Synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5-dicyanopyridines by tandem reaction

Article abstract of DOI:10.1007/s11164-012-0984-0

A novel basic ionic liquid, 1-(2-aminoethyl)pyridinium hydroxide, containing both Bronsted base and Lewis base sites has been used as an efficient catalyst for the synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5- dicyanopyridines. The condensation and oxidation tandem reaction of aldehydes, malononitrile, and thiols, performed in aqueous ethanol, afforded reasonable to good yields within 30-60 min. After the reaction, the catalyst could be recycled and reused. A possible mechanism to account for the tandem reaction is proposed. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-012-0984-0

Res Chem Intermed
DOI 10.1007/s11164-012-0984-0
Synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,
5
-dicyanopyridines by tandem reaction
Dong Hao
Yang Jin-ming
•
Zhong Yun-lei
Fang Dong
•
Shen Xiao-peng
•
•
Received: 4 December 2012 / Accepted: 17 December 2012
Ó Springer Science+Business Media Dordrecht 2013
Abstract A novel basic ionic liquid, 1-(2-aminoethyl)pyridinium hydroxide, con-
taining both Brønsted base and Lewis base sites has been used as an efficient catalyst
for the synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5-dicyanopyridines. The
condensation and oxidation tandem reaction of aldehydes, malononitrile, and thiols,
performed in aqueous ethanol, afforded reasonable to good yields within 30–60 min.
After the reaction, the catalyst could be recycled and reused. A possible mechanism to
account for the tandem reaction is proposed.
Keywords 2-Amino-4-phenyl-6-(phenylsulfanyl)-3,5-dicyanopyridine Á
Synthesis Á Basic ionic liquid Á Catalyst Á Tandem reaction
Introduction
The pyridine ring is an important constituent of a wide range of naturally occurring
and synthetic bioactive compounds, pharmaceuticals, and functional materials [1].
Among these, substitution of the 6-position of the pyridine ring with thio-containing
groups furnishes a class of medicinally significant compounds, for example
antiprion agents [2, 3], non-nucleoside agonists of the human adenosineA1 receptor
[
4], and an inhibitor of HIV-1 integrase [5]. Substituted pyridine derivatives are
important heterocyclic compounds, because many have biological activity as
potential antimicrobial and anti-inflammatory agents, acetylcholinesterase inhibi-
tors, analgesics, bactericides, and muscle relaxants [6–8].
D. Hao Á Z. Yun-lei Á S. Xiao-peng Á Y. Jin-ming Á F. Dong (&)
Department of Pharmaceutical Engineering, Yancheng Normal University, Yancheng 224002,
Jiangsu, People’s Republic of China
e-mail: fangdong106@sina.com
F. Dong
50 Kai Fang Da Dao, Yancheng 224002, Jiangsu, People’s Republic of China
123

D. Hao et al.
Several methods for synthesis of substituted pyridines have been reported in
recent years. One convenient method involving three-component coupling of
aldehydes, malononitrile, and thiols in the presence of bases and Lewis acids, for
example triethylamine [6], 1,8-diazabicyclo[5.4.0]undec-7-ene [7], piperidine and
tetrabutylammonium hydroxide [8], ZnCl [9], silica nanoparticles [10], KF–Al O
2
2
3
[
11], TBAF [12], have led to the direct formation of these compounds.
In recent years, functionalized ionic liquids have attracted increasing attention
because of their specific properties, for example negligible vapor pressure, wide
liquid range, and high thermal stability, etc., making them a more environmentally
benign alternative to volatile organic solvents and/or catalysts [13]. Their use as
reaction media and/or catalytic systems eliminates both the solvent emission and
catalytic recycling problems of traditional chemical procedure. In addition, basic
functionalized ionic liquids have been found to have dual function (solvent and
catalyst) in multi-component reactions (MCRs) [14], affording higher yields and
selectivity than traditional catalysts. In fact, use of basic ionic liquids as catalysts is
a topic with ongoing activity, and the development and investigation of such ionic
liquids for multi-component reactions is, currently, extremely important. However,
very few papers have reported the synthesis of 2-amino-4-phenyl-6-(phenylsulfa-
nyl)-3,5-dicyanopyridines in the presence of ionic liquids. Ranu et al. [15] first used
the basic ionic liquid [bmim]OH as novel reaction medium to produce highly
substituted pyridines. Very recently, Tian and Guo reported synthesis of 2-amino-4-
phenyl-6-(phenylsulfanyl)-3,5-dicyanopyridines by using the imidazolium-based
ionic liquid [bmim]BF as reaction medium [16]. In fact, searching for new, readily
4
available, and environmentally benign catalysts for these compounds is still being
actively pursued.
In our previous work, novel, efficient, recyclable, and eco-friendly SO H-
3
functional acidic ionic liquids were designed and prepared successfully. Their
catalytic performance in MCRs was also investigated [17, 18]. In continuation of our
work on the study of ionic liquid-catalyzed MCRs, we synthesized some 2-amino-4-
phenyl-6-(phenylsulfanyl)-3,5- dicyanopyridines in the presence of an novel basic
ionic liquid, 1-(2-aminoethyl)pyridinium hydroxide ([AEPy][OH]) in aqueous
ethanol. Thio-groups were introduced to the 6-position of the pyridines ring by
three-component tandem reaction of aldehydes, malononitrile, and thiols (Scheme 1).
Results and discussion
The synthetic approach used a basic ionic liquid, 1-(2-aminoethyl)pyridinium
hydroxide ([AEPy][OH]), which contains a Brønsted base as the cation and a Lewis
base as the anion, in the two-step reaction (Scheme 2). The catalyst is a light yellow oil
which dissolves in such polar solvents as water, CH OH, C H OH, CH CN, and
3
2
5
3
acetone, and partly dissolves in non-polar solvents, for example CH Cl , ether, and
2
2
benzene.
In initial experiments on catalytic activity, benzaldehyde, malononitrile, and
thiophenol were used as model reactants in 1:1 (v/v) EtOH–H O at room tempera-
ture for different lengths of time to investigate catalytic performance (Table 1).
2
1
23

Synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5
R2
CHO
SH
S
N
NH2
CN
R2
CN
R1
Cat
EtOH/H O
+
2
+
NC
CN
2
R1
1
2
3
4
Cat:
HO
N
NH2
[AEPy][OH]
Scheme 1 Synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5-dicyanopyridine
+
BrCH2CH2NH2 ·HBr
Br
N
N
NH2·HBr
NaOH
HO
NH2
N
Scheme 2 Preparation of 1-(2-aminoethyl)pyridinium hydroxide [AEPy][OH]
It was shown that almost no desired product could be detected when a mixture of
benzaldehyde, malononitrile, and thiophenol was stirred at room temperature for
1
80 min in the absence of basic ionic liquids (entry 1), which indicated that the
catalysts were absolutely necessary for this one-pot three-component tandem reaction.
Among these catalysts, [AEPy][OH] was the best for this tandem reaction under these
conditions; the optimized reaction conditions are listed in Table 1 (entry 5).
Subsequently, the reusability of [AEPy][OH] and two other basic ionic liquids in
the same model condensation reaction was investigated for economic and
environmental reasons (Fig. 1). On completion of the reaction the product was
separated by filtration and the filtrate containing the catalyst was reused in the next
run without further purification. The results showed the three basic ionic liquids
could be reused six times with little decrease of the yields.
To optimize the reaction conditions, different polar solvents were then selected as
reaction medium. The results are summarized in Table 2. Among the six reaction
media, this type of reaction was accomplished successfully in polar solvents, for
example CH CN, EtOH, and 1:1 (v/v) EtOH–H O. The chemical industry is under
3
2
considerable pressure to replace many of the volatile organic compounds (VOCs)
123

D. Hao et al.
Table 1 Effect of different
catalysts on the synthesis of a-
aminophosphonates
Entry
Catalyst
Molar ratio
mol %)
Time
(min)
Yield
(%)
(
1
–
–
180
30
30
30
30
30
30
30
30
30
30
–
2
[AEPy][OH]
[AEPy][OH]
[AEPy][OH]
[AEPy][OH]
[AEPy][OH]
[AEPy][OH]
[BPy][OH]
[BMIM][OH]
[TMA][OH]
[TBA][OH]
3
5
8
35
62
71
85
85
86
45
56
35
32
3
4
5
10
12
15
10
10
10
10
6
7
8
Reaction conditions:
9
benzaldehyde (10 mmol),
malononitrile (20 mmol),
thiophenol (10 mmol), 10 mL
10
1
1
2
EtOH–H O, r.t.
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
[
[
[
AEPy][OH]
BPy][OH]
BMIM][OH]
1
2
3
4
5
6
Reuse time
Fig. 1 The reusability of three basic ionic liquids
that are currently used as solvents in organic synthesis. To overcome these
problems, one approach is to use the water as environmentally benign medium.
Considering the reaction rate and yield, a 1:1 mixture of EtOH and H O was
2
confirmed to be the optimum medium.
This condensation reaction with different aldehydes, malononitrile, and thiols in
the presence of [AEPy][OH] as catalyst was then investigated under the optimized
reaction conditions described above; the results are presented in Table 3. It is
readily apparent that this one-pot, three-component condensation was complete
within 30–60 min and the products were isolated, by filtration, in reasonable to good
yields ranging from 76–89 %. Aromatic aldehydes carrying either electron-donating
or electron-withdrawing substituents afforded good yields of 2-amino-4-phenyl-6-
(
phenylsulfanyl)-3,5-dicyanopyridine. For thiols it was noteworthy that compounds
with substituents in both the 2-position (entries 10–14) and the 4-position (entry 15,
6) reacted smoothly in this tandem procedure.
1
1
23

Synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5
Table 2 [AEPy][OH]-catalyzed model reaction in different solvents
Entry
Solvent
Time (min)
Isolated yield (%)
1
2
3
4
5
6
H
2
O
30
30
30
30
30
30
65
56
85
86
26
85
DMF
EtOH
CH
3
2
CN
Cl
CH
2
2
EtOH–H O
Reaction conditions: benzaldehyde (10 mmol), malononitrile (20 mmol), thiophenol (10 mmol), 10 mL
solvents, r.t.
Table 3 [BDMAP][OH]-catalyzed three-component reaction
a
Entry
R
1
R
2
Time (min)
Isolated yields (%)
mp (°C) [Ref.]
1
2
3
4
5
6
7
8
9
4-CH
3
3
O
H
30
30
30
30
30
30
30
30
60
30
30
45
30
45
30
30
85
86
84
85
83
85
81
89
80
80
81
76
85
89
86
88
238–240 [7]
206–208 [11]
310–312 [7]
216–218 [8]
250–252 [8]
220–222 [8]
253–255 [6]
216–218 [11]
286–288 [11]
229–231 [8]
206–208 [8]
176–178 [8]
216–218 [6]
231–233 [8]
234–236 [7]
242–244 [7]
4-CH
H
4-OH
H
H
H
4-F
H
4-Cl
3-Br
H
H
3-OCH -4-OH
3
H
4-NO
2
H
10
11
12
13
14
15
16
4-CH
3
O
2-NH
2-NH
2-NH
2-NH
2-NH
2
2
2
2
2
4-CH
3
4-OH
H
4-Cl
H
4-CH
3
3
4-Cl
4-CH
Reaction conditions: benzaldehyde (10 mmol), malononitrile (20 mmol), thiophenol (10 mmol), solvent
0 mL EtOH–H O, r.t.
The products were identified by H NMR, and by comparison of physical data (m.p) with those reported
1
2
a
1
in the literature
The results obtained with benzaldehyde, malononitrile, and thiophenol under the
optimized conditions were compared with literature results reported for use of other
catalysts in this reaction. Table 4 shows that the novel basic ionic liquid
[
AEPy][OH] was a relatively a good catalyst for synthesis of 2-amino-4-phenyl-
-(phenylsulfanyl)-3,5-dicyanopyridine.
Last, with the above experimental results to hand, a plausible mechanism of this
6
tandem reaction is proposed in Scheme 3. This is different from those proposed
elsewhere. It is suggested that both reactants and intermediates are activated by the
cation and anion of [AEPy][OH].
123

D. Hao et al.
Table 4 Comparison of our results with those from previously reported methods
Entry
Catalyst
Reaction conditions
10 % H
O in EtOH/35 °C
EtOH/reflux
EtOH/reflux or EtOH/MW
EtOH/r.t.
Time
Yield (%) [Ref.]
1
2
3
4
5
6
7
DBU
2
15 min
3 h
80 [7]
Piperidine
88 [8]
ZnCl
KF.Al
[bmim]OH
2
2 h or 2 min
30 min
1.1 h
65 [9]
2
O
3
87 [11]
92 [15]
82 [16]
85 [This work]
EtOH/r.t.
[bmim]BF
4
50 °C
30 min
30 min
[AEPy][OH]
2
1:1 (v/v) EtOH–H O/r.t.
HO
N
R1
NH2
O
OH
R1
R1
H
O
NC
NC
NC
NC
CN
H
CN
CN
CN
H
H
N
OH
H N
2
N
R1
H
NH
R1
CN
S
R2
R1
H
S
R2
CN
H
NC
H
NC
NC
NC
HO
H
NH
R2
R2S
NC
2
N
NH2
CN
N
R S
N
NH2
S
O2 (air)
NC
CN
NC
CN
R1
R1
H
H
R1
Scheme 3 Possible mechanism of the tandem reaction
Conclusions
In summary, a readily available, bi-functional alkaline ionic liquid [AEPy][OH]
containing Brønsted and Lewis base sites has been used as a novel catalyst for the
tandem synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5-dicyanopyridine;
thio-groups were, therefore, introduced into the pyridine ring. The merit of this
anion–cation cooperative catalytic methodology is that it is simple, highly efficient,
and environmentally benign.
1
23

Synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5
Experimental
Melting points were determined by use of an X -Data microscope apparatus. IR
6
spectra were acquired on a Bruker Vector 22 spectrometer and are expressed in
-
cm (KBr). H NMR spectra were acquired on a Bruker DRX300 (300 MHz)
1
1
1
3
spectrometer. C NMR spectra were acquired on a Bruker DRX300 (75.5 MHz)
spectrometer. Elemental analysis was performed with a Perkin–Elmer C elemental
analyzer. Mass spectra were acquired with an automated Finnigan TSQ Quantum
Ultra AM (Thermal) LC–MS spectrometer. All chemicals (AR grade) were
commercially available and used without further purification.
Synthesis of 1-(2-aminoethylhydrobromide)pyridinium bromide
To a solution of 7.91 g pyridine (0.10 mol) in 30 mL acetonitrile was added 20.49 g
2
-bromoethylamine hydrobromide (0.10 mol). The mixture was stirred under
nitrogen for 2 h at 80–85 °C. On completion, the solvent was removed by
distillation and the residue was washed with ethanol (10 mL 9 3) to furnish 90 %
yield of a white solid product, mp 170–172 °C.
Synthesis of 1-(2-aminoethyl)pyridinium hydroxide [AEPy][OH]
To a solution of 14.2 g of the above intermediate (0.05 mol) in 50 mL ethanol was
added 4 g NaOH (0.10 mol). The mixture was then stirred for 6 h at room
temperature. Solvents were then removed by evaporation in vacuo and the residue
was extracted with dry ethanol. The salts thus separated were filtered and the
solvents were removed by evaporation. The yellow oil obtained was washed
successively with chloroform and ether. After drying for 2 h in vacuo at 80 °C,
9
6 % yield of [AEPy][OH] was obtained. Selected spectral data for the pyridinium-
based basic ionic liquid [AEPy][OH] are:
1
H NMR (300 MHz, D O): d = 3.25 (t, 2H, J = 6.3 Hz, N–C–CH –NH ), 4.49
2
2
2
(
t, 2H, J = 6.3 Hz, N–CH –C–NH ), 7.38 (m, 2H, Py–H), 7.75 (m, 1H, Py–H), 8.65
2 2
?
d, 2H, J = 7.5 Hz, Py–H) ppm; MS: m/z = 140.19 (M ).
(
General procedure for synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,
-dicyanopyridines
5
In a typical experiment, aldehyde (10 mmol) and malononitrile (20 mmol) in 10 mL
:1 (v/v) EtOH–H O were added, with stirring, to [AEPy][OH] (1.0 mmol) in a
1
2
round-bottomed flask. The mixture was stirred at room temperature for 1 min and
then the thiol (10 mmol) was added. The mixture was stirred continuously. On
completion, monitored by TLC, the solid was separated by filtration and dried under
1
vacuum. The product was identified by H NMR, and physical data (m.p.) compared
with those in the literature. The catalyst [AEPy][OH] contained in the filtrate could
be used for subsequent cycles without any treatment. All products were characterized
1
by IR, H NMR, and m.p., by comparison with literature data (Table 4).
123

D. Hao et al.
Selected data for compounds 4
2-Amino-4-(4-chlorophenyl)-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (entry 6,
C H N SCl)
1
9 11 4
1
Yellow solid; m.p. 220–222 °C, H NMR (300 MHz, DMSO-d ): d, 7.87 (brs, 2H,
6
NH), 7.69–7.49 (m, 9H, Ar–H).
2
-Amino-4-phenyl-6-(2-aminophenyl)sulfanylpyridine-3,5-dicarbonitrile (entry 13,
C H N S)
1
9 13 5
1
Yellow solid; m.p. 216–218 °C, H NMR (300 MHz, DMSO-d ): d, 7.62 (brs, 2H,
6
NH), 7.55–6.60 (m, 9H, Ar–H), 5.35 (brs, 2H, NH).
2-Amino-4-phenyl-6-(4-tolyl)sulfanylpyridine-3,5-dicarbonitrile (entry 15,
C H N SCl)
1
9 11 4
1
Yellow solid; m.p. 234–236 °C, H NMR (300 MHz, DMSO-d ): d, 7.80 (brs, 2H,
6
NH), 7.56–7.54 (m, 5H, Ar–H), 7.47 (d, J = 7.8 Hz, 2H, Ar–H), 7.30 (d,
J = 7.8 Hz, 2H, Ar–H), 2.37 (s, 3H, CH3).
Acknowledgments We express our sincere thanks to the Ministry of Science and Technology of the
P.R. China (11C26213201395), Jiangsu Provincial Department of Education (2012JSSPITP2413), and the
Key Laboratory of Organic Synthesis of Jiangsu Province (KJS1112) for financial assistance.
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