Tetrahedron Letters
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,
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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
a b s t r a c t
Article history:
The transformation of aldoximes to nitriles using acetic anhydride as dehydration agent under mild reac-
tion 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.
Received 6 September 2013
Revised 12 November 2013
Accepted 21 November 2013
Available online 1 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Dehydration
Aldoximes
Nitriles
Acetic anhydride
Synthesis
Nilvadipine
Nitrile is an important synthetic intermediate for pharmaceuti-
cals, pesticides, dyes, and material sciences.1 The strong electron
withdrawing effects and excellent hydrogen bond acceptor proper-
ties 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 devel-
opment.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 substi-
tution of alkyl halides with cyanides, oxidation of amines,4 and
dehydration of amides and aldoximes.5 Among these, the dehydra-
tion of oximes into nitriles is one of the most suitable and attrac-
tive 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.
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-nitrobenzo-
nitrile 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).
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 condi-
tions41a,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
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
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0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.