An efficient cyanosilylation of aldehydes with trimethylsilyl cyanide catalysed by MgI2 etherate

Article abstract of DOI:10.3184/174751912X13445841618558

A convenient procedure for the synthesis of cyanohydrins by the addition of trimethylsilyl cyanide to aromatic aldehydes, heteroaromatic aldehydes, aliphatic aldehydes and unsaturated aldehydes catalysed by MgI2 etherate (MgI₂(OEt2)n) in good to excellent yields is described.

Full text of DOI:10.3184/174751912X13445841618558

566 RESEARCH PAPER
OCTOBER, 566–567
JOURNAL OF CHEMICAL RESEARCH 2012
An efficient cyanosilylation of aldehydes with trimethylsilyl cyanide
catalysed by MgI2 etherate
Yanping Wang, Meiling Feng, Yingshuai Liu and Xingxian Zhang*
College of Pharmaceutical Sciences, Zhejiang University ofTechnology, Hangzhou, Zhejiang 310032, P. R. China
A convenient procedure for the synthesis of cyanohydrins by the addition of trimethylsilyl cyanide to aromatic
aldehydes, heteroaromatic aldehydes, aliphatic aldehydes and unsaturated aldehydes catalysed by MgI2 etherate
(MgI2•(OEt2)n) in good to excellent yields is described.
Keywords: aldehyde, trimethylsilyl cyanide, cyanohydrins, MgI2 etherate
Cyanohydrins serve as useful precursors to many important
classes of organic compounds (e.g., β-amino alcohols,
α-hydroxy aldehydes, and α-hydroxy acids). Consequently, con-
siderable attention has been taken to design efficient methods
for their synthesis.1,2 Among them, the Lewis acid-catalysed
cyanosilylation of aldehydes with trimethylsilyl cyanide has
been widely used in the construction of the carbon–carbon
bond in generating cyanohydrins. Metal halides, such as
AlCl3,3 BF3,4 BiBr3,5 InBr3,6 LnCl3 (Ln = La, Ce, Sm),7 SnCl4,4
or electron-withdrawing groups (Table 1, entries 6–9) afforded
the corresponding products in high yields. Moreover, the cya-
nosilylation of unsaturated aldehydes exclusively provided
the 1,2-adduct (Table 1, entry 10). In addition, heteroaromatic
aldehydes gave good yields (Table 1, entries 11–13). Aliphatic
aldehydes also worked well. It is worth noting that the more
sterically hindered pivaldehyde afforded the desired product in
good yield. However, electronically deactivated aromatic
ketones and aliphatic ketones do not undergo this reaction even
after a long time at room temperature (Table 1, entries 16–17)
This is due to the lower reactivity of ketones, compared to
aldehydes, towards trimethylsilyl cyanide.
The high coordinating ability of the magnesium (II) towards
the oxygen atom of the carbonyl moiety is presumably respon-
sible for the effective activation of the aldehydic carbonyl.
To examine the halide anion effect, halogen analogs of MgI2
etherate, MgCl2 etherate and MgBr2 etherate were compared
under parallel reaction conditions (10 mol % of catalyst) in
the cyanosilylation reaction of aryl aldehydes with TMSCN,
respectively. MgCl2 etherate and MgBr2 etherate were less
effective in terms of substrate conversion yield and gave
moderate yields. Apparently, the unique reactivity of MgI2
etherate is attributed to the dissociative character of iodide
counter-ion and a more Lewis acidic cationic [MgI]+ species.
All the compounds were characterised by their 1H NMR
spectra and by comparison with known compounds.
(n-C4H9)2SnCl2 or (C6H5)2SnCl2, TiCl4,4 ZnI2,9 and LiCl10 are
8
known to be Lewis acid catalysts for the cyanosilylation of
aldehydes. Chiral Lewis acid–Lewis base combined catalysts
have been successfully applied to the asymmetric reaction.11,12
However, the traditional methods using Lewis acids such as
AlCl3, BF3•Et2O and SnCl4 must be carried out under strictly
anhydrous conditions, which are difficult to be handled espe-
cially on a large scale. Water-tolerant Lewis acids lanthanide
triflates are rather expensive. Consequently, the development
of less expensive, environmentally benign, and easily handled
promoters for the cyanosilylation of aldehydes is still highly
desirable.
Due to their abundant, inexpensive and nontoxic character,
Lewis acid Mg(II) catalysts have been widely utilised in
various organic reactions.13 In our previous papers,14,15 we have
demonstrated that MgI2 etherate can efficiently catalyse the
allylation of aldehydes with allylstannane and the Clauson–
Kass condensation of primary amines with 2,5-dimethoxytet-
rahydrofuran. In continuation of our research, we now report
a simple and efficient procedure for the cyanosilylation of
aldehydes with TMSCN catalysed by MgI2 etherate under mild
reaction conditions in good to excellent yields (Scheme 1).
In conclusion, we have demonstrated the unique reactivity
of MgI2 etherate in the cyanosilylation of aromatic aldehydes,
Table 1 The cyanosilylation of aldehydes with trimethylsilyl
a
cyanide catalysed by MgI2•(OEt2)n
Entry
R
Time/h
Productb
Yield/%c
Results and discussion
We initiated our studies by carrying out the cyanosilylation
of benzaldehyde with trimethylsilyl cyanide in the presence of
10 mol% of freshly prepared MgI2 etherate (1.0 M in Et2O/
benzene 1:2) 16 in untreated CH2Cl2 at room temperature. After
stirring for 4.0 h, the desired cyanohydrins were obtained in
93% yield. In order to clarify the scope of this reaction, several
aldehydes were examined in the presence of 10 mol% MgI2
etherate. The results were summarised in Table 1. As shown in
Table 1, the reaction proceeded smoothly at room temperature
and provided good to excellent yields (Table 1, entries 1–9).
Of the various aldehydes which were screened, aromatic
aldehydes with either electron-donating (Table 1, entries 3–5)
1
2
Ph
β-Naphthyl
4-MeC6H4
4
4
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
NAd
NA
93
94
92
93
93
98
95
94
96
86
88
83
88
90
88
NRe
NR
3
5
4
3-MeC6H4
4
5
4-MeOC6H4
4-NO2C6H4
4-FC6H4
2-ClC6H4
2-BrC6H4
4
6
2
7
3
8
4
9
4
10
11
12
13
14
15
16
17
(E)-PhCH=CH
2-Furyl
3-Me-2-thiophenyl
2-Indolyl
CH3CH2
(CH3)3C
4-NO2C6H4COCH3
Cyclopentanone
5
5
5
4
5
5
12
12
a The reaction was carried out by addition of aldehyde and
trimethylsilyl cyanide catalysed by 10 mol% of MgI2•(OEt2)n at
room temperature in untreated CH2Cl2.
Scheme 1 MgI2 etherate-catalysed the cyanosilylation of
b All products were identified by their 1H NMR spectra.
c Yields of products isolated by column chromatography.
d NA, Not available.
aldehydes with TMSCN.
e NR, No reaction.
* Correspondent. E-mail: zhangxx@ zjut.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 567
1H), 6.20 (dd, J = 6.0, 16.0 Hz, 1H), 6.83 (d, J = 16.0 Hz, 1H),
7.25–7.40 (m, 5H).
heteroaromatic aldehydes, unsaturated aldehydes and aliphatic
aldehydes with TMSCN. This catalytic reaction enables
the cyanosilylation to be carried out under essentially neutral
conditions in untreated CH2Cl2 at room temperature in good to
excellent yields. Further investigation on the catalytic reactiv-
ity of MgI2 etherate in other C–C bond forming reactions is
underway.
2-Furyl-2-hydroxyacetonitrile (1k):20 Yellowish oil, Rf = 0.27 (20%
EtOAc in petroleum ether), δH 4.60 (br s, 1H), 5.54 (s, 1H), 6.38 (dd,
J = 1.8, 3.2 Hz, 1H), 6.61 (dd, J = 1.6, 3.6 Hz, 1H), 7.44 (d, J = 1.5 Hz,
1H).
2-(3-Methylthiophene)-2-hydroxyacetonitrile (1l):24 Yellowish oil,
Rf = 0.24 (20% EtOAc in petroleum ether), δH 2.31 (s, 3H), 3.79 (br s,
1H), 5.71 (s, 1H), 6.87 (d, J = 5.0 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H).
2-(2-Indolyl)-2-hydroxyacetonitrile (1m):20 Brownish oil, Rf = 0.23
(33% EtOAc in petroleum ether), δH 4.43 (br s, 1H), 5.47 (s, 1H),
7.33–7.68 (m, 5H).
Experimental
Silica gel (200–300 mesh) and light petroleum ether (PE, b.p.
60–90 °C) were used for product purification by flash column
1
2-Hydroxy-butanenitrile (1n):22 Pale yellowish oil, Rf = 0.18 (33%
EtOAc in petroleum ether), δH 1.15 (t, J = 7.5 Hz, 3H), 1.84–1.90 (m,
2H), 4.42 (t, J = 6.6 Hz, 1H).
chromatography. H NMR spectra were taken on a Bruker AM-500
spectrometer with TMS as an internal standard and CDCl3 as solvent.
The reactions monitoring was accomplished by TLC on silica gel
polygram SILG/UV 254 plates. All compounds were identified by 1H
NMR and are in good agreement with those reported.
2-Hydroxy-3,3-dimethylbutanenitrile (1o):18 Pale yellowish oil,
Rf = 0.54 (33% EtOAc in petroleum ether), δH 1.08 (s, 9H), 4.12 (s,
1H).
Synthesis of cyanohydrins; typical procedure
A stirred benzaldehyde solution of (5 mmol) in CH2Cl2 (20 mL) was
treated with freshly prepared MgI2 etherate (0.5 mmol) at room
temperature, followed by the addition of a solution of trimethylsilyl
cyanide (6 mmol) in CH2Cl2 (10 mL) via a syringe. The resulting reac-
tion mixture was stirred at r.t. for 4.0 h and quenched with saturated
Na2S2O3 aqueous solution. Extractive workup with CH2Cl2 and chro-
matographic purification of the crude product on silica gel gave the
2-phenyl-2-hydroxyacetonitrile in 93% yield.
Financial support from the Zhejiang Province Natural Science
Foundation of China (Project Y4100692)
Received 11 June 2012; accepted 2 July 2012
Paper 1201368 doi: 10.3184/174751912X13445841618558
Published online: 28 September 2012
2-Phenyl-2-hydroxyacetonitrile (1a):17 Pale yellowish oil, Rf = 0.36
(33% EtOAc in petroleum ether), δH 4.45 (br s, 1H), 5.48 (s, 1H),
7.42–7.43 (m, 3H), 7.48-50 (m, 2H).
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2-Naphthalene-2-hydroxyacetonitrile (1b):18 Pale yellowish oil,
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1H), 7.51–7.54 (m, 1H), 7.57–7.61 (m, 1H), 7.63–7.66 (m, 1H), 7.84
(d, J = 7.0 Hz, 1H), 7.94–7.97 (m, 2H), 8.16 (d, J = 8.5 Hz, 1H).
2-(4-Methylphenyl)-2-hydroxyacetonitrile (1c):19 Pale yellowish
oil, Rf = 0.28 (20% EtOAc in petroleum ether), δH 2.39 (s, 3H), 4.38
(br s, 1H), 5.44 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz,
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(br s, 1H), 5.49 (s, 1H), 7.25–7.36 (m, 4H).
2-(4-Methoxyphenyl)-2-hydroxyacetonitrile (1e):20 Yellowish oil,
Rf = 0.14 (30% EtOAc in petroleum ether), δH 3.79 (s, 3H), 5.41 (s,
1H), 6.90 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H).
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2-(4-Nitrophenyl)-2-hydroxyacetonitrile (1f):17 Yellowish oil,
Rf = 0.17 (20% EtOAc in petroleum ether), δH 5.71 (s, 1H), 7.76 (d,
J = 8.8 Hz, 2H), 8.32 (d, J = 8.8 Hz, 1H).
2-(4-Fluorophenyl)-2-hydroxyacetonitrile (1g):20 Yellowish oil,
Rf = 0.23 (20% EtOAc in petroleum ether), δH 3.51 (br s, 1H), 5.53
(s, 1H), 7.12–7.16 (m, 2H), 7.50–7.53 (m, 2H).
2-(2-Chlorophenyl)-2-hydroxyacetonitrile (1h):21 Pale yellowish
oil, Rf = 0.41 (20% EtOAc in petroleum ether), δH 4.64 (br s, 1H), 5.83
(s, 1H), 7.31–7.35 (m, 2H), 7.37–7.39 (m, 1H), 7.66–7.70 (m, 1H).
2-(2-Bromophenyl)-2-hydroxyacetonitrile (1i):22 Pale yellowish oil,
Rf = 0.34 (33% EtOAc in petroleum ether), δH 4.24 (br s, 1H), 5.82
(s, 1H), 7.28 (t, J = 1.0 Hz, 1H), 7.41 (t, J = 1.0 Hz, 1H), 7.60 (d,
J = 1.0 Hz, 1H), 7.71 (d, J = 1.0 Hz, 1H).
4-Phenyl-2-hydroxy-3-butenenitrile (1j):23 Yellowish oil, Rf = 0.21
(20% EtOAc in petroleum ether), δH 4.23 (br s, 1H), 5.12 (d, J = 6.0 Hz,

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