An efficient and facile one-pot synthesis of cyanohydrin esters from carbonyl compounds catalyzed by iron(III) chloride

Article abstract of DOI:10.1016/j.tetlet.2005.09.003

A variety of cyanohydrin esters were readily prepared from carbonyl compounds with trimethylsilyl cyanide and acid anhydride under the influence of a catalytic amount of iron(III) chloride in a convenient one-pot procedure.

Full text of DOI:10.1016/j.tetlet.2005.09.003

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7487–7490
An efficient and facile one-pot synthesis of cyanohydrin esters
from carbonyl compounds catalyzed by iron(III) chloride
Katsuyuki Iwanami, Masaru Aoyagi and Takeshi Oriyama*
Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512, Japan
Received 12 August 2005; revised 1 September 2005; accepted 2 September 2005
Available online 19 September 2005
Abstract—A variety of cyanohydrin esters were readily prepared from carbonyl compounds with trimethylsilyl cyanide and acid
anhydride under the influence of a catalytic amount of iron(III) chloride in a convenient one-pot procedure.
Ó 2005 Elsevier Ltd. All rights reserved.
O-Protected cyanohydrin derivatives constitute versatile
intermediates in organic synthesis,1 and several direct
methods for their preparation have been reported so
far. Cyanohydrin silyl ethers are prepared from car-
bonyl compounds with trialkylsilyl cyanide under the
influence of Lewis acids,2 Lewis bases,3 or organocata-
lyst.4 For cyanohydrin alkyl ethers, we recently demon-
strated a convenient one-pot synthesis directly from
aldehydes with trimethylsilyl cyanide (TMSCN) and
alkoxytrimethylsilane catalyzed by iron(III) chloride.5,6
On the other hand, O-acyl protected cyanohydrins also
attract the interest of many organic chemists.7 Sydnes
et al. reported that reaction of acylals with trimethylsilyl
cyanide in the presence of titanium(IV) chloride afforded
the corresponding cyanohydrin esters.8 Kagan et al. de-
scribed a one-pot esterification of O-trimethylsilyl pro-
tected cyanohydrins using 2 equiv of acid anhydride or
acid chloride catalyzed by scandium triflate.9 Synthesis
of cyanohydrin esters from carbonyl compounds using
acyl cyanide10 as a cyanating agent is a straightforward
and promising method. Actually, by this methodology,
O-acyl protected cyanohydrins are prepared from the
parent aldehydes in the presence of a base.11 Recently,
we developed an efficient cyanobenzoylation of alde-
hydes with benzoyl cyanide in the absence of a catalyst
in DMSO.12,13 However, it is difficult to prepare various
types of acylated cyanohydrins because commercially
available acyl cyanides are limited and comparatively
expensive.14 Although cyanohydrin esters can be also
prepared directly from aldehydes with alkali metal cya-
nide and acid anhydride, excessive amounts (4 equiv) of
an acylating agent, and metal cyanide are needed.15 In
addition, almost all examples of the preparation of O-
acyl cyanohydrins reported so far are restricted to ace-
tate and benzoate.
Herein, we wish to report a novel and convenient one-
pot preparation of various cyanohydrin esters from car-
bonyl compounds with trimethylsilyl cyanide as a safer
cyanating agent and readily available acid anhydride
under the influence of
iron(III) chloride.
a
catalytic amount of
First, we undertook to examine one-pot preparation of
O-acyl protected cyanohydrin from the corresponding
aldehyde catalyzed by iron(III) chloride via in situ-gen-
erated acylal (1,1-gem-diacetate). A mixture of benzalde-
hyde and 5 mol % of iron(III) chloride was treated with
2.0 equiv of acetic anhydride at 0 °C; after 10 min,
1.5 equiv of trimethylsilyl cyanide was added and stirred
for additional 2 h at room temperature. The usual work-
up of the reaction mixture afforded the desired product,
a-(acetoxy)phenylacetonitrile, in 65% yield (Method A:
Scheme 1). In contrast, when acetic anhydride was
added to the reaction mixture of benzaldehyde and
OAc
Ac2O, FeCl3
TMSCN
rt, 2 h
PhCHO
Ph
CN
65%
CH3NO2
0 oC, 10 min
Keywords: Cyanation; Cyanohydrin ester; Trimethylsilyl cyanide; Acid
anhydride; Carbonyl compound; Iron(III) chloride.
*
Scheme 1. One-pot preparation of cyanohydrin acetate (Method A).
Corresponding author. Tel.: +81 29 228 8368; fax: +81 29 228
(Molar ratio of benzaldehyde/Ac2O/TMSCN/FeCl3 = 1:2.0:1.5:0.05.)
8403; e-mail: tor@mx.ibaraki.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.003

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K. Iwanami et al. / Tetrahedron Letters 46 (2005) 7487–7490
Table 3. Synthesis of various cyanohydrin acetates from carbonyl
OAc
TMSCN, FeCl3
Ac2O
rt, 2 h
compoundsa
PhCHO
Ph
CN
84%
CH3NO2
0 oC, 20 min
TMSCN
Ac2O
rt
O
R
NC
R
OAc
R'
FeCl3
CH3NO2, 0 oC, 30 min
R'
Scheme 2. One-pot preparation of cyanohydrin acetate (Method B).
(Molar ratio of benzaldehyde/TMSCN/Ac2O/FeCl3 = 1:1.5:2.0:0.05.)
Entry
Carbonyl compound
Time of the
Yieldb/%
second step/h
trimethylsilyl cyanide, the yield was increased to 84%
(Method B: Scheme 2).
1
2
3
4
PhCHO
3
3
3
3
6
9
6
6
12
5
4
3
4
3
12
3
3
94
82
80
91
91
56
95
73
93
85
89
89
91
62
79
80
91
90
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
2,4,6-Me3C6H2CHO
4-MeOC6H4CHO
4-BrC6H4CHO
4-AcC6H4CHO
4-MeO2CC6H4CHO
1-Naphthaldehyde
2-Naphthaldehyde
PhCH2CH2CHO
cyclo-C6H11CHO
t-BuCHO
After preliminary investigations using method B, we
found that treatment with 1.2 equiv of trimethylsilyl
cyanide at 0 °C for 30 min at the first step and employ-
ment of 1.5 equiv of acetic anhydride gave the best result
as shown in Table 1 (entry 4). A screening of solvents
revealed that nitromethane as a solvent gave the best
result (Table 2, entry 1).
5
6c
7
8
9
10
11
12d
13
14
15e
16
17
18
The reaction was conducted under the optimal condi-
tions16 with various aromatic and aliphatic aldehydes
and ketones. The successful results are summarized in
Table 3. In the case of benzaldehyde having an elec-
tron-donating group such as tolualdehydes, the corre-
sponding cyanohydrin acetate could be obtained in
good to high yields (entries 2–4). Especially, a sterically
Acetophenone
Benzylacetone
Cyclopentanone
Cyclohexanone
5
a Molar ratio of carbonyl compound/TMSCN/Ac2O/FeCl3 =
1:1.2:1.5:0.05.
b Isolated yield of purified product.
c CH3CN was used as a solvent.
Table 1. Optimization of the reaction conditionsa
d The reaction of the second step was performed at 60 °C.
e 2.5 equiv of Ac2O was used.
OAc
TMSCN
Ac2O
rt, 2 h
PhCHO
Ph
CN
FeCl3
CH3NO2
hindered aldehyde, mesitaldehyde, gave the correspond-
ing O-acetyl cyanohydrin in 91% yield (entry 5), but
with p-anisaldehyde, the desired product was obtained
in 56% yield (entry 6) because of the messiness of the
reaction mixture. As regards benzaldehyde having an
electron-withdrawing group, the corresponding acetate
was also obtained in good to excellent yields (entries
7–9), and the ester function is tolerated under these reac-
tion conditions (entry 9). Starting from 1- and 2-naph-
thaldehyde, the desired products were obtained in 85%
and 89% yield, respectively (entries 10 and 11). Simi-
larly, aliphatic aldehydes, 3-phenylpropionaldehyde
and cyclohexanecarbaldehyde afforded cyanohydrin
acetate in high yields (entries 12 and 13). Even in the
case of sterically hindered pivalaldehyde, the desired
product was obtained in 62% yield (entry 14). Further-
more, we have found that this reaction is similarly effec-
tive for aromatic, aliphatic, and alicyclic ketones (entries
15–18) to yield the corresponding O-acetyl protected
cyanohydrins in good to high yields.
Entry Temperature of Time of the
the first step/°C first step/min of Ac2O
Equivalent Yieldb/%
1
2
3
4
5
6
7c
0
0
0
0
0
rt
0
0
10
20
30
30
30
30
1.5
1.5
1.5
1.5
1.2
1.5
1.5
52
52
90
92
86
88
83
a Molar ratio of benzaldehyde/TMSCN/FeCl3 = 1:1.2:0.05.
b Isolated yield of purified product.
c 1.5 equiv of acetyl chloride was used instead of acetic anhydride.
Table 2. Effect of solventsa
OAc
CN
TMSCN
Ac2O
rt
PhCHO
Ph
FeCl3
0 oC, 30 min
Entry
Solvent
Time of the second step/h
Yieldb/%
Next, to clarify the generalization of this useful transfor-
mation, we investigated other acid anhydrides instead of
acetic anhydride, as illustrated in Table 4. Reaction with
propionic anhydride, isobutyric anhydride, or crotonic
anhydride gave the corresponding cyanohydrin esters
in high yields (entries 1–3). On the other hand, when
pivalic anhydride or benzoic anhydride was used as an
acylating agent, though the reaction of the second step
needed higher temperature or longer reaction time, the
1
2
3
4
5
6
CH3NO2
CH2Cl2
CH3CN
DMF
Toluene
THF
3
12
12
12
12
12
94
81
38
29
27
0
a Molar ratio of benzaldehyde/TMSCN/Ac2O/FeCl3 = 1:1.2:1.5:0.05.
b Isolated yield of purified product.

K. Iwanami et al. / Tetrahedron Letters 46 (2005) 7487–7490
Table 4. Synthesis of various cyanohydrin esters from carbonyl compoundsa
7489
TMSCN
(R''CO)2O
O
NC
R
OCOR''
R'
FeCl3
CH3NO2, 0 oC, 30 min
R
R'
Entry
Carbonyl compound
R00
Et
Temperatures of the second step/°C
Time of the second step/h
Yieldb/%
1
2
3
4
5c
6
7
8
9c
PhCHO
PhCHO
PhCHO
PhCHO
rt
rt
rt
60
60
60
60
rt
3
3
3
2
12
3
3
12
9
95
94
89
89
77
83
82
87
68
i-Pr
CH3CH@CH
t-Bu
Ph
t-Bu
Ph
t-Bu
Ph
PhCHO
PhCH2CH2CHO
PhCH2CH2CHO
Cyclopentanone
Cyclopentanone
rt
a Molar ratio of carbonyl compound/TMSCN/acid anhydride/FeCl3 = 1:1.2:1.5:0.05.
b Isolated yield of purified product.
c 1.1 equiv of Bz2O was used.
OTMS
CN
(3) a broad range of aldehydes and ketones can be ap-
plied, (4) mild reaction conditions, and (5) experimental
convenience. Further investigations to broaden the
scope and synthetic applications of this efficient cyana-
tion are under way in our laboratory.
TMSCN (1.2 equiv.)
PhCHO
Ph
FeCl3 (5 mol%)
CH3NO2, 0 oC, 30 min
quant.
Scheme 3. Cyanosilylation of benzaldehyde catalyzed by iron(III)
chloride.
References and notes
1. (a) Gregory, R. J. H. Chem. Rev. 1999, 3649; (b) Brunel,
J.-M.; Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43, 2752;
(c) Chen, F.-X.; Feng, X. Synlett 2005, 892; (d) Achard, T.
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Org. Chem. 1993, 58, 159; (e) Yang, Y.; Wang, D. Synlett
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Tetrahedron Lett. 1998, 39, 3823; (g) Bandini, M.; Cozzi,
P. G.; Melchiorre, P.; Umani-Ronchi, A. Tetrahedron
Lett. 2001, 42, 3041; (h) Azizi, N.; Saidi, M. R. Phosphorus
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OAc
Ac2O (1.5 equiv.)
OTMS
CN
Ph
CN
98%
FeCl3 (5 mol%)
Ph
CH3NO2, rt, 15 min
Scheme 4. Direct O-acetylation of cyanohydrin TMS ether catalyzed
by iron(III) chloride.
corresponding cyanohydrin pivaloates or benzoates
were also obtained in good to high yields (entries 4–9).
Concerning the reaction mechanism, when the reaction
of entry 1 in Table 3 was quenched after the completion
of the first step, the corresponding trimethylsilyl ether,
a-(trimethylsiloxy)phenylacetonitrile, was detected by
1H NMR analysis,17 as shown in Scheme 3. On the other
hand, when the isolated cyanohydrin TMS ether18 was
treated with 1.5 equiv of acetic anhydride in the presence
of 5 mol % of iron(III) chloride, the corresponding ace-
tate, a-(acetoxy)phenylacetonitrile, was obtained readily
in 98% yield (Scheme 4). These experimental results sug-
gest that the present cyanoacylation proceeds via cyano-
hydrin trimethylsilyl ether as an intermediate.
3. (a) Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. Chem.
Lett. 1991, 537; (b) Tian, S.-K.; Deng, L. J. Am. Chem.
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Synlett 2004, 1077.
5. Iwanami, K.; Oriyama, T. Chem. Lett. 2004, 33, 1324.
6. Other iron(III) chloride-catalyzed useful reactions of silyl-
substituted nucleophiles: (a) Watahiki, T.; Oriyama, T.
Tetrahedron Lett. 2002, 43, 8959; (b) Watahiki, T.;
Akabane, Y.; Mori, S.; Oriyama, T. Org. Lett. 2003, 5,
3045; (c) Iwanami, K.; Seo, H.; Tobita, Y.; Oriyama, T.
Synthesis 2005, 183; (d) Iwanami, K.; Yano, K.; Oriyama,
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707; (e) Kawasaki, Y.; Fujii, A.; Nakano, Y.; Sakaguchi,
In conclusion, we have developed an efficient one-pot
synthesis of O-acyl protected cyanohydrins starting
from a variety of parent carbonyl compounds. The pres-
ent reaction has the following synthetic advantages: (1) a
catalytic amount of iron(III) chloride promotes both
cyanation and O-acylation, in contrast to the known
cyanation of carbonyl compounds, (2) various ester
types of a protecting group for the hydroxyl function
are obtained by using readily available acid anhydride,

7490
K. Iwanami et al. / Tetrahedron Letters 46 (2005) 7487–7490
S.; Ishii, Y. J. Org. Chem. 1999, 64, 4214; (f) Hanefeld, U.;
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16. Typical procedure: To a suspension of anhydrous
iron(III) chloride (2.5 mg, 0.015 mmol) and benzaldehyde
(30 lL, 0.30 mmol) in nitromethane (2 mL) was added
trimethylsilyl cyanide (48 lL, 0.36 mmol) and stirred at
0 °C under an argon atmosphere. After 30 min, acetic
anhydride (42 lL, 0.45 mmol) was added and stirred for
3 h at room temperature. The reaction mixture was
quenched with a phosphate buffer (pH 7), and the organic
materials ware extracted with CH2Cl2, washed with brine,
and dried over Na2SO4. a-(Acetoxy)phenylacetonitrile
(48.7 mg, 94%) was isolated by thin-layer chromatography
on silica gel.
10. Hunig, S.; Schaller, R. Angew. Chem., Int. Ed. Engl. 1982,
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13. Catalyst-free DMSO-promoted synthesis of cyanohydrin
carbonates from aldehydes: Iwanami, K.; Hinakubo, Y.;
Oriyama, T. Tetrahedron Lett. 2005, 46, 5881.
14. Acyl cyanide can be synthesized from the corresponding
acid halide with metal cyanide or trimethylsilyl cyanide:
(a) Haase, K.; Hoffmann, H. M. R. Angew. Chem., Int. Ed.
Engl. 1982, 21, 83; (b) Herrmann, K.; Simchen, G.
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17. The yield was determined by 1H NMR analysis (400 MHz)
using 1,1,2,2-tetrachloroethane as an internal standard.
18. a-(Trimethylsiloxy)phenylacetonitrile was prepared inde-
pendently according to the literature procedure: Rasmus-
sen, J. K.; Heilmann, S. M. Org. Synth. Coll. Vol. 7 1990,
521.