होम Tetrahedron Letters Ac2O/K2CO3/DMSO: an efficient and practical reagent system for the synthesis of nitriles from...

Ac2O/K2CO3/DMSO: an efficient and practical reagent system for the synthesis of nitriles from aldoximes

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Tetrahedron Letters 55 (2014) 639–641

Contents lists available at ScienceDirect

Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Ac2O/K2CO3/DMSO: an efficient and practical reagent system for the
synthesis of nitriles from aldoximes
Yaoping Song a, Dongguo Shen a, Qinghua Zhang b, Bo Chen b, Guangyu Xu a,⇑
a
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and Chemical Engineering, Hunan Normal University,
Changsha 410081, China
b
Research and Development, Hunan Fangsheng Pharmaceuticals Limited, Changsha 410205, China

a r t i c l e

i n f o

Article history:
Received 6 September 2013
Revised 12 November 2013
Accepted 21 November 2013
Available online 1 December 2013
Keywords:
Dehydration
Aldoximes
Nitriles
Acetic anhydride
Synthesis
Nilvadipine

a b s t r a c t
The transformation of aldoximes to nitriles using acetic anhydride as dehydration agent under mild reaction conditions is reported. The reaction, which proceeds under weak alkaline condition, allows for the
conversion of a range of aldoximes including aromatic aldoximes, alphatic aldoximes, and heterocyclic
aldoximes in good to excellent yields. This method has also been successfully applied to the synthesis
of calcium channel blocker nilvadipine in pilot scale.
Ó 2013 Elsevier Ltd. All rights reserved.

Nitrile is an important synthetic intermediate for pharmaceuticals, pesticides, dyes, and material sciences.1 The strong electron
withdrawing effects and excellent hydrogen bond acceptor properties of nitrile make it widely used in the design of drug molecules.
There are over 30 nitrile-containing drugs in the pharmaceutical
market with 20 additional nitrile-containing leads in clinical development.2 Numerous methods to synthesize nitriles have been
documented in the literature, such as the Sandmeyer reaction,3
metal-catalyzed cyanation of aryl halides, the nucleophilic substitution of alkyl halides with cyanides, oxidation of amines,4 and
dehydration of;  amides and aldoximes.5 Among these, the dehydration of oximes into nitriles is one of the most suitable and attractive strategies for the synthesis of nitriles as the availability of
starting material and the avoidance of very toxic cyanide ion. In
recent years a number of efficient reagents and conditions have
been reported for the dehydration of aldoximes to nitriles,6–40
and the search for better reagents continues.
Acetic anhydride as a common and cheap dehydrating agent has
been reported in the conversion of aldoximes to nitrile but with
unsatisfactory results.41 It always proceeds under acidic conditions41a,b or in aqueous alkaline solution41c or used both as solvent
and reactant,41d–f the acid-sensitive functional group such as ester
was partly cleaved. The hydration of nitriles to the corresponding

⇑ Corresponding author. Fax: +86 731 88872531.
E-mail address: gyxu@hunnu.edu.cn (G. Xu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.079

primary amides was also observed.42 In some cases, the primary
amide formed in the reaction could hardly be removed from
nitriles by a conventional crystallization purification. To solve
these problems, we tried to convert aldoximes to nitriles using
acetic anhydride under weak alkaline conditions. After several
attempts, we found treatment of m-nitrobenzaldehyde oxime with
Ac2O/K2CO3 in DMSO at room temperature afforded m-nitrobenzonitrile in 50% yield (Table 1, entry 1). The reaction rate increases
with temperature up to 50 °C, above which there is no change in
rate for the conversion of aldoxime (Table 1, entries 2–7). At
50 °C, reaction can be completed in 10 h with excellent yield
(94%). The reaction was monitored by HPLC and no byproduct
3-nitrobenzamide was detected. Then several solvents, such as
dimethylsulfoxide, THF, DMF, 1,4-dioxane, acetone, and MeCN
were screened (Table 1, entries 8–12), and the results showed that
dimethylsulfoxide was the best choice (see Scheme 1). The effect of
various organic and inorganic bases on the model reaction was
investigated (Table 1, entries 13–16). It is clear that K2CO3 gave
the best result. Very low yield was obtained using organic base
Et3N and pyridine. In the absence of base, very little conversion
was observed even though the reaction time was prolonged to
48 h (Table 1, entry 17).
This method43 was applied for conversion of a range of aromatic
aldoximes to corresponding nitriles in high yields (Table 2).
Electronic variation on the aromatic substituents had little effect
on the yield of the reaction (Table 2, entries 1–8). It was interesting
that the dehydration of benzaldehyde oxime proceeded slowly

640

Y. Song et al. / Tetrahedron Letters 55 (2014) 639–641

Table 1
Screen of reaction conditionsa

Table 2
Dehydration of various aldoximes using K2CO3 and Ac2Oa

Entry

Base

Temp. (°C)

Sol.

Time (h)

Yieldb (%)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3
Et3N
Pyridine
Na2CO3
—

25
40
50
60
70
80
90
50
50
50
50
50
50
50
50
50
50

DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
1,4-Dioxane
Acetone
MeCN
THF
DMSO
DMSO
DMSO
DMSO
DMSO

24
24
10
5
3
2
1
10
10
10
10
10
10
10
10
10
48

50
75
94
92
90
94
93
50
<5
<5
<5
<5
30
11
10
45
<5

Reaction conditions: aldoximes44 (1.5 mmol), Ac2O (3 mmol), weak base
(3 mmol), solvent (6 mL).
b
Isolated yields.

Entry

Substrate

Product

H
C N OH

Reaction time (h)

Yieldb (%)

10

91

16

92

30

95

12

89

3.5

95

24

96c

11

87

21

95

24

90

24

88

40

75

48

55

CN

1

NO2

NO2

OCH3

OCH3
2

HC N OH

CN
Cl

Cl
3

HC N OH

CN

Cl
HC N OH

CN

a

H
C N OH

4

5

C N

Ac2O, base

Cl

O2N
HC N OH

O2N

CN

solvent

NO2

NO2

6

CN

HC N OH
Scheme 1.
7

under these conditions, we can improve the reaction temperature
to complete it. Benzonitrile could be isolated in 96% yield after
24 h (90 °C) (entry 6). It is worth noting that the ester group would
not be hydrolyzed under these conditions (entry 8). Furthermore,
trans-cinnamoxime was also compatible with the employed reaction conditions with no isomerization of the double bonds (entry
9). In addition, as a typical heteroaromatic aldoxime, 2-pyridinealdoxime was smoothly converted into 2-pyridylnitrile in good yield
(entry 10). Aliphatic aldoximes could also be employed as good
substrates to afford the corresponding aliphatic nitriles, but the
conversion rate was much slower than aromatic aldoximes (entries
11 and 12). For example, valeraldoxime was dehydrated to give
valeronitrile in only 55% yield, and the improvement of temperature had little effect on the reaction conversion. All the structures
of products were characterized by 1H NMR and MS and the data
were identical with literature records.
The possible reaction mechanism for conversion of aldoxime to
nitrile using acetic anhydride in the presence of base is shown in
Scheme 2. It includes reaction of the aldoxime with acetic anhydride to form O-acetyl-oxime, which was subsequently attacked
by base to form the nitrile compound and acetate anion.
We next applied this method to the synthesis of nilvadipine,
which is an effective antihypertensive drug (Scheme 3). According
to the reported procedure, two byproducts (III and IV) would appear, and they should be removed by column chromatography
using the mixture of benzene and ethyl acetate as eluent.45 We also
found that these two byproducts cannot be eliminated after two
recrystallization in our lab. According to our developed method
no formation of these two byproducts was observed in the dehydration step, we can get the final product with 99.9% purity and
85.1% yield (dehydration step after one recrystallization) at pilot
scale.
In conclusion, a practical and efficient method has been established for the conversion of aldoximes to the corresponding nitriles
using acetic anhydride as dehydration agent in the presence K2CO3

HC N OH

CN
COOCH3

COOCH3
8

CH N OH

CN

HC N OH

CN

9

10

11
12

N

5
3

C N OH
H
N
OH
N

N

CN
CN
4
CN

OH

a
Reaction conditions: aldoximes (1.5 mmol), K2CO3(3 mmol), Ac2O (3 mmol),
DMSO (6 mL), 50 °C.
b
Isolated yield.
c
Yields were obtained from reactions running at 90 °C.

R C N O H
H
(HCO3-) B-

+

O
H3C C
H3C C
O

-

O

-AcO

B-(HCO3-)
H
O
R C N O C CH3

R C N
+
CH3CO2-

Scheme 2.

and DMSO. The availability of dehydration agent, mild reaction
conditions, simple experimental procedure, high efficiency, and
selectivity are advantages of the current method.

Y. Song et al. / Tetrahedron Letters 55 (2014) 639–641

NO2
O

NO2

O

O

(1) H2NOH.HCl

O
H

N
H
I

(2) Ac2O

O

O

O

O
N
H
II

O

NO2

NO2
O

O

O

O
N
H
III

CN

O

O

O
NH2

OH
N
H
IV

O

CN

Scheme 3.

Acknowledgements
This work was supported by Changsha Administration of Science & Technology (K1205035-31) and Program for Science and
Technology Innovative Research Team in Higher Educational Institute of Hunan Province.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2013.11.079.
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43. A general procedure for the preparation of nitrile from aldoxime using acetic
anhydride as the dehydration agent: K2CO3 (3 mmol) was added to a stirred
mixture of aldoxime (1.5 mmol) and 6 mL DMSO, followed by Ac2O (3 mmol).
The resulting mixture was stirred at 50 °C for a specified period (Table 2). After
the reaction was completed, 30 mL water was added then extracted with
CH2Cl2 (10  3 mL). The organic phase was washed with water (10  3 mL)
then dried with anhydrous Na2SO4. The solvent was evaporated under vacuum
to give the nitrile products.
44. All of the aldoxime used in this method were synthesized in excellent yields by
a mixture of 1.0 equiv of the aldehydes, 1.4 equiv of NH2OHHCl, and 2.0 equiv
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