Highly enantioselective cyanosilylation of ketones catalyzed by a bifunctional Ti(IV) complex

Article abstract of DOI:10.1016/j.tet.2007.10.093

A bifunctional catalyst system composed of (S)-prolinamide (2a), titanium(IV) isopropoxide, and phenolic N-oxide (3f) exhibited high catalytic efficiency in the enantioselective cyanosilylation of ketones. In the presence of 2.5 mol % catalyst, a variety

Full text of DOI:10.1016/j.tet.2007.10.093

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 147e153
www.elsevier.com/locate/tet
Highly enantioselective cyanosilylation of ketones catalyzed by
a bifunctional Ti(IV) complex
Ke Shen a, Xiaohua Liu a, Qinghan Li a, Xiaoming Feng a,b,
*
a Key Laboratory of Green Chemistry and Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
b State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
Received 10 August 2007; received in revised form 17 October 2007; accepted 19 October 2007
Available online 30 October 2007
Abstract
A bifunctional catalyst system composed of (S )-prolinamide (2a), titanium(IV) isopropoxide, and phenolic N-oxide (3f) exhibited high cata-
lytic efficiency in the enantioselective cyanosilylation of ketones. In the presence of 2.5 mol % catalyst, a variety of aromatic and aliphatic
ketones were converted into the corresponding tertiary cyanohydrin O-TMS ethers in excellent yields (up to 96%) and high enantioselectivities
(up to 96% ee). A proposed catalytic cycle was illustrated to explain the origin of the asymmetric induction.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Bifunctional catalysis; Cyanosilylation; Ketone; Titanium
1. Introduction
In the process of seeking for the appropriate chiral ligands, we
synthesized 2a structurally similar to 1a15 and 1b16 (Fig. 1),
both of which were efficient ligands in the asymmetric cyano-
silylation of aldehydes. Herein, we wish to describe the enan-
tioselective cyanosilylation of ketones catalyzed by
a bifunctional 2aeTi(IV)e3f complex.
The cyanosilylation of ketones is one of the most popular
strategies to afford tertiary cyanohydrins which can be easily
converted into versatile biologically active molecules and nat-
ural products.1,2a,14b Many synthetic methods have been devel-
oped to accomplish the asymmetric cyanosilylation of ketones
successfully.2 The majority of chiral catalysts used in this re-
action are chiral metal complexes,3e9a cinchona alkaloid cata-
lysts,10 chiral oxazaborolidinium ions,11 thiourea catalysts,12
and amino acid salts.13 In recent years, the synergistic activa-
tion by the combination of Lewis acids and Lewis bases is re-
markable in asymmetric catalysis.14 This dual activation
concept has been successfully applied to the asymmetric addi-
tion of TMSCN to ketones, especially by Shibasaki’s sugar-de-
rivated bifunctional catalyst2c,4 and our group’s dual activation
method.7 We initiated our study on the asymmetric cyanosily-
lation of ketones with a bifunctional catalyst, which was com-
posed of chiral ligand with central metal and achiral N-oxide.
2. Results and discussion
2.1. Catalyst survey
A series of chiral ligands 2aej and achiral N-oxides 3aei
(Fig. 2) were synthesized according to the reported meth-
ods.7d,9b,17 The catalyst components were screened in the
OH
X
X
Ph
Ph
1a: X=
1b: X=
2a: X=
N
OH
N
O
P
Ph
Ph
A
O
Ph
Ph
N
H
* Corresponding author. Fax: þ86 28 8541 8249.
E-mail address: xmfeng@scu.edu.cn (X. Feng).
Figure 1. Structures of chiral ligands based on the backbone of A.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.093

148
K. Shen et al. / Tetrahedron 64 (2008) 147e153
2a R1=Me, R2=diphenylmethyl
a significant effect on the results (Table 1, entries 1e7). Com-
plex 2aeTi(IV) containing diphenylmethylamide moiety gave
the best enantioselectivity (Table 1, entry 1). Ligands derived
from other amide groups, no matter bulkier ones or the ones of
less steric hindrance, only gave inferior asymmetric induction
(Table 1, entries 2e7). It was noteworthy that halogen
and bulky tert-butyl moieties on the phenolic units of the
ligands led to decrease in enantioselectivities (Table 1, entries
8e10).
R2
NH
R2
HN
2b R1=Me, R2=2-methylphenyl
2c R1=Me, R2=2-t-butyl-phenyl
2d R1=Me, R2=cyclohexyl
O
O
N
N
OH
2e R1=Me, R2=adamantyl
2f R1=Me, R2=2-naphthyl
2g R1=Me, R2= (S)-1-(4-methoxyphenyl)ethanyl
2h R1=t-Bu, R2=diphenylmethyl
2i R1=Cl, R2=diphenylmethyl
2j R1=Br, R2=diphenylmethyl
R1
2
3a R3=H, R4=H, R5=Me
OH
R5
Then, 2aeTi(OiPr)4 was chosen to investigate the achiral
N-oxides 3aei. This bifunctional catalyst 2aeTi(IV)e3 was
prepared in situ (see Section 4 for details). To our delight,
the reactivity was greatly improved by the addition of 3aeg
under the prescribed condition (Table 1, entries 11e17). A
dramatic switching of enantioselectivity was dependent on
the structure of N-oxides. As shown in entries 12 and 13 (Table
1), a slight erosion in enantioselectivity was observed when 3b
or 3c was used. This demonstrated that methoxyl or phenyl
substitute at ortho position of phenolic group was not appro-
priate. Improvement in the enantioselectivity could be
achieved by employing 3e and 3f, which could be attributed
to the large hindrance of adamantyl (Table 1, entries 15 and
16). 62% ee was obtained with 2aeTi(IV)e3f complex (Table
1, entry 16). The sharp decrease in enantioselectivity was ob-
served when 3g was employed, which could be partly due to
the less flexible six-membered ring of N-oxide moiety (Table
1, entry 17). While simple N-oxides with no coordinative phe-
nolic group were used, only poor results were obtained (Table
1, entries 18 and 19). This observation might be explained by
the strong binding between Lewis acid and Lewis base result-
ing in the deterioration of the catalytic capability. It was found
that acetophenone was converted into the corresponding prod-
uct with 29% ee when Ti(OiPr)4 was replaced by Al(OiPr)3
(Table 1, entry 20 vs 16). Simultaneously, no product was ob-
served by employing Zr(OiPr)4 or Zn(OTf)2. Thus, complex
2aeTi(IV)e3f was the optimal catalyst for further
investigation.
3b R3=H, R4=Ph, R5=Me
R4
N+
R5
-
3c R3=H, R4=OMe, R5=Me
3d R3=t-Bu, R4=t-Bu, R5=Me
3e R3=t-Bu, R4=adamantyl, R5=Me
3f R3=t-Bu, R4=adamantyl, R5=Et
O
R3
3
3g R3=t-Bu, R4=adamantyl, R5= CH2
5
-
O
-
O
N+
N+
3h
3i
Figure 2. Structures of ligands 2 and N-oxides 3.
asymmetric cyanosilylation of acetophenone 4a (Table 1). We
began our efforts to evaluate the reactivity of 2eTi(OiPr)4
complex. As depicted in entries 1e10 (Table 1), electronic
and steric tuning of the ligand was crucial for the reactivity
and enantioselectivity. The amide moiety of the ligand had
Table 1
Asymmetric cyanosilylation of acetophenone catalyzed by 2emetale3
complex
5 mol% 2/Metal/3
O
OTMS
CN
TMSCN (1.5 equiv.)
*
Ph
Ph
CH2Cl2, - 20 °C
4a
5a
Entrya Ligand Central metal N-Oxide t (h) Yieldb (%) eec (%)
1
2a
2b
2c
2d
2e
2f
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Al(OiPr)3
d
d
d
d
d
d
d
d
d
d
3a
3b
3c
3d
3e
3f
48
48
48
48
48
48
48
48
48
48
12
12
12
12
12
12
12
12
12
6
55
39
43
42
30
40
37
33
39
33
82
91
88
88
92
94
72
36
48
96
51
20
24
24
40
30
28
42
47
37
49
45
43
47
58
62
35
29
38
29
2
3
4
5
2.2. Evaluation of the molar ratio of 2a, 3f, and
Ti(OiPr)4
6
7
2g
2h
2i
8
The molar ratio of 2a, 3f, and Ti(OiPr)4 was finely tuned to
obtain the optimum enantioselectivity. The results are summa-
rized in Table 2. It was clearly showed that the molar ratio of
1/1/1 was crucial for both enantioselectivity and reactivity
(Table 2, entry 3). Others only led to lower yields or enantio-
selectivity (Table 2, entries 1, 2, and 4e6).
9
10
11
12
13
14
15
16
17
18
19
20
a
2j
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3g
3h
3i
2.3. Optimization of reaction conditions
3f
The solvent effect was investigated and the results are listed
in Table 3. The reactions proceeded more rapidly in ether sol-
vents (Table 3, entries 1 and 2), but more sluggishly in CH3CN
(Table 3, entry 3). Toluene provided equal enantioselectivity
as THF, whereas the reaction rate was lower (Table 3, entry
4 vs 2). Although the transformation proceeded better in
Et2O than in THF at ꢀ20 ꢁC, lower temperature led to
Conditions: 5 mol % 1igand 2/indicated central metal/N-oxide 3 (1/1/1)
was used, concentration of acetophenone was 0.25 M in CH2Cl2, TMSCN
was 1.5 equiv at ꢀ20 ꢁC under the argon atmosphere.
b
Isolated yield.
Determined by GC on Chirasil DEX CB. The absolute configuration of the
c
major product was R, determined by comparison with the reported values of
optical rotation (Ref. 12).

K. Shen et al. / Tetrahedron 64 (2008) 147e153
149
Table 2
Effect of the molar ratio of the three components on the yield and
enantioselectivity
Table 4
Effects of catalyst loading and concentration of substrate on the asymmetric
cyanosilylation of acetophenone
Entrya
Loading of the catalyst (mol %)
Yieldb (%)
eec (%)
Entrya Catalyst loading Concentration of
t (h) Yieldb (%) eec (%)
(mol %)
acetophenone (mol/L)
2a
3f
Ti(OiPr)4
1
2
3
4
5
6
7
8
9
10
7.5
5
0.25
0.25
0.25
0.25
0.25
0.5
30
36
48
48
60
48
48
48
48
99
93
90
89
67
90
93
96
99
86
86
86
87
85
86
87
90
88
1
2
3
4
5
6
a
5
5
5
5
5
5
2.5
2.5
2.5
5
76
82
90
84
94
85
50
57
62
52
60
55
5
5
2.5
1
5
10
5
10
10
2.5
2.5
2.5
2.5
10
0.75
1
Conditions: concentration of acetophenone was 0.25 M in CH2Cl2,
TMSCN was 1.5 equiv at ꢀ20 ꢁC for 12 h under the argon atmosphere.
1.5
b
Isolated yield.
Determined by GC on Chirasil DEX CB. The absolute configuration of the
Conditions: reactions were carried out with 2a/Ti(OiPr)4/3f complex (1/1/1),
a
c
in THF at ꢀ45 ꢁC, TMSCN was 1.5 equiv under the argon atmosphere.
major product was R, determined by comparison with the reported values of
optical rotation (Ref. 12).
b
Isolated yield.
Determined by GC on Chirasil DEX CB. The absolute configuration of the
c
product was R, determined by comparison with the reported values of optical
rotation (Ref. 12).
a dramatic decrease in reactivity (Table 3, entry 6 vs 1), while
remarkable increase of enantioselectivity could be accomp-
lished in THF at ꢀ45 ꢁC with 90% yield and 86% ee by pro-
longing reaction time (Table 3, entry 7 vs 2). Further
decreasing the temperature to ꢀ78 ꢁC gave very low yield (Ta-
ble 3, entry 8 vs 7). Hence, THF was the appropriate solvent.
The effect of catalyst loading was screened and the results
are listed in Table 4. Increasing catalyst loading had little in-
fluence on the enantioselectivity, but it increased the reaction
rate to some extent (Table 4, entries 1 and 2). When the cata-
lyst loading was reduced to 1 mol %, the yield decreased to
67% (Table 4, entry 5). Thus the 2.5 mol % catalyst was con-
sidered to be the practical amount. The reaction concentration
also had effect on the reaction rate and enantioselectivity.
When the concentration of acetophenone was increased from
0.25 to 1.0 M, the yield was increased from 89 to 96% and
up to 90% ee was achieved (Table 4, entries 6e8 vs 4). Addi-
tionally, further increase of the concentration of acetophenone
to 1.5 M led to a slight loss of enantioselectivity (Table 4, en-
try 9). Consequently, the optimal working condition was
2.5 mol % 2a/Ti(OiPr)4/3f (1/1/1) at the concentration of
acetophenone 1.0 M in THF at ꢀ45 ꢁC.
2.4. Scope of the substrates
As described in Table 5, 2aeTi(OiPr)4e3f was proved to be
general for the enantioselective cyanosilylation of a wide
range of ketones under the optimized conditions. The ortho
and para fluoro-substituted aromatic ketones gave the same
enantioselectivity as acetophenone (Table 5, entries 2 and 3
vs 1). Moreover, 4-chloroacetophenone and 4-methoxyaceto-
phenone were converted into the desired products in 89% ee
with 90 and 88% yields, respectively (Table 5, entries 5 and
7). The electronic character of ortho or para substituent of
acetophenone was not crucial for the enantioselectivity (Table
5, entries 2, 3, and 5e7). 3-Chloroacetophenone afforded
higher enantioselectivity (Table 5, entry 4 vs 1). When hetero-
cyclic ketone 4h was subjected to the reaction, up to 92% ee
was attained (Table 5, entry 8). Steric bulkier ketones such
as b-acetonaphthone and a-tetralone afforded the correspond-
ing cyanohydrin ethers with 96 and 85% ee, respectively (Ta-
ble 5, entries 9 and 10). a,b-Unsaturated ketone 4k was well
tolerated and gave 1,2-addition product exclusively in 92%
yield with 91% ee. Moreover, simple aliphatic and a,b-satu-
rated ketones afforded the desired products in high yields
with good enantioselectivities (Table 5, entries 12e16).
Table 3
Solvents evaluation on the asymmetric cyanosilylation of acetophenone
Entrya
Solvent
T (ꢁC)
t (h)
Yieldb (%)
eec (%)
2.5. Mechanism investigation
1
2
3
4
5
6
7
8
a
Et2O
THF
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ45
ꢀ45
ꢀ78
12
12
12
12
12
48
48
48
99
98
32
75
63
32
90
15
78
72
27
72
61
85
86
85
Nonlinear effects in asymmetric synthesis and stereoselec-
tive reactions reflect molecular interactions and complexity in
reaction mechanism.18 NLE study manifested that a double-
shape curve was apparent from the experimental data in
2aeTi(OiPr)4e3f complex catalytic system (Fig. 3). Here,
we considered that the different catalyst species including
monomeric species (Fig. 4, model B), dimeric species (Fig. 4,
model C), and other higher order species might coexist in the
catalytic process. Either B or C could act as a bifunctional
catalyst through a similar dual activation pathway.
CH3CN
Toluene
CH2Cl2
Et2O
THF
THF
Conditions: reactions were carried out with 5 mol % 2a/Ti(OiPr)4/3f com-
plex (1/1/1), concentration of acetophenone was 0.25 M in indicated solvent,
TMSCN was 1.5 equiv under the argon atmosphere.
b
Isolated yield.
Determined by Chiral GC analysis on Chirasil DEX CB. The absolute con-
c
Therefore, a simplified asymmetric catalytic cycle with a
bifunctional pathway is illustrated in Scheme 1. Tridentate
figuration of the product was R, determined by comparison with the reported
values of optical rotation (Ref. 12).

150
K. Shen et al. / Tetrahedron 64 (2008) 147e153
Table 5
Scope of enantioselective cyanosilylation of ketones
100
2.5 mol% 2a-3f-Ti(OiPr)4
90
O
OTMS
TMSCN (1.5 equiv.)
CN
R2
*
R1
Entrya Ketone 4
R2
4a-p
THF, - 45 °C
R1
80
70
60
50
40
30
20
10
0
5a-p
Product t (h) Yieldb eec Conf.g
5
(%)
(%)
1
2
3
4
5
6
7
4a R¼H
5a
5b
5c
5d
5e
5f
48
36
36
36
48
60
60
96
93
90
93
90
91
88
90
90
90
94
89
86
89
R
4b R¼o-F
4c R¼p-F
4d R¼m-Cl
4e R¼p-Cl
4f R¼p-Me
O
R
R
R
R
R
4g R¼p-OMe 5g
O
O
8
9
4h
4i
5h
5i
60
60
78
89
92
R
R
S
O
96d
0
20
40
60
80
100
ee % of ligand (S)-2a
Figure 3. NLE study in the asymmetric cyanosilylation of acetophenone cata-
lyzed by 2aeTi(OiPr)4e3f.
10
11
4j
5j
60
36
80
92
85
O
O
N+ O-
4k
5k
91e
R
R
H
PrOi
N
O
Ligand 2a
Ti
Ligand 2a
N-oxide 3f
N
N
O
O
N
N
O
Ti
12
13
4l
5l
48
36
92
89
89
62
OiPr
Ti
OiPr
O
N+ O-
O
H
N
H
N+ O-
N-oxide 3f
O
B: monomeric species
C: dimeric species
4m
5m
Figure 4. Hypothesis of two species.
O
14
15
4n
4o
5n
5o
36
36
95
92
82
75
R
R
between R group of the ketone and two phenyl groups of the
amide might direct the activated CN attacked the carbonyl
group from the less hindered side. Then the corresponding
O-TMS ethers 5 could be released with the regeneration of
the catalyst.
O
O
16
4p
5p
36
90
71f
a
3. Conclusion
Conditions: reactions were carried out with 0.5 mmol of ketone,
0.75 mmol of TMSCN in 0.5 mL THF for 36e60 h at ꢀ45 ꢁC catalyzed by
2.5 mol % 2a/Ti(OiPr)4/3f (1/1/1) complex under the argon atmosphere.
b
In summary, we have developed a new strategy for asym-
metric cyanosilylation of ketones using a new bifunctional
Isolated yield.
Unless other specified, enantiomeric excess was determined by GC on
c
Chirasil DEX CB.
d
R3O
NR4
Determined by HPLC on Chiralcel OJ.
Determined by HPLC on Chiralcel OD.
Ti
e
OiPr
R4N
7
H
f
O
one-pot
Determined by HPLC on Chiralcel AD; ee was determined after conver-
sion to the corresponding benzyl carboxylate (Ref. 4a).
+
+
Ti(OiPr)4
2a
3f
N+ O-
g
The absolute configurations were determined by comparison with the
reported values of optical rotation (Refs. 5, 7e, and 12).
O
R1
R2
NR4
OTMS
CN
4
R3O
*
+
OiPr
ligand 2a could coordinate with Ti(OiPr)4 through oxygen
atom and two amide moieties, meanwhile, 3f could assemble
with titanium through phenolic group to form 7. Titanium(IV)
could act as a Lewis acid to activate carbonyl group and N-
oxide moiety could act as Lewis base to activate TMSCN,
simultaneously. In transition state 9, the large steric hindrance
Ti
9
R1
R2
(CH3)3SiCN
8
R4N
O
H
5
O
N+ O-
CH3
CH3
Si
H3C
R2
R1
NC
Scheme 1. Proposed asymmetric catalytic cycle.

K. Shen et al. / Tetrahedron 64 (2008) 147e153
151
catalyst. Attractive features of the reaction are the high enan-
tioselectivity (up to 96% ee), the low catalyst loading
(2.5 mol %), and the ease of catalyst preparation. Based on
the experimental results, catalyst species in this reaction and
a plausible catalytic cycle were proposed. The applications
of this bifunctional catalyst system in other asymmetric cata-
lytic reactions are currently under investigations.
34.07, 31.66, 29.16, 18.23, 8.83 ppm. HRMS (ESI) calcd for
C25H39NO2 (MþH)þ: 386.3054, found: 386.3053.
4.3. Typical procedure for the catalytic cyanosilylation
of ketones
The catalyst was prepared on a 0.0125 mmol scale by mix-
ing Ti(OiPr)4 (1 M in toluene, 12.5 mL), 2a (8.7 mg), and 3f
(4.8 mg) in a molar ratio of 1/1/1 in THF under an argon atmo-
sphere at 35 ꢁC. After cooling to 23 ꢁC, the corresponding ke-
tone (0.5 mmol) was added to this solution, followed by the
addition of TMSCN (187 mL, 4 M in THF, 0.75 mmol) at
ꢀ45 ꢁC. The contents were stirred at ꢀ45 ꢁC and the reaction
was monitored by TLC. The residue was purified by silica gel
column chromatograghy (petroleum ether/diethyl ether, 100/1,
v/v) to afford the corresponding cyanohydrin trimethylsilyl
ether.
4. Experimental
4.1. General remarks
1H NMR spectra were recorded on a 300 or 400 MHz spec-
trometer. Chemical shifts are reported in parts per million with
the solvent reference as the internal standard (CHCl3:
d 7.26 ppm). Data are reported as follows: chemical shift,
integration, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet), and coupling constants (Hz). 13C
NMR spectra were recorded on a 75 or 100 MHz spectrometer
with complete proton decoupling. Chemical shifts are reported
in parts per million with the solvent reference as the internal
standard (CHCl3: d 77.2 ppm). Melting points were measured
on a Mel-Temp apparatus and were uncorrected. Enantio-
meric excesses (ee) were determined by HPLC or GC. Opti-
4.3.1. 2-Trimethylsilyloxy-2-phenylpropanenitrile (5a)
Yield 96%, 90% ee. 1H NMR (300 MHz, CDCl3): d 0.19 (s,
9H), 1.87 (s, 3H), 7.38e7.58 (m, 5H) ppm. GC analysis (Var-
ian, CP-Chirasil DEX CB, 0.25 mmꢂ25 m, 105 ꢁC, 7.5 psi): tR
(minor)¼23.9 min, tR (major)¼24.7 min. [a]2D2 þ20.5 (c 0.325,
CH2Cl2, 90% ee). [Lit.12 [a]D24 ꢀ22.3 (c 1.0, CHCl3, 97% ee)].
T
cal rotations were reported as follows: [a]D (c¼g/100 mL,
in solvent). HRMS was recorded on a commercial apparatus
(ESI Source). All reagents were commercially available and
used directly, except for acetophenone and TMSCN, which
were distilled under argon. Solvents were all purified by
the usual methods. The chiral ligands 2aej and achiral N-
oxides 3aei were synthesized according to the reported
methods.7d,9b,17
4.3.2. 2-Trimethylsilyloxy-2(20-fluorophenyl)propanenitrile
(5b)
1
Yield 90%, 90% ee. H NMR (400 MHz, CDCl3): d 0.26
(s, 9H), 1.94 (s, 3H), 7.07e7.12 (m, 1H), 7.16e7.20 (m,
1H), 7.33e7.38 (m, 1H), 7.56e7.60 (m, 1H) ppm. 13C NMR
(100 MHz, CDCl3): d 1.0, 30.8, 68.4, 116.5, 120.6, 124.2,
126.7, 130.6, 159.4 ppm. GC analysis (Varian, CP-Chirasil
DEX CB, 0.25 mmꢂ25 m, 105 ꢁC, 7 psi): tR (minor)¼
27.9 min, tR (major)¼28.5 min. [a]2D2 þ14.7 (c 0.196, CH2Cl2,
90% ee). [Lit.7b [a]D26 ꢀ12.7 (c 1.18, CHCl3, 76% ee)].
4.2. Physical data of ligand 2a and N-oxide 3f
4.2.1. (2S,20S )-1,10-(2-Hydroxy-5-methyl-1,3-phenylene)bis-
(methylene)bis(N-benzhydrylpyrrolidine-2-carboxamide) (2a)
White powder, mp: 84e86 ꢁC. [a]D25 ꢀ33.4 (c 0.50,
4.3.3. 2-Trimethylsilyloxy-2(40-fluorophenyl)propanenitrile
(5c)
1
CHCl3). H NMR (400 MHz, CDCl3, 25 ꢁC, TMS): d 7.59e
Yield 90%, 90% ee. 1H NMR (400 MHz, CDCl3): d 0.18 (s,
9H), 1.84 (s, 3H), 7.06e7.10 (m, 2H), 7.51e7.54 (m,
2H) ppm. 13C NMR (100 MHz, CDCl3): d 1.0, 33.5, 71.0,
115.6, 121.4, 126.5, 138.0, 162.2 ppm. GC analysis (Varian,
CP-Chirasil DEX CB, 0.25 mmꢂ25 m, 115 ꢁC, 8 psi): tR (mi-
nor)¼16.6 min, tR (major)¼17.2 min. [a]2D2 þ17.2 (c 0.276,
CH2Cl2, 90% ee). [Lit.7e [a]D22 þ17.6 (c 2.7, CH2Cl2, 92%
ee)].
7.61 (d, J¼8.4 Hz, 2H), 7.18e7.30 (m, 20H), 6.71 (s, 2H),
6.25e6.28 (d, J¼8.4 Hz, 2H), 3.99e4.03 (d, J¼12.8 Hz, 2H),
3.34e3.38 (d, J¼12.8 Hz, 2H), 3.18e3.22 (m, 2H), 2.91e2.96
(m, 2H), 2.35e2.41 (m, 2H), 2.34 (s, 3H), 1.69e2.03 (m,
8H) ppm. 13C NMR (100 MHz, CDCl3, 25 ꢁC, TMS):
d 172.77, 153.58, 141.71, 141.64, 129.35, 128.58, 128.41,
127.51, 127.44, 127.31, 127.14, 123.47, 66.68, 56.41,
53.09, 30.16, 23.34, 20.40 ppm. HRMS (ESI) calcd for
C45H48N4O3 (MþH)þ: 693.3799, found: 693.3790.
4.3.4. 2-Trimethylsilyloxy-2(30-chlorophenyl)propanenitrile
(5d)
4.2.2. N,N-Diethyl-(2-hydroxyl-3-adamantyl-5-tert-
butylbenzyl)amine N-oxide (3f)
Yield 93%, 94% ee. 1H NMR (300 MHz, CDCl3): d 0.22 (s,
9H), 1.86 (s, 3H), 7.34e7.55 (m, 4H) ppm. 13C NMR
(75 MHz, CDCl3): d 1.0, 33.4, 70.9, 121.0, 122.7, 124.8,
128.8, 129.9, 134.6, 144.0 ppm. GC analysis (Varian, CP-Chir-
asil DEX CB, 0.25 mmꢂ25 m, 105 ꢁC, 7.5 psi): tR (minor)¼
70.4 min, tR (major)¼71.9 min. [a]2D2 þ22.5 (c 0.214, CH2Cl2,
94% ee). [Lit.7e [a]D26 þ19.6 (c 2.88, CH2Cl2, 90% ee)].
White powder, mp: 158e160 ꢁC. 1H NMR (400 MHz,
CDCl3, 25 ꢁC, TMS): d 7.31 (m, 1H), 6.84 (m, 1H), 4.37 (s,
2H), 3.25e3.30 (q, 4H), 2.19 (m, 6H), 2.05 (m, 3H), 1.72e
1.81 (m, 6H), 1.34 (s, 9H), 1.29e1.33 (m, 6H) ppm. 13C
NMR (100 MHz, CDCl3, 25 ꢁC, TMS): d 157.48, 139.37,
138.42, 126.28, 116.92, 69.01, 59.13, 45.23, 40.34, 37.21,

152
K. Shen et al. / Tetrahedron 64 (2008) 147e153
4.3.5. 2-Trimethylsilyloxy-2(40-chlorophenyl)propanenitrile
(5e)
(major)¼70.4 min. [a]D22 þ17.2 (c 0.235, CH2Cl2, 85% ee).
[Lit.7e [a]D22 þ12.9 (c 1.44, CHCl3, 86% ee)].
1
Yield 90%, 89% ee. H NMR (400 MHz, CDCl3): d 0.19
(s, 9H), 1.83 (s, 3H), 7.37e7.39 (m, 2H), 7.47e7.49 (m,
2H) ppm. GC analysis (Varian, CP-Chirasil DEX CB, 0.25 mmꢂ
25 m, 125 ꢁC, 8 psi): tR (minor)¼28.4 min, tR (major)¼
29.1 min. [a]2D2 þ18.1 (c 0.225, CH2Cl2, 89% ee). [Lit.7e
[a]2D5 þ18.2 (c 2.06, CH2Cl2, 90% ee)].
4.3.11. 2-Trimethylsilyloxy-2-methyl-4-phenyl-3-
butenenitrile (5k)
Yield 92%, 91% ee. 1H NMR (300 MHz, CDCl3): d 0.27 (s,
9H), 1.77 (s, 3H), 6.15 (d, J¼15.9 Hz, 1H), 6.91 (d,
J¼15.9 Hz, 1H), 7.33e7.45 (m, 5H) ppm. 13C NMR
(75 MHz, CDCl3): d 1.3, 30.8, 69.9, 120.6, 126.8, 128.5,
128.7, 129.5, 130.9, 135.1 ppm. HPLC (Chiralcel OD, 2-prop-
anol/n-hexane¼1/99, flow: 0.5 mL/min, 254 nm): tR (minor)-
¼10.1 min, tR (major)¼11.6 min. [a]2D2 þ58.6 (c 0.207,
CH2Cl2, 91% ee). [Lit.12 [a]D25 ꢀ61.9 (c 1.0, CHCl3, 96% ee)].
4.3.6. 2-Trimethylsilyloxy-2(40-methylphenyl)propanenitrile
(5f)
Yield 91%, 86% ee. 1H NMR (400 MHz, CDCl3): d 0.16 (s,
9H), 1.84 (s, 3H), 2.36 (s, 3H), 7.19e7.21 (m, 2H), 7.41e7.44
(m, 2H) ppm. GC analysis (Varian, CP-Chirasil DEX CB,
0.25 mmꢂ25 m, 105 ꢁC, 7.5 psi): tR (minor)¼43.2 min, tR
(major)¼43.9 min. [a]D22 þ17.9 (c 0.173, CH2Cl2, 86% ee).
[Lit.7e [a]D25 þ22.1 (c 2.44, CH2Cl2, 92% ee)].
4.3.12. 2-Trimethylsilyloxy-2-methyl-4-phenylbutanenitrile
(5l)
Yield 92%, 89% ee. 1H NMR (300 MHz, CDCl3): d 0.29 (s,
9H), 1.65 (s, 3H), 2.02e2.08 (m, 2H), 2.80e2.91 (m, 2H),
7.22e7.33 (m, 5H). GC analysis (Varian, CP-Chirasil DEX
CB, 0.25 mmꢂ25 m, 130 ꢁC, 7.5 psi): tR (major)¼34.5 min,
tR (minor)¼33.9 min. [a]2D2 þ11.2 (c 0.305, CH2Cl2, 89%
ee). [Lit.5 [a]D22 þ9.7 (c 1.78, CHCl3, 80% ee)].
4.3.7. 2-Trimethylsilyloxy-2(40-methoxyphenyl)-
propanenitrile (5g)
Yield 88%, 89% ee. 1H NMR (400 MHz, CDCl3): d 0.19 (s,
9H), 1.87 (s, 3H), 3.85 (s, 3H), 6.90e6.93 (m, 2H), 7.44e7.49
(m, 2H) ppm. 13C NMR (100 MHz, CDCl3): d 33.41, 55.33,
71.28, 113.89, 121.81, 126.06, 134.04, 159.80 ppm. GC anal-
ysis (Varian, CP-Chirasil DEX CB, 0.25 mmꢂ25 m, 105 ꢁC,
7.5 psi): tR (minor)¼114.4 min, tR (major)¼116.5 min. [a]D22
þ21.8 (c 0.189, CH2Cl2, 89% ee). [Lit.5 [a]D20 þ22.6
(c 1.09, CHCl3, 91% ee)].
4.3.13. 2-Trimethylsilyloxy-2-methyl-3-methylbutanenitrile
(5m)
Yield 89%, 62% ee. 1H NMR (400 MHz, CDCl3): d 0.24 (s,
9H), 1.03 (t, J¼6 Hz, 6H), 1.53 (s, 3H), 1.84e1.87 (m,
1H) ppm. GC analysis (Varian, CP-Chirasil DEX CB,
0.25 mmꢂ25 m, 60 ꢁC, 8 psi): tR (major)¼17.3 min, tR (mi-
nor)¼16.9 min. [a]D22 ꢀ1.0 (c 0.291, CH2Cl2, 62% ee).
[Lit.7e [a]D22 ꢀ1.1 (c 1.66, CH2Cl2, 90% ee)].
4.3.8. 2-Trimethylsilyloxy-(10-thiophene)-1-carbonitrile (5h)
Yield 78%, 92% ee. 1H NMR (300 MHz, CDCl3): d 0.20 (s,
9H), 2.00 (s, 3H), 6.98e7.00 (m, 1H), 7.21e7.34 (m, 2H) ppm.
13C NMR (75 MHz, CDCl3): d 0.78, 33.40, 68.24, 120.82,
124.70, 125.97, 126.61, 146.27 ppm. GC analysis (Varian,
CP-Chirasil DEX CB, 0.25 mmꢂ25 m, 110 ꢁC, 7 psi):
tR (major)¼22.8 min, tR (minor)¼22.0 min. [a]2D2 þ51.6
(c 0.196, CH2Cl2, 92% ee). [Lit.12 [a]D22 ꢀ57.6 (c 1.0, CHCl3,
97% ee)].
4.3.14. 2-Trimethylsilyloxy-2-methylheptanenitrile (5n)
Yield 95%, 82% ee. 1H NMR (400 MHz, CDCl3): d 0.20 (s,
9H), 2.43e2.47 (m, 1H), 2.70e2.74 (m, 1H), 2.97e3.02 (m,
1H), 3.10e3.15 (m, 1H), 7.28 (d, J¼7.2 Hz, 1H), 7.31 (t,
J¼14.4 Hz, 1H), 7.35e7.37 (m, 1H), 7.55 (d, J¼7.2 Hz,
1H) ppm. 13C NMR (100 MHz, CDCl3): d 1.5, 14.2, 22.7,
24.2, 29.1, 31.7, 43.6, 69.9, 122.4 ppm. GC analysis (Varian,
CP-Chirasil DEX CB, 0.25 mmꢂ25 m, 80 ꢁC, 8 psi): tR (mi-
nor)¼35.5 min, tR (major)¼36.7 min. [a]2D2 þ1.5 (c 0.184,
CH2Cl2, 82% ee). [Lit.7e [a]D22 þ1.0 (c 1.62, CH2Cl2, 79% ee)].
4.3.9. 2-Trimethylsilyloxy-2(20-naphthyl)propanenitrile (5i)
Yield 89%, 96% ee. 1H NMR (300 MHz, CDCl3): d 0.22 (s,
9H), 1.97 (s, 3H), 7.54e7.66 (m, 3H), 7.90e7.93 (m, 3H),
8.07 (d, J¼1.8 Hz, 1H) ppm. HPLC (Chiralcel OJ, 2-propa-
nol/n-hexane¼0.5/99.5, flow: 0.5 mL/min, 254 nm): tR (mi-
nor)¼5.9 min, tR (major)¼7.9 min. [a]2D2 þ14.2 (c 0.194,
CH2Cl2, 96% ee). [Lit.12 [a]D20 ꢀ14.2 (c 1.0, CHCl3, 97% ee)].
4.3.15. 2-Trimethylsilyloxy-2-methylpentanenitrile (5o)
Yield 92%, 75% ee. 1H NMR (400 MHz, CDCl3): d 0.23 (s,
9H), 0.97 (t, J¼6 Hz, 3H), 1.55e1.59 (m, 4H), 2.18 (s,
3H) ppm. 13C NMR (100 MHz, CDCl3): d 1.3, 13.8, 17.7,
30.9, 45.5, 69.6, 122.2 ppm. GC analysis (Varian, CP-Chirasil
DEX CB, 0.25 mmꢂ25 m, 60 ꢁC, 8 psi): tR (minor)¼
24.5 min, tR (major)¼25.3 min. [a]2D2 þ1.0 (c 0.300, CH2Cl2,
75% ee). [Lit.7e [a]D22 ꢀ0.9 (c 1.6, CH2Cl2, 80% ee)].
4.3.10. Trimethylsilyloxy-1,2,3,4-tetrahydronaphthane-
carbonitrile (5j)
Yield 80%, 85% ee. 1H NMR (300 MHz, CDCl3): d 0.24 (s,
9H), 2.02e2.08 (m, 2H), 2.22e2.26 (m, 1H), 2.32e2.36 (m,
1H), 2.83e2.87 (m, 2H), 7.11e7.14 (m, 1H), 7.27e7.30 (m,
2H), 7.66e7.69 (m, 1H). 13C NMR (75 MHz, CDCl3): d 1.3,
18.6, 28.2, 37.6, 69.8, 122.0, 126.6, 127.9, 129.0, 129.2,
135.6, 136.0. GC analysis (Varian, CP-Chirasil DEX CB,
0.25 mmꢂ25 m, 120 ꢁC, 8 psi): tR (minor)¼68.8 min, tR
4.3.16. 2-Cyclohexyl-2-(trimethylsilyloxy)propanenitrile
(5p)4a
1
Yield 90%, 71% ee. H NMR (CDCl3): d 7.40e7.26 (m,
5H), 5.20 (s, 2H), 3.05 (s, 2H), 1.82e1.58 (m, 5H), 1.37 (s,
3H), 1.37e1.04 (m, 6H). 13C NMR (CDCl3): d 177.3, 135.4,

K. Shen et al. / Tetrahedron 64 (2008) 147e153
153
M.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 8647e8651; (e) Yabu, K.;
Masumoto, S.; Kanai, M.; Curran, D. P.; Shibasaki, M. Tetrahedron Lett.
2002, 43, 2923e2926.
128.6, 128.5, 128.2, 76.9, 67.3, 45.6, 27.3, 26.3, 26.2, 26.1,
25.6. HPLC (Chiralcel AD, 2-propanol/hexane¼5/95,
0.5 mL/min, 220 nm): tR (minor)¼8.06 min, tR (major)¼
8.72 min. [a]2D2 þ6.25 (c 0.170, CH2Cl2, 71% ee). [Lit.4a
[a]2D5 þ15.1 (c 1.52, CHCl3, 90% ee)].
5. Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2002, 41, 1009e1012.
6. (a) Shen, Y. C.; Feng, X. M.; Zhang, G. L.; Jiang, Y. Z. Synlett 2002,
1353e1355; (b) Shen, Y. C.; Feng, X. M.; Li, Y.; Zhang, G. L.; Jiang,
Y. Z. Eur. J. Org. Chem. 2004, 129e137.
Acknowledgements
7. (a) Chen, F. X.; Feng, X. M.; Qin, B.; Zhang, G. L.; Jiang, Y. Z. Org. Lett.
2003, 5, 949e952; (b) Chen, F. X.; Qin, B.; Feng, X. M.; Zhang, G. L.;
Jiang, Y. Z. Tetrahedron 2004, 60, 10449e10460; (c) He, B.; Chen,
F. X.; Li, Y.; Feng, X. M.; Zhang, G. L. Tetrahedron Lett. 2004, 45,
5465e5467; (d) He, B.; Chen, F. X.; Li, Y.; Feng, X. M.; Zhang, G. L.
Eur. J. Org. Chem. 2004, 4657e4666; (e) Chen, F. X.; Zhou, H.; Liu,
X. H.; Qin, B.; Feng, X. M. Chem.dEur. J. 2004, 10, 4790e4797.
8. Xiong, Y.; Huang, X.; Gou, S. H.; Weng, Y. H.; Feng, X. M. Adv. Synth.
Catal. 2006, 348, 538e544.
We thank the National Nature Science Foundation of China
(No. 20602025) for financial support. We also thank Sichuan
1
University Analytical and Testing Center for H NMR and
13C NMR spectral analysis.
References and notes
9. (a) Li, Q. H.; Liu, X. H.; Wang, J.; Shen, K.; Feng, X. M. Tetrahedron
Lett. 2006, 47, 4011e4014; (b) Li, Q. H.; Chang, L.; Liu, X. H.; Feng,
X. M. Synlett 2006, 1675e1678.
1. For reviews on the synthesis and applications of cyanohydrins, see: (a)
North, M. Synlett 1993, 807e820; (b) Effenberger, F. Angew. Chem.
1994, 106, 1609e1619; Angew. Chem., Int. Ed. Engl. 1994, 33, 1555e
1564; (c) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649e3682; (d) Mori,
A.; Inoue, S. Cyanation of Carbonyl and Amino Groups. In Comprehen-
sive Asymmetric Synthesis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Heidelberg, 1999; pp 983e992; (e) Ojima, I. Catalytic
Asymmetric Synthesis; Wiley: New York, NY, 2000; pp 235e284; (f)
Smith, M. B.; March, J. March’s Advanced Organic Chemistry, 5th ed.;
Wiley & Sons: New York, NY, 2001; pp 1239e1240; (g) North, M.
Tetrahedron: Asymmetry 2003, 14, 147e176; (h) North, M. Science of
Synthesis; Murahash, S.-I., Ed.; Thieme: Stuttgart, 2004; Vol. 19,
pp 235e284; (i) Special symposium for the synthesis of nonracemic cya-
nohydrins, see:Tetrahedron 2004, 60, 10371e10377.
10. (a) Tian, S. K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195e6196; (b)
Tian, S. K.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900e9901.
11. Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384e5387.
12. Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964e8965.
13. Liu, X. H.; Qin, B.; Zhou, X.; He, B.; Feng, X. M. J. Am. Chem. Soc.
2005, 127, 12224e12225.
14. (a) Ma, J. A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566e4583; (b)
Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989e
1999; (c) Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49, 511e
524; (d) Rawlands, G. J. Tetrahedron 2001, 57, 1865e1882; (e) Shibasaki,
M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. 1997, 36, 1236e1256.
´
´
15. Trost, B. M.; Martınez-Sanchez, S. Synlett 2005, 0627e0630.
16. Kim, Y. B.; Kim, M. K.; Kang, S. H.; Kim, Y. H. Synlett 2005, 1995e
1998.
2. For reviews on the catalytic asymmetric cyanation of aldehydes and
ketones, see: (a) Brunel, J. M.; Holmes, I. P. Angew. Chem., Int. Ed. 2004,
43, 2752e2778; (b) Chen, F. X.; Feng, X. M. Synlett 2005, 892e899; (c)
Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491e
1508; (d) Achard, T. R. J.; Clutterbuck, L. A.; North, M. Synlett 2005,
1828e1847.
17. (a) Kazuhiko, N.; Nobuhiro, H.; Isao, S. Tetrahedron Lett. 1997, 38,
5005e5008; (b) Dimmock, J. R.; Erciyas, E.; Kuma, P.; Hetherington,
M.; Quail, J. W.; Pugazhenthi, U.; Arpin, S. A.; Hayes, S. J.; Allen,
T. M.; Halleran, S.; Clercq, E. D.; Balzarini, J.; Stables, J. P. Eur. J.
Med. Chem. 1997, 32, 583e594.
3. Belokon, Y. N.; Green, B.; Ikonnikov, N. S.; North, M. Tetrahedron Lett.
1999, 40, 8147e8150.
18. (a) Guillaneux, D.; Zhao, S. H.; Samuel, O.; Rainford, D.; Kagan, H. B.
J. Am. Chem. Soc. 1994, 116, 9430e9439; (b) Avalos, M.; Babiano, R.;
Cintas, P.; Jimenez, J. L.; Placios, J. C. Tetrahedron: Asymmetry 1997,
8, 2997e3017; (c) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed.
1998, 37, 2922e2959; (d) Blackmond, D. G. Acc. Chem. Res. 2000, 33,
402e411.
4. (a) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000,
122, 7412e7413; (b) Hamashima, Y.; Kanai, M.; Shibasaki, M. Tetra-
hedron Lett. 2001, 42, 691e694; (c) Yabu, K.; Masumoto, S.; Yamasaki,
S.; Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 9908e9909; (d) Masumoto, S.; Suzuki, M.; Kanai,