One-pot conversion of aldehyde sodium bisulfites into nitriles

Article abstract of DOI:10.1080/00397911.2010.548890

Direct conversion of aldehyde sodium bisulfites to the corresponding nitriles can be easily performed by the reaction of an aldehyde sodium bisulfites with a slight execss of hydroxylamine hydrochloride in refluxing toluene and in the presence of 1.0 equivalents of pyridine as catalyst.

Full text of DOI:10.1080/00397911.2010.548890

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One-Pot Conversion of Aldehyde Sodium
Bisulfites into Nitriles
a
a
a
a
Jintao Zhu , Guangwei Song , Guoxin Yao & Gang Chen
a
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou,
Zhejiang, China
Accepted author version posted online: 27 Oct 2011.Version of
record first published: 26 Mar 2012.
To cite this article: Jintao Zhu, Guangwei Song, Guoxin Yao & Gang Chen (2012): One-Pot Conversion
of Aldehyde Sodium Bisulfites into Nitriles, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 42:13, 1934-1940
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Synthetic Communications , 42: 1934–1940, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.548890
ONE-POT CONVERSION OF ALDEHYDE SODIUM
BISULFITES INTO NITRILES
Jintao Zhu, Guangwei Song, Guoxin Yao, and Gang Chen
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou,
Zhejiang, China
GRAPHICAL ABSTRACT
Abstract Direct conversion of aldehyde sodium bisulfites to the corresponding nitriles can be
easily performed by the reaction of an aldehyde sodium bisulfites with a slight execss of
hydroxylamine hydrochloride in refluxing toluene and in the presence of 1.0 equivalents
of pyridine as catalyst.
Keywords Aldehyde sodium bisulfite; hydroxylamine hydrochloride; nitriles
INTRODUCTION
Cyanation is a common transformation and has important practical value in
organic synthesis. The nitrile group is not only an effective biological group in pes-
[1]
ticides, medicines, and dyes, but also has been the source of a wide range of bioac-
tive compounds such as amines, amides, aldehydes, ketones, carboxylic acids, and
[
esters. The versatile nitriles are used for preparation of thiazole analogs as antic-
2]
[
3]
[4]
ancer antibiotics,
1,2-diarylimidazoles as potent anti-inflammatory agents,
[
5]
-oxazolines with antimitotic and neuroprotective activity, and other molecules
2
possessing a broad spectrum of biological activity.
[
6]
Because of these interesting features, several methods to synthesize the nitriles
have been developed. One of the most general procedures for preparation of nitriles
is the nucleophilic substitution reaction of alkyl halides and diazonium salts with
[7]
metal cyanides. The other alternative procedures are oxidation of alcohols or
[
8]
[9]
amines, conversion of alkenes and alkynes to nitriles, and direct conversion of
[
10]
aldehydes into nitriles using various reagents.
However, most of the reported
methods are deficient in some respects such as hazardous reagents, expensive cataly-
sis, vigorous reaction conditions, unsatisfactory yields, and tedious workup.
Received September 11, 2009.
Address correspondence to Jintao Zhu, Department of Chemistry, Zhe Jiang Sci-Tech University,
Hangzhou 310018, China. E-mail: zhujintao1968@yahoo.com.cn
1
934

CONVERSION OF BISULFITE ADDUCTS INTO NITRILES
1935
Scheme 1. Synthesis of nitriles from corresponding aldehyde sodium bisulfites.
Aldehyde groups are able to react with sodium bisulfite to form bisulfite
[
11]
adducts.
The adducts are not only used extensively in diverse products such as
[
12]
[13]
vitamin K3 and houttuynium sodium bisulfate, but also in purification of ther-
mally unstable aldehydes such as phenylacetaldehyde because aldehyde groups can
be easily liberated from the bisulfite adducts when treated with acidic or basic aque-
ous solution. The high efficacy and ease of purification procedures prompted us to
investigate application of bisulfite adducts to synthesize nitriles. To the best of our
knowledge, no studies are known in the literature exploiting this system to synthesize
nitriles.
Herein, we report a simple and safe method for the direct transformation of
bisulfite adduct into nitriles by treatment with hydroxylamine hydrochloride in base
following azeotropic separation of water (Schemes 1 and 2).
The reaction conditions were established using phenylacetaldehyde sodium
bisulfite as the model substrate (entry 2j, Table 1). A mixture of phenylacetaldehyde
sodium bisulfite and hydroxylamine hydrochloride was stirred under different con-
ditions, and the results are summarized in Table 2. Reactions with no bases provided
lower product formation, but by increasing the amount of pyridine from 0.2 equiv. to
1
.1 equiv., the conversion improved moderately. Under similar reaction conditions,
triethylamine, sodium carbonate, and sodium bicarbonate shown poor activities.
The general applicability of this method was further evaluated for structurally
diverse bisulfite adducts under optimized reaction conditions using pyridine (Table 1).
The reactivity depends on the nature of bisulfite adducts used. Thus, the aromatic
nucleus (having electron-donating substituents) was smoothly converted to the corre-
sponding nitriles in good yields but required long reaction times (Table 1, entries 2d,
2e, 2g), while the aromatic nucleus with electron-withdrawing groups had the
opposite effect (Table 1, entries 2a, 2b). In the case of p-hydroxybenzaldehyde sodium
Scheme 2. Plausible reaction mechanism for the synthesis of nitriles.

1936
J. ZHU ET AL.
Table 1. Conversion of aldehydes sodium bisulfite into nitriles
a
ꢀ
Mp or bp ( C)=mmHg (lit.)
Entry
R
Time (h)
Yield (%)
[
14]
2a
7
69
108–109 (lit. 109–110)
[
15]
2
2
2
b
9
12
11
77
80
88
92–94 (lit. 93–94)
[
16]
c
56=5 (lit. 191=760)
[17]
d
97–98 (lit. 98)
[
15]
2e
14
92
67–68 (lit. 68)
[
18]
2
2
2
f
12
13
9
51
85
72
111–112 (lit. 113)
[
18]
g
h
43–45 (lit. 45)
[
18]
115=6 (lit. 265=760)
[
17]
2
i
j
11.5
11
84
76
64–66 (lit. 66-67)
[
18]
2
92=6 (lit. 233.5=760)
a
1
The products were characterized by comparison of their mp or bp, TLC, IR, and H NMR data with
those of authentic samples.
b
Yields of pure compounds after distillation or recrystallization.
bisulfite (Table 1, entry 2f), apart from this observation, we obtained moderate yields
of p-hydroxybenzonitrile.
In summary, we have reported a new, simple, efficient, and suitable for a
large-scale procedure for the preparation of nitriles via a one-pot reaction. This
straightforward method has the advantage of convenient operation, ready avail-
ability of the reagent, and good yields.

CONVERSION OF BISULFITE ADDUCTS INTO NITRILES
1937
Table 2. Optimization studies for the conversion of phenylacetaldehyde
a
bisulfite adduct into nitrile
b
Yield (%)
Entry
Base
Amount of base (equiv.)
1
2
3
4
5
6
7
8
–
–
17
27
52
80
82
73
60
54
Pyridine
Pyridine
Pyridine
Pyridine
0.2
0.5
1.0
1.1
1.1
1.1
1.1
Et
Na
NaHCO
3
N
2
CO
3
3
a
Reaction conditions: phenylacetaldehyde sodium bisulfite (10 mmol),
hydroxylamine hydrochloride (11 mmol), 12 h.
b
Isolated yield.
EXPERIMENTAL
A mixture of hydroxylammonium chloride (11 mmol) and aldehyde sodium
ꢀ
bisulfite (10 mmol) in toluene (100 mL) was heated at 80 C. Pyridine (10 mmol)
was added to this mixture with stirring over a period of 10 min. The flask content
was refluxed, and water was separated using a Dean–Stark water trap. The reaction
was monitored by thin-layer chromatography (TLC) or gas chromatography (GC)
After completion of the reaction, charcoal was added and stirred for 30 min, and
then the mixture was filtered. Toluene was removed from the filtrate in vacuo to give
the crude nitriles. Solid nitriles were purified by recrystallization from aqueous etha-
nol. Liquid nitriles were purified by a short-path distillation under reduced pressure.
2-Nitrobenzonitrile (Table 2, Entry 2a)
1
H NMR (400 MHz, CDCl ): d 8.46–8.28 (m, 1H), 8.03–7.90 (m, 1H),
3
þ
7
.90–7.78 (m, 2H). MS m=z: 148 [M ].
4-Chlorobenzonitrile (Table 2, Entry 2b)
1
H NMR (400 MHz, CDCl ): d 7.61 (d, 2H, J ¼ 7.7 Hz), 7.52–7.39 (m, 2H). MS
3
þ
m=z: 137 [M ].
Benzonitrile (Table 2, Entry 2c)
1
H NMR (400 MHz, CDCl ): d 7.71–7.54 (m, 3H), 7.48 (t, 2H, J ¼ 7.6 Hz). MS
3
þ
m=z: 103 [M ].
4-Benzyloxybenzonitrile (Table 2, Entry 2d)
1
H NMR (400 MHz, CDCl ): d 7.59 (d, 2H, J ¼ 8.8 Hz), 7.48–7.35 (m, 5H),
3
þ
7
.05 (dd, 2H, J ¼ 24.6 Hz, J ¼ 8.7 Hz), 5.14 (d, 2H, J ¼ 16.3 Hz). MS m=z: 209 [M ].
1
2

1938
J. ZHU ET AL.
3,4-Dimethoxybenzonitrile (Table 2, Entry 2e)
1
H NMR (400 MHz, CDCl ): d 7.30 (d, 1H, J ¼ 8.3 Hz), 7.09 (s, 1H), 6.91 (d,
3
þ
1
H, J ¼ 8.3 Hz), 3.96 (dd, 6H, J ¼ 27.5 Hz, J ¼ 11.1 Hz). MS m=z: 163 [M ].
1
2
4-Hydroxybenzonitrile (Table 2, Entry 2f)
1
H NMR (400 MHz, CDCl ): d 7.56 (d, 2H, J ¼ 8.3 Hz), 6.94 (d, 2H,
3
þ
J ¼ 8.3 Hz), 6.61 (s, 1H). MS m=z: 119 [M ].
Piperonylonitrile (Table 2, Entry 2g)
1
H NMR (400 MHz, CDCl ): d 7.22 (d, 1H, J ¼ 8.2 Hz), 7.05 (s, 1H), 6.87 (d,
3
þ
1
H, J ¼ 7.0 Hz), 6.08 (s, 2H). MS m=z: 147 [M ].
4-Chlorophenylacetonitrile (Table 2, Entry 2h)
1
H NMR (400 MHz, CDCl ): d 7.36 (d, 2H, J ¼ 8.5 Hz), 7.27 (d, 2H,
3
þ
J ¼ 7.8 Hz), 3.73 (s, 2H). MS m=z: 151 [M ].
4-Benzyloxyphenylacetonitrile (Table 2, Entry 2h)
1
H NMR (400 MHz, CDCl ): d 7.40 (q, 4H, J ¼ 7.5 Hz), 7.34 (d, 1H,
3
J ¼ 7.2 Hz), 7.23 (d, 2H, J ¼ 8.4 Hz), 6.97 (d, 2H, J ¼ 8.4 Hz), 5.07 (s, 2H), 3.68 (s,
þ
2
H). MS m=z: 223 [M ].
Phenylacetonitrile (Table 2, Entry 2j)
1
H NMR (400 MHz, CDCl ): d 7.43–7.26 (m, 6H), 3.73 (s, 2H). MS m=z:
3
þ
1
17 [M ].
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