Ultrasound-promoted synthesis of 2-amino-6-(arylthio)-4-arylpyridine-3,5- dicarbonitriles using ZrOCl2·8H2O/NaNH2 as the catalyst in the ionic liquid [bmim]BF4 at room temperature

Article abstract of DOI:10.1016/j.tetlet.2011.10.031

We herein present an efficient and environmentally benign protocol for the synthesis of 2-amino-6-(arylthio)-4-arylpyridine-3,5-dicarbonitrile derivatives via the three-component condensation of a variety of aldehydes, arylthiols, and malononitrile cataly

Full text of DOI:10.1016/j.tetlet.2011.10.031

Tetrahedron Letters 52 (2011) 6779–6782
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ultrasound-promoted synthesis of 2-amino-6-(arylthio)-4-arylpyridine-3,5-
dicarbonitriles using ZrOCl2Á8H2O/NaNH2 as the catalyst in the ionic liquid
[bmim]BF4 at room temperature
⇑
Mohammad Reza Poor Heravi , Farnazalsadat Fakhr
Payame Noor University, Department of Chemistry, 19395-4697 Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2011
Revised 12 September 2011
Accepted 7 October 2011
Available online 14 October 2011
We herein present an efficient and environmentally benign protocol for the synthesis of 2-amino-6-(aryl-
thio)-4-arylpyridine-3,5-dicarbonitrile derivatives via the three-component condensation of a variety of
aldehydes, arylthiols, and malononitrile catalyzed by ZrOCl2Á8H2O/NaNH2 (20 mol %) in the ionic liquid
[bmim]BF4 under ultrasound irradiation at room temperature.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ultrasound irradiation
Ionic liquids
ZrOCl2Á8H2O/NH2
Thioarylpyridines
Dicarbonitrile
Compounds possessing
a
2-amino-3,5-dicarbonitrile-6-thio-
base-catalyzed reactions.15 Ultrasonic-assisted organic synthesis
as a green approach is a powerful technique employed for organic
reactions leading to higher yields, shorter reaction times, and
milder conditions, and is considered a processing aid in terms of
energy conservation and waste minimization compared with
traditional methods.15a,16,17 We report herein, a simple, mild and.
expeditious synthesis of 2-amino-6-(arylthio)-4-arylpyridine-3,5-
dicarbonitrile derivatives in high yields by the reaction of aryl alde-
hydes 1a–j, thiols 2a–d, and malononitrile (3) catalyzed by
ZrOCl2Á8H2O/NaNH2 in the ionic liquid [bmim]BF4 under ultra-
sound irradiation at room temperature.
In order to avoid the disadvantages of volatility and toxicity that
many organic solvents demonstrate, we employed an ionic liquid
in this three-component reaction as an environmentally benign
medium. The reaction of arylaldehydes 1a–j, thiols 2a–d, and mal-
ononitrile (3) in [bmim]BF4 catalyzed by ZrOCl2Á8H2O/NaNH2 un-
der mild conditions and ultrasonic irradiation at 25 °C, afforded
high yields of 2-amino-6-(arylthio)-4-arylpyridine-3,5-dicarbo-
nitriles 4aa–ja, 4ab, 4gb, 4hb, 4ec, 4ic, 4ad, and 4bd (Scheme 1).
In the search for optimum conditions, the reaction of benzalde-
hyde (1a), 2,3,4,5,6-pentafluorobenzenethiol (2a), and malononit-
rile (3) in the presence of ZrOCl2Á8H2O/NaNH2 as the catalyst in
[bmim]BF4 was examined as a model system (Scheme 2).
pyridine ring system exhibit diverse pharmacological activities
and are useful as anti-prion,1 anti-hepatitis B,2 antibacterial,3 and
anticancer agents,4 and as potassium channel openers for the treat-
ment of urinary incontinence.5 In addition, several of these com-
pounds were discovered to be highly selective ligands for
adenosine receptors,6 which are recognized as potential targets
for the development of new drugs for the treatment of Parkinson’s
disease, hypoxia/ischemia, asthma, kidney disease, epilepsy, and
cancer.7 A three-component condensation of an aldehyde, malono-
nitrile, and a thiol represents an important existing procedure for
the synthesis of 2-amino-3,5-dicarbonitrile-6-thiopyridines.
Generally, this condensation has been carried out under basic con-
ditions using bases such as, Et3N, DABCO,8 piperidine, morpholine,
thiomorpholine, pyrrolidine, DIPEA, pyridine, 2,4,6-collidine,
DMAP, aniline, N-methylaniline, N,N-dimethylaniline, and
N,N-diethylaniline.9 Moreover, the basic ionic liquid 1-methyl-3-
butylimidazolium hydroxide ([bmim]OH),10 DBU11 and TBAH12
were also found to be efficient basic catalysts for the synthesis of
such polysubstituted pyridines. However, most of these methods
suffer from the formation of side products, which results in lower
yields of the desired products. This three-component condensation
has been carried out using a Lewis acid catalyst (ZnCl2)13 and boric
acid,14 which show improved results when compared to the
A summary of the optimization studies is provided in Table 1. In
the absence of zirconium oxychloride, sodium amide, [bmim]BF4
and sonication, or elements of these, no reaction took place (Table
1, entries 1–3 and 5–6). Next we screened various combinations of
⇑
Corresponding author. Tel.: +98 242522 4021/2; fax: +98 242522 6932.
E-mail addresses: heravimr@yahoo.com, heravimr@gmail.com (M.R. Poor Her-
avi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.031

6780
M. R. Poor Heravi, F. Fakhr / Tetrahedron Letters 52 (2011) 6779–6782
Ar1
CN
CN
NC
.
CN
ZrOCl2 8H2O/NaNH2
Ar1
CHO
2
+
+
Ar2
SH
[bmim]BF4, ))))
SAr2
H2N
N
1a-j
2a-d
3
4aa-4ja
4ab, 4gb, 4hb
4ec, 4ic
4ad, 4bd
Ar1:C6H5, o-NO2C6H4, p-CH3C6H4, p-Me2NC6H4, p-BrC6H4, 2,4-(NO2)2C6H3,
p-FC6H4, p-CF3C6H4, 2-naphthyl, 2-furyl
Ar2: C6F5, C6H5, p-BrC6H4, 2-naphthyl
Scheme 1. Synthesis of 2-amino-6-(arylthio)-4-arylpyridine-3,5-dicarbonitrile derivatives 4.
SH
O
F
F
F
F
NC
CN
S
CN
CN
.
ZrOCl2 8H2O/NaNH2
H
2
+
+
[bmim]BF4, ))))
H2N
N
F
F
F
F
1a
2a
+
3
F
F
4aa
Scheme 2. Standard model reaction.
Table 3
Recycling studies on [bmim]BF4
Table 1
Optimization of the catalytic systema
Runa
Time (min)
Yieldb (%)
Entry
Reaction system
Time (min)
Yieldb (%)
1
2
3
4
5
10
10
10
12
15
92
92
91
90
88
1
2
3
4
5
6
7
8
—
120
120
120
120
120
120
120
120
120
120
5
—
—
—
15
—
ZrOCl2Á8H2O
NaNH2
ZrOCl2Á8H2O/NaNH2
[bmim]BF4
))))
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol),
NaNH2 (20 mol %), [bmim]BF4 (2 mL), ultrasound irradiation, rt.
3
(2 mmol), ZrOCl2Á8H2O/
—
[bmim]BF4,))))
ZrOCl2Á8H2O/[bmim]BF4
ZrOCl2Á8H2O/[bmim]BF4,))))
Trace
30
40
35
95
b
Isolated yield.
9
10
11
Table 4
ZrOCl2Á8H2O/NaNH2, [bmim]BF4
Synthesis of 2-amino-6-(arylthio)-4-arylpyridine-3,5-dicarbonitrile derivatives 4
ZrOCl2Á8H2O/NaNH2, [bmim]BF4,))))
Entry
Ar1
Ar2
Time (min)
Product
Yielda (%)
Note: Bold values denotes are optimized conditions.
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3 (2 mmol), catalyst (20 mol %),
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C6H5
C6F5
C6F5
C6F5
C6F5
C6F5
C6F5
C6F5
C6F5
C6F5
C6F5
C6H5
C6H5
10
5
15
20
15
2
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
92
97
90
90
91
95
95
98
95
93
91
93
94
92
93
94
97
rt.
o-NO2C6H4
p-CH3C6H4
p-Me2NC6H4
p-BrC6H4
2,4-(NO2)2C6H3
p-FC6H4
p-CF3C6H4
2-Naphthyl
2-Furyl
C6H5
p-FC6H4
p-CF3C6H4
p-BrC6H4
2-Naphthyl
C6H5
b
Isolated yield.
Table 2
Effect of the catalyst concentrationa
5
2
Entry
ZrOCl2Á8H2O/NaNH2 (mol %)
Yieldb (%)
10
20
15
5
10
10
5
1
2
3
4
5
5
10
15
20
25
45
69
81
92
91
4ja
4ab
4gb
4hb
4ec
4ic
C6H5
p-BrC6H4
p-BrC6H4
2-Naphthyl
2-Naphthyl
Note: Bold values denotes are optimized conditions.
15
12
4ad
4bd
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3 (2 mmol), [bmim]BF4 (2 mL),
o-NO2C6H4
ultrasound irradiation, rt.
b
a
Isolated yield.
Isolated yield.

M. R. Poor Heravi, F. Fakhr / Tetrahedron Letters 52 (2011) 6779–6782
6781
Zr4+
H
O
CN
CN
HO
X
CN
CN
1a-j
N
C
NaNH2/[bmim]BF4, ))))
H
X
N
C
H
CN
CN
-H2O
X
3
A
X
X
X
S
Ar2
2a-d
H
H
H
CN
NC
CN
3
NC
CN
NC
CN
CN
C
N
C
N
N
N
S
Zr4+/NaNH2/[bmim]BF4, ))))
H2N
N
S
H
Ar2
Zr4+/NaNH2/[bmim]BF4, ))))
Ar2
B
X
X
Air/[O]
NC
CN
S
NC
CN
S
H2N
N
H2N
N
H
Ar2
Ar2
4aa-ja, 4ab, 4gb, 4hb, 4ec, 4ic, 4ad, 4bd
Scheme 3. Proposed mechanism for the synthesis of 2-amino-6-(arylthio)-4-arylpyridine-3,5-dicarbonitrile derivatives 4.
19
the above components. The product 4aa was obtained in moderate
15%, trace, 30%, 40%, and 35% yields within 120 min (Table 1, en-
tries 4 and 7–10). However, the use of zirconium oxychloride/so-
dium amide in [bmim]BF4 under sonication proved to be the
most efficient system which gave a 95% yield of product within
5 min (Table 1, entry 11).
To determine the appropriate concentration of the zirconium
oxychloride catalyst, we investigated the model reaction at differ-
ent concentrations. The product was obtained in yields ranging
from 45% to 92% (Table 2). The results showed that 20 mol % of zir-
conium oxychloride/sodium amide was sufficient to carry out the
reaction smoothly.
NaNH2 catalyzed Michael addition of the second molecule of
malononitrile to the Knoevenagel adduct A, followed by thiolate
addition to a C„N group of the adduct and cyclization to give
the dihydropyridine. Aromatization and oxidation (air) under the
reaction conditions led to pyridine derivative 4 (Scheme 3).
In conclusion, we have reported an environmentally benign
method for the synthesis of 2-amino-6-(arylthio)-4-arylpyridine-
3,5-dicarbonitrile derivatives via the three-component reaction of
arylaldehydes, malononitrile, and thiols using ZrOCl2Á8H2O/NaNH2
as the catalyst in the ionic liquid [bmim]BF4 under ultrasound irra-
diation. The advantages of this procedure are mild reaction condi-
tions, high yields, and operational simplicity.
We next studied the catalytic activity of recycled [bmim]BF4 in
the synthesis of 4aa. The reactions were complete within 2–20 min
and the products were easily isolated by extraction with ethyl ace-
tate. The remaining ionic liquid containing the catalyst was recov-
ered and reused in subsequent reactions with only a gradual
decrease in the activity being observed. For instance, 2-amino-6-
(perfluorophenylthio)-4-phenylpyridine-3,5-dicarbonitrile deriva-
tive 4aa was obtained in 92%, 92%, 91%, 90%, and 88% yields over
five cycles (Table 3).
In order to demonstrate the efficiency and scope of the present
method, we performed the reactions of a variety of arylaldehydes
1a–j, 2,3,4,5,6-pentafluorobenzenethiol, and nonfluorinated aryl-
thiols 2a–d with malononitrile (3) at room temperature in
[bmim]BF4. As shown in Table 4, aromatic substrates containing
electron-withdrawing groups (halide, nitro, trifluoromethyl) or
electron-donating groups (alkyl, N,N-dimethylamino), reacted well
with 3 to give the corresponding products 4 in high yields under
the optimized reaction conditions (Table 4, entries 1–17).
In accordance with the mechanism outlined by Evdokimov
et al.,18 the reaction is thought to proceed through ZrOCl2Á8H2O/
Acknowledgment
We are grateful to Payame Noor University, Tehran, Iran for
financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.031.
References and notes
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M. R. Poor Heravi, F. Fakhr / Tetrahedron Letters 52 (2011) 6779–6782
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ZrOCl2Á8H2O/NaNH2 (20 mol %) and [bmim]BF4 (2 mL) was sonicated at 25 °C
for 10 min. After completion of the reaction as indicated by TLC, the mixture
was extracted with EtOAc (3 Â 10 mL). The combined organic layers were
dried, concentrated in vacuo and purified by column chromatography on silica
gel (Merck, 100–200 mesh, EtOAc-hexane, 6%) to afford pure 2-amino-6-
(perfluorophenylthio)-4-phenylpyridine-3,5-dicarbonitrile (4aa).
7. Fredholm, B. B.; Ijzerman, A. P.; Jackobson, K. A.; Klotz, K. N.; Linden, J.
Pharmacol. Rev. 2001, 53, 527–552.
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Med. Chem. 2006, 49, 607–609.
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Kormienko, A. J. Org. Chem. 2007, 72, 3443–3447.
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Mallu, K. R. R.; Ankathi, V. M.; Rao, P. S. Tetrahedron Lett. 2009, 50, 3897–3900.
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Characterization data of representative compounds:
2-Amino-6-(perfluorophenylthio)-4-phenylpyridine-3,5-dicarbonitrile
(4aa).
0.384 g (92%); pale yellow solid; mp 214–215 °C. IR (KBr) (m
max/cmÀ1): 3520,
3075, 2196, 1635, 1510, 1455, 810. 1H NMR (CDCl3, 500 MHz): d 6.17 (s, 2H, –
NH2), 7.30 (tt, 1H, J = 1.8, 7.3 Hz, Ar-H), 7.35 (tt, 2H, J = 1.8, 7.3, Ar-H), 7.43–7.46
(m, 2H, Ar-H). 13C NMR (CDCl3, 125 MHz): d 111.01, 112.33, 114.18, 115.02,
1
127.20, 128.25, 129.31, 129.14, 129.49, 131.20 (dd, JCF = 254.5 Hz,
1
2
2JCF = 15.3 Hz, C-2, C-6), 133.23 (dd, JCF = 253.8 Hz, JCF = 15.2 Hz, C-3, C-5),
135.17 (dd, 1JCF = 254.0 Hz, 2JCF = 15.0 Hz, C-4), 158.46, 159.76, 169.81. 19F NMR
(CDCl3, 470 MHz): À67.61, À85.83, À97.09. MS (EI), m/z (%) 418 (M+, 70), 418
(100), 386 (45), 251 (65). HRMS (EI) Found: M+, 418.0341. C19H7F5N4S requires
M+, 418.0310. Anal. Calcd for C19H7F5N4S: C, 54.55; H, 1.69; N, 13.39; S, 7.66.
Found: C, 54.21; H, 1.86; N, 13.65; S, 7.54.
15. (a) Xu, H.; Liao, W.-M.; Li, H.-F. Ultrson. Sonochem. 2007, 14, 779–782; (b)
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Stefani, H. A. Tetrahedron Lett. 2007, 48, 1845–1848; (c) Sridhar, M.;
Ramanaiah, B. C.; Narsaiah, C.; Mahesh, B.; Kumaraswamy, M.; Mallu, K. K.
R.; Ankathi, V. M.; Rao, P. S. Tetrahedron Lett. 2009, 50, 3897–3901.
16. Poor Heravi, M. R. J. Fluorine Chem. 2008, 129, 217–221.
17. (a) Guzen, K. P.; Guarezemm, A. S.; Orfao, A. T. G.; Cella, R.; Pereiraa, C. M. P.;
Stefani, H. A. Tetrahedron Lett. 2007, 48, 1845–1848; (b) Poor Heravi, M. R.
Ultrason. Sonochem. 2009, 16, 361–366.
18. Evdokimov, N. M.; Megadov, I. V.; Kireev, A. S.; Konienko, A. Org. Lett. 2006, 8,
899–902.
19. Typical experimental procedure: A mixture of benzaldehyde (1a) (1 mmol),
2,3,4,5,6-pentafluorobenzenethiol (2a) (1 mmol), malononitrile (3) (2 mmol),
2-Amino-6-(perfluorophenylthio)-4-p-tolylpyridine-3,5-dicarbonitrile
(4ca).
0.381 g (90%); white solid; mp 201–202 °C. IR (KBr) (
m
max/cmÀ1): 3432, 3100,
2921, 2201, 1651, 1532, 1443, 723. 1H NMR (CDCl3, 500 MHz): d 3.75 (s, 3H,
CH3), 6.34 (s, 2H, –NH2), 7.58 (d, 2H, J = 2.1 Hz, Ar-H), 7.89 (d, 2H, J = 2.1, Ar-H).
13C NMR (CDCl3, 125 MHz): d 87.64, 112.17, 112.86, 114.87, 123.87, 125.36,
1
2
126.55, 127.31, 128.77, 130.84, 132.27 (dd, JCF = 250.4 Hz, JCF = 16.1 Hz, C-2,
1
2
C-6), 134.33 (dd, JCF = 251.4 Hz, JCF = 15.0 Hz, C-3, C-5), 136.58 (dd,
1JCF = 250.6 Hz, JCF = 15.0 Hz, C-4), 155.78, 157.29, 163.83. 19F NMR (CDCl3,
2
470 MHz): À66.99, À83.98, À99.21. MS (EI), m/z (%) 432 (M+, 70), 360 (100),
265 (55), 416 (20). HRMS (EI) Found: M+, 432.3701. C20H9F5N4S requires M+,
432.2109. Anal. Calcd for C19H7F5N4S: C, 55.56; H, 2.10; N, 12.96; S, 7.42.
Found: C, 55.65; H, 2.32; N, 12.87; S, 7.51.