Cyanosilylation of ketones catalyzed by quaternary ammonium salt and N-oxide

Article abstract of DOI:10.1055/s-2004-820045

Dibenzyldimethyl ammonium bromide and triethanolamine N-oxide catalyze the formation of cyanohydrin trimethylsilyl ethers of ketones in 80-99% yield.

Full text of DOI:10.1055/s-2004-820045

LETTER
1077
Cyanosilylation of Ketones Catalyzed by Quaternary Ammonium Salt
and N-Oxide
C
yanosilylation of
u
Ketone
s
Cat
i
alyzed by Qu
Z
aternary
A
mm
o
h
nium
S
alt an
o
d
N
-
oxide u,a Fu-Xue Chen,a Bo Qin,a Xiaoming Feng,*a Guolin Zhangb
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, 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, P. R. China
Received 14 February 2004
Table 1 The Addition of TMSCN to Acetophenonea
Abstract: Dibenzyldimethyl ammonium bromide and triethanol-
amine N-oxide catalyze the formation of cyanohydrin trimethylsilyl
ethers of ketones in 80–99% yield.
O
OTMS
CN
R2
quaternary ammonium salt
TMSCN
+
R1
R2
R1
N-oxide
Key words: cyanohydrins, ketones, N-oxides, quaternary ammoni-
um salts, organocatalysis
Entry
Catalyst(s)
Yield (%) b
1
2
3
20 mol% 1
20 mol% 4
0
0
Cyanation reaction of carbonyl compounds is one of the
most powerful procedures for the synthesis of polyfunc-
tionalized molecules.1 Among various cyanating reagents
such as KCN or NaCN and HCN, trimethylsilyl cyanide
(TMSCN) is a safe and more effective cyanide source for
nucleophilic addition to carbonyl compounds under mild
conditions.2 Its addition to keto compounds affords cy-
anohydrin trimethylsiyl ethers, which are useful interme-
diates for the synthesis of cyanohydrins and related
compounds. Various catalysts including Lewis acids and
Lewis bases have been used to promote this transforma-
tion.3,4 Among them, the catalysts usually contain metals.
Although the metal derivatives offer tremendous benefits,
they are also the source of increasing problems.5 There-
fore, new catalytic methods based on metal-free organic
molecules have been developed in the last few years.6,7
However, there are few examples of the cyanosilylation of
ketones employing organocatalysts.8 Herein, we reported
the use of quaternary ammonium salt and N-oxide as com-
binatorial catalysts for cyanosilylation of ketones.
20 mol% 1 + 20 mol% 4
68
a Conditions: 23 °C, 24 h, concentration of acetophenone, 0.13 M in
CH2Cl2.
b Isolated yields.
the N-oxides that contain one or two ethylol groups have
relatively lower catalytic activity (Table 2, entries 3–5).
The catalytic activities of aromatic amine N-oxide and
heterocyclic amine N-oxide are moderate (Table 2, entries
1, 7). The aliphatic amine N-oxide without the ethylol
group gives the lower yield (Table 2, entry 2). The exam-
ined phosphine oxides do not show any catalytic activity
as well as pyridine N-oxide (Table 2, entries 6, 8 and 9).
And then, we investigated the use of a reduced catalyst
loading. When the catalysts 1 and 2 were employed, the
catalyst loading could be reduced to 2.5 mol% without
affecting the reaction rate and the yield (Table 3). It was
found that excellent yield could be obtained by increasing
In the preliminary study, we investigated the addition of
TMSCN to acetophenone in the presence of the easily pre-
pared dibenzyldimethyl ammonium bromide (1) (20
mol%) and N,N-dimethylaniline N-oxide (4) (20 mol%).
Fortunately, the product was obtained in 68% yield after
24 h at room temperature (Table 1, entry 3), while neither
1 nor 4 (Figure 1) was enough to promote the addition of
TMSCN to acetophenone (Table 1, entries 1 and 2).
Additionally, this reaction was found to be insensitive to
air and moisture. Hence, there was no need for an inert
atmosphere.
Subsequently, a series of bases have been examined. The
results are summarized in Table 2. The highest yield is ob-
tained in the presence of triethanolamine N-oxide, while
SYNLETT 2004, No. 6, pp 1077–1079
Advanced online publication: 25.03.2004
0
6.
0
5.
2
0
0
4
Figure 1
DOI: 10.1055/s-2004-820045; Art ID: U04104ST
© Georg Thieme Verlag Stuttgart · New York

1078
H. Zhou et al.
LETTER
Table 4 Catalytic Addition of TMSCN to Ketones using 1 and 2 a
Table 2 Catalytic Addition of TMSCN to Acetophenonea
Entry
1
Ketone
Time (h)
15
Yield (%) b
Entry
Lewis base
4
Yield (%) b
C6H5COCH3
95
92
93
99
98
99
99
99
99
99
93
80
99
99
1
2
3
4
5
6
7
8
9
68
46
82
64
64
0
2
4-FC6H4COCH3
4-MeC6H4COCH3
C6H5COCH2CH3
4-O2NC6H4COCH3
2-Acetonaphthone
(E)-C6H5CH=CHCOCH3
C6H5CH2CH2COCH3
2-Octanone
11
TMNO
2
3
22
4
12
BDENO
DBENO
PyNO
NMNO
P(O)Ph3
HMPA
5
46
6
16
7
14
60
0
8
12
9
11
0
a All the reactions were carried out with 2 equiv. TMSCN in CH2Cl2
at 23 °C with the quaternary ammonium salt 1 (20 mol%) and the
bases (20 mol%) along with 0.13 M of acetophenone during 24 h.
b Isolated yields after flash column chromatography.
10
11
12
13
14
Cyclohexanone
a-Tetralone
16
36
b-Tetralone
12
c TMNO = trimethylamine N-oxide; BDENO = N-benzyl-N,N-dieth-
anolamine N-oxide; DBENO = N,N-dibenzylethanolamine N-oxide;
PyNO = Pyridine N-oxide; NMNO = N-methylmorpholine N-oxide;
P(O)Ph3 = triphenyl phosphine oxide; HMPA = hexamethyl
phosphorous triamide.
4-Phenylcyclohexanone
2-Acetylthiophene
12
72
a Conditions: 2.5 mol% of 1, 2.5 mol% of 2, substrate concentration
2.2 M in CH2Cl2, 23 °C. For typical procedure, see ref.9
b Isolated yields.
the substrate concentration (Table 3, entries 3 and 4). This
is in agreement with our previous report.3a In addition, the
N-oxide 2 alone can catalyze this transformation although
the yield is low (Table 3, entry 1).
Moreover, we also made an attempt to investigate the
enantioselective cyanosilylation of ketones by chiral qua-
ternary ammonium salt. In CH2Cl2 solvent and at 0 °C, the
use of 20 mol% chiral quaternary ammonium salt 3 and N-
oxide 4 as catalysts for cyanosilylation of acetophenone
gave 2-trimethylsilyloxy-2-phenylpropanenitrile in 10%
isolated yield with 20% ee after 80 hours.
Under the optimized conditions (2.5 mol% of 1, 2.5 mol%
of 2), the cyanosilylation of a wide range of ketones was
investigated with results shown in Table 4. Most of aro-
matic, conjugated and aliphatic ketones afforded the cor-
responding products in excellent yields within 11–16
hours (Table 4, entries 1–13) with three exceptions
(Table 4, entries 3, 5 and 11). It is a pity that the problem
of low reaction rate of cyanosilylation of heterocyclic
ketone is still not solved (Table 4, entry 14).
At present the mechanistic detail of this conversion
remains obscure. As one explanation, we speculate that
the role of N-oxide may be a Lewis base to activate the
TMSCN,3a–c,4a–e,4h–j and the positively charged N atom of
quaternary ammonium salt attracts the O atom of carbonyl
group and thus activates the carbonyl group.
Table 3 Catalytic Addition of TMSCN to Acetophenone Mediated
by 1 and 2a
In summary, the use of dibenzyldimethyl ammonium bro-
mide and triethanolamine N-oxide as catalysts for cyanos-
ilylation of ketones has been described. This method is
effective for the cyanation of aliphatic ketones and aro-
matic ketones in low catalyst loading and mild conditions.
In addition, the catalysts are inexpensive and easily pre-
pared. Further mechanistic study and the enantioselective
version of this transformation are underway in our labora-
tory.
Entry
Catalysts load- Concentration of Time (h) Yield (%)b
ing (mol%)
1:2
acetophenone
(M)
1
2
3
4
0:20
0.13
0.13
1.1
24
24
24
15
23
82
95
95
20:20
2.5:2.5
2.5:2.5
2.2
a All the reactions were carried out with 2 equiv. TMSCN in CH2Cl2
Acknowledgment
at 23 °C.
b Isolated yields.
The authors thank the National Natural Science Foundation of
China (No. 20225206, 20390050 and 20372050) and the Ministry
of Education, P. R. China (No. 01144, 104209 and others) for finan-
cial support.
Synlett 2004, No. 6, 1077–1079 © Thieme Stuttgart · New York

LETTER
Cyanosilylation of Ketones Catalyzed by Quaternary Ammonium Salt and N-Oxide
1079
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(9) Typical Procedure: To a mixture of ketone (1.1 mmol),
dibenzyldimethyl ammonium bromide (0.027 mmol) and
triethanolamine N-oxide (0.027 mmol) in CH2Cl2 (0.5 mL)
was added trimethylsilyl cyanide (2.2 mmol, 2 equiv.) at r.t.
The reaction was monitored by TLC, and after the reaction
period described in Table 4, the reaction mixture was
concentrated under reduced pressure and purified by silica
gel column to give the pure product with Et2O–petroleum
ether (1:100) as the eluent.
Synlett 2004, No. 6, 1077–1079 © Thieme Stuttgart · New York