Highly efficient double-activation catalysts for the synthesis of ketone cyanohydrins

Article abstract of DOI:10.1055/s-2004-831167

Tertiary cyanohydrin trimethylsilyl ethers were synthesized in excellent chemical yields by using salen-Al complex (0.25 mol%) and N-oxide (0.5 mol%) without solvent at ambient temperature. The relationship between the ligand structure and catalyst effici

Full text of DOI:10.1055/s-2004-831167

2266
PAPER
Highly Efficient Double-Activation Catalysts for the Synthesis of Ketone
Cyanohydrins
D
ouble-Activa
u
tion Catalyst
-
s for the
X
Synthesis of
K
eto
u
ne Cyanohyd
e
rins Chen,a Xiaohua Liu,a Bo Qin,a Hui Zhou,a Xiaoming Feng,*a Guolin Zhangb
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry, Sichuan Univer-
sity, Chengdu 610064, P. R. China
Fax +86(28)85418249; E-mail: xmfeng@scu.edu.cn
b
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, P. R. China
Received 30 April 2004; revised 24 May 2004
1a R1 = R2 = H
N
N
Abstract: Tertiary cyanohydrin trimethylsilyl ethers were synthe-
sized in excellent chemical yields by using salen-Al complex (0.25
mol%) and N-oxide (0.5 mol%) without solvent at ambient temper-
ature. The relationship between the ligand structure and catalyst ef-
ficiency is discussed. Preliminary mechanistic studies were carried
out, and transition states were proposed accounting for the action of
the double-activation catalysts.
1b R1 = t-Bu, R2 = H
1c R1 = R2 = t-Bu
1d R1 = H, R2 = MeO
1e R1 = H, R2 = Cl
1f R1 = R2 = Cl
R2
OH HO
R2
k
R1
R1
1
1g R1 = H, R2 = Br
n N
HO
N
Key words: addition reactions, aluminum, ketones, Schiff bases,
nitriles
tBu
tBu
OH
1c n = 2
2a n = 4
2b n = 6
tBu
tBu
2
Tertiary cyanohydrins are versatile intermediates in the
context of organic synthesis.1 They can be easily convert-
ed into a-hydroxy carbonyl compounds, b-amino alcohols
and g-lactones. In the literature, Lewis acids, Lewis bases
and bifunctional catalysts have been employed to catalyze
the addition of TMS-CN to ketones.2,3 These reports also
provided useful methods to construct quaternary C cen-
ters.4
O
N
3a R1 = R2 = Me, R3 = Ph
3b R1 = R2 = Me, R3 = o'-Tol
3c R1 = R2 = Me, R3 = p'-Tol
3d R1 = R2 = Me, R3 = c-hexyl
3e R1 = R2 = R3 = Me
R3
R1
R2
3
Figure 1 Ligands evaluated in this study.
We have previously communicated double-activation cat-
alysts to achieve the ketone cyanohydrins in excellent
yields under low catalyst loading.5 Our strategy involves
the simultaneous activation of the substrate ketone by
Lewis acid and TMS-CN by N-oxide Lewis base. There-
fore, this reaction can be performed with less than 0.5
mol% catalysts and without solvent. In this paper, the re-
lationship between the catalyst efficiency and structure of
the ligands is described, along with substrate generality
and mechanistic proposal.
Optimization of the Catalyst
To assess the catalytic reactivity of ligands 1a–g and 2a–
b, their complexes with Ti(Oi-Pr)4 were used to catalyze
the addition of TMS-CN to acetophenone (4a) giving cy-
anohydrin trimethylsilyl ether (5a) as the model reaction
[Equation (1)]. Results are listed in Table 1. The substitu-
ents on the salicylidene phenolic rings of the ligands
played an important role on the catalyst reactivity. Two
tert-butyl groups at the 3¢,5¢-positions (1c) showed more
catalytic reactivity than 5¢-tert-butyl- or 3¢-H-substituted
one (Table 1, entry 3 vs 1and 2). While the electron-do-
nating methoxy substituted ligand gave moderate yield of
the product, halogenated ones exhibited poor catalytic re-
activity (Table 1, entries 4–7). Elongation of the carbon
chain of 1c led to ligands 2a–b with reduced catalytic ca-
pabilities (Table 1, entries 8, 9).
In our group, salen titanium complex has been previously
utilized as a Lewis acid to activate the carbonyl group in
the hydrocyanation of aldehydes,6 as well as bisquilonine
N-oxides as Lewis base to activate the nucleophile in the
addition of TMS-CN to aldoimines (Strecker reaction).7
Combining these procedures, a double-activation catalyst
system has been developed to compensate for the low re-
activity of ketones. Thus, a series of salen ligands 1a–g,
2a–b and N-oxides 3 (Figure 1) were prepared and ap-
plied to the catalytic addition of TMS-CN to ketones with-
out solvent.
Some Lewis acid metal reagents were examined, with re-
sults listed in Table 2. Complexes of alkyloxy metals with
1c could effectively catalyze the addition of TMS-CN to
acetophenone (Table 2, entries 1–3). However, complex-
es of 1c with trifluoromethane sulfonates converted ace-
tophenone in relatively low chemical yields (Table 2,
entries 4–5). Curiously, Et3Al gave the highest yield, but
trace amount of the product was obtained using Et2Zn
(Table 2, entry 7 vs 8).
SYNTHESIS 2004, No. 14, pp 2266–2272
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x.
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x
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0
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Advanced online publication: 13.08.2004
DOI: 10.1055/s-2004-831167; Art ID: F06404SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Double-Activation Catalysts for the Synthesis of Ketone Cyanohydrins
2267
A series of N-oxides and other dipolar compounds were
then investigated in the cyanosilylation of acetophenone.
As depicted in Table 4, N,N-dimethylaniline N-oxide (3a)
showed more catalytic reactivity than o¢-methyl (3b) and
p¢-methyl compounds (3c) (Table 4, entries 1–3). Howev-
er, alkyl amine N-oxide 3d–e converted acetophenone in
relatively low yields (Table 4, entries 4, 5). It is worth not-
ing that 0.5 mol% of NMO and 0.25 salen-Al complex
showed competitive reactivity (Table 4, entry 6) with
Kim’s 30 mol% NMO alone in that case.2n Compounds
containing a P=O dipolar moiety could slowly promote
this conversion under these conditions (Table 4, entries 7,
8), which is in agreement with the observations by
Shibasaki3f–3h and Denmark.8
Table 1 Structural Effect of Ligands on the Catalytic Cyanosilyla-
tion of Acetophenonea
O
NC OTMS
+
TMSCN
Ph
(1)
Ph
5a
4a
Entry
Ligand
1a
Yield (%)b Entry
Ligand
1f
Yield (%)b
trace
trace
65
1
2
3
4
5
39
6
7
8
9
1b
37
1g
1c
90
2a
1d
56
2b
67
1e
trace
a Conditions: 1/2-Ti(Oi-Pr)4 complex (10 mol%), 3a (10 mol%), 0 °C,
72 h, TMS-CN (2 equiv), [PhCOCH3] = 0.27 M in CH2Cl2.
b Isolated yields.
Table 4 Effects of the Lewis Bases on the Addition of TMS-CN to
Acetophenonea
Entry
Lewis base
3a
Yield (%)b
1
2
3
4
5
6c
7
8
90
25
74
71
89
97
20
41
Table 2 Metal Scanning for the Cyanosilylation of Acetophenonea
3b
Entry
Lewis acid
Ti(Oi-Pr)4
Zr(Oi-Pr)4
Al(Oi-Pr)3
Sc(OTf)3
Cu(OTf)2
ZrCl4
Time (h)
72
Yield (%)b
3c
1
2
3
4
5
6
7
8
90
3d
72
51
3e
72
48
NMO
Ph3P=O
HMPA
67
36
67
NR
16
72
a Conditions: 1c–AlEt3 complex (10 mol%), 3a (10 mol%), TMS-CN
(2 equiv), [PhCOCH3] = 0.27 M in THF, 0 °C, 11 h.
b Isolated yields.
ZnEt2
67
trace
98
AlEt3
67
c This reaction was carried out neatly under the optimized conditions:
1c–AlEt3 complex (0.25 mol%), NMO (0.5 mol%), 11 h, TMS-CN
(1.2 equiv), and see the experimental section.
a Conditions: 1c–M complex (10 mol%), 3a (10 mol%), 0 °C, 67–72
h, TMS-CN (2 equiv), [PhCOCH3] = 0.27 M in CH2Cl2.
b Isolated yields.
The molar ratio between 1c, AlEt3 and 3a was intensely
studied with results summarized in Table 5. Increasing the
amount of 3a, the reaction was accelerated stepwise as a
result of strengthened activation of the nucleophile TMS-
CN (Table 5, entries 1–3). The highest reaction rate was
recorded when 2 equiv 3a with respect to 1c–AlEt3 com-
plex was loaded (Table 5, entry 4). Further increasing the
amount of 3a yielded poor catalyst efficiency (Table 5,
entry 5). In terms of chemical yield, the optimum molar
ratio between the Lewis acid and the Lewis base is 1:2.
Any changes to the equal molar ratio of 1c to AlEt3 result-
ed in a decrease in yield of 5a to certain extent (Table 5,
entries 6, 7).
Solvents also affected the reaction rate to certain extent as
illustrated in Table 3. CH2Cl2 and MeCN gave compara-
ble low yields (Table 3, entries 1, 2). However, this reac-
tion proceeded very fast when it was performed in THF or
aromatic solvents. Toluene is the choice of solvent at this
stage (Table 3, entry 4).
Table 3 Solvent Effect on the Addition of TMSCN to Acetophen-
onea
Entry
Solvent
CH2Cl2
MeCN
THF
Yield (%)b
1
2
3
4
41
33
86
90
Catalyst loading, substrate concentration and reaction
temperature have comprehensive effects on the reaction
rate of the cyanosilylation of acetophenone. These three
factors were optimized as a whole with regard to the reac-
tion rate, with results listed in Table 6. As the catalyst
loading reducing from 10 to 5, 2 and 1 mol% the reaction
rate suffered a sharp decrease (Table 6, entries 1–4). For-
tunately, the retarded reaction rate caused by the low cat-
toluene
a Conditions: 1c–AlEt3 complex (10 mol%), 3a (10 mol%), 0 °C, 15
h, TMS-CN (2 equiv), [PhCOCH3] = 0.27 M.
b Isolated yields.
Synthesis 2004, No. 14, 2266–2272 © Thieme Stuttgart · New York

2268
F.-X. Chen et al.
PAPER
Table 5 Effect of Molar Ratio Between 1c, 3a and AlEt3 on the Cy- can be achieved with 1c–AlEt3 complex (0.25 mol%) and
anosilylation of Acetophenonea
3a (0.5 mol%) at room temperature without solvent.
Entry
1c–AlEt3–3a (mol%)
10:10:1.5
10:10:5
Yield (%)b
Table 7 Cyanosilylation of Ketones Catalyzed by 1c–AlEt3 and 3aa
1
2
3
4
5
6
7
43
89
90
93
87
78
86
Entry Ketone
Product Time (h) Yield (%)b
4
5
1
2
4a PhCOCH3
5a
5b
5c
5d
5e
5f
13
15
11
11
14
13
11
12
11
15
12
11
15
99
90
88
94
85
85
93
97
97
89
90
93
84
10:10:10
4b 4-MeC6H4COMe
4c 4-FC6H4COMe
10:10:20
3
10:10:30
4
4d 3-ClC6H4COMe
4e 4-O2NC6H4COMe
4f 2-acetonaphthone
4g (E)-PhCH=CHCOMe
4h PhCH2CH2COMe
5:10:10
5
12:10:10
a Conditions: indicated amount of the catalysts, 0 °C, 11 h, TMSCN
(2 equiv), [PhCOCH3] = 0.27 M in THF.
b Isolated yields.
6
7
5g
5h
8
alyst loading could be retained by increasing the substrate
concentration from 0.27 up to 1.1 M (Table 6, entries 5–
7). Moreover, increasing the reaction temperature from
0 °C to r.t. led to a further improvement to the reaction
rate (Table 6, entry 8). At room temperature this reaction
could be completed within 20 h without solvent at a level
of catalyst loading down to 0.25 mol% (Table 6, entries 9,
10). And now, only 1.2 equiv TMS-CN was needed to
complete the reaction. However, this transformation pro-
ceeded very slowly with 0.1 mol% of the catalysts
(Table 6, entry 11). Therefore, the best catalyst efficiency
9
4i 4-phenylcyclohexanone 5i
10
11
12
13
4j a-tetralone
5j
4k a-indanone
4l 2-octanone
5k
5l
4m 2-acetylthiophene
5m
a All reactions were carried out with 1c–AlEt3 complex (0.25 mol%),
3a (0.5 mol%), TMS-CN (1.2 equiv) and no solvent at r.t.
b Isolated yields.
Table 8 Control Experimentsa
Table 6 Optimization of the Catalyst Loading, Substrate Concen-
tration and Temperature on the Addition of TMS-CN to Acetophen-
onea
Entry 1c–AlEt3 (mol%) 3a (mol%)
Yield (%)b
1
-
10
-
0
19
99
91
Entry
1c–AlEt3 [4a] (M)b Temp
Time
(h/d)
Yield
(%)c
2
10
10
10
(%)
10
5
(°C)
3
10
10
1
2
0.27
0.27
0.27
0.27
0.55
0.82
1.1
0
11 h
11 h
11 h
11 h
11 h
11 h
18 h
10 h
6 h
93
89
34
3
4c
0
a All reactions were carried out at 0 °C in toluene for 11 h with indi-
cated amount of catalyst(s) and TMS-CN (2 equiv).
b Isolated yields.
3
2
0
4
1
0
c In this case, the catalysts 1c–AlEt3 and 3a were mixed to generate
the catalyst at the start of the reaction, not following the typical dou-
ble-activation catalysis procedure.
5
1
0
10
31
96
97
99
99
90
6
1
0
7
1
0
Substrate Generality
8
1
1.1
23
23
23
23
Under the optimized conditions, a wide range of aliphatic,
aromatic, cyclic and heterocyclic ketones 4a–n was con-
verted into corresponding cyanohydrin TMS ethers 5a–n.
The results in Table 7 reveal that the double-activation
catalysts, composed of salen-aluminum complex and
amine N-oxide, have a good substrate generality. Elec-
tron-deficient and electron-rich aromatic ketones
(Table 7, entries 1–6), along with a,b-saturated and a,b-
unsaturated ones (Table 7, entries 7, 8) exhibited a similar
high reaction rate. Aliphatic, normal cyclic and sterically
9
0.5
2.9
10d
11d
0.25
0.1
-
11 h
2 d
-
a All reactions were carried out with 2 equivof 3a to the indicated
amount of 1c–AlEt3 complex, and TMS-CN (2 equiv) in toluene un-
less otherwise indicated.
b Corrected concentration to the total reaction mixture volume.
c Isolated yields.
d This was performed with TSMS-CN (1.2 equiv) and no solvent.
Synthesis 2004, No. 14, 2266–2272 © Thieme Stuttgart · New York

PAPER
Double-Activation Catalysts for the Synthesis of Ketone Cyanohydrins
2269
hindered cyclic ketones were cyanosilylated smoothly Figure 2). As [A] and [B] attract and approach each other,
(Table 7, entries 9–12). The double-activation catalysts the transition state [C] is proposed and undergoes ‘in-
also tolerated heterocyclic ketone as substrate (Table 7, tramolecular’ transfer of cyanide to ketone releasing the
entry 13).
cyanohydrin TMS ether and the catalysts, salen-Al com-
plex and N-oxide.
Practical and efficient double-activation catalysts have
been developed for the addition of TMS-CN to ketones.
Using salen-Al complex (0.25 mol%) and N-oxide (0.5
mol%) aliphatic, aromatic, cyclic and heterocyclic ke-
tones were converted to corresponding cyanohydrin TMS
ethers in good to excellent chemical yields without sol-
vent. Preliminary mechanistic studies supported that
salen-Al complex played the role of Lewis acid to activate
carbonyl group and N-oxide the role of Lewis base to ac-
tivate TMS-CN. Thus the double-activation catalysts
could be loaded at such a low level with excellent catalyst
efficiency. Further efforts will be directed toward the ap-
plication of the double-activation catalysis to the enantio-
selective cyanosilylation of ketones and other reactions in
this line.12
Preliminary Mechanistic Studies
In order to identify the double-activation catalysis, a se-
ries of control experiments were carried out with the re-
sults listed in Table 8. The cyanosilylation of
acetophenone did not occur with N-oxide 3a alone
(Table 8, entry 1). While salen-Al complex 1c promote
this reaction in very low yield (Table 8, entry 2), addition-
al activation of the nucleophilic TMS-CN by N-oxide 3a
accelerated this addition to a very fast reaction rate
(Table 8, entry 3). Direct evidence of the coordination be-
tween N-oxide and TMS-CN was obtained from 1H NMR
(400 MHz, CDCl3) studies. The chemical shift of free
TMS-CN is located at dH = 0.35. However, in the presence
of N-oxide a new signal appeared at dH = 0.17 as a result
of condensed electron density around the silicon atom
caused by the coordination of N-oxide to TMS-CN. How-
ever a weak binding between the salen-Al complex and N-
oxide, the general concern of combined use of a Lewis
acid and a Lewis base, 9,10 was observed (Table 8, entry 4).
Although stable metal complexes with N-oxides were re-
ported in the literature,11 this study shows the feasibility of
application of Lewis acid and Lewis base to double-acti-
vation catalysis in the cyanosilylation of ketones. These
results suggested that, in this case, the catalysts worked in
a double-activation model, i.e. salen-Al complex as the
Lewis acid to activate the carbonyl group ([A], Figure 2)
and N-oxide as the Lewis base to activate TMS-CN ([B],
1H NMR spectra were recorded on an INOVA 400 (400 MHz) or on
a Bruker (300 MHz) instrument. Chemical shifts are reported in
ppm from tetramethylsilane with the solvent resonance as the inter-
nal standard (CDCl3, d = 7.26). Data are listed as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet),
coupling constants (J, Hz), integration, and assignment. 13C NMR
data were collected on an INOVA 400 (100 MHz) or on a Bruker
(75 MHz) apparatus. Chemical shifts are reported in ppm from the
tetramethylsilane as internal standard. Elemental analyses were per-
formed on a Carlo-1160 instrument. All ketones, TMS-CN, metal
reagents and substituted salicylal were purchased from Acros, Ald-
rich and Fluka, and used directly without further purification.
Petroleum ether refers to the fraction with bp 60–90 ºC.
N,N¢-Bis(salicylidene)ethylene-1,2-diimine (1a)6d
CH3
This kind of salen ligand was prepared according to the literature.6d
Yellow crystals; mp 126–127 °C.
O
O
1H NMR (400 MHz, CDCl3): d = 3.93 (s, 4 H, CH2CH2), 6.86 (td,
7.6 Hz, 1.6 Hz, 2 H, aromatic H), 6.94 (d, 8.4 Hz, 2 H, aromatic H),
7.22 (dd, 7.6, 1.6 Hz, 2 H, aromatic H), 7.27–7.31 (m, 2 H, aromatic
H), 8.31 (s, 2 H, 2CH=N), 13.22 (s, 2 H, 2 ArOH).
Al
N
O
N
13C NMR (100 MHz, CDCl3): d = 59.7, 116.9, 118.58, 118.64,
131.4, 132.4, 160.9, 166.5.
A
N,N¢-Bis(3¢-tert-butylsalicylidene)ethylene-1,2-diimine (1b)6d
Yellow crystals; mp 147–148 °C.
C
N O
N
Si
1H NMR (400 MHz, CDCl3): d = 1.43 (s, 18 H, 2 t-Bu), 3.93 (s, 4
H, CH2CH2), 6.80 (t, 7.8 Hz, 2 H, aromatic H), 7.09 (dd, 7.6, 1.6 Hz,
2 H, aromatic H), 7.31 (dd, 8.0 Hz, 1.6 Hz, 2 H, aromatic H), 8.38
(s, 2 H, 2 CH=N).
13C NMR (100 MHz, CDCl3): d = 29.3, 34.8, 59.5, 117.8, 118.5,
129.5, 129.8, 137.3, 160.3, 167.2.
B
CH3
C
N
O
O
O
N
Si
N
N,N¢-Bis(3¢,5¢-di-tert-butylsalicylidene)ethylene-1,2-diimine
Al
(1c)6d
O
Yellow crystals; mp 186–187 °C.
N
1H NMR (400 MHz, CDCl3): d = 1.28 (s, 18 H, 2 t-Bu), 1.43 (s, 18
H, 2 t-Bu), 3.92 (m, 4 H, CH2CH2), 7.06 (d, 2.4 Hz, 2 H, aromatic
H), 7.36 (d, 2.4 Hz, 2 H, aromatic H), 8.38 (s, 2H, 2 CH=N), 13.65
(s, 2 H, 2ArOH).
C
Figure 2 Proposed transition states
Synthesis 2004, No. 14, 2266–2272 © Thieme Stuttgart · New York

2270
F.-X. Chen et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 29.4, 31.4, 34.1, 35.0, 59.6, 117.8,
Mp 66–69 °C.
126.0, 127.0, 136.6, 140.0, 158.0, 167.6.
1H NMR (400 MHz, CDCl3): d = 3.66 (s, 6 H, CH3), 7.39–7.50 (m,
3 H, aromatic H), 7.93 (d, 8.0 Hz, 2 H, aromatic H).
13C NMR (100 MHz, CDCl3): d = 62.7, 119.7, 129.1, 129.3, 153.6.
N,N¢-Bis(5¢-methyoxysalicylidene)ethylene-1,2-diimine (1d)6b
Yellow crystals; mp 164–165 °C.
1H NMR (400 MHz, CDCl3): d = 3.74 (s, 6 H, 2 MeO), 3.93 (s, 4 H,
CH2CH2), 6.73 (d, 2.8 Hz, 2 H, aromatic H), 6.87 (d, 8.8 Hz, 2 H,
aromatic H), 6.90 (dd, 8.8, 2.8 Hz, 2 H, aromatic H), 8.29 (s, 2 H, 2
CH=N), 12.71 (s, 2 H, 2 ArOH).
13C NMR (100 MHz, CDCl3): d = 55.8, 59.8, 114.8, 117.6, 118.2,
119.4, 151.9, 155.0, 166.2.
N,N-Dimethyl-N-(2¢-methylphenyl)amine N-Oxide (3b)13
Mp 46–48 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.73 (s, 3 H, CH3), 3.46 [s, 6
H, (CH3)2N)], 7.22–7.27 (m, 3 H, aromatic H), 8.10 (d, 7.6 Hz, 2 H,
aromatic H).
13C NMR (100 MHz, DMSO-d6): d = 21.7, 61.6, 120.6, 126.4,
128.5, 130.8, 133.7.
N,N¢-Bis(5¢-chlorosalicylidene)ethylene-1,2-diimine (1e)6b
Yellow crystals; mp 179–181 °C.
1H NMR (400 MHz, CDCl3): d = 3.96 (s, 4 H, CH2CH2), 6.95 (d,
9.2 Hz, 2 H, aromatic H), 7.22 (dd, 11.2, 2.4 Hz, 2 H, aromatic H),
7.26 (d, 0.8 Hz, 2 H, aromatic H), 8.30 (s, 2 H, 2 CH=N), 13.14 (s,
2 H, 2 ArOH).
N,N-Dimethyl-N-(4¢-methylphenyl)amine N-Oxide (3c)13
Mp 102–106 °C.
1H NMR (600 MHz, DMSO-d6): d = 2.08 (s, 3 H, CH3), 2.32 [s, 6
H, (CH3)2N], 7.25 (d, 8.4 Hz, 2 H, aromatic H), 7.93 (d, 8.4 Hz, 2
H, aromatic H).
13C NMR (100 MHz, DMSO-d6): d = 20.4, 62.7, 120.2, 129.1,
138.1, 152.4.
13C NMR (100 MHz, CDCl3): d = 59.6, 118.6, 119.2, 123.3, 130.6,
132.3, 159.6, 165.4.
N,N¢-Bis(3¢,5¢-dichlorosalicylidene)ethylene-1,2-diimine (1f)6b
N-Cyclohexyl-N,N-dimethylamine N-Oxide (3d)13
Mp 96–98 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.03–2.09 (m, 1 H, cyclic H),
2.16–2.35 (m, 4 H, cyclic H), 2.55–2.58 (m, 1 H, cyclic H), 2.77–
2.81 (m, 2 H, cyclic H), 3.20–3.23 (m, 2 H, cyclic H), 3.49 (s, 1 H,
cyclic H), 3.93 [s, 6 H, (CH3)2N)].
Yellow crystals; mp 211–212 °C.
1H NMR (400 MHz, CDCl3): d = 4.01 (s, 4 H, CH2CH2), 7.15 (d,
2.4 Hz, 2 H, aromatic H), 7.40 (d, 2.4 Hz, 2 H, aromatic H), 8.28 (s,
2 H, 2 CH=N), 13.97 (s, 2 H, 2ArOH).
13C NMR (100 MHz, CDCl3): d = 59.0, 119.3, 122.7, 123.1, 129.2,
132.5, 156.1, 165.3.
13C NMR (100 MHz, DMSO-d6): d = 24.99, 25.03, 26.5, 55.1, 76.6.
N,N¢-Bis(5¢-bromosalicylidene)ethylene-1,2-diimine (1g)6b
Yellow crystals; mp 193–195 °C.
1H NMR (400 MHz, CDCl3): d = 3.96 (s, 4 H, CH2CH2), 6.85 (d,
8.8 Hz, 2 H, aromatic H), 7.36 (dd, 8.8, 2.4 Hz, 2 H, aromatic H),
7.39 (d, 2.4 Hz, 2 H, aromatic H), 8.29 (s, 2 H, 2 CH=N), 13.16 (s,
2 H, 2 ArOH).
N,N,N-Trimethylamine N-Oxide (3e)13
Mp 79–83 °C.
1H NMR (400 MHz, DMSO-d6): d = 3.31 (s, 9 H, 3 CH3).
13C NMR (100 MHz, DMSO-d6): d = 61.2.
13C NMR (100 MHz, CDCl3): d = 55.6, 110.2, 119.0, 119.9, 133.6,
Cyanosilylation of Ketones; Standard Experimental Procedure
AlEt3 (8.0 mL, 2 M in hexane, 0.0016 mmol) was stirred with 1c (8.0
mg, 0.0016 mmol) in anhyd toluene (0.1 mL) at r.t. for 1 h under an
N2 atmosphere. To the resulting catalyst (20 mL) was added ace-
tophenone (0.14 mL, 1.2 mmol), followed by the addition of a solu-
tion of 3a (0.8 mg, 0.0006 mmol) in TMS-CN (1.4 mmol, 1.2
equiv). The reaction was performed at 23 °C. At completion, the re-
action mixture was purified (silica gel column; Et2O–petroleum
ether, 1:100) to give the pure product. The desired 2-phenyl-2-tri-
methylsilyloxy-propanenitrile (5a) was obtained.
135.2, 160.0, 165.3.
N,N¢-Bis(3¢,5¢-di-tert-butylsalicylidene)butylene-1,4-diimine
(2a)6e
Yellow crystals; mp 144–145 °C.
1H NMR (400 MHz, CDCl3): d = 1.30 (s, 18 H, 2 t-Bu), 1.44 (s, 18
H, 2 t-Bu), 1.81 (s, 4 H, CH2CH2), 3.63 (s, 4 H, 2 CH2), 7.08 (d, 2.0
Hz, 2 H, aromatic H), 7.37 (d, 2.0 Hz, 2 H, aromatic H), 8.36 (s, 2
H, 2 CH=N), 13.89 (s, 2 H, 2 ArOH).
13C NMR (100 MHz, CDCl3): d = 28.5, 29.4, 31.5, 34.4, 35.0, 59.3,
117.8, 125.8, 126.7, 136.6, 139.9, 158.1, 165.9.
Yield: 263 mg (99%); colorless oil.
2-Trimethylsilyloxy-2-phenylpropanenitrile (5a)2m
Yield: 99%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.19 [s, 9 H, (CH3)3Si], 1.87 (s, 3
H, CH3), 7.38–7.58 (m, 5 H, aromatic H).
N,N¢-Bis(3¢,5¢-di-tert-butylsalicylidene)hexylene-1,6-diimine
(2b)6e
Yellow crystals; mp 120–122 °C.
1H NMR (400 MHz, CDCl3): d = 1.30 (s, 18 H, 2 t-Bu), 1.45 (s, 22
H, 2 t-Bu, CH2CH2), 1.72 (t, 6.0 Hz, 4 H, 2 CH2), 3.57 (t, 6.4 Hz, 4
H, 2 CH2), 7.08 (d, 2.4 Hz, 2 H, aromatic H), 7.37 (d, 2.0 Hz, 2 H,
aromatic H), 8.34 (s, 2 H, 2 CH=N), 13.98 (s, 2 H, 2 ArOH).
13C NMR (100 MHz, CDCl3): d = 26.8, 29.4, 30.7, 31.5, 34.1, 35.0,
59.4, 117.8, 125.7, 126.6, 136.6, 139.8, 158.2, 165.6.
2-Trimethylsilyloxy-2-(4¢-methylphenyl)propanenitrile (5b)2m
Yield: 57%; colorless oil.
1H NMR (400 MHz, CDCl3): d = 0.16 [s, 9 H, (CH3)3Si], 1.84 (s, 3
H, CH3), 2.36 (s, 3 H, ArCH3), 7.21 (m, 2 H, aromatic H), 7.43 (m,
2 H, aromatic H).
Anal. Calcd for C13H19NOSi: C, 66.90, H, 8.21; N, 6.00. Found: C,
66.78; H, 8.03; N, 6.39.
N,N-Dimethylaniline N-Oxide (3a)13
These N-oxides were prepared by oxidization of the corresponding
amines according to the literature report.12 Most of them could be
recrystallized from diethyl ether.
2-Trimethylsilyloxy-2-(4¢-fluorophenyl)propanenitrile (5c)
Yield: 88%; colorless oil.
Synthesis 2004, No. 14, 2266–2272 © Thieme Stuttgart · New York

PAPER
Double-Activation Catalysts for the Synthesis of Ketone Cyanohydrins
2271
1H NMR (400 MHz, CDCl3): d = 0.18 [s, 9 H, (CH3)3Si], 1.84 (s, 3
H, CH3), 7.08 (m, 2 H, aromatic H), 7.52 (m, 2 H, aromatic H).
1-Trimethylsilyloxy-1-indanyl-1-carbonitrile (5k)3j
Yield: 90%; colorless oil.
13C NMR (100 MHz, CDCl3): d = 1.0, 33.5, 71.0, 115.6 (d, 2JCCF
=
1H NMR (600 MHz, CDCl3): d = 0.20 [s, 9 H, (CH3)3Si], 2.43–2.47
(m, 1 H, cyclic H), 2.70–2.74 (m, 1 H, cyclic H), 2.97–3.02 (m, 1 H,
cyclic H), 3.10–3.15 (m, 1 H, cyclic H), 7.28 (d, 7.2 Hz, 1 H, aro-
matic H), 7.31 (t, 14.4 Hz, 1 H, aromatic H), 7.36 (td, 14.4, 1.2 Hz,
1 H, aromatic H), 7.55 (d, 7.2 Hz, 1 H, aromatic H).
3
21.9 Hz), 121.4, 126.5 (d, JCCCF = 8.5 Hz), 138.0, 162.2 (d,
1JCF = 246.4 Hz).
2-Trimethylsilyloxy-2-(3¢-chlorophenyl)propanenitrile (5d)
Yield: 94%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.22 [s, 9 H, (CH3)3Si], 1.86 (s, 3
H, CH3), 7.34–7.55 (m, 4 H, aromatic H).
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.
2-Trimethylsilyloxy-2-methyloctanenitrile (5l)2m
Yield: 93%; colorless oil.
1H NMR (600 MHz, CDCl3): d = 0.24 [s, 9 H, (CH3)3Si], 0.90 (t,
13.6 Hz, 3 H, CH2CH3), 1.31–1.36 (m, 6 H, alkyl H), 1.43–1.46 (m,
1 H, alkyl H), 1.51–1.54 (m, 1 H, alkyl H), 1.57 (s, 3 H, CCH3),
1.66–1.75 (m, 2 H, alkyl H).
Anal. Calcd for C12ClH16NOSi: C, 56.79; H, 6.35; N, 5.52. Found:
C, 56.61; H, 6.39; N, 5.90.
2-Trimethylsilyloxy-2-methyl-(2¢-thiophenyl)propanenitrile
2-Trimethylsilyloxy-2-(4¢-nitrophenyl)propanenitrile (5e)2m
Yield: 85%; white solid.
(5m)
Yield: 84%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.26 [s, 9 H, (CH3)3Si], 1.89 (s, 3
H, CH3), 7.75 (d, 9.0 Hz, 2 H, aromatic H), 8.30 (d, 9.0 Hz, 2 H, aro-
matic H).
1H NMR (300 MHz, CDCl3): d = 0.20 [s, 9 H, (CH3)3Si], 2.00 (s, 3
H, CH3), 7.00 (m, 1 H, aromatic H), 7.21–7.34 (m, 2 H, aromatic H).
13C NMR (CDCl3, 75 MHz): d = 0.8, 33.4, 68.2, 120.8, 124.7, 126.0,
126.6, 146.3.
2-Trimethylsilyloxy-2-(2¢-naphthyl)propanenitrile (5f)2m
Yield: 85%; white solid.
1H NMR (300 MHz, CDCl3): d = 0.22 [s, 9 H, (CH3)3Si], 1.97 (s, 3
H, CH3), 7.54–7.66 (m, 3 H, aromatic H), 7.90–7.93 (m, 3 H, aro-
matic H), 8.07 (d, 1.8 Hz, 1 H, aromatic H).
Anal. Calcd for C10H15NOSiS: C, 53.33; H, 6.66; N, 6.22. Found:
C, 53.48; H, 6.94; N, 6.43.
Acknowledgment
2-Trimethylsilyloxy-2-methyl-4-phenyl-3-butenenitrile (5g)2m
Yield: 93%; white solid.
1H NMR (300 MHz, CDCl3): d = 0.27 [s, 9 H, (CH3)3Si], 1.77 (s, 3
H, CH3), 6.15 (d, 15.9 Hz, 1 H, CH=), 6.91 (d, 15.9 Hz, 1 H, CH=),
7.33–7.45 (m, 5 H, aromatic H).
The authors thank the NSFC (No. 20225206, 20390050 and
20372050) and the Ministry of Education, China (No. 01144,
104209 and others) for financial support. Dr. F.-X. Chen thanks
China Postdoctoral Science Foundation.
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.
References
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2-Trimethylsilyloxy-2-methyl-4-phenylbutanenitrile (5h)2m
Yield: 97%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.29 [s, 9 H, (CH3)3Si], 1.65 (s, 3
H, CH3), 2.02–2.08 (m, 2 H, CH2), 2.80–2.91 (m, 2 H, CH2), 7.22–
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1-Trimethylsilyloxy-1-(4¢-phenylcyclohexyl)-1-carbonitrile
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(5i)2m
Yield: 97%; white solid.
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25.8, 3.6 Hz, 2 H, cyclic H), 1.82–1.89 (m, 2 H, cyclic H), 1.98 (m,
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Yield: 89%; colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.24 [s, 9 H, (CH3)3Si], 2.06 (m,
2 H, cyclic H), 2.23 (m, 1 H, cyclic H), 2.35 (m, 1 H, cyclic H), 2.85
(m, 2 H, cyclic H), 7.13 (m, 1 H, aromatic H), 7.29 (m, 2 H, aromatic
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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.
Anal. Calcd for C14H19NOSi: C, 68.52, H, 7.80; N, 5.71. Found: C,
68.30; H, 7.70; N, 6.11.
Synthesis 2004, No. 14, 2266–2272 © Thieme Stuttgart · New York

2272
F.-X. Chen et al.
PAPER
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Synthesis 2004, No. 14, 2266–2272 © Thieme Stuttgart · New York