2-Hydroxyethylammonium acetate: A reusable task-specific ionic liquid promoting one-pot, three-component synthesis of 2-amino-3,5-dicarbonitrile-6- thio-pyridines

Article abstract of DOI:10.1016/j.crci.2012.10.011

2-Hydroxyethylammonium acetate (2-HEAA) as a task-specific ionic liquid, efficiently promotes one-pot three-component reaction of aryl/heteroaryl/alkyl aldehydes with aryl/alkyl thiols and malononitrile at room temperature. This protocol offers several advantages such as using a reusable and cost-effective ionic liquid, being amenable to scale-up and produces the corresponding 2-amino-3,5-dicarbonitrile-6-thio-pyridines in a short reaction time (5 min) and in good to high yields.

Full text of DOI:10.1016/j.crci.2012.10.011

C. R. Chimie 16 (2013) 279–286
Contents lists available at SciVerse ScienceDirect
Comptes Rendus Chimie
www.sciencedirect.com
´
Full paper/Memoire
2-Hydroxyethylammonium acetate: A reusable task-specific ionic
liquid promoting one-pot, three-component synthesis of 2-amino-3,
5-dicarbonitrile-6-thio-pyridines
*
Sara Sobhani , Moones Honarmand
Department of Chemistry, College of Sciences, University of Birjand, Birjand 414, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
2-Hydroxyethylammonium acetate (2-HEAA) as a task-specific ionic liquid, efficiently
promotes one-pot three-component reaction of aryl/heteroaryl/alkyl aldehydes with aryl/
alkyl thiols and malononitrile at room temperature. This protocol offers several
advantages such as using a reusable and cost-effective ionic liquid, being amenable to
scale-up and produces the corresponding 2-amino-3,5-dicarbonitrile-6-thio-pyridines in
a short reaction time (5 min) and in good to high yields.
Received 1st September 2012
Accepted after revision 22 October 2012
Available online 28 December 2012
Keywords:
2-Amino-3,5-dicarbonitrile-6-thio-pyridine
´
ß 2012 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Ionic liquid
Aldehydes
Thiol
Malononitrile
1. Introduction
ment of new drugs for the treatment of diseases such as
Parkinson, hypoxia/ischemia, asthma, epilepsy [8] and
The synthesis of 2-amino-3,5-dicarbonitrile-6-thio-
pyridine derivatives has attracted much attention of
organic chemists for their various biological activities.
Compounds containing a 2-amino-3,5-dicarbonitrile-6-
thio-pyridine ring system are useful as anti-prion [1],
anti-hepatitis B virus [2], anti-bacterial [3], and anticancer
[4] agents and as potassium channel openers for
treatment of urinary incontinence [5]. These compounds
were reported to inhibit PrPSc accumulation in scrapie-
infected mouse neuroblastoma cells (ScN2a) [1a], MAPK-
activated PK-2 [4b], IKK-2 for treating HBV infection [2],
and modulate androgen receptor function [6]. In addition,
it was found that several of these compounds are selective
ligands towards adenosine receptors [7]. They were
recently recognized as potential targets in the develop-
Creutzfeldt-Jacob [1a,b] and also kidney problems [8]. One
of the most significant existing methods for the synthesis
of 2-amino-3,5-dicarbonitrile-6-thio-pyridines involves
the three-component condensation of aldehyde, malono-
nitrile, and thiol [9]. The condensation has been carried
out under basic conditions using various bases including
Et3N, DABCO [10], DBU [11], TBAH, piperidine [12],
nanocrystaline MgO (NAP-MgO) [13], nano silica [14],
KF/alumina [15], basic alumina [16], TBAF [17], sodium
silicate [18], K2CO3 [19] and microporous molecular
sieves [20]. Some acids such as ZrOCl2.8H2O [21], ZnCl2
[22], o-iodoxybenzoic acid (IBX) [23] and H3BO3 [24] were
also addressed for the promotion of this reaction.
Moreover, ionic liquids such as [bmIm]OH [25] and
[bmIm]Br [26] were found to catalyze the synthesis of
polysubstituted pyridines. However, some of these pro-
tocols suffer from drawbacks such as formation of
inevitable side products, prolonged reaction times, low
yields, harsh reaction conditions, tedious workup and use
of expensive and environmentally toxic catalysts as well
* Corresponding author.
E-mail addresses: sobhanisara@yahoo.com, ssobhani@birjand.ac.ir
(S. Sobhani).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.10.011

280
S. Sobhani, M. Honarmand / C. R. Chimie 16 (2013) 279–286
R
N
as solvents. Thus, organic chemists have struggled to
overwhelm these shortcomings and develop efficient
methods for these nucleus using milder non-hazardous
and inexpensive reagents.
In recent years, room temperature ionic liquids have
received considerable attention as an alternative green
reaction medium for numerous organic reactions due to
their favorable properties, such as good solvating
capability, wide liquid range, negligible vapor pressure,
tunable polarity, high thermal stability and ease of
NC
CN
R'
2-HEAA
rt, 5 min
CH (CN)
R' SH
2
+
2
R
CHO
+
2
H2N
S
Scheme 1. Synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines.
2. Results and discussion
Initially, we have optimized different reaction param-
eters for the synthesis of 2-amino-4-phenyl-6-(phenyl-
sulfanyl)-3,5-pyridinedicarbonitrile (1) using one-pot
three-component reaction of benzaldehyde, malononitrile
and thiophenol (Table 1).
recyclability [27]. Ionic liquids have also played
a
significant role in controlling the reactions as catalysts
[28]. The major concern in using ionic liquids as reaction
media in industrial process is the cost of the ionic liquid,
which would be directly dependent on the price of the
cations and anions that are used for their production
[29]. The currently popular ionic liquids incorporate
expensive cations such as alkyl methyl imidazolium or
dialkyl imidazolium and expensive anions such as
tetrafluroborate or hexaflurophosphate. Thus, introduc-
ing of cost-effective ionic liquids as reaction media is
indispensable. Moreover, despite the great attention for
methylimidazolium (mIm) based-ionic liquids, taken
from EC50 data, the other existed ionic liquids are better
candidates [30].
As it is summarized in Table 1, 0.5 mL of 2-HEAA
efficiently promoted the reaction leading to the desired
product 1 in excellent yield (Entry 3). A similar reaction in
the presence of [EtNH3+][AcOꢀ] proceeded with a longer
reaction time (2.5 h) compared with 2-HEAA (5 min) and
produced the desired product in low yield (Entry 4). The
obtained results showed the specific role of OH group of 2-
HEAA in imparting the catalytic property and indicated
that 2-HEAA could act not only as a solvent but also as a
functionalized or task-specific ionic liquid in this method.
The same reaction was not successful in the absence of 2-
HEAA even after 24 h (Entry 5). It was also found that the
reaction outcome does not dependent on the anion in
[HO(CH2)2NH3+][Yꢀ] or the length of the alkyl chain in
[HO(CH2)nNH3+][AcOꢀ] (Entries 6–11). Increasing interest
of organic chemists for the use of water as a solvent of
choice and its unique properties encouraged us to examine
the present reaction in water (Entry 12). Reaction in
aqueous media was observed to proceed in a short reaction
time (5 min) but produced the desired product in moderate
yield (69%) due to the formation of a by-product.
As part of our continued interest on the development of
new eco-friendly methods for the synthesis of organic
compounds [31], we have recently synthesized
b-phos-
phonomalonates, 4-substituted 2-amino-4H-chromenes
and bis(pyrazolyl)methanes in the presence of task-
specific ionic liquids [32]. In this connection, herein, we
wish to report 2-hydroxyethylammonium acetate (2-
HEAA) [33] as a task-specific ionic liquid for the synthesis
of 2-amino-3,5-dicarbonitrile-6-thio-pyridines at room
temperature (Scheme 1).
Table 1
Synthesis of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile (1) in the presence of different [X(CH2)nNH3+][Yꢀ].
SH
CHO
[X(CH2)nNH3+][Y-] NC
CN
S
2
CH2(CN)2
+
+
rt
H2N
N
1
Entry
[X(CH2)nNH3+][Yꢀ
]
Amount of IL (mL)
Time (min)
Yielda (%)
1
n = 2, X = OH, Y = AcO
n = 2, X = OH, Y = AcO
n = 2, X = OH, Y = AcO
n = 2, X = H, Y = AcO
–
0.125
0.25
0.5
0.5
–
5
88
88
96
48b
0
2
5
3
5
4
2.5 h
5
24 h
5
6
n = 2, X = OH, Y = CF3CO2
n = 2, X = OH, Y = HCO2
n = 2, X = OH, Y = CH3SO3
n = 2, X = OH, Y = NO3
n = 3, X = OH, Y = AcO
n = 5, X = OH, Y = AcO
n = 2, X = OH, Y = AcO
0.5
0.5
0.5
0.5
0.5
0.5
0.5
95
96
95
96
96
98
69b
7
5
8
5
9
5
10
11
12c
5
5
5
a
Isolated yield. Conditions: benzaldehyde (1 mmol), malononitrile (2 mmol), thiophenol (1 mmol).
The desired product (1) plus a mixture of by-products were formed.
H2O was used as solvent.
b
c

S. Sobhani, M. Honarmand / C. R. Chimie 16 (2013) 279–286
281
Table 2
Synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridine derivatives in the presence of 2-HEAA at room temperature.
R
NC
CN
2-HEAA (0.5mL)
rt, 5 min
CH (CN)
R' SH
2
R
CHO
+
+
2
2
R'
H2N
N
1-12
S
Entry
1
R
R0
Product
Yielda (%)
96
MP (8C) Found
MP (8C) Reported [ref]
1
219–220
215–216 [9]
2
2
85
222–223
222–224 [25]
Cl
3
4
3
4
86
86
212–213
228–229
208–211 [25]
228–230 [25]
Me
Cl
5
6
5
6
78
76
228–229
238–239
228–229 [15]
OMe
Me
238 [11]
7
8
9
7
8
9
84
81
72
238–240
305–306
218–220
236 [11]
305–306 [10]
–
N
10
11
Me
10
11
90
70
224–225
178–179
225–226 [9]
n-Bu
182–183 [34]

282
S. Sobhani, M. Honarmand / C. R. Chimie 16 (2013) 279–286
Table 2 (Continued)
R
NC
CN
2-HEAA (0.5mL)
rt, 5 min
CH (CN)
R' SH
2
R
CHO
+
+
2
2
R'
H2N
N
1-12
S
Entry
12
R
R0
Product
Yielda (%)
85b
MP (8C) Found
MP (8C) Reported [ref]
12
310–311
–
CHO
a
Isolated yield. Conditions: aldehyde/malononitrile/thiophenol: 1/2/1.
Conditions: aldehyde/malononitrile/thiophenol: 1/4/2.
b
After performing the reaction of benzaldehyde, mal-
As the results of Table 2 indicates, 2-amino-3,5-
ononitrile and thiophenol in the presence of 2-HEAA
(0.5 mL as the optimal amount), water was added to the
reaction mixture, and the product was filtered off and
purified by recrystallization in EtOH. The ionic liquid was
recovered after evaporation of the filtrate and drying in
vacuo at 100 8C for 24 h. Elemental analysis showed high
purity of the recovered ionic liquid. A similar reaction in
the presence of recovered ionic liquid proceeded well to
produce the desired product 1 after 5 min in 95% yield.
This protocol was also easily amenable to scale-up. For
example, the reaction of benzaldehyde, malononitrile and
thiophenol in a semi scale-up procedure (10 times) in the
presence of 2-HEAA was carried out successfully and the
desired product was isolated in 92% yield.
dicarbonitrile-6-thio-pyridines 1–6 were produced from
a series of various substituted benzaldehyde and thiophe-
nol in good to high yields (Entries 1–6). 1-Naphthaldehyde
as a polynuclear aldehyde and pyridine-3-carbaldehyde as
a heteroaromatic aldehyde underwent the condensation
reaction to afford the corresponding pyridines in good
yields (Entries 7 and 8). Interestingly, 2-HEAA efficiently
promoted the synthesis of 2-amino-3,5-dicarbonitrile-6-
thio-pyridines using aliphatic aldehydes and thiols
(Entries 9–11). It is worth to note that both carbonyl
groups in terephthalaldehyde reacted with malononitrile
and thiophenol and produced the desired product 12 in
85% yield (Entry 12).
In accordance with the mechanism delineated by
Evdokinov et al. and Guo et al. [9], the first step of the
process involves the Knoevenagel condensation of an
aldehyde with malononitrile to form the corresponding
Knoevenagel product A. The reaction proceeds through
To investigate the scope and general applicability of this
procedure, the synthesis of 2-amino-3,5-dicarbonitrile-6-
thio-pyridines was studied using different aldehydes and
thiols under optimized reaction conditions (Table 2).
CN
HSR' +
H2O
NC
NC
R
CN
A
CN
CN
O
+
R
H
AcO
H
C
3 N
OH
OH
AcO
H3N
H
H
CN
N
R
C
R
NC
HN
CN
SR'
N
N
H
SR'
N
R
OH
AcO
H
3N
R
NC
CN
SR'
NC
CN
SR'
H2N
N
H
B
H2N
N
1-12
Scheme 2. Suggested mechanism for the synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines in the presence of 2-HEAA.

S. Sobhani, M. Honarmand / C. R. Chimie 16 (2013) 279–286
283
Table 3
Synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines in the presence of reported reagents or catalysts.
Entry
1
Catalyst or reagent
Et3N or DABCO
Aldehyde/Thiol
Time
Yield (%)a [ref]
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
2 h [9], 40–90 min [10]
2 h [9], 40–90 min [10]
2 h [9], 40–90 min [10]
20–48 [9], 55–96 [10]
20–29 [9], 39–55 [10]
21–47 [9], 42–92 [10]
2
3
KF/alumina
ZnCl2
Aryl/Aryl
5–70 min
56–93 [15]
Aryl/Aryl
2 min–2.5 h
3 min–2.5 h
50–77 [22]
46 [22]
Alkyl/Aryl
4
5
Sodium silicateb
NAP-MgO
Aryl/Aryl
1 h
78–82 [18]
Aryl/Aryl
2–9 h
4–8 h
48–69 [13]
41–56 [13]
Aryl/Alkyl
6
Piperidine or TBAH
Aryl/Aryl
1–24 h
1–24 h
40–67 [12]
5–6 [12]
Alkyl/Aryl
7
Microporous molecular sieves
Aryl/Aryl
Aryl/Aryl
Aryl/Aryl
Aryl/Aryl
Aryl/Aryl
30–120 min
8–50 min
10–40 min
0.5–1.5 h
78–91 [21]
80–94 [24]
75–91 [11]
62–92 [25]
75-86 [26]
8
H3BO3
9
DBU
10
11
12
[bmlm]OH
[bmlm]Br
Nano silica
4–12 min
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
2.5–3 h
6 h
70–85 [14]
60 [14]
6 h
60–65 [14]
13
14
15
ZrOCl2.8H2O/NaNH2/[bmim]BF4
Aryl/Aryl
Aryl/Aryl
2–20 min
90–98 [21]
79–90 [16]
Basic alumina
TBAF
50–100 min
Aryl/Aryl
45–120 min
87–96 [17]
62–64 [17]
Alkyl/Aryl
420–630 min
16
K2CO3/KMnO4
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
40–180 min
90 min
70–89 [19]
80 [19]
75–90 min
60–61 [19]
17
18
IBX
Aryl/Aryl
1.5–2.5 h
69–83 [23]
2-HEAA
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
5 min
5 min
5 min
76–96c
72–90c
70c
a
Isolated yield.
b
c
GC yield.
This work.
thiolate addition to nitrile of the Knoevenagel product A
followed by Michael addition of the second molecule of
malononitrile to the adduct and produces dihydropyr-
we have compared our results obtained using 2-HEAA with
some of those reported in the literature for the synthesis
of 2-amino-3,5-dicarbonitrile-6-thio-pyridines (Table 3).
These results indicate well the superior activity of 2-HEAA
than those of other promoters especially for the synthesis
of 2-amino-3,5-dicarbonitrile-6-thio-pyridines from ali-
phatic aldehydes or thiols. Most of the reported methods
also suffer from lack of generality for the synthesis of 2-
amino-3,5-dicarbonitrile-6-thio-pyridines from arylalde-
hydes/arylthiols, alkylaldehydes/arylthiols and arylalde-
hydes/alkylthiols.
idine (B). Aromatization of
B under the reaction
conditions gives pyridine 1–12 (Scheme 2). In this
three-component reaction, it is supposed that dual
activation of substrates by 2-HEAA has taken place.
The Lewis base moiety of the catalyst (OH) activates the
+
malononitrile and thiol, and its Lewis acid moiety (NH3
)
activates the aldehyde and nitrile of the Knoevenagel
product A. To show the role of the hydroxyl group in the
Knoevenagel condensation, the reaction of benzaldehyde
and malononitrile in the presence of 2-HEAA and
ethylammonium acetate was studied. The reactions
proceed with the same yield and rate. These results
showed that in the first step of the mechanism
(Knoevenagel condensation), hydroxyl group of 2-HEAA
does not play any role.
3. Conclusion
In summary, a facile, economical and green protocol for
one-pot three-component condensation of aldehydes,
malononitrile and thiols in the presence of 2-HEAA as a
task-specific ionic liquid has been described. Surprisingly,
this ionic liquid efficiently promoted the condensation of
both aromatic and aliphatic aldehydes and thiols with
In order to show the merit of the present method for the
synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines,

284
S. Sobhani, M. Honarmand / C. R. Chimie 16 (2013) 279–286
malononitrile leading to 2-amino-3,5-dicarbonitrile-6-
thio-pyridines in good to high yields in a short reaction
time (5 min). All the reactions proceed under nearly
neutral conditions reducing the possibility of unwanted
side reactions. In addition, the present protocol offers
several advantages such as using a reusable and cost-
effective ionic liquid, an environmentally benign reaction
media avoiding hazardous organic solvents and toxic
catalysts, and being amenable to scale-up.
4.4.2. 2-Amino-4-(4-chloro-phenyl)-6-phenylsulfanyl-
pyridine-3,5-dicarbonitrile (2)
308.5 mg, 85%; mp 222–223 8C; 1H NMR (400 MHz,
DMSO-d6): dH (ppm) 7.88 (2H, br, NH2), 7.68 (2H, d,
J = 8.4 Hz, Ar), 7.61 (4H, d, J = 8.4 Hz, Ar), 7.53–7.50 (3H, m,
Ar); 13C NMR (100.6 MHz, DMSO-d6): dC (ppm) 166.7,
159.9, 158.0, 135.8, 135.3, 133.2, 130.9, 130.3, 130.0, 129.4,
127.5, 115.7, 115.3, 93.7, 87.6; IR (KBr) (
(NH), 3331 (NH), 2200 (CN).
n
max/cmꢀ1): 3470
4.4.3. 2-Amino-4-(4-methyl-phenyl)-6-phenylsulfanyl-
pyridine-3,5-dicarbonitrile (3)
4. Experimental
294.1 mg, 86%; mp 212–213 8C; 1H NMR (400 MHz,
4.1. Materials and techniques
DMSO-d6): dH (ppm) 7.81 (2H, br, NH2), 7.62–7.60 (2H, m,
Ar), 7.52–7.50 (3H, m, Ar), 7.45 (2H, d, J = 7.6 Hz, Ar), 7.39
(2H, d, J = 8.0 Hz, Ar), 2.42 (3H, s, CH3); 13C NMR
(100.6 MHz, DMSO-d6): dC (ppm) 166.6, 160.1, 159.2,
140.8, 135.3, 131.4, 130.2, 129.9, 129.8, 128.9, 127.6, 115.9,
115.6, 93.8, 87.4, 21.4; IR (KBr) (
3318 (NH), 2200 (CN).
Chemicals were purchased from Merck and Fluka
Chemical Companies. NMR spectra were recorded in
ppm in DMSO on a Bruker Avance DPX-400 instrument
using TMS as internal standard. Elemental analysis for C, H,
N and S were obtained using a Elementar, Vario EL III. IR
spectra were run on a Perkin–Elmer 780 instrument.
Melting points were determined by Buchi 510 apparatus
and are uncorrected. The purification of the products and
the progress of the reactions were accomplished by TLC on
silica-gel polygram SILG/UV254 plates.
n
max/cmꢀ1): 3460 (NH),
4.4.4. 2-Amino-6-(4-chloro-phenylsulfanyl)-4-phenyl-
pyridine-3,5-dicarbonitrile (4)
312.1 mg, 86%; mp 228–229 8C; 1H NMR (400 MHz,
DMSO-d6): dH (ppm) 7.89 (2H, br, NH2), 7.63 (3H, d,
J = 8.4 Hz, Ar), 7.60–7.56 (6H, m, Ar); 13C NMR (100.6 MHz,
DMSO-d6): dC (ppm) 166.3, 160.0, 159.1, 137.2, 135.3,
134.3, 130.9, 129.9, 129.2, 128.9, 126.5, 115.7, 115.5, 93.7,
4.2. Typical procedure for the synthesis of 2-HEAA
2-HEAA was prepared according to the previously
87.6; IR (KBr) (
(CN).
n
max/cmꢀ1): 3438 (NH), 3315 (NH), 2203
reported procedure [33].
A solution of acetic acid
(50 mmol, 3.00 g) in EtOH (1.5 mL) was added dropwise
to a stirring solution of 2-aminoethanol (50 mmol, 3.05 g)
in EtOH (1.5 mL) at room temperature within 1 h. The
resultant solution was stirred at room temperature for
another 20 h. EtOH was removed in vacuo and the oil in
residue was dried in vacuo at 50 8C for 48 h to give 2-HEAA
as a yellow viscous liquid (pH = 7.96 at 25 8C, b.p. 191 8C,
density = 1.11 g cmꢀ3 at 25 8C, electrochemical stability =
4.4.5. 2-Amino-6-(4-methoxy-phenylsulfanyl)-4-phenyl-
pyridine-3,5-dicarbonitrile (5)
279.2 mg, 78%; mp 228–229 8C; 1H NMR (400 MHz,
DMSO-d6):
dH (ppm) 7.79 (2H, br, NH2), 7.59–7.55 (5H, m,
Ar), 7.52 (2H, d, J = 8.4 Hz, Ar), 7.07 (2H, d, J = 8.4 H, Ar), 3.83
(3H, s, OCH3); IR (KBr) (
2100 (CN).
n
max/cmꢀ1): 3427 (NH), 3322 (NH),
between ꢀ0.6 and 0.7 V, conductivity = 263.3
m
s cmꢀ1).
4.4.6. 2-Amino-6-(4-methyl-phenylsulfanyl)-4-phenyl-
pyridine-3,5-dicarbonitrile (6)
4.3. General procedure for the synthesis of 2-amino-3,5-
dicarbonitrile-6-thio-pyridines in the presence of 2-HEAA
259.9 mg, 76%; mp 238–239 8C; 1H NMR (400 MHz,
DMSO-d6): dH (ppm) 7.84 (2H, br, NH2), 7.63–7.57 (6H, m,
A
mixture of aldehyde (1 mmol), malononitrile
Ar), 7.52–7.50 (3H, m, Ar), 2.51 (3H, s, CH3); IR (KBr) (nmax/
(2 mmol), thiol (1 mmol) and 2-HEAA (0.5 mL) was stirred
at room temperature for 5 min. H2O (20 mL) was added to
the reaction mixture and the resulting solid was filtered
and washed with H2O (2 ꢁ 10 mL). Pure product was
obtained from the resulting solid by recrystallization in
EtOH. Ionic liquid was recovered after evaporation of the
filtrate and drying in vacuo at 100 8C for 24 h.
cmꢀ1): 3467 (NH), 3348 (NH), 2195 (CN).
4.4.7. 2-Amino-4-(2-naphthyl)-6-phenylsulfanyl-pyridine-
3,5-dicarbonitrile (7)
317.5 mg, 84%; mp 238–240 8C; 1H NMR (400 MHz,
DMSO-d6): dH (ppm) 8.18 (1H, s, Ar), 8.13 (1H, d, J = 8.8 Hz,
Ar), 8.09–8.05 (2H, m, Ar), 7.89 (2H, br, NH2), 7.71–7.64
(5H, m, Ar), 7.54–7.52 (3H, m, Ar); 13C NMR (100.6 MHz,
DMSO-d6): dC (ppm) 166.7, 160.1, 159.2, 135.4, 133.8,
132.7, 131.9, 130.2, 130.0, 129.0, 128.9, 128.3, 128.2, 127.6,
4.4. Spectral data for known 2-amino-3,5-dicarbonitrile-6-
thio-pyridines
125.9, 115.9, 115.6, 94.1, 87.7; IR (KBr) (
(NH), 3301 (NH), 2170 (CN).
n
max/cmꢀ1): 3431
4.4.1. 2-Amino-4-phenyl-6-phenylsulfanyl-pyridine-3,5-
dicarbonitrile (1)
314.8 mg, yield 96%; mp 219–220 8C; 1H NMR
(400 MHz, DMSO-d6): dH (ppm) 7.84 (2H, br, NH2), 7.63–
4.4.8. 2-Amino-4-(3-pyridinyl)-6-phenylsulfanyl-pyridine-
3,5-dicarbonitrile (8)
266.5 mg, 81%; mp 305–306 8C; 1H NMR (400 MHz,
DMSO-d6): dH (ppm) 8.80–8.78 (2H, m, Ar), 8.07 (1H, d,
7.59 (7H, m, Ar), 7.53–7.51 (3H, m, Ar); IR (KBr) (nmax
/
cmꢀ1): 3471 (NH), 3349 (NH), 2196 (CN).

S. Sobhani, M. Honarmand / C. R. Chimie 16 (2013) 279–286
285
[2] H. Chen, W. Zhang, R. Tam, A.K. Raney, PCT Int. Appl. WO 2005058315
A1 20050630, 2005.
[3] S.B. Levy, M.N. Alekshun, B.L. Podlogar, K. Ohemeng, A.K. Verma,
T. Warchol, B. Bhatia, T. Bowser, M. Grier, US Patent Appl.,
2005124678 A1 20050609, 2005.
J = 7.6 Hz, Ar), 7.94 (2H, br, NH2), 7.67–7.61 (3H, m, Ar),
7.53–7.52 (3H, m, Ar); IR (KBr) (
3290 (NH), 2200 (CN).
n
max/cmꢀ1): 3360 (NH),
[4] (a) M.T. Cocco, C. Congiu, V. Lilliu, V. Onnis, Eur. J. Med. Chem. 40 (2005)
1365;
4.4.9. 2-Amino-4-methyl-6-phenylsulfanyl-pyridine-3,5-
dicarbonitrile (10)
(b) D.R. Anderson, N.W. Stehle, S.A. Kolodziej, E.J. Reinhard, PCT Int.
Appl. WO 2004055015 A1 20040701, 2004.
[5] H. Harada, S. Watanuki, T. Takuwa, K. Kawaguchi, T. Okazaki, Y. Hirano,
C. Saitoh, PCT Int. Appl. WO 2002006237 A1 20020124, 2002.
[6] A.A. Nirschl, L.G. Hamann, US Pat. Appl. Publ. US 2,005,182,105 A1
20,050,818, 2005.
[7] (a) M.W. Beukers, L.C.W. Chang, J.K.F.D. Ku¨ nzel, T. Mulder- Krieger,
R.F. Spanjersberg, J. Brussee, A.P.I. Jzerman, J. Med. Chem. 47 (2004)
3707;
239.4 mg, 90%; mp 224–225 8C; 1H NMR (400 MHz,
DMSO-d6): dH (ppm) 7.71 (2H, br, NH2), 7.58–7.56 (2H, m,
Ar), 7.50–7.47 (3H, m, Ar), 2.46 (3H, s, CH3); IR (KBr) (nmax
/
cmꢀ1): 3396 (NH), 3310 (NH), 2202 (CN).
4.4.10. 2-Amino-4-phenyl-6-(n-butylsulfanyl)-pyridine-3,5-
dicarbonitrile (11)
(b) L.C.W. Chang, J.K.F.D. Ku¨ nzel, T. Mulder-Krieger, R.F. Spanjers-
berg, S.F. Roerink, G. Hout, M.W. Beukers, J. Brussee, A.P.I. Jzerman, J.
Med. Chem. 48 (2005) 2045;
(c) U. Rosentreter, T. Kraemer, M. Shimada, W. Huebsch, N. Diedrichs,
T. Krahn, K. Henninger, J.P. Stasch, DE 10238113 A1 20030618, 2003;
(d) U. Rosentreter, T. Kraemer, A. Vaupel, W. Huebsch, N. Diedrichs,
T. Krahn, K. Dembowsky, J.P. Stasch, M. Shimada, WO 2002079195 A1
20021010, 2002;
215.6 mg, 70%; mp 178–179 8C; 1H NMR (400 MHz,
DMSO-d6): dH (ppm) 8.04 (2H, br, NH2), 7.58–7.53 (5H, m,
Ar), 3.25 (2H, t, J = 7.2 Hz, CH2), 1.69–1.62 (2H, m, CH2),
1.48-1.39 (2H, m, CH2), 0.93 (3H, t, J = 7.2 Hz, CH3); 13C
NMR (100.6 MHz, DMSO-d6):
dC (ppm) 167.7, 160.1, 158.7,
134.5, 130.8, 129.2, 128.9, 115.9, 115.8, 94.0, 86.0, 31.2,
29.7, 21.8, 14.0; IR (KBr) (
(NH), 2200 (CN).
(e) U. Rosentreter, T. Kraemer, A. Vaupel, W. Huebsch, N. Diedrichs,
T. Krahn, K. Dembowsky, J.P. Stasch, WO 2002070520 A1 20020912,
2002;
(f) U. Rosentreter, T. Kraemer, A. Vaupel, W. Huebsch, N. Diedrichs,
T. Krahn, K. Dembowsky, J.P. Stasch, WO 2002070485 A1 20020912,
2002;
n
max/cmꢀ1): 3452 (NH), 3313
4.5. Spectral data for unknown 2-amino-3,5-dicarbonitrile-
6-thio-pyridines
(g) U. Rosentreter, R. Henning, M. Bauser, T. Kraemer, A. Vaupel,
W. Huebsch, K. Dembowsky, O. Salcher-Schraufstaetter, J.P. Stasch,
T. Krahn, E. Perzborn, WO 2001025210 A2 2001041 2, 2001.
[8] B.B. Fredholm, A.P.I. Jzerman, K.A. Jacobson, K.N. Klotz, J. Linden,
Pharmacol. Rev. 53 (2001) 527.
[9] (a) N.M. Evdokimov, I.V. Magedov, A.S. Kireev, A. Kornienko, Org. Lett. 8
(2006) 899;
(b) K. Guo, M.J. Thompson, T.R.K. Reddy, R. Mutter, B. Chen. Tetrahe-
dron 63 (2007) 5300.
[10] N.M. Evdokimov, A.S. Kireev, A.A. Yakovenko, M.Y. Antipin, I.V. Mage-
dov, A. Kornienko, J. Org. Chem. 72 (2007) 3443.
[11] R. Mamgain, R. Singh, D.S. Rawat, J. Heterocycl. Chem. 46 (2009) 69.
[12] K. Guo, M.J. Thompson, B. Chen, J. Org. Chem. 74 (2009) 6999.
[13] M.L. Kantam, K. Mahendar, S. Bhargava, J. Chem. Sci. 122 (2010) 63.
[14] S. Banerjee, G. Sereda, Tetrahedron Lett. 50 (2009) 6959.
[15] K.N. Singh, S.K. Singh, ARKIVOC xiii (2009) 153.
[16] P.V. Shinde, B.B. Shingate, M.S. Shingare, Bull. Korean Chem. Soc. 32
(2011) 459.
[17] P.V. Shinde, B.B. Shingate, M.S. Shingare, Chin. J. Chem. 29 (2011) 1049.
[18] M.M. Heravi, M. Khorshidi, Y.S. Beheshtia, B. Baghernejad, Bull. Korean
Chem. Soc. 31 (2010) 1343.
[19] S. Mishra, R. Ghosh, Synth. Commun. 42 (2012) 2229.
[20] P.V. Shinde, V.B. Labade, B.B. Shingate, M.S. Shingare, J. Mol. Catal. A:
Chem. 336 (2011) 100.
[21] M.R. Poor Heravi, F. Fakhr, Tetrahedron Lett. 52 (2011) 6779.
[22] M. Sridhar, B.C. Ramanaiah, C. Narsaiah, B. Mahesh, M. Kumaras-
wamy, K.K.R. Mallu, V.M. Ankathi, P.S. Rao, Tetrahedron Lett. 50
(2009) 3897.
[23] S. Takale, J. Patil, V. Padalkar, R. Pisal, A. Chaskar, J. Braz. Chem. Soc. 23
(2012) 966.
[24] P.V. Shinde, S.S. Sonar, B.B. Shingate, M.S. Shingare, Tetrahedron Lett. 51
(2010) 1309.
[25] B.C. Ranu, R. Jana, S. Sowmiah, J. Org. Chem. 72 (2007) 3152.
[26] A. Davoodnia, P. Attar, H. Eshghi, A. Morsali, N. Tavakoli-Hoseini, A.
Tavakoli-Nishaburi, Asian. J. Chem. 23 (2011) 1273.
[27] (a) T. Welton, Chem. Rev. 99 (1999) 2071;
4.5.1. 2-Amino-4-phenethyl-6-phenylsulfanyl-pyridine-3,5-
dicarbonitrile (9)
256.3 mg, 72%; mp 218–220 8C; [Found: C, 70.37; H,
4.51; N, 15.61; S, 8.86. C21H16N4S requires C, 70.76; H,
4.52; N, 15.72; S, 9.00%]; 1H NMR (400 MHz, DMSO-d6): dH
(ppm) 7.77 (2H, br, NH2), 7.59–7.57 (2H, m, Ar), 7.50–7.47
(3H, m, Ar), 7.35 (2H, t, J = 7.2 Hz, Ar), 7.28–7.22 (3H, m, Ar),
3.03–2.99 (2H, m, CH2), 2.92-2.89 (2H, m, CH2); 13C NMR
(100.6 MHz, DMSO-d6): dC (ppm) 166.3, 160.4, 160.1,
139.9, 135.2, 130.1, 129.9, 129.1, 128.7, 127.6, 127.1, 115.4,
115.0, 93.9, 87.6, 36.1, 35.1; IR (KBr) (
(NH), 3344 (NH), 2215 (CN).
n
max/cmꢀ1): 3442
4.5.2. 1,4-bis(2-amino-6-phenylsufanyl-4-pyridyl-3,5-
dicarbonitrile)benzene (12)
492.1 mg, 85%; mp 310–311 8C; [Found: C, 66.27; H,
3.18; N, 19.29; S, 11.43. C32H18N8S2 requires C, 66.42; H,
3.14; N, 19.36; S, 11.08%]; 1H NMR (400 MHz, DMSO-d6):
d
H (ppm) 7.90 (4H, br, NH2), 7.80 (4H, s, Ar), 7.64–7.62 (4H,
m, Ar), 7.54–7.51 (6H, m, Ar); 13C NMR (100.6 MHz, DMSO-
d6): dC (ppm) 166.8, 160.2, 158.2, 139.5, 136.1, 135.3,
129.9, 129.4, 127.5, 115.7, 115.4, 93.7, 87.5; IR (KBr) (nmax
/
cmꢀ1): 3407 (NH), 3325 (NH), 2216 (CN).
Acknowledgements
(b) P. Wasserscheid, W. Keim, Angew. Chem. Int. Ed. 39 (2000) 3772;
(c) T. Welton, Coord. Chem. Rev. 248 (2004) 2459;
(d) X. Mi, S. Luo, J.P. Cheng, J. Org. Chem. 7 (2005) 2338.
[28] (a) R.V. Hangarge, D.V. Jarikoteb, M.S. Shingare, Green Chem. 4 (2002)
266;
We thank University of Birjand Research Council for
their support on this work.
(b) V. Singh, S. Kaur, V. Sapehiyi, Catal. Commun. 6 (2005) 57.
[29] P. Wasserscheid, T. Welton (Eds.), Ionic Liquid in Synthesis, Wiley-VCH,
Weinheim, 2004.
References
[30] R.F.M. Frade, C.A.M. Afonso, Hum. Exp. Toxicol. 29 (2010) 1038.
[31] (a) S. Sobhani, Z. Pakdin Parizi, Tetrahedron 67 (2011) 3540;
(b) S. Sobhani, Z. Pakdin Parizi, N. Razavi, Appl. Catal. A: Chem. 169
(2011) 409;
[1] (a) V. Perrier, A.C. Wallace, K. Kaneko, J. Safar, S.B. Prusiner, F.E. Cohen,
Proc. Natl Acad. Sci. U S A 97 (2000) 6073;
(b) T.R.K. Reddy, R. Mutter, W. Heal, K. Guo, V.J. Gillet, S. Pratt, B. Chen, J.
Med. Chem. 46 (2006) 607;
(c) S. Sobhani, A. Vafaee, J. Iran. Chem. Soc. 7 (2010) 227;
(d) S. Sobhani, A. Vafaee, Synthesis (2009) 1909;
(c) B.C.H. May, J.A. Zorn, J. Witkop, J. Sherrill, A.C. Wallace, G. Legname,
S.B. Prusiner, F.E. Cohen, J. Med. Chem. 50 (2007) 65.

286
S. Sobhani, M. Honarmand / C. R. Chimie 16 (2013) 279–286
(e) S. Sobhani, Z. Tashrifi, Heteroat. Chem. (2009) 109;
[32] (a) S. Sobhani, M. Honarmand, J. Iran. Chem. Soc. 9 (2012) 661;
(b) S. Sobhani, R. Nasseri, M. Honarmand, Can. J. Chem. (2012), http://
dx.doi.org/10.1139/v2012-059.
[33] S.J. Zhang, X.L. Yuan, Y.H. Chen, Y.Q. Zhang, Chin Patent 10069408.5,
2005.
(f) S. Sobhani, Z. Tashrifi, Synth. Commun. 39 (2009) 120;
(j) S. Sobhani, E. Safaei, M. Asadi, F. Jalili, J. Organomet. Chem. 693
(2008) 3313;
(h) S. Sobhani, E. Safaei, M. Asadi, F. Jalili, Z. Tashrifi, J. Porphyrins
Phthalocyanines 12 (2008) 849.
[34] Z.Q. Wang, Z.M. Ge, T.M. Cheng, R.T. Li, Synlett. (2009) 2020.