 4H), 8.26 (s, 2H); 13C NMR (400 MHz,
CD3COCD3): d=19.5, 19.6, 27.6, 59.7, 62.1, 117.2, 137.1,
166.9; ESI-MS: m/z (%)=523 ([M+H]+, 100); anal. calcd.
for C30H42N4O4: C 68.94, H 8.10, N 10.72; found: C 68.82, H
8.16, N 10.60.
transition state model shown below (Figure 2) to sup-
port all the experimental observations and to be con-
sistent with the S absolute configuration for all secon-
dary alcohol products. The diphenylsilane could only
approach the re-face of the aromatic ketones due to
steric hindrance.
General Experimental Procedure for Hydrosilylation
In conclusion, we have synthesized the new D2-
symmetrical chiral tetraoxazoline 2 in high yield from
1,2,4,5-benzenetetracarboxylic acid and l-valinol via a
one-pot reaction, and have demonstrated that tetra-
ACHTUNGTRENNUNGoxazoline 2 has the ability to achieve high enantiose-
lectivity in the asymmetric hydrosilylation of aromatic tion of the addition, the reaction mixture was stirred in air
The ligand 2 (0.02 mmol) and CuF2 (0.04 mmol) were mixed
in 5 mL CH2Cl2 and refluxed for 30 min, and cooled to
À58C, then ketone (2.0 mmol) was added to the above mix-
ture. Thereafter, a solution of diphenylsilane (3.2 mmol) in
3 mL CH2Cl2 was added dropwise at À58C. After comple-
at the same temperature until the ketone had disappeared.
The reaction solution was quenched with methanol
(1.0 mL), and then acidified with dilute hydrochloric acid at
08C and the organic layer was separated. The aqueous layer
was extracted with diethyl ether or dichloromethane, and
the organic layers were combined and dried with anhydrous
Na2SO4. After purification by column chromatography on
silica gel with CH2Cl2, the configuration of the product was
determined by optical rotation and the enantiomeric excess
was determined by HPLC analysis with chiral stationary
phases.
ketones with diphenylsilane. The cheap and easy syn-
thesis of the tetraoxazoline-Cu(II) complex, the high
selectivity, and the mild reaction conditions including
water- and air-tolerance make our method potentially
useful.
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Wei Jie Li and Sheng Xiang Qiu
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Acknowledgements
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The work was financially supported by the Guangdong Pro-
vincial Research Foundation for Basic Research, China
(Grant No. 04J004) and the National Research Foundation,
South Africa (Grant No. SFP 2007072300021).
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