A C2-symmetric chiral bipyridyldiol-titanium complex as a catalyst for the asymmetric trimethylsilylcyanation of substituted benzaldehydes

Article abstract of DOI:10.1016/j.tetasy.2005.05.035

This article describes a novel C₂-symmetric ligand that comprises a central bipyridine-pinene-derived core and two functionalized two diphenylmethanol subunits. The [8′-(hydroxy-diphenyl-methyl)-10,10, 10′,10′-tetramethyl-[5,5′]bi[6-aza-tricyclo[7.1.1.0 ^2,7]undecyl]-2(7),3,5,2′(7′),3′, 5′-hexane-8-yl]-diphenyl-methanol 1 is an effective catalyst in the enantioselective addition of trimethylsilylcyanide to various aromatic aldehydes with asymmetric inductions of up to 98% ee. Importantly, the correlation between Hammett substituent constants and the enantiomeric excess, and the electron-releasing group at the meta- and para-positions of substituted benzaldehydes were demonstrated to be associated with the high enantioselectivity of the trimethylsilylcyanation reaction that involves trimethylsilylcyanide.

Full text of DOI:10.1016/j.tetasy.2005.05.035

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2704–2710
A C2-symmetric chiral bipyridyldiol–titanium complex as a
catalyst for the asymmetric trimethylsilylcyanation of substituted
benzaldehydes
Pei-Ting Lee and Chinpiao Chen*
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974, Taiwan, ROC
Received 9 May 2005; accepted 26 May 2005
Available online 16 August 2005
Abstract—This article describes a novel C2-symmetric ligand that comprises a central bipyridine-pinene-derived core and two func-
tionalized two diphenylmethanol subunits. The [80-(hydroxy-diphenyl-methyl)-10,10,100,100-tetramethyl-[5,50]bi[6-aza-tricyclo-
[7.1.1.02,7]undecyl]-2(7),3,5,20(70),30,50-hexane-8-yl]-diphenyl-methanol 1 is an effective catalyst in the enantioselective addition of
trimethylsilylcyanide to various aromatic aldehydes with asymmetric inductions of up to 98% ee. Importantly, the correlation
between Hammett substituent constants and the enantiomeric excess, and the electron-releasing group at the meta- and para-posi-
tions of substituted benzaldehydes were demonstrated to be associated with the high enantioselectivity of the trimethylsilylcyanation
reaction that involves trimethylsilylcyanide.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
bipyridyl-diol 1 derived from (1R)-(+)-a-pinene. Herein,
ligand 1 was utilized as the enantioselective catalyst of
the trimethylsilylcyanation reaction of the substituted
benzaldehydes.
Optically active cyanohydrins are very useful synthons
for the synthesis of various valuable classes of chiral
compounds, including a-hydroxy carboxylic acids,1 a-
hydroxy aldehydes,2 a-hydroxy ketones,3 and b-amino
alcohols.4 Numerous, efficient asymmetric biological
and chemical methods have been reported for obtaining
such compounds, the most important of which is the
asymmetric silylcyanation of aldehydes with trimeth-
ylsilylcyanide catalyzed by a Lewis acid, including
Ti(O-i-Pr)4,5 TiCl4,6 AlCl3,7 R2AlCl,8 and others,9 in
the presence of the chiral ligands, including Schiff bases,
diols, diamides, phosphorus compounds, and others.
Many effective chiral ligands have free hydroxyl groups
or amino groups that produce the Lewis acid center of
the catalyst by coordinating with the Lewis acid. This
asymmetric carbon–carbon bond forming process has
a wide range of synthetic applications in the pharmaceu-
tical and agrochemical industries. Previous work10 in
this laboratory elucidated the catalytic addition of dieth-
ylzinc to various substituted benzaldehydes, providing
alcohols with an (S)-configuration with an enantiomeric
excess that typically ranged from 3% to 99% using cata-
lytic amounts of titanium tetraisopropoxide and chiral
N
N
OH
HO
Ph
Ph
Ph
Ph
1
2. Results and discussion
In the asymmetric trimethylsilylcyanation of benzalde-
hyde using trimethylsilylcyanide, in the presence of chi-
ral ligand 1 and Ti(O-i-Pr)4 in various solvents (Table 1)
at room temperature, the enantiomeric excesses of acetic
acid cyano-phenyl-methyl ester were acquired: in dichlo-
romethane (34%), in acetonitrile (17%), in toluene
(14%), in diethyl ether (5%), and in tetrahydrofuran
(5%). Therefore, dichloromethane was chosen as the
reaction solvent in the following reactions. The same
reactions were performed in dichloromethane at various
temperatures (Table 2), with the enantiomeric excesses
of acetic acid cyano-phenyl-methyl ester obtained at
25 °C (28%), 0 °C (34%), ꢀ40 °C (43%), and ꢀ78 °C
*
Corresponding author. E-mail: chinpiao@mail.ndhu.edu.fw
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.035

P.-T. Lee, C. Chen / Tetrahedron: Asymmetry 16 (2005) 2704–2710
2705
Table 1. Enantiomeric excess (%) of the trimethylsilylcyanation of
benzaldehyde in the presence of Ti(IV)-1 complex in various solvents
below. A solution of ligand 1 and Ti(O-i-Pr)4 in dichloro-
methane was stirred at room temperature for 1 h after
which a solution of substituted benzaldehyde in dichloro-
methane was added. The temperature was then reduced
to ꢀ78 °C, and the trimethylsilylcyanide added and stir-
red for 40 h. The reaction mixture was quenched by add-
ing 1 M HCl and ethyl acetate. After purification by
flash chromatography, the cyanohydrins were converted
to the corresponding acetate by acetic anhydride, and
the enantiomeric excesses of the product determined
by HPLC. Table 4 presents the yields, ee%, and the spe-
cific rotation. The absolute configurations of all prod-
ucts were determined by comparing the signs of the
specific rotations (aD) as indicated in the literature.
1. 5 mol% Ti(O-i-Pr)4
O
OH
CN
Ac2O, py
CH2Cl2
OAc
CN
5mol% 1, solvent
Ph
H
Ph
Ph
2. TMSCN, rt
3. HCl
Entry
Solvents
Yield (%)
ee (%)
1
2
3
4
5
THF
Ether
52
60
51
66
70
5
7
Toluene
CH3CN
CH2Cl2
14
17
34
The electronic effects in the asymmetric hydrobora-
tions,11 epoxidations,12 and alkylations10 have been
reported. However, the influence of purely electronic
effects on the extent of asymmetric induction seem not
to have been systematically investigated. In our previous
study,10 the Hammett substituent constants were
strongly correlated with the enantiomeric excesses of
the alkylation of meta-substituted benzaldehydes using
diethylzinc. Importantly, the electron-releasing substitu-
ents on the para-position of the substituted benzaldehy-
des performed high enantioselectivity during alkylation
using diethylzinc. In contrast, electron-withdrawing sub-
stituents on the meta-position of substituted benzaldehy-
des performed high enantioselectivity. Moreover, the
weaker electron-withdrawing and electron-releasing on
the ortho-position of substituted benzaldehydes showed
higher enantioselectivity.
Table 2. Enantiomeric excess (%) of the trimethylsilylcyanation of
benzaldehyde in the presence of Ti(IV)-1 complex at various temper-
atures
1. 5 mol% Ti(O-i-Pr)4
O
Ac2O, py
CH2Cl2
OH
CN
OAc
CN
5mol% 1, CH2Cl2
Ph
H
Ph
Ph
2. TMSCN
3. HCl
Entry
Temp (°C)
Yield (%)
ee (%)
1
2
3
4
25
0
73
73
75
80
28
34
43
58
ꢀ40
ꢀ78
(58%). Accordingly, the following asymmetric reactions
were conducted in dichloromethane at ꢀ78 °C. The
asymmetric trimethylsilylcyanation of benzaldehyde
using trimethylsilylcyanide, in the presence of various
amounts of ligand 1 yielded enantiomeric excesses of
acetic acid cyano-phenyl-methyl ester, as presented in
Table 3. The optimal amount of catalyst was 5 mol %
of ligand 1 (59% ee).
The asymmetric trimethylsilylcyanation of substituted
benzaldehydes using trimethylsilylcyanide was per-
formed in the presence of catalyst Ti(IV)-1 complex.
Hammett substituent constants were strongly correlated
with the enantiomeric excesses produced by the tri-
methylsilylcyanation of meta- and para-substituted benz-
aldehydes using TMSCN. Importantly, the more
strongly electron-releasing substituents at the meta-
and para-positions exhibited higher enantiomeric
excesses (m-Me, 69%; m-OMe, 57%; p-OMe, 71%; p-Me,
70%), while the more strongly electron-withdrawing
substituents at the meta- and para-positions exhibited
lower enantiomeric excesses (m-Cl, 15%; m-CN, 8%;
p-Cl, 9%; p-CN, 2%) (Figs. 1 and 2). The moderately
electron-releasing substituents at the ortho-position
exhibited higher enantiomeric excesses (o-Me, 98%),
while the more strongly electron-withdrawing and elec-
tron-releasing substituents at the ortho-position exhib-
ited lower enantiomeric excesses (o-Cl, 3%; o-OMe,
39%) (Fig. 3). In comparison with the results of the
alkylation of substituted benzaldehydes using diethyl-
zinc, and the asymmetric trimethylsilylcyanation of
substituted benzaldehydes using trimethylsilylcyanide,
we found the electron-releasing substituents on the
para-position of the substituted benzaldehydes per-
formed high enantioselectivity. The electron-releasing
substituents of benzaldehydes may enhance the p–p
interaction between the phenyl group of ligand 1 and
the aromatic ring of benzaldehyde. Therefore, the aro-
matic ring of the benzaldehydes may be tightly fixed
Table 3. Enantiomeric excess (%) of the trimethylsilylcyanation of
benzaldehyde in the presence of various amounts of ligand 1
1. n mol% MLx
Ac2O, py
CH2Cl2
O
m mol% L*, CH2Cl2
OH
CN
OAc
CN
Ph
H
2. TMSCN
3. HCl
Ph
Ph
Entry
L*
(mol%)
MLx
(mol %)
Temp
(°C)
Yield
(%)
ee
(%)
1
2
3
4
5
6
10
10
5
Ti(O-i-Pr)4 (10)
Ti(O-i-Pr)4 (5)
Ti(O-i-Pr)4 (5)
Et2Zn (10)
ꢀ78
ꢀ78
ꢀ78
rt
80
85
86
70
—
95
36
43
59
7
5
5
Et2Zn (10)
VOSO4 (5)
ꢀ78
rt
—
6
5
The asymmetric trimethylsilylcyanation of substituted
benzaldehyde using trimethylsilylcyanide was performed
in the presence of catalyst Ti(IV)-1 complex as described

2706
P.-T. Lee, C. Chen / Tetrahedron: Asymmetry 16 (2005) 2704–2710
Table 4. The yield and enantiomeric excess (ee%) of the trimethylsilylcyanation of substituted benzaldehydes with Ti(IV)-1 complex
1. 5 mol% Ti(O-i-Pr)4
5 mol% 1, CH2Cl2
OH
CN
OAc
CN
O
Ac2O, py
CH2Cl2
H
R
R
R
2. TMSCN, -78oC
3. HCl
Entry
R
Yield (%)a ee (%) Substituent constants13 Cyanohydrin [a]T (T °C, c) CH2Cl2 Acetate [a]T (T °C, c) CH2Cl2
D
D
1
H
o-OMe
86
45
59
39
57
71
98
69
70
3
r, 0
ꢀ15.0 (23.7, 1.15)
ꢀ4.3 (24.2, 0.64)
ꢀ10.4 (24.2, 0.26)
ꢀ4.1 (24.0, 1.13)
ꢀ3.1 (24.0, 1.10)
ꢀ17.0 (23.7, 1.54)
ꢀ3.0 (23.6, 1.20)
ꢀ3.1 (23.2, 1.60)
ꢀ0.9 (24.0, 1.93)
ꢀ0.9 (23.9, 0.40)
ꢀ5.6 (24.0, 1.15)
ꢀ6.2 (16.0, 1.15)
ꢀ0.5 (22.0, 1.15)
2
ro, +0.12
rm, +0.12
rp, ꢀ0.27
ro, +0.29
rm, ꢀ0.07
rp, ꢀ0.17
ro, +1.28
rm, +0.37
rp, +0.23
rm, +0.56
rp, +0.66
ꢀ14.0 (19.0, 1.09)
ꢀ14.5 (24.0, 1.41)
ꢀ15.5 (24.0, 1.13)
ꢀ26.7 (24.2, 1.85)
ꢀ25.8 (24.2, 1.10)
ꢀ26.3 (24.2, 1.41)
ꢀ1.2 (19.4, 2.06)
ꢀ16.7 (24.2, 1.51)
—
3
m-OMe 53
4
p-OMe
o-Me
m-Me
p-Me
o-Cl
83
80
45
88
84
35
11b
54
62
5
6
7
8
9
m-Cl
p-Cl
15
9
8c
2c
10
11
12
m-CN
p-CN
ꢀ15.0 (22.8, 1.29)
ꢀ3.5 (22.6, 1.48)
a The yield of corresponding cyanohydrins.
b The yield was counted based on acetate.
c The enantiomeric excesses were determined by pivalate.
0.6
0.35
0.3
p-CN
o-Cl
0.5
0.4
0.3
0.2
0.1
0
0.25
0.2
0.15
0.1
o-OCH3
o-CH3
0.05
0
p-Cl
p-CH3
p-OCH3
H
0
0
0.2
0.4
0.6
0.8
1
1.2
1.4
δo
-0.4
-0.2
0.2
0.4
0.6
0.8
δp
Figure 3. The correlation of substituent constants (ro) and the 1/ee%
of the trimethylsilylcyanation of ortho-substituted benzaldehydes in the
presence of Ti(IV)-1 complex.
Figure 1. The correlation of substituent constants (rp) and the 1/ee%
of the trimethylsilylcyanation of para-substituted benzaldehydes in the
presence of Ti(IV)-1 complex.
Bipyridinyldiol 1 acted as an interesting chiral catalyst
of the enantioselective addition of TMSCN to various
substituted benzaldehydes, yielding cyanohydrins of an
(S)-configuration with enantiomeric excesses, generally
ranging from 2% to 98%. Importantly, the electron-
releasing substituents at the meta- and para-positions
of the substituted benzaldehydes were highly enantiose-
lective during cyanation using TMSCN. In contrast,
electron-withdrawing substituents at the meta- and
para-positions of substituted benzaldehydes were only
weakly enantioselective. Other asymmetric reactions
are currently being investigated to rationalize this
correlation.
0.18
m-CN
0.16
0.14
0.12
0.1
m-Cl
0.08
0.06
0.04
0.02
0
m-OCH3
m-CH3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
δm
Figure 2. The correlation of substituent constants (rm) and the 1/ee%
of the trimethylsilylcyanation of meta-substituted benzaldehydes in the
presence of Ti(IV)-1 complex.
4. Experimental section
4.1. General
and thus open the Si-face of the carbonyl group for
alkylation and induced the higher enantioselectivity.
All reactions were carried out in anhydrous solvents.
THF and diethyl ether were distilled from sodium-
benzophenone under argon. Toluene, CH3CN, CH2Cl2,
and hexane were distilled from CaH2. H NMR spectra
were obtained at 300 or 500 MHz (as indicated), and
3. Conclusion
1
Herein, a chiral bipyridinyldiol 1 was prepared from
highly enantiopure (>97% ee) of (1R)-(+)-a-pinene.10

P.-T. Lee, C. Chen / Tetrahedron: Asymmetry 16 (2005) 2704–2710
2707
13C NMR spectra were obtained at 75.5 or 125.7 MHz
using a Bruker NMR spectrometer. Chemical shifts (d)
are reported in ppm relative to CDCl3 (7.26 and
77.0 ppm). Mass spectra (MS) were obtained using a
Micromass Platform II mass spectrometer at 70 eV.
High resolution mass spectra (HRMS) were obtained
using a Finnigan/Thermo Quest MAT 95XL mass spec-
trometer. Infrared spectra were recorded using an ATI
Mattson spectrometer. All asymmetric reactions were
conducted in dry glassware under nitrogen using a stan-
dard glovebox. Enantiomeric excesses were determined
using Lab Alliance Series III high-performance liquid
chromatography (HPLC) with a Chiracel OD-H chiral
column (Daicel Chemical Industries, LTD). Optical
rotations were measured using a JASCO P-1010 polari-
meter at the indicated temperature using a sodium lamp
(D line, 589 nm). Flash column chromatography was
performed using MN silica gel 60 (70–230 mesh) pur-
chased from Macherey-Nagel. TMSCN was obtained
from Sigma–Aldrich Co.
CHCl3)}. 1H NMR (300 MHz, CDCl3, d): 7.51–7.46
(m, 5H), 6.41 (s, 1H), 2.17 (s, 3H). 13C NMR
(125.7 MHz, CDCl3, d): 170.5, 133.8, 131.3, 130.2,
128.8, 117.7, 64.2, 20.3. IR (KBr, thin film): 3037,
2944, 1753, 1216, 1023, 697 cmꢀ1. MS m/z: 176
(M++1, 2), 167 (21), 149 (21), 147 (9), 133 (79), 91
(44), 41 (100).
4.2.3. Hydroxy-(2-methoxy-phenyl)-acetonitrile. Yield:
19
D
25
D
45%. ½aꢁ ¼ ꢀ14.0 (c 1.09, CH2Cl2) {lit.5k ½aꢁ
¼
þ19.4 (c 1.0, CHCl3) for (R)-enantiomer in 72% ee}.
1H NMR (300 MHz, CDCl3, d): 7.44-7.38 (m, 2H),
7.05–6.97 (m, 2H), 5.55 (d, J = 9.0 Hz, 1H), 3.97 (s,
3H), 3.34 (d, J = 9.0 Hz, 1H). 13C NMR (75.5 MHz,
CDCl3, d): 156.7, 131.1, 128.0, 123.6, 121.1, 118.8,
111.1, 60.4, 55.7. IR (KBr, thin film): 33778, 2832,
1602, 1255, 1022, 909 cmꢀ1. MS m/z: 164 (M++1, 1),
147 (6), 133 (100), 115 (16), 91 (9).
4.2.4. Acetoxy-(2-methoxy-phenyl)-acetonitrile. Yield:
24.2
D
20
D
96%. ½aꢁ
¼ ꢀ10.4 (c 0.26, CH2Cl2) {lit.14f ½aꢁ
¼
ꢀ19.6 (c 1.6, CHCl3)}. 1H NMR (300 MHz, CDCl3,
d): 7.57 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H),
7.04 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.71
(s, 1H), 2.17 (s, 3H). 13C NMR (125.7 MHz, CDCl3,
d): 169.1, 157.0, 131.6, 128.1, 120.6, 120.1, 116.1,
111.1, 58.2, 55.0, 18.8. IR (KBr, thin film): 2943, 1756,
1257, 1215, 1024, 757 cmꢀ1. MS m/z: 206 (M++1, 2),
147 (44), 133 (27), 73 (100), 57 (61). HRMS-FAB
(m/z): [M+1]+ calcd for C11H11NO3, 205.0746; found,
205.0739.
4.2. Typical procedure for the enantioselective addition
of TMSCN to aldehydes catalyzed by the complex of
Ti-ligand 1
The general procedure was demonstrated using benzal-
dehyde. To a solution of ligand 1 (10.6 mg, 14.9 lmol)
in CH2Cl2 (0.3 mL) was added Ti(O-i-Pr)4 (4.4 lL,
14.8 lmol) and the mixture stirred for 1 h at room tem-
perature. The reaction mixture was cooled to ꢀ78 °C,
and benzaldehyde (30 lL, 0.3 mmol) in CH2Cl2
(0.3 mL) and trimethylsilylcyanide (12 lL, 0.9 mmol)
was added. Following stirring for 40 h at this tempera-
ture, 1 M HCl (6 mL) and ethyl acetate (12 mL) were
added to the reaction solution. After further stirring
for 4 h at room temperature, neutralizing the aqueous
layer with 2 M NaOH, extracting with ethyl acetate,
drying over anhydrous magnesium sulfate and concen-
trating the reaction mixture followed by column chro-
matography (eluent: hexane/acetone 6:1) yielded the
expected (S)-cyanohydrin. After the specific rotation
was measured, the pure cyanohydrin (0.19 mmol) was
directly converted into the corresponding acetates by
reaction with acetic acid anhydride (0.066 mL) and pyr-
idine (0.03 mL) in CH2Cl2 (1 mL) at room temperature
for 12 h. After concentration, the residue was purified
by column chromatography (eluent: hexane/acetone
4:1) to yield the acetylated cyanohydrin, which was used
for further analysis.
4.2.5. Hydroxy-(3-methoxy-phenyl)-acetonitrile. Yield:
24
D
20
D
53%. ½aꢁ ¼ ꢀ14.5 (c 1.41, CH2Cl2) {lit.14a ½aꢁ ¼ þ22.8
1
(c 1.5, CHCl3) for (R)-enantiomer in 58% ee}. H NMR
(300 MHz, CDCl3, d): 7.37 (t, J = 8.0 Hz, 1H), 7.11 (d,
J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H),
5.53 (s, 1H), 3.84 (s, 3H), 2.63 (br, 1H). 13C NMR
(75.5 MHz, CDCl3, d): 159.9, 136.6, 130.2, 118.8, 118.7,
115.4, 111.9, 63.3, 55.4. IR (KBr, thin film): 3418, 2938,
1604, 1265, 1038, 855 cmꢀ1. MS m/z: 164 (M++1, 1), 147
(4), 133 (100), 119 (20), 115 (38), 91 (22).
4.2.6. Acetoxy-(3-methoxy-phenyl)-acetonitrile. Yield:
24
D
20
D
97%. ½aꢁ ¼ ꢀ4.1 (c 1.23, CH2Cl2) {lit.14f ½aꢁ ¼ ꢀ4.8
1
(c 2.5, CHCl3)}. H NMR (300 MHz, CDCl3, d): 7.36
(t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.04–6.97
(m, 2H), 6.38 (s, 1H), 3.84 (s, 3H), 2.18 (s, 3H). 13C
NMR (125.7 MHz, CDCl3, d): 170.5, 161.6, 135.1,
131.4, 120.8, 117.6, 116.7, 114.4, 64.1, 55.9, 20.3. IR
(KBr, thin film): 2928, 1752, 1685, 1216, 1023,
786 cmꢀ1. MS m/z: 207 (M++1, 4), 167 (24), 147 (31),
133 (100), 69 (68), 57 (92).
23.7
4.2.1. Hydroxy-phenyl-acetonitrile. Yield: 86%. ½aꢁ
¼
D
27
D
ꢀ15.0 (c 1.15, CH2Cl2) {lit.14c ½aꢁ ¼ þ28.9 (c 1.1,
CHCl3) for (R)-enantiomer in 63% ee}. 1H NMR
(300 MHz, CDCl3, d): 7.55–7.51 (m, 2H), 7.47–7.43 (m,
3H), 5.53 (s, 1H), 3.20 (br, 1H). 13C NMR (75.5 MHz,
CDCl3, d): 135.2, 129.9, 129.2, 126.6, 118.8, 63.6. IR
(KBr, thin film): 3430, 2260, 1700, 1600 cmꢀ1. MS m/z:
134 (M++1, 6), 133 (56), 105 (63), 73 (100). HRMS-EI
(m/z): [M]+ calcd for C8H7NO, 133.0528; found,
133.0517.
4.2.7. Hydroxy-(4-methoxy-phenyl)-acetonitrile. Yield:
24
D
20
D
83%. ½aꢁ ¼ ꢀ15.5 (c 1.13, CH2Cl2) {lit.14a ½aꢁ
¼
þ41.7 (c 1.4, CHCl3) for (R)-enantiomer in 91% ee}.
1H NMR (300 MHz, CDCl3, d): 7.46 (d, J = 6.7 Hz,
2H), 6.95 (d, J = 6.7 Hz, 2H), 5.48 (s, 1H), 3.83 (s,
3H), 3.30 (br, 1H). 13C NMR (75.5 MHz, CDCl3, d):
160.6, 128.3, 127.4, 119.0, 114.5, 63.2, 55.4. IR (KBr,
thin film): 3421, 2937, 2840, 1611, 1465, 1306, 1254,
24.2
4.2.2. Acetoxy-phenyl-acetonitrile. Yield: 96%. ½aꢁ
¼
D
20
D
ꢀ4.3 (c 0.64, CH2Cl2) {lit.14f ½aꢁ ¼ ꢀ7.2 (c 2.3,

2708
P.-T. Lee, C. Chen / Tetrahedron: Asymmetry 16 (2005) 2704–2710
1178, 834, 769 cmꢀ1. MS m/z: 164 (M++1, 1), 147 (6),
133 (100), 75 (73), 57 (36).
2), 133 (100), 131 (9), 115 (33), 75 (47), 57 (24), 45 (13).
HRMS-FAB (m/z): [M+1]+ calcd for C9H9NO,
147.0684; found, 147.0664.
4.2.8. Acetoxy-(4-methoxy-phenyl)-acetonitrile. Yield:
24
D
20
D
23.2
97%. ½aꢁ ¼ ꢀ3.1 (c 1.10, CH2Cl2) {lit.14f ½aꢁ ¼ þ19.0
4.2.14. Acetoxy-o-p-tolyl-acetonitrile. Yield: 97%. ½aꢁ
¼
D
1
(c 1.6, CHCl3)}. H NMR (300 MHz, CDCl3, d): 7.45
(d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.36 (s,
1H), 3.84 (s, 3H), 2.14 (s, 3H). 13C NMR (75.5 MHz,
CDCl3, d): 169.1, 161.2, 129.7, 123.9, 116.4, 114.6,
62.6, 55.5, 20.5. IR (KBr, thin film): 2939, 1754, 1612,
1216, 1028, 829 cmꢀ1. MS m/z: 206 (M++1, 1), 163 (3),
147 (4), 133 (100), 91 (5), 75 (69).
ꢀ3.1 (c 1.60, CH2Cl2) {lit.14g [a]D = ꢀ29.0 (c 1.4, C6H6)}.
1H NMR (300 MHz, CDCl3, d): 7.41 (d, J = 8.1 Hz, 2H),
7.26 (d, J = 8.1 Hz, 2H), 6.37 (s, 1H), 2.39 (s, 3H), 2.17
(s, 3H). 13C NMR (125.7 MHz, CD3OD, d): 170.5, 141.7,
130.9, 130.8, 128.9, 117.8, 64.1, 21.3, 20.3. IR (KBr, thin
film): 2968, 1753, 1366, 1217, 1020, 814, 528 cmꢀ1. MS
m/z: 190 (M++1, 6), 148 (41), 133 (100), 119 (43), 91 (49),
71 (26), 55 (65). HRMS-FAB (m/z): [M+1]+ calcd for
C11H11NO2, 189.0790; found, 189.0791.
24.2
4.2.9. Hydroxy-o-tolyl-acetonitrile. Yield: 80%. ½aꢁ
¼
D
26
ꢀ26.7 (c 1.85, CH2Cl2) {lit.14e ½aꢁ ¼ ꢀ26.4 (c 2.0,
D
C6H6) for (R)-enantiomer in 92% ee}. 1H NMR
(300 MHz, CDCl3, d): 7.61 (d, J = 7.8 Hz, 1H), 7.32 (t,
J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 1H), 5.68 (d,
J = 6.2 Hz, 1H), 2.46 (s, 3H). 13C NMR (75.5 MHz,
CDCl3, d): 136.2, 133.0, 131.2, 129.9, 126.9, 126.6, 118.7,
61.5, 18.7. IR (KBr, thin film): 3419, 2926, 1606, 1291,
1039, 936 cmꢀ1. MS m/z: 148 (M++1, 4), 146 (19), 133
(100), 109 (14), 75 (43). HRMS-FAB (m/z): [M+1]+ calcd
for C9H9NO, 147.0664; found, 147.0684.
4.2.15. (2-Chloro-phenyl)-hydroxy-acetonitrile. Yield: 84%.
19.4
D
20
D
½aꢁ
¼ ꢀ1.2 (c 2.06, CH2Cl2) [lit.14b ½aꢁ ¼ þ3.4 (c 0.9,
CHCl3) for S enantiomer in 91% ee]. 1H NMR
(300 MHz, CDCl3, d): 7.74–7.71 (m, 1H), 7.48–7.37 (m,
3H), 5.88 (d, J = 6.6 Hz, 1H), 2.87 (d, J = 6.6 Hz, 1H).
13C NMR (75.5 MHz, CDCl3, d): 132.6, 132.4, 130.9,
129.9, 128.2, 127.6, 118.0, 60.6. IR (KBr, thin film): 3410,
2923, 1594, 1192, 1035, 942 cmꢀ1. MS m/z: 168 (M++1,
3), 141 (8), 139 (13), 133 (100), 91 (6), 77 (6), 73 (9).
23.7
4.2.10. Acetoxy-o-tolyl-acetonitrile. Yield: 96%. ½aꢁ
¼
4.2.16. Acetoxy-(2-chloro-phenyl)-acetonitrile. Yield:
D
24
22
D
1
ꢀ17.0 (c 1.54, CH2Cl2). H NMR (300 MHz, CDCl3, d):
7.57–7.55 (m, 1H), 7.38–7.24 (m, 3H), 6.52 (s, 1H), 2.4
(s, 3H), 2.18 (s, 3H). 13C NMR (125.7 MHz, CD3OD,
d): 170.4, 138.1, 132.3, 131.7, 131.4, 129.4, 127.3, 117.42,
62.6, 20.1, 18.9. IR (KBr, thin film): 2934, 1754, 1372,
1214, 1022, 961, 758 cmꢀ1. MS m/z: 190 (M++1, 1), 149
(16), 133 (100), 115 (17), 75 (75). HRMS-FAB (m/z):
[M+1]+ calcd for C11H11NO2, 189.0790; found, 189.0783.
97%. ½aꢁ ¼ ꢀ0.9 (c 1.93, CH2Cl2) {lit.14d ½aꢁ
¼
D
ꢀ54.4 (c 0.8, CHCl3)}. 1H NMR (300 MHz, CDCl3,
d): 7.74–7.71 (m, 1H), 7.48–7.37 (m, 3H), 6.72 (s, 1H),
2.20 (s, 3H). 13C NMR (125.7 MHz, CDCl3, d): 170.2,
134.3, 133.0, 131.4, 131.2, 130.5, 129.0, 116.6, 61.8,
20.0. IR (KBr, thin film): 3069, 2940, 1758, 1476,
1443, 1372, 1212, 758, 569 cmꢀ1. MS m/z: 210 (M++1,
2), 167 (7), 147 (43), 133 (16), 91 (20), 73 (100), 57 (62).
24.2
4.2.11. Hydroxy-m-tolyl-acetonitrile. Yield: 45%. ½aꢁ
¼
4.2.17. (3-Chloro-phenyl)-hydroxy-acetonitrile. Yield:
D
22
D
24.2
D
22
D
ꢀ25.8 (c 1.10, CH2Cl2) {lit.14d ½aꢁ ¼ ꢀ41.3 (c 0.5, CHCl3)
35%. ½aꢁ
¼ ꢀ16.7 (c 1.51, CH2Cl2) {lit.14d ½aꢁ
¼
for (S)-enantiomer in 92% ee}. 1H NMR (300 MHz,
CDCl3, d): 7.37–7.31 (m, 3H), 7.27–7.23 (m, 1H), 5.50 (s,
1H), 3.20–2.90 (br, 1H), 2.40 (s, 3H). 13C NMR
(75.5 MHz, CDCl3, d): 139.0, 135.0, 130.4, 128.9, 127.2,
123.6, 119.0, 63.3, 21.2. IR (KBr, thin film): 3419, 2924,
1610, 1250, 1039, 949 cmꢀ1. MS m/z: 148 (M++1, 1), 132
(100), 131 (5), 75 (83), 57 (43).
ꢀ54.4 (c 0.8, CHCl3) for (S)-enantiomer in 97% ee}.
1H NMR (300 MHz, CDCl3, d): 7.55 (s, 1H), 7.44–
7.41 (m, 3H), 5.55 (d, J = 6.7 Hz, 1H), 2.87 (d,
J = 6.7 Hz, 1H). 13C NMR (75.5 MHz, CDCl3, d):
136.7, 135.0, 130.4, 129.9, 126.7, 124.6, 118.5, 62.5. IR
(KBr, thin film): 3410, 2904, 1597, 1194, 1041,
940 cmꢀ1. MS m/z: 168 (M++1, 4), 151 (6), 133 (100),
91 (26), 77 (16).
23.6
4.2.12. Acetoxy-m-tolyl-acetonitrile. Yield: 97%. ½aꢁ
¼
D
1
ꢀ3.0 (c 1.20, CH2Cl2). H NMR (300 MHz, CDCl3, d):
7.34–7.26 (m, 4H), 6.37 (s, 1H), 2.40 (s, 3H), 2.17 (s,
3H). 13C NMR (125.7 MHz, CD3OD, d): 170.5, 140.4,
133.7, 131.9, 130.1, 129.4, 125.9, 117.7, 64.2, 21.3, 20.3.
IR (KBr, thin film): 3024, 2925, 1755, 1214, 1023, 898,
699 cmꢀ1. MS m/z: 190 (M++1, 2), 149 (32), 133 (33),
119 (51), 91 (47), 73 (78), 44 (100). HRMS-FAB (m/z):
[M+1]+ calcd for C11H11NO2, 189.0790; found, 189.0765.
4.2.18. Acetoxy-(3-chloro-phenyl)-acetonitrile. Yield:
23.9
D
22
D
95%. ½aꢁ
¼ ꢀ0.9 (c 0.40, CH2Cl2) {lit.14d ½aꢁ
¼
ꢀ39.4 (c 0.8, CHCl3)}. 1H NMR (300 MHz, CDCl3,
d): 7.52 (s, 1H), 7.40 (m, 3H), 6.38 (s, 1H), 2.19 (s,
3H). 13C NMR (125.7 MHz, CDCl3, d): 170.3, 136.0,
135.9, 131.8, 128.8, 127.2, 117.2, 63.5, 20.2. IR (KBr,
thin film): 3067, 2941, 1762, 1477, 1443, 1372, 1215,
788, 690 cmꢀ1. MS m/z: 210 (M++1, 0.1), 167 (3), 133
(100), 91 (3), 75 (5), 57 (4).
24.2
4.2.13. Hydroxy-p-tolyl-acetonitrile. Yield: 88%. ½aꢁ
¼
D
22
ꢀ26.3 (c 1.41, CH2Cl2) {lit.14d ½aꢁ ¼ ꢀ48.5 (c 0.5,
4.2.19. Acetoxy-(4-chloro-phenyl)-acetonitrile. Yield:
D
24
D
25
D
CHCl3) for (S)-enantiomer in 94% ee}. 1H NMR
(300 MHz, CDCl3, d): 7.41 (d, J = 8.0 Hz, 2H), 7.25 (d,
J = 8.0 Hz, 2H), 5.49 (s, 1H), 2.97 (br, 1H), 2.39 (s, 3H).
13C NMR (75.5 MHz, CDCl3, d): 140.0, 132.4, 129.8,
126.7, 118.8, 63.5, 21.2. IR (KBr, thin film): 3400, 2922,
1260, 1031, 1018, 818, 534 cmꢀ1. MS m/z: 148 (M++1,
28%. ½aꢁ ¼ ꢀ5.6 (c 1.15, CH2Cl2) {lit.14h ½aꢁ
¼
ꢀ13.9 (c 1.0, CHCl3) for (R)-enantiomer in 99% ee}.
1H NMR (300 MHz, CDCl3, d): 7.49–7.41 (m, 4H),
6.38 (s, 1H), 2.17 (s, 3H). 13C NMR (75.5 MHz, CDCl3,
d): 168.8, 136.6, 130.6, 130.2, 129.5, 129.3, 115.7, 62.1,
20.4. IR (KBr, thin film): 2940, 1756, 1599, 1215,

P.-T. Lee, C. Chen / Tetrahedron: Asymmetry 16 (2005) 2704–2710
2709
1016, 821 cmꢀ1. MS m/z: 210 (M++1, 0.3), 107 (1.8), 147
References
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210.0311.
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54%. ½aꢁ
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D
(300 MHz, CDCl3, d): 7.87 (s, 1H), 7.81 (d,
J = 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.60 (t,
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3396, 2230, 1435, 1149, 1041, 968 cmꢀ1. MS m/z: 159
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(23), 57 (77).
4.2.21.
2,2-Dimethylpropioxy-(3-cyano-phenyl)-aceto-
16
1
nitrile. Yield: 91%. ½aꢁ ¼ ꢀ6.2 (c 1.15, CHCl3). H
D
NMR (300 MHz, CDCl3, d): 7.80–7.75 (m, 3H), 7.64–
7.59 (m, 2H), 6.43 (s, 1H), 1.26 (s, 9H). 13C NMR
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130.9, 130.3, 117.6, 115.3, 113.7, 61.7, 38.9, 25.8. IR
(KBr, thin film): 2977, 1752, 1586, 1271, 1034,
894 cmꢀ1. MS m/z: 243 (M++1, 1), 133 (100), 115 (14),
75 (33), 57 (98). HRMS-FAB (m/z): [M+1]+ calcd for
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22
1
nitrile. Yield: 94%. ½aꢁ ¼ ꢀ0.5 (c 1.15, CH2Cl2). H
D
NMR (300 MHz, CDCl3, d): 7.77 (d, J = 8.4 Hz, 2H),
7.63 (d, J = 8.4 Hz, 2H), 6.45 (s, 1H), 1.26 (s, 9H). 13C
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128.1, 117.7, 115.3, 114.4, 61.9, 38.9, 26.8. IR (KBr, thin
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242.1055; found, 243.1125.
Acknowledgements
The authors thank Ms. L. M. Hsu at Instruments Cen-
ter, National Chung Hsing University, and Ms. H. C.
Tan at Instrument Center, National Tsing Hwa Univer-
sity for their help in obtaining HRMS and 13C NMR
spectra, and the National Science Council the Republic
of China for financially supporting this research under
contract NSC 92-2113-M-259-006.

2710
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