Enantioselective cyanosilylation of ketones by a catalytic double-activation method with an aluminium complex and an N-oxide

Article abstract of DOI:10.1002/chem.200400506

Double-activation catalysis promises high catalytic efficiency in the enantioselective cyanosilylation of ketones through the combined use of a Lewis acid and a Lewis base. Catalyst systems composed of a chiral salen-Al complex and an N-oxide have high ca

Full text of DOI:10.1002/chem.200400506

FULL PAPER
Enantioselective Cyanosilylation of Ketones by a Catalytic Double-
Activation Method with an Aluminium Complex and an N-Oxide
Fu-Xue Chen,[a] Hui Zhou,[a] Xiaohua Liu,[a] Bo Qin,[a] Xiaoming Feng,*[a]
Guolin Zhang,[b] and Yaozhong Jiang[c]
Abstract: Double-activation catalysis
promises high catalytic efficiency in the
enantioselective cyanosilylation of ke-
tones through the combined use of a
Lewis acid and a Lewis base. Catalyst
systems composed of a chiral salen–Al
complex and an N-oxide have high cat-
alytic turnovers (200 for aromatic ke-
tones, 1000 for aliphatic ones). With
these catalysts, a wide range of aliphat-
ic and aromatic ketones were convert-
ed under mild conditions into tertiary
cyanohydrin O-TMS ethers in excellent
yields and with high enantioselectivities
(94% ee for aromatic ketones, 90% ee
for aliphatic ones). Preliminary mecha-
nistic studies revealed that the salen–
Al complex played the role of a Lewis
acid to activate the ketone and the N-
oxide that of a Lewis base to activate
TMSCN; that is, double activation.
Keywords: asymmetric catalysis
·
cyanohydrins · double activation ·
enantioselectivity · ketones
Introduction
Optically active cyanohydrins are versatile intermediates in
organic synthesis.[1,2] Enantioselective cyanosilylation and
cyanocarbonation of ketones with the aid of metal-based
Lewis acids[3–6] and organic bases[7] have been reported as
the common approaches for the asymmetric synthesis of
non-racemic tertiary cyanohydrins. These reports provide
useful methods for the enantioselective construction of qua-
ternary stereocenters from prochiral ketones.[1] However,
the development of asymmetric cyanosilylation of ketones is
still a challenge in terms of catalyst efficiency and substrate
generality. Here we describe an advance toward this goal
through double-activation catalysis (Scheme 1).[8]
Scheme 1. General concept of the double-activation catalysis.
addition of TMSCN (TMS = trimethylsilyl) to aldehydes by
salen–TiIV complexes,[10a,b] and bifunctional N-oxide titanium
complex-catalyzed enantioselective cyanosilylation of ke-
tones.[10c,d] Subsequently, a double-activation catalyst system
for the syntheses of racemic and non-racemic cyanohydrins
has been developed.[11] Our strategy involves the simulta-
neous activation of the substrate ketone by Lewis acid and
of the reagent TMSCN by Lewis base (Scheme 1). Guided
by this hypothesis, series of metal complexes with ligands
1a–n (Figure 1) and N-oxides 2a–e (Figure 2) were prepared
and applied to the asymmetric cyanosilylation of ketones,
with high catalytic turnovers of up to 1000.
We have recently reported asymmetric Strecker reactions
promoted by stoichiometric chiral N-oxides,[9] asymmetric
[a] Dr. F.-X. Chen, H. Zhou, X. Liu, B. Qin, Prof. X. Feng
Key Laboratory of Green Chemistry
and Technology (Sichuan University)
Ministry of Education, College of Chemistry
Sichuan University
Chengdu 610064 (China)
Fax : (+86)288-541-8249
Results and Discussion
E-mail: xmfeng@scu.edu.cn
Optimization of the catalysts: Building on the understanding
of the catalytic capability of salen–metal complexes in the
asymmetric addition of TMSCN to carbonyl com-
pounds,[10a,11] complexes of different metals with 1a were
used to catalyze the cyanosilylation of acetophenone at
À208C with 2 equiv TMSCN with respect to acetophenone
as the model reaction. The results are summarized in
[b] Prof. G. Zhang
Chengdu Institute of Biology
Chinese Academy of Sciences
Chengdu 610041 (China)
[c] Prof. Y. Jiang
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences
Chengdu 610041 (China)
4790
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200400506
Chem. Eur. J. 2004, 10, 4790 – 4797

4790 – 4797
ligand was beneficial to the enantioselectivity (Table 2,
entry 5 vs entries 1–4). The presence of the larger adaman-
tanyl group at the 3’-position even abolished the asymmetric
inductivity completely (Table 2, entry 4). Substituents at the
5’-position also had important effects on the ee values: it
could be seen that an appropriate electron-deficient group
at the 5’-position of the ligand produced a higher enantiose-
lectivity than an electron-rich or a sterically bulky one
(Table 2, entries 6–11). The catalyst derived from the 5’-
bromo-substituted 1k exhibited the highest enantioselectivi-
ty. Tetradentate analogue (1l) gave poor enantioselectivity
(Table 2, entry 12). Selected bidentate ligands and tridentate
mono-Schiff bases had no asymmetric inductivity at all
(Table 2, entries 13–17).
Table 2. Effect of the ligand structure on the enantioselectivity.[a]
Entry
1[c]
2
3
4
Ligand
Yield [%]
ee [%][b]
Figure 1. Ligands evaluated in this study.
1a
1b
1c
1d
1e
1 f
45
99
99
trace
52
83
70
53
0
81
75
5
6
94
7
8
1g
1h
7382
99
81
83
73
88
51
0
0
0
0
9
1i
1j
1k
1l
1m
1n
(R)-binol
l-taddol
50
99
96
45
ND
19
trace
12
10
11
12
13
14
15
16
Figure 2. N-oxides assessed in this study.
[a] All reactions were carried out with chiral Al complex (1:1, 2 mol%)
and N-oxide 2d (1 mol%) at À208C over 24 h, TMSCN (2 equiv), con-
centration of acetophenone = 0.8m in CH2Cl2. [b] Determined by chiral
GC analysis on Chirasil DEX CB. [c] This was performed at À208C for
120 h with the indicated amount of the catalysts, concentration of aceto-
phenone = 0.12m in CH2Cl2.
Table 1. Et3Al gave more promising enantioselectivity than
Ti(OiPr)4 (Table 1, entries 1 and 2). Although Et2AlCl ex-
hibited higher enantioselective inductivity than Et2AlCN
and Al(OiPr)3, the chemical yield was poor (Table 1, en-
tries 5 vs 3/4). Other metals such as Ni(acac)2 and Cu(OTf)2
catalyzed this reaction but with no enantioselectivity
(Table 1, entries 7 and 8). Et3Al was thus chosen to assess
the following ligands.
Tetradentate, tridentate, and bidentate ligands (see
Figure 1) were then examined for enantioselectivity, with
the results listed in Table 2. The data suggested that smaller
H atom at the 3’-position of the phenolic ring in the salen
To investigate the effect of the third Et group attached to
the aluminium in 1k·Et3Al complex, series of counterions
were employed to generate the Lewis acids. The results in
Table 3demonstrate that counterions had slight effect on
the enantioselectivity. Sterically hindered phenolic ions de-
creased the enantioselectivity slightly (Table 3, entries 1–3),
but the reaction rate sharply (Table 3, entry 3). Other phe-
nolic ions showed few effects on the ee values (Table 3, en-
tries 4–6). Further, 13C NMR analysis indicated that this Et
group did not exchange with cyanide under the reaction
conditions.[12]
Table 1. Asymmetric cyanosilylation of acetophenone catalyzed by Lewis
acids and N-oxides.[a]
Entry
Lewis acid (mol%)
2d [mol%]
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
1a·Ti(OiPr)4 (2)
1a·AlEt3 (2)
1a·Al(OiPr)3 (2)
1a·Et2AlCN (2)
1a·Et2AlCl (2)
1a·Et2Zn (2)
1
1
1
1
1
1
1
1
11
45
17
36
trace
trace
trace
80
74
83
14
56
87
72
0
Solvent effects were studied next, with the results sum-
marized in Table 4. In moderately polar solvents, this trans-
formation proceeded with comparable enantioselectivities
(Table 4, entries 1–3). THF was the most favorable solvent
for enantioselectivity (Table 4, entry 4). Use of more polar
solvents, however, reduced the enantioselectivities (Table 4,
entry 5). No reaction occurred in the dipolar solvent DMSO
(Table 4, entry 6).
1a·Ni(acac)2 (2)
1a·Cu(OTf)2 (2)
0
[a] All reactions were carried out at À208C for 78 h with the indicated
amount of the catalysts, TMSCN (2 equiv), concentration of acetophe-
none = 0.8m in CH2Cl2. [b] Determined by chiral GC analysis on Chira-
sil DEX CB.
Various N-oxides[13a] and other dipolar molecules were
evaluated in the model reaction, with the results listed in
Chem. Eur. J. 2004, 10, 4790 – 4797
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X. Feng et al.
FULL PAPER
Table 3. Counterion effect on the enantioselectivity.[a]
Table 5. Asymmetric cyanosilylation of acetophenone catalyzed by
1k·AlEt3 complex and Lewis bases.[a]
Entry
1
Counterion
none
Yield [%]
96
ee [%][b]
Entry
Lewis base
Yield [%]
ee [%][b]
88
1
2
3
4
5
6
2a
2b
2c
2d
2e
Ph3PO
98
98
92
95
96
62
28
65
81
90
75
88
2
99
77
72
3
27
[a] All reactions were carried out with 1k·AlEt3 complex (1:1, 2 mol%)
and Lewis base (1 mol%) at À208C over 24 h, TMSCN (2 equiv), con-
centration of acetophenone = 0.8m in THF. [b] Determined by chiral
GC analysis on Chirasil DEX CB.
4
5
76
95
86
80
6
9381
(Table 6, entries 6–8). The practical level of catalyst for this
reaction is 0.5 mol%. Fortunately, the greatly reduced reac-
tion rate caused by low catalyst loading could be overcome
to some extent by increasing the concentration (Table 6, en-
tries 7–8). It was not to be recommended that this transfor-
mation be performed with no solvent (Table 6, entry 9).
[a] All reactions were carried out with 1k·AlEt3 complex (1:1, 2 mol%)
and N-oxide 2d (1 mol%) at À208C over 24 h, TMSCN (2 equiv), con-
centration of acetophenone = 0.8m in CH2Cl2. [b] Determined by chiral
GC analysis on Chirasil DEX CB.
Table 4. Solvent effect on the enantioselectivity.[a]
Entry
Solvent
Yield [%]
ee [%][b]
1
2
CH2Cl2
Et2O
96
95
88
87
Table 6. Effects of the catalyst loading and the metal/ligand ratio on the
enantioselectivity.[a]
3benzene
99
86
Entry 1k/Et3Al/2d
[PhCOCH3]
[m]
t [h/
d]
Yield
[%]
ee
4
5
6
THF
CH3CN
DMSO
95
89
NR
90
77
–
[mol%]
[%][b]
1
2
5:5:2.5
2:2:1
0.8
0.8
24 h
24 h
82
24 h
24 h
36 h
46 h
16 d
20 d
41
95
77
90
[a] All reactions were carried out with 1k·AlEt3 complex (1:1, 2 mol%)
and N-oxide 2d (1 mol%) at À208C over 24 h, TMSCN (2 equiv), con-
centration of acetophenone = 0.8m. [b] Determined by GC analysis on
Chirasil DEX CB.
32.5:2:1
0.8
24 h
86
4
5
6
7
8
9
2.2:2:1
1.8:2:1
1:1:0.5
0.5:0.5:0.25
0.09:0.09:0.045
0.01:0.01:0.005
0.8
0.8
0.8
1.5
2.4
no solvent
97
99
98
94
99
trace
85
88
92
93
94
63
Table 5. Cyclic and acyclic tertiary amine N-oxides exhibited
varying enantioselectivities (Table 5, entries 1–3). Aromatic
tertiary aniline N-oxide (2d) was the best Lewis basic com-
plementary catalyst (Table 5, entry 4). The presence of a
methyl substituent on the phenyl ring of 2d was not benefi-
cial to the enantioselectivity (Table 5, entry 5). Dipolar
phosphine oxide was able to promote this reaction with a
moderate enantioselectivity (Table 5, entry 6) by activating
the nucleophilic TMSCN.[5,14] There are a great many exam-
ples of stable complexes between N-oxides and diverse met-
als,[13b] but in this case N-oxides and metal complexes could
be used cooperatively to catalyze the enantioselective cya-
nosilylation of ketones, which removed concerns relating to
binding between Lewis acid and Lewis base.[8b] N-Oxides
have frequently been employed in asymmetric organic syn-
thesis.[13c–e]
[a] All reactions were carried out at À208C in THF with TMSCN
(2 equiv) under the conditions indicated. [b] Determined by GC analysis
on Chirasil DEX CB.
Temperature clearly affected the enantioselectivity, as
shown in Table 7. The optimum enantioselectivity—of
93% ee—was obtained on reduction of the temperature
from 0 to À208C (Table 7, entries 1–2). Curiously, any fur-
ther decrease in the reaction temperature greatly reduced
the enantioselectivities (Table 7, entries 3–4).
Table 7. Temperature effect on the enantioselectivity.[a]
The catalyst loading and ratio were investigated intensive-
ly, with the results summarized in Table 6. Higher catalyst
loading (5 mol%) was inferior to lower loading (2 mol%) in
terms of catalyst efficiency (Table 6, entries 1 vs 2), which
might be a result of the increased possibility of binding be-
tween Lewis acid and Lewis base at higher catalyst concen-
trations in the reaction mixture (see Table 9, entry 4). Any
deviation of the molar ratio of 1k to AlEt3 from 1:1 resulted
in a certain decrease in the enantioselectivity (Table 6,
entry 2 vs 3/4/5). Interestingly, a slightly higher enantioselec-
tivity was obtained if a lower catalyst loading was applied
Entry
T [8C]
Yield [%]
ee [%][b]
1
2
3
4
0
95
94
81
14
87
93
57
66
À20
À40
À78
[a] All reactions were carried out with 1k·AlEt3 complex (1:1, 0.5 mol%)
and Lewis base (0.25 mol%) at À208C over 46 h, TMSCN (2 equiv), con-
centration of acetophenone = 1.5m in THF. [b] Determined by GC anal-
ysis on Chirasil DEX CB. In summary, the optimum catalyst efficiency
could be achieved under these conditions: 1k·AlEt3 complex (0.1–
0.5 mol%), N-oxide 2d (0.05–0.25 mol%), TMSCN (2 equiv), [ketone] =
2.4–1.5m in THF, À208C.
4792
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Enantioselective Cyanosilylation
4790 – 4797
Table 8. Enantioselective cyanosilylation of ketones catalyzed by 1k·AlEt3 complex and N-oxide 2d.[a]
or b-acetonaphthone, however,
gave smaller ee values than ace-
tophenone (Table 8, entries 9,
10 vs 1). Aliphatic ketones en-
joyed catalytic turnovers as
high as 1000 with excellent
chemical yields and moderate
to excellent enantioselectivities
(Table 8, entries 11–13). Nota-
bly the non-functionalized alkyl
ketone 3m was converted with
such high enantioselectivity
(Table 8, entry 13) for the first
Entry
1
Ketone
3
Method
t [h/d]
Yield [%]
ee [%][b]
A
B
46 h
16 d
94
99
93[c]
94
3a
A
B
48 h
9.5 d
99
99
92
90
2
3b
3
4
3c
3d
A
A
28 h
66 h
98
99
92 time.
About the mechanism: To pro-
vide insight into the mecha-
nism, control experiments were
performed. As shown in
Table 9, neither 1k·AlEt3 com-
plex nor the N-oxide 2d on its
own was effective enough to ac-
90
92
5
6
3e
3 f
A
24 h
99
A
B
3 2 h
9 d
99
99
88
92
celerate
TMSCN
the
to
addition
acetophenone
of
(Table 9, entries 1, 2). Only
when these two were used syn-
ergistically in a double-activa-
tion way could this transforma-
A
B
40 h
7 d
99
99
86
90
7
8
3g
3h
tion
perform
excellently
A
B
3 6 h
9 d
95
95
90
90
(Table 9, entry 3). In addition,
when the N-oxide was mixed
with the Lewis acid at the start
of the reaction, rather than by
following the typical procedure
(see Experimental Section), the
product was obtained with com-
parable enantioselectivity but in
low yield (Table 9, entry 4 vs.
3).
Moreover, in comparison
with other dipolar molecules
such as chiral N-oxides[9,13c–f]
and phosphine oxide,[14] the N-
oxide 2d in this system should
act as Lewis base rather than
additively[15] to coordinate to,
and thus activate, the nucleo-
phile TMSCN. Entries 5 and 6
in Table 9 also collaterally pro-
vide evidence for the double-
activation hypothesis with the
A
B
40 h
13d
92
99
84
87
9
3i
3j
A
B
3 d
16 d
96
99
79
10
81(>99)[d]
11
12
3k
3l
B
B
36 h
36 h
99
95
79
80
13
3m
B
36 h
80
90
[a] Method A: 1k·AlEt3 complex (1:1, 0.5 mol%), 2d (0.25 mol%), TMSCN (2 equiv), À208C, [ketone] =
1.5m in THF. Method B: 1k·AlEt3 complex (1:1, 0.1 mol%), 2d (0.05 mol%), TMSCN (2 equiv), À208C,
[ketone] = 2.4m in THF. [b] Determined by GC analysis on Chirasil DEX CB. [c] The absolute configuration
was established as R by comparison of the sign of the optical rotation value with that in the literature
(ref. [5c]). [d] Determined by HPLC analysis on Chiralpak OJ. The ee value in parentheses was obtained after
recrystallization of the product from n-hexane.
Substrate generality: This highly efficient catalyst system
tolerated a wide range of aromatic, aliphatic, heterocyclic,
and sterically bulky cyclic ketones as the substrates under
the optimized conditions. As depicted in Table 8, aromatic
and bulky cyclic ketones were converted into the corre-
sponding O-TMS cyanohydrins (4a–m) both in excellent
chemical yields (94–99%) and with excellent enantioselec-
tivities (90–94% ee; Table 8, entries 1–8). The ethyl ketone
use of (R)-binol titanium complex and (R)-3,3’-dimethyl-
2,2’-biquinoline N,N’-dioxide (OBIQ).[13c] Direct evidence of
the coordination of the N-oxide to TMSCN was observed by
1H NMR analyses.[16] Therefore, salen–Al complex and N-
oxide should work cooperatively in the model of asymmetric
double-activation catalysis, the aluminium complex as a
Lewis acid to activate the substrate ketone and the N-oxide
as a Lewis base to activate the TMSCN.
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X. Feng et al.
FULL PAPER
Table 9. Control experiments.[a]
Experimental Section
Entry
1k [mol%]
2d [mol%]
Yield [%]
ee [%][b]
1
General: H NMR spectra were recorded on a Varian Unity INOVA 400
machine (400 MHz) or on Bruker instruments (600, 300 MHz). Chemical
shifts are reported in ppm from tetramethylsilane with the solvent reso-
nance as the internal standard (CDCl3, dH = 7.26). Data are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
m = multiplet), coupling constants (Hz), integration, and assignment.
13C NMR data were also collected on a Varian Unity INOVA 400 ma-
chine (100 MHz) or on Bruker instruments (150, 75 MHz) with complete
proton decoupling. Chemical shifts are reported in ppm from tetrame-
1
2
30.5
4[c]
5[d]
6[d]
0
0.5
0.25
0
94
0.25
0
0
–
–
0.25
93
0.5
21
11
21
92
43
51
(R)-binol·Ti(OiPr)4
(R)-binol·Ti(OiPr)4
(Æ)-OBIQ
(R)-OBIQ
[a] Conditions: À208C, 46 h, TMSCN (2 equiv), [PhCOCH3] = 1.5m in
THF. [b] Determined by GC analysis on Chirasil DEX CB. [c] 1k, AlEt3,
and 2d were mixed together at the start of the reaction to generate the
catalyst at RT for 1 h, followed by addition of acetophenone and
TMSCN. [d] This was carried out with 20 mol% of the titanium complex
and 20 mol% of OBIQ at 08C over 84 h, [PhCOCH3] = 0.12m, OBIQ =
3,3’-dimethyl-2,2’-biquinoline N,N’-dioxide (ref. [13c]).
thylsilane with the solvent resonance as internal standard (CDCl3, dC
=
77.0). Elemental analyses were performed on a Carlo-1160 apparatus.
Enantiomer ratios were determined by chiral GC analysis on Varian
Chirasil DEX CB or by chiral HPLC analysis on Daicel Chiralcel OD/OJ
in comparison with the authentic racemates. Optical rotation data were
recorded on a Perkin–Elmer Polarimeter-341. All ketones, TMSCN, sub-
stituted salicylal and chiral molecules [(1S,2S)-diamines, (1R,2S)-amino
alcohol, (R)-binol, l-taddol)] were purchased from Acros, Aldrich, and
Fluka, and were used directly without further purification. Solvents were
purified by conventional methods.
Consequently, the two components were activated as cor-
responding intermediates A and B as shown in Figure 3, in
which an isocyanide species was involved.[17] The activated
nucleophile and substrate attracted and approached one an-
other, and so the transition state C was formed.[18] Forma-
(1S,2S)-Salen (1a):[10a] m.p. 195–1978C (lit. 199–2008C);[10a] [a]2D2
= +
33.3 (c = 0.6, CHCl3) [lit. [a]2D0 +32.4 (c = 0.25, CHCl3)];[10a] 1H
=
NMR (400 MHz, CDCl3): d = 1.22 (d, J = 1.6 Hz, 18H; 2”C(CH3)3),
À
tion of the more stable O Si bond then promoted the intra-
À
1.42 (d, J = 2.0 Hz, 18H; 2”C(CH3)3), 4.73(d, J = 1.6 Hz, 2H; CH
molecular transfer of cyanide to carbonyl group, yielding
the product cyanohydrin O-TMS ether. Further mechanistic
investigations should be aimed at illustrating the actual cata-
lytic cycle of the double-activation catalysis.
CH), 6.98 (m, 2H; aromatic H), 7.16–7.20 (m, 10H; aromatic H), 7.31 (d,
J = 2.4 Hz, 2H; aromatic H), 8.40 (d, J = 1.2 Hz, 2H; 2”CH=N), 13.60
(d, J = 2.0 Hz, 2H; 2”ArOH, exchangeable with D2O) ppm; 13C NMR
(100 MHz, CDCl3): d = 29.4, 31.4, 34.0, 35.0, 80.1, 117.8, 126.3, 127.1,
127.4, 128.0, 128.2, 136.3, 139.8, 140.0, 157.9, 167.2 ppm.
(1S,2S)-Salen (1b):[10a] m.p. 69–718C; [a]D22 = À140.4 (c = 0.99, CH2Cl2);
1H NMR (400 MHz, CDCl3): d = 1.41 (s, 18H; 2”tBu), 2.18 (s, 6H; 2”
À
Me), 4.68 (s, 2H; CH CH), 6.77 (d, J = 1.6 Hz, 2H; aromatic H), 7.05
(d, J = 1.6 Hz, 2H; aromatic H), 7.17–7.21 (m, 10H; aromatic H), 8.30
(s, 2H; 2”CH=N), 13.50 (s, 2H; 2”ArOH) ppm; 13C NMR (100 MHz,
CDCl3): d = 20.6, 29.3, 34.7, 80.2, 118.2, 126.5, 127.4, 128.0, 128.3, 130.0,
130.6, 136.7, 140.0, 157.9, 166.9 ppm.
(1S,2S)-Salen (1c): m.p. 109–1108C; 1H NMR (400 MHz, CDCl3): d =
À
4.76 (s, 2H; CH CH), 7.09 (d, J = 2.4 Hz, 2H; aromatic H), 7.12–7.15
(m, 4H; aromatic H), 7.20–7.23(m, 6H; aromatic H), 7.83 (d,
J =
2.8 Hz, 2H; aromatic H), 8.27 (s, 2H; 2”CH=N), 14.07 (s, 2H; 2”Ar-
OH) ppm; 13C NMR (100 MHz, CDCl3): d = 80.0, 119.4, 122.5, 123.4,
127.7, 128.1, 128.7, 129.5, 132.6, 138.0, 155.6, 164.6 ppm; HRMS (ESI):
calcd for C28H20Cl4N2O2: 557.0352; found 557.0356 [M+H]+.
(1S,2S)-Salen (1d): The precursor 3-adamantanyl-5-tert-butylsalicylalde-
hyde was synthesized similarly to the literature procedure.[19] M.p.
128–1308C; 1H NMR (400 MHz, CDCl3): d = 1.33 (s, 9H; tBu), 1.79 (s,
6H; adamantanyl H), 2.09–2.14 (m, 9H; adamantanyl H), 7.33 (d, J =
1.6 Hz, 1H; aromatic H), 7.53(s, 1H; aromatic H), 9.86 (s, 1H;
CHO) ppm; 13C NMR (100 MHz, CDCl3): d = 28.9, 31.3, 34.3, 37.0, 37.2,
Figure 3. The proposed intermediates and transition state involved in the
enantioselective cyanosilylation of ketones by double-activation catalysis.
40.2, 119.9, 127.7, 132.0, 137.8, 141.7, 159.3, 197.5 ppm; IR (KBr): n˜max
=
2954, 1649, 1618, 1459 cmÀ1
.
Compound 1d: m.p. 190–1928C; [a]D22
=
À75.0 (c
=
1.2, CH2Cl2);
1H NMR (400 MHz, CDCl3): d = 1.22 (s, 18H; 2”tBu), 1.57 (s, 4H; ada-
Conclusion
mantanyl H), 1.84 (m, 10H; adamantanyl H), 2.08–2.16 (m, 16H; ada-
À
mantanyl H), 4.72 (s, 2H; CH CH), 6.97 (s, 2H; aromatic H), 7.18 (m,
10H; aromatic H), 7.26 (d, J = 1.2 Hz, 2H; aromatic H), 8.40 (s, 2H; 2”
CH=N), 13.52 (s, 2H; 2”ArOH) ppm; 13C NMR (100 MHz, CDCl3): d =
29.1, 31.4, 34.1, 37.2, 40.2, 80.1, 117.9, 126.3, 127.1, 127.3, 128.0, 128.2,
136.6, 139.8, 140.0, 158.2, 167.4 ppm; IR (KBr): n˜max = 1626 cmÀ1 (CH=
N); HRMS (ESI): calcd for C56H68N2O2: 801.5354 [M+H]+; found
801.5374 [M+H]+.
In conclusion, the work in this paper has demonstrated the
feasibility of the application of double-activation catalysis in
asymmetric addition of TMSCN to aromatic and aliphatic
ketones. It is efficient and practical. The catalyst has high
catalytic turnover (200 for aromatic ketones, 1000 for ali-
phatic ones) and gives excellent yields (up to 99%) and
competitive enantioselectivities (up to 94% ee for aromatic
ketones, up to 90% ee for aliphatic ones). Further efforts
should be devoted to the optimization of the catalyst to en-
hance both enantioselectivity and reactivity, and also to
mechanistic clarification of this reaction.
(1S,2S)-Salen (1e):[10a] m.p. 155–1568C; [a]D22 = À12.4 (c = 1.37, CH2Cl2)
1
{lit. [a]2D0 = À11.9 (c = 1.0, CHCl3)}[10a]; H NMR (400 MHz, CDCl3): d
À
= 4.73(s, 2H; CH CH), 6.81 (dt, J = 8.4, 2.0 Hz, 2H; aromatic H), 6.95
(d, J = 8.4 Hz, 2H; aromatic H), 7.11–7.28 (m, 14H; aromatic H), 8.29
(s, 2H; 2”CH=N), 13.32 (s, 2H; 2”ArOH) ppm; 13C NMR (100 MHz,
CDCl3): d = 80.2, 116.9, 118.5, 118.7, 127.6, 127.8, 128.3, 131.7, 132.5,
139.3, 160.9, 166.1 ppm
4794
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4790 – 4797

Enantioselective Cyanosilylation
4790 – 4797
(1S,2S)-Salen (1 f): m.p. 55–568C; [a]2D2 = +13.0 (c = 1.61, CH2Cl2); 1H
N,N-Dimethylaniline N-oxide (2d):[13a] 1H NMR (400 MHz, CDCl3): d =
3.66 (s, 6H; CH3), 7.39–7.50 (m, 3H; aromatic H), 7.93 (d, J = 8 Hz,
2H; aromatic H) ppm; 13C NMR (100 MHz, CDCl3): d = 62.7, 119.7,
129.1, 129.3, 153.6 ppm.
N-Oxide (2e):[13a] 1H NMR (600 MHz, [D6]DMSO): d = 2.08 (s, 3H;
CH3), 2.32 (s, 6H; (CH3)2N), 7.25 (d, J = 8.4 Hz, 2H; aromatic H), 7.93
(d, J = 8.4 Hz, 2H; aromatic H) ppm. 13C NMR (150 MHz, [D6]DMSO):
d = 20.4, 62.7, 120.2, 129.1, 138.1, 152.4 ppm.
À
NMR (400 MHz, CDCl3): d = 2.21 (s, 6H; 2”Me), 4.69 (s, 2H; CH
CH), 6.86 (m, 2H; aromatic H), 6.92 (m, 2H; aromatic H), 7.06–7.09 (m,
2H; aromatic H), 7.16–7.21 (m, 10H; aromatic H), 8.26 (s, 2H; 2”CH=
N), 13.07 (s, 2H; 2”ArOH) ppm; HRMS (ESI): calcd for C30H28N2O2:
449.2224; found 449.2222 [M+H]+.
(1S,2S)-Salen (1g):[10a] m.p. 91–938C [lit. 89–918C];[10a] [a]D22 = +12.0 (c
=
3.58, CH2Cl2) {lit. [a]2D0 4.0, CH2Cl2)};[10a] 1H NMR
= +4.9 (c =
(400 MHz, CDCl3): d = 3.70 (s, 6H; 2”CH3O), 4.71 (s, 2H; CH CH),
6.64 (s, 2H; aromatic H), 6.89 (m, 4H; aromatic H), 7.16–7.21 (m, 10H;
aromatic H), 8.26 (s, 2H; 2”CH=N), 12.82 (s, 2H; 2”ArOH) ppm; 13C
NMR (100 MHz, CDCl3): d = 55.8, 80.3, 114.9, 117.6, 118.1, 119.8, 127.6,
127.8, 128.4, 139.3, 152.0, 155.1, 165.9 ppm.
(R)-3,3’-Dimethyl-2,2’-bisquinoline N,N’-dioxide (OBIQ):[13c] This com-
À
pound was prepared and resolved by the literature procedure.[13c] m.p.
223–2258C; [a]2D0
=
À88.6 (c
=
0.64, CHCl3); 1H NMR (400 MHz,
CDCl3): 2.27 (s, 6H; 2”CH3), 7.73–7.64 (m, 6H; aromatic H), 7.86 (d, J
= 7.6 Hz, 2H; H5 and H5’), 8.72 (d, J = 9.2 Hz, 2H; H8 and H8’) ppm;
13C NMR (100 MHz, CDCl3): 17.7, 119.8, 125.1, 127.3, 128.9, 129.1, 130.0,
131.6, 140.1 ppm.
1
(1S,2S)-Salen (1h): m.p. 188–1908C; [a]2D2 = À8.3( c = 1.32, CH2Cl2); H
À
NMR (400 MHz, CDCl3): d = 1.23(s, 18H; 2” tBu), 4.72 (s, 2H; CH
Asymmetric addition of TMSCN to ketones
CH), 6.89 (d, J = 8.8 Hz, 2H; aromatic H), 7.12 (d, J = 0.8 Hz, 2H; aro-
matic H), 7.15–7.19 (m, 10H; aromatic H), 7.31 (dd, J = 8.8, 1.2 Hz, 2H;
aromatic H), 8.34 (s, 2H; 2”CH=N), 13.12 (s, 2H; 2”ArOH) ppm; 13C
NMR (100 MHz, CDCl3): d = 31.3, 33.9, 80.2, 116.3, 117.9, 127.5, 127.9,
128.2, 128.3, 129.9, 139.6, 141.4, 158.6, 166.6 ppm; HRMS (ESI): calcd for
C36H40N2O2: 533.3163; found 533.3173 [M+H]+.
Typical procedure for Method A (0.5 mol%): Et3Al (9 mL, 25 wt% in
hexane, 0.016 mmol) was stirred under N2 atmosphere with 1k (8.3mg,
0.016 mmol) in THF (0.4 mL) at 238C for 1 h. After the addition of ace-
tophenone (3a, 0.4 mL, 3.3 mmol), the reaction mixture was cooled to
À208C; subsequently a solution of 2d (1.2 mg, 0.008 mmol) was added
which had been separately treated with TMSCN (0.9 mL, 6.6 mmol) in
THF (0.4 mL) at 238C for 1 h. The reaction was allowed to proceed at
À208C. At completion, the reaction mixture was concentrated and
placed on a silica gel column to give the pure product with diethyl ether/
petroleum ether (1:100 v/v) as the eluent. The desired 2-trimethylsilyl-
oxy-2-phenylpropanenitrile (4a) was obtained as a colorless oil (0.7 g,
94%). The ee was determined as 93% by chiral GC analysis on Chirasil
DEX CB.
(1S,2S)-Salen (1i): m.p. 188–1908C; [a]2D2 = À64.8 (c = 1.1, CH2Cl2); 1H
À
NMR (400 MHz, CDCl3): d
=
4.79 (s, 2H; CH CH), 7.04 (d, J
=
8.8 Hz, 2H; aromatic H), 7.20–7.24 (m, 10H; aromatic H), 7.29 (d, J =
7.6 Hz, 2H; aromatic H), 7.38 (t, J = 7.6 Hz, 6H; aromatic H), 7.45 (d, J
= 7.6 Hz, 4H; aromatic H), 7.51 (dd, J = 8.8, 0.8 Hz, 2H; aromatic H),
8.38 (s, 2H; 2”CH=N), 13.38 (s, 2H; 2”ArOH) ppm; 13C NMR
(100 MHz, CDCl3): d
= 80.2, 117.4, 118.6, 126.5, 126.8, 127.7, 127.8,
128.4, 128.8, 130.1, 131.4, 132.0, 139.3, 140.1, 160.4, 166.3 ppm; HRMS
Typical procedure for method B (0.1 mol%): Et3Al (4.5 mL, 25 wt% in
hexane, 0.008 mmol) was stirred with 1k (4.2 mg, 0.008 mmol) in THF
(0.2 mL) at 238C for 1 h under N2 atmosphere. After the addition of ace-
tophenone (3a, 1.0 mL, 8.4 mmol), the reaction mixture was cooled to
À208C; subsequently a solution of 2d (0.6 mg, 0.004 mmol) was added
which had been separately treated with TMSCN (2.2 mL, 16 mmol) at
238C for 1 h. The reaction was allowed to proceed at À208C. At comple-
tion, the reaction mixture was concentrated and placed on a silica gel
column to give the pure product with diethyl ether/petroleum ether
(1:100 v/v) as the eluent. The desired 2-trimethylsilyloxy-2-phenylpropa-
nenitrile (4a) was obtained as a colorless oil (1.8 g, 99%). The ee was de-
termined by chiral GC analysis on Chirasil DEX CB to be 94%.
(ESI): calcd for C40H32N2O2: 573.2537; found 573.2544 [M+H]+.
(1S,2S)-Salen (1j):[10a] m.p. 101–1048C (lit. 86–888C);[10a] [a]D22 = À12.7 (c
=
1.12, CH2Cl2) {lit. [a]D20
=
À12.2 (c
=
1.0, CH2Cl2)};[10a] 1H NMR
À
(400 MHz, CDCl3): d = 4.75 (s, 2H; 2”CH CH), 6.92 (d, J = 8.8 Hz,
2H; aromatic H), 7.10 (d, J = 2.8 Hz, 2H; aromatic H), 7.16–7.25 (m,
12H; aromatic H), 8.18 (s, 2H; 2”CH=N), 13.26 (s, 2H; 2”ArOH) ppm;
13C NMR (100 MHz, CDCl3): d = 80.0, 118.6, 119.2, 123.4, 127.7, 127.9,
128.6, 130.7, 132.6, 138.8, 159.5, 165.1 ppm;
(1S,2S)-Salen (1k):[10a] This kind of salen ligands was prepared according
to the literature.[10a] [a]D22 = À22.9 (c = 1.54, CH2Cl2) {lit. [a]2D0 = À2.2
(c = 1.0, CH2Cl2)};[10a] 1H NMR (400 MHz, CDCl3): d = 4.75 (s, 2H;
À
CH CH), 6.87 (d, J = 8.8 Hz, 2H; aromatic H), 7.16–7.26 (m, 12H; aro-
2-Trimethylsilyloxy-2-phenylpropanenitrile (4a): 1.80 g, 99% yield,
94% ee, colorless oil; [a]D22
=
+16.9 (c = 2.58, CH2Cl2, 94% ee) [lit.
matic H), 7.34–7.37 (m, 2H; aromatic H), 8.18 (s, 2H; 2”CH=N), 13.29
(s, 2H; 2”ArOH) ppm; 13C NMR (100 MHz, CDCl3): d = 80.0, 110.3,
119.0, 119.8, 127.7, 127.9, 128.6, 133.7, 135.4, 138.8, 160.0, 165.0 ppm.
[a]2D0
= +21.9 (c =
1.18, CHCl3, 93 %ee)];[5c] 1H NMR (300 MHz,
CDCl3): d = 0.19 (s, 9H; (CH3)3Si), 1.87 (s, 3H; CH3), 7.38–7.58 (m, 5H;
aromatic H) ppm; GC (CP-Chirasil DEX CB, 0.25 mm”25 m, column
temperature = 1108C (isothermal), inject temperature = 2008C, detec-
tor temperature = 2508C, inlet pressure = 8 psi): tr (minor) = 20.0 min,
tr (major) = 20.6 min.
(1S,2S)-Salen (1l):[20] m.p. 206–2078C (lit. 200–2038C);[20] [a]D22 = +323.8
(c = 1.3, CH2Cl2) {lit. [a]D20 = À315 (c = 4.0, CH2Cl2 for (1R,2R)-enan-
tiomer)};[20] 1H NMR (400 MHz, CDCl3): d = 1.23(s, 18H; 2” tBu), 1.41
(s, 18H; 2”tBu), 1.48 (m, 2H; cyclic H), 1.72–1.96 (m, 6H; cyclic H),
À
1-Trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile
(4b):
3.30–3.33 (m, 2H; CH CH), 6.98 (d, J = 2.4 Hz, 2H; aromatic H), 7.30
367 mg, 99% yield, 92% ee; [a]2D2 = +10.1 (c = 1.44, CH2Cl2, 92% ee);
1H NMR (300 MHz, CDCl3): d = 0.24 (s, 9H; (CH3)3Si), 2.06 (m, 2H;
CH2), 2.23(m, 1H; CH 2), 2.35 (m, 1H; CH2), 2.85 (m, 2H; CH2), 7.13
(m, 1H; aromatic H), 7.29 (m, 2H; aromatic H), 7.67 (m, 1H; aromatic
(d, J = 2.0 Hz, 2H; aromatic H), 8.30 (s, 2H; 2”CH=N), 13.72 (s, 2H;
2”ArOH) ppm; 13C NMR (100 MHz, CDCl3): d = 24.3, 29.4, 31.4, 33.3,
34.0, 34.9, 72.4, 117.8, 126.0, 126.7, 136.3, 139.8, 158.0, 165.8 ppm.
(1R,2S)-Mono-Schiff
base
(1m):[10b]
m.p.
124–1268C
(lit.
H) ppm; 13C NMR (75 MHz, CDCl3): d
= 1.3, 18.6, 28.2, 37.6, 69.8,
125.6–126.08C);[10b] [a]D22 = À16.8 (c = 0.55, CH2Cl2) {lit. [a]2D0 = À17 (c
122.0, 126.6, 127.9, 129.0, 129.2, 135.6, 136.0 ppm; elemental analysis
calcd (%) for C14H19NOSi: C 68.52, H 7.80, N 5.71; found C 68.30, H
7.70, N 6.11; GC (CP-Chirasil DEX CB, 0.25 mm”25 m, column temper-
ature = 1308C (isothermal), inject temperature = 2008C, detector tem-
=
0.6, CHCl3)};[10b] 1H NMR (600 MHz, CDCl3): d
= 2.06 (d, J =
À
2.0 Hz, 1H; =CH OH), 4.53(d, J = 7.0 Hz, 1H; CHN=C), 5.06 (d, J =
7.0 Hz, 1H; CH OH), 6.82 (s, 1H; aromatic H), 6.95 (d, J = 7.9 Hz;
1H; aromatic H), 7.09 (d, J = 7.9 Hz; 1H; aromatic H), 7.26–7.40 (m,
11H; aromatic H), 8.08 (s, 1H; CH=N), 13.15 (s, 1H; ArOH) ppm.
N-Oxide (2a):[13a] The N-oxides 2a–e were obtained by direct oxidization
of the corresponding tertiary amines,[13a] except for 2b (NMO), which
was purchased from Acros; 1H NMR (400 MHz, [D6]DMSO): d = 3.31
(s, 9H; 3”CH3) ppm; 13C NMR (100 MHz, [D6]DMSO): d = 61.2.
N-Oxide (2c):[13a] 1H NMR (400 MHz, [D6]DMSO): d = 2.03–2.09 (m,
1H; cyclic H), 2.16–2.35 (m, 4H; cyclic H), 2.55–2.58 (m, 1H; cyclic H),
2.77–2.81 (m, 2H; cyclic H), 3.20–3.23 (m, 2H; cyclic H), 3.49 (s, 1H;
cyclic H), 3.93 (s, 6H; (CH3)2N)) ppm; 13C NMR (100 MHz, [D6]DMSO):
d = 24.99, 25.03, 26.5, 55.1, 76.6 ppm.
À
perature
(minor) = 46.9 min.
1-Trimethylsilyloxy-(1’-indane)-1-carbonitrile (4c): 362 mg, 98% yield,
92% ee, colorless oil; [a]D22
+28.8 (c = 2.34, CH2Cl2, 92% ee) [lit.
[a]2D0 1.52, CHCl3, 88% ee)];[6a] 1H NMR (600 MHz,
+31.6 (c
= 2508C, inlet pressure = 8 psi): tr (major) = 46.1 min, tr
=
=
=
CDCl3): d = 0.20 (s, 9H; (CH3)3Si), 2.43–2.47 (m, 1H; cyclic H), 2.70–
2.74 (m, 1H; cyclic H), 2.97–3.02 (m, 1H; cyclic H), 3.10–3.15 (m, 1H;
cyclic H), 7.28 (d, J = 7.2 Hz, 1H; aromatic H), 7.31 (t, J = 14.4 Hz,
1H; aromatic H), 7.36 (td, J = 1.2 Hz, 14.4 Hz, 1H; aromatic H), 7.55
(d, J = 7.2 Hz, 1H; aromatic H) ppm; GC (Chirasil DEX CB, 0.25 mm”
25 m, column temperature = 1208C (isothermal), inject temperature =
Chem. Eur. J. 2004, 10, 4790 – 4797
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4795

X. Feng et al.
FULL PAPER
2008C, detector temperature = 2508C, inlet pressure = 8 psi): tr (major)
= 38.4 min, tr (minor) = 38.9 min.
1.0 mLminÀ1, 238C, UV 254 nm): tr (major)
= 6.0 min, tr (minor) =
7.1 min.
2-Trimethylsilyloxy-2-methylheptanenitrile (4k): 1.73g, 99% yield,
79% ee, colorless oil; [a]2D2 = +1 (c = 1.62, CH2Cl2, 79% ee); 1H NMR
(600 MHz, CDCl3): d = 0.20 (s, 9H; (CH3)3Si), 2.43–2.47 (m, 1H; cyclic
H), 2.70–2.74 (m, 1H; cyclic H), 2.97–3.02 (m, 1H; cyclic H), 3.10–3.15
(m, 1H; cyclic H), 7.28 (d, J = 7.2 Hz, 1H; aromatic H), 7.31 (t, J =
14.4 Hz, 1H; aromatic H), 7.36 (td, J = 1.2 Hz, 14.4 Hz, 1H; aromatic
H), 7.55 (d, J = 7.2 Hz, 1H; aromatic H) ppm; 13C NMR (150 MHz,
CDCl3): d = 1.5, 14.2, 22.7, 24.2, 29.1, 31.7, 43.6, 69.9, 122.4 ppm; GC
(Chirasil DEX CB, 0.25 mm”25 m, column temperature = 1008C (iso-
thermal), inject temperature = 2008C, detector temperature = 2508C,
inlet pressure = 8 psi): tr (major) = 15.4 min, tr (minor) = 15.7 min.
1-Trimethylsilyloxy-(1’-thiophene)-1-carbonitrile (4d): 330 mg, 99%
yield, 90% ee, colorless oil; [a]2D2 = +13.6 (c = 2.13, CH2Cl2, 90% ee);
1H NMR (300 MHz, CDCl3): d = 0.20 (s, 9H; (CH3)3Si), 2.00 (s, 3H;
CH3), 7.00 (m, 1H; aromatic H), 7.21–7.34 (m, 2H; aromatic H) ppm;
= 0.78, 33.40, 68.24, 120.82, 124.70,
125.97, 126.61, 146.27 ppm; elemental analysis calcd (%) for
C10H15NOSSi (225.4): C 53.29, H 6.71, N 6.21; found C 53.48, H 6.94, N
13C NMR (CDCl3, 75 MHz): d
6.43; GC (Chirasil DEX CB, 0.25 mm”25 m, column temperature
=
1108C (isothermal), inject temperature = 2008C, detector temperature
= 2508C, inlet pressure = 8 psi): tr (minor) = 19.6 min, tr (major) =
20.3min.
2-Trimethylsilyloxy-2-methylpentanenitrile (4l): 1.30 g, 95% yield,
80% ee [(1R,2R)-1k was used in this case], colorless oil; [a]2D2 = À0.9 (c
= 1.6, CH2Cl2, 80% ee); 1H NMR (600 MHz, CDCl3): d = 0.23(s, 9H;
(CH3)3Si), 0.97 (t, J = 6 Hz, 3H; CH3), 1.57 (m, 4H; CH2CH2), 2.18 (s,
3H; CH3) ppm; 13C NMR (150 MHz, CDCl3): d = 1.3, 13.8, 17.7, 30.9,
45.5, 69.6, 122.2 ppm; GC (Chirasil DEX CB, 0.25 mm”25 m, column
temperature = 658C (isothermal), inject temperature = 2008C, detector
temperature = 2508C, inlet pressure = 8 psi): tr (minor) = 11.0 min, tr
(major) = 11.2 min.
2-Trimethylsilyloxy-2-(4’-methylphenyl)propanenitrile (4e): 353 mg, 99%
yield, 92% ee; [a]D22 = +22.1 (c = 2.44, CH2Cl2, 92% ee) [lit. [a]2D0 = +
21.3( c = 1.28, CHCl3, 90% ee)];[5c] 1H NMR (400 MHz, CDCl3): d =
0.16 (s, 9H; (CH3)3Si), 1.84 (s, 3H; CH3), 2.36 (s, 3H; ArCH3), 7.21 (m,
2H; aromatic H), 7.43(m, 2H; aromatic H) ppm; elemental analysis
calcd (%) for C13H19NOSi: C 66.90, H 8.21, N 6.00; found C 66.78, H
8.03, N 6.39; GC (CP-Chirasil DEX CB, 0.25 mm”25 m, column temper-
ature = 1058C (isothermal), inject temperature = 2008C, detector tem-
perature
= 2508C, inlet pressure = 8 psi): tr (minor) = 43.0 min, tr
2-Trimethylsilyloxy-2-methyl-3-methylbutanenitrile (4m): 1.11 g, 80%
(major) = 43.8 min.
yield, 90% ee [(1R,2R)-1k was used in this case], colorless oil; [a]D22
À1.1 (c = 1.66, CH2Cl2, 90% ee); H NMR (600 MHz, CDCl3): d = 0.24
(s, 9H; (CH3)3Si), 1.03(t, J =6 Hz, 6H; (CH3)2CH), 1.53(s, 3H; CH 3),
1.86 (hept, J = 6 Hz, 1H; (CH3)2CH) ppm; 13C NMR (150 MHz, CDCl3):
=
2-Trimethylsilyloxy-2-(4’-fluorophenyl)propanenitrile (4 f): 1.60 g, 99%
yield, 92% ee, colorless oil; [a]2D2 = 17.6 (c = 2.7, CH2Cl2, 92% ee); 1H
NMR (400 MHz, CDCl3): d = 0.18 (s, 9H; (CH3)3Si), 1.84 (s, 3H; CH3),
7.08 (m, 2H; aromatic H), 7.52 (m, 2H; aromatic H) ppm; 13C NMR
1
d
= 1.2, 17.0, 26.0, 39.1, 73.5, 121.6 ppm; GC (Chirasil DEX CB,
2
(100 MHz, CDCl3): d = 1.0, 33.5, 71.0, 115.6 (d, JCCF = 21.9 Hz), 121.4,
0.25 mm”25 m, column temperature = 658C (isothermal), inject temper-
ature = 2008C, detector temperature = 2508C, inlet pressure = 8 psi): tr
(minor) = 19.0 min, tr (major) = 19.4 min.
3
1
126.5 (d, JCCCF = 8.5 Hz), 138.0, 162.2 (d, JCF = 246.4 Hz) ppm; GC
(CP-Chirasil DEX CB, 0.25 mm”25 m, column temperature
(isothermal), inject temperature
=
1158C
=
2008C, detector temperature
=
=
2508C, inlet pressure
=
8 psi): tr (minor)
=
17.0 min, tr (major)
17.6 min.
2-Trimethylsilyloxy-2-(4’-chlorophenyl)propanenitrile (4g): 1.80 g, 99%
yield, 90% ee, colorless oil; [a]D22
+18.2 (c = 2.06, CH2Cl2, 90% ee)
[lit. [a]2D0 +29.5 (c = 1.04, CHCl3, 92% ee)];[5c] 1H NMR (400 MHz,
Acknowledgments
=
=
The authors thank the NSFC (Nos. 20225206, 20390050, and 20372050)
and the Ministry of Education, China (Nos. 01144, 104209, and others)
for financial support. Dr. F.X. Chen thanks the China Postdoctoral Sci-
ence Foundation.
CDCl3): d = 0.19 (s, 9H; (CH3)3Si), 1.83(s, 3H; CH 3), 7.38 (m, 2H; aro-
matic H), 7.48 (m, 2H; aromatic H) ppm; 13C NMR (100 MHz, CDCl3):
d = 1.0, 33.5, 71.0, 121.2, 126.1, 128.8, 134.6, 140.7 ppm; elemental analy-
sis calcd (%) for C12ClH16NOSi: C 56.79, H 6.35, N 5.52; found C 56.82,
H 6.41, N 5.93; GC (CP-Chirasil DEX CB, 0.25 mm”25 m, column tem-
perature = 1258C (isothermal), inject temperature = 2008C, detector
temperature = 2508C, inlet pressure = 8 psi): tr (minor) = 29.1 min, tr
(major) = 29.9 min.
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2-Trimethylsilyloxy-2-(3’-chlorophenyl)propanenitrile (4h): 370 mg, 95%
yield, 90% ee, colorless oil; [a]2D2 = +19.6 (c = 2.88, CH2Cl2, 90% ee);
1H NMR (300 MHz, CDCl3): d = 0.22 (s, 9H; (CH3)3Si), 1.86 (s, 3H;
CH3), 7.34–7.55 (m, 4H; aromatic H) 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; ele-
mental analysis calcd (%) for C12ClH16NOSi: C 56.79, H 6.35, N 5.52;
found C 56.61, H 6.39, N 5.90; GC (CP-Chirasil DEX CB, 0.25 mm”
25 m, column temperature = 1058C (isothermal), inject temperature =
2008C, detector temperature = 2508C, inlet pressure = 8 psi): tr (minor)
= 57.1 min, tr (major) = 58.0 min.
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2-Trimethylsilyloxy-2-phenylbutanenitrile (4i): 1.80 g, 99% yield, 87% ee,
colorless oil; [a]D22 = +15.7 (c = 1.22, CH2Cl2, 87% ee) [lit. [a]2D0 = +
19.4 (c = 1.39, CHCl3, 88% ee)];[5c] 1H NMR (300 MHz, CDCl3): d =
0.15 (s, 9H; (CH3)3Si), 0.99(t, J = 7.2 Hz, 3H; CH3), 1.92–2.23(m, 2H;
CH2), 7.40(m, 3H; aromatic H), 7.50(m, 2H; aromatic H) ppm; GC (CP-
Chirasil DEX CB, 0.25 mm”25 m, column temperature = 1108C (iso-
thermal), inject temperature = 2008C, detector temperature = 2508C,
inlet pressure = 8 psi): tr (minor) = 25.6 min, tr (major) = 26.9 min.
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2-Trimethylsilyloxy-2-(2’-naphthyl)propanenitrile (4j): 2.16 g, 99% yield,
>99% ee (after recrystallization of the product with 81% ee from n-
hexane), white solid; [a]D22 = À9.5 (c = 0.58, CH2Cl2, >99% ee) [lit.
[a]2D0
= +12.6 (c =
1.99, CHCl3, 94% ee)];[5c] 1H NMR (300 MHz,
CDCl3): d = 0.22 (s, 9H; (CH3)3Si), 1.97 (s, 3H; CH3), 7.54–7.66 (m, 3H;
aromatic H), 7.90–7.93(m, 3H; aromatic H), 8.07 (d, J = 1.8 Hz, 1H; ar-
omatic H) ppm; HPLC (Chiralcel OJ, iPrOH/n-hexane, 0.5:99.5 v/v,
4796
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4790 – 4797

Enantioselective Cyanosilylation
4790 – 4797
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[16] 1H NMR (400 MHz, CDCl3) shows that the chemical shift of
TMSCN is dH = 0.35 ppm. After it has coordinated to N-oxide 2d,
however, a new signal appears at dH = 0.17 ppm.
[17] R. Noyori, S. Murata, M. Suzuki, Tetrahedron 1981, 37, 3899–3910.
[18] TMSCN appears to be involved in the rate-determining step be-
cause more than an equivalent quantity (2 equiv) of it relative to
the ketones was needed to give the optimum reaction rate and enan-
tioselectivity.
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[12] 13C NMR (150 MHz, CDCl3) shows two signals at dC = 9.4 and dC
= 17.9 ppm remaining unchanged both during the catalyst genera-
tion in the absence of TMSCN and during the reaction period,
which suggested that the third Et attached to the Al atom of
1k·AlEt3 complex did not exchange with CN. For methyl-Al-salen
complex, see: a) J. K. Myers, E. N. Jacobsen, J. Am. Chem. Soc.
1999, 121, 8959–8960. For other examples of Al-salen complexes,
see: b) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120,
5315–5316; c) D. A. Atwood, M. J. Harvey, Chem. Rev. 2001, 101,
37, and references therein; d) D. A. Evans, J. M. Janey, N. Magome-
Received: May 23, 2004
Published online: August 17, 2004
Chem. Eur. J. 2004, 10, 4790 – 4797
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4797