SnO nanoparticles as an efficient catalyst for the one-pot synthesis of chromeno[2,3-b]pyridines and 2-amino-3,5-dicyano-6-sulfanyl pyridines

Article abstract of DOI:10.1039/c4ra04769a

SnO nanoparticles have been used as an efficient catalyst for the preparation of chromeno[2,3-b]pyridines and 2-amino-3,5-dicyano-6-sulfanyl pyridines under reflux conditions in ethanol in good to excellent yields. This flexible and nano-catalytic procedure showed good recyclability and provides a clean condensation reaction in a short reaction time. This journal is

Full text of DOI:10.1039/c4ra04769a

RSC Advances
View Article Online
View Journal | View Issue
PAPER
SnO nanoparticles as an efficient catalyst for the
one-pot synthesis of chromeno[2,3-b]pyridines and
2-amino-3,5-dicyano-6-sulfanyl pyridines†
Cite this: RSC Adv., 2014, 4, 50668
*
Javad Safaei-Ghomi, Hossein Shahbazi-Alavi and Elham Heidari-Baghbahadorani
Received 20th May 2014
Accepted 29th September 2014
SnO nanoparticles have been used as an efficient catalyst for the preparation of chromeno[2,3-b]pyridines
and 2-amino-3,5-dicyano-6-sulfanyl pyridines under reflux conditions in ethanol in good to excellent
yields. This flexible and nano-catalytic procedure showed good recyclability and provides a clean
condensation reaction in a short reaction time.
DOI: 10.1039/c4ra04769a
www.rsc.org/advances
an interesting challenge. Multi-component reactions (MCRs)
present a wide range of possibilities for molecular diversity per
1. Introduction
step with a minimum of synthetic time, outlay, labour and
waste production.20–25 Chromeno[2,3-b]pyridines show inter-
esting characteristics which make them attractive targets for the
synthesis via MCRs. Consequently, MCRs have been paid much
attention by synthetic organic chemists worldwide.
Similarly nanoparticles have undergone extensive examina-
tion in the past decade. Due to their insolubility in reaction
solvents renders them easily separable from the reaction
mixture. Heterogeneous catalysis offers several advantages over
the homogeneous counterpart, such as easy recovery, simple
recycling without losing their activity and enhanced stability of
the catalyst which can make synthetic processes cheaper, safer
and greener.26–32 Therefore, the possibility of performing
multicomponent reactions under mild conditions with a
heterogeneous catalyst could enhance their effectiveness from
economic and ecological points of view.
The pyridine ring system is a structural component of a large
number of biologically active compounds. Heterocycles with the
pyridine moiety exhibit various pharmacological activities such
as anti-bacterial,1 anticancer,2 antiprion3 potassium channel
opening,4 IKK-binhibitors,5 potent inhibitor of HIV-1 integrase.6
Among the pyridine derivatives, 2-amino-3,5-dicyano-6-sulfanyl
pyridines exhibit a broad range of biological properties such as
treatment of the Hepatitis B Foundation infections,7 Creutz-
feldt–Jacob disease, Parkinson's disease, hypoxia/ischemia,
asthma, kidney disease, epilepsy and cancer.8–10 Condensed
pyridines are known for their versatile biological activities, for
example chromeno[2,3-b]pyridines have a number of pharma-
cological properties. Chromenopyridines are fused heterocyclic
compounds that exhibit antibacterial (including antituber-
cular),11 anti-proliferative (cytotoxic activity against the human
solid tumor HT-29 cell lines),12 antirheumatic,13 cancer che-
mopreventive and chemother-apeutic agent,14 antimyopic,15
antihistaminic,16 and antiasthmatic17 activities. Several
compounds derived from these libraries were identied to
inhibit mitogen-activated protein kinase-activated protein
kinase 2 (MK-2) and suppress the expression of TNFa in U937
cells18 and possess gastric antisecretory activity in rats and
dogs.19 Some other examples of chromenopyridine derivatives
are the prominent drug molecules mlexanox (trade name Aph-
thasol), an antiallergic and topical antiulcer agent, and pros-
noprofen (as NSAIDs), that have been reported (Fig. 1).
We wish to report herein a highly efficient procedure for the
preparation of chromeno[2,3-b]pyridines and 2-amino-3,5-
Synthesis of bioactive compounds should be facile, exible,
rapid and practical in organic synthesis. Therefore, looking for
efficient and concise methods for the synthesis of pyridines is
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, P.O.
Box 87317-51167, Kashan, Islamic Republic of Iran. E-mail: safaei@kashanu.ac.ir;
Fax: +98-361-5912397; Tel: +98-361-5912385
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra04769a
Fig. 1 Biologically important chromenopyridines.
50668 | RSC Adv., 2014, 4, 50668–50677
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
size of SnO has been found to be 28 nm for 18 min and 40 nm
for 12 min. The XRD pattern of the SnO nanoparticles was
shown in Fig. 2 (under irradiation of microwave for 18 min). The
results show that SnO nanoparticles were obtained with an
average diameter of 26–28 nm as conrmed by XRD analysis.
The morphology and particle size of SnO nanoparticles, was
investigated by scanning electron microscopy (SEM) (Fig. 3).
The SEM images show particles with diameters in the range of
nanometers.
Scheme 1 Synthesis of chromeno[2,3-b]pyridines and 2-amino-3,5-
dicyano-6-sulfanyl pyridines using SnO nanoparticles.
Initially, we had explored and optimized different reaction
parameters for the synthesis of 2-amino-3,5-dicyano-6-sulfanyl
pyridines by the condensation reaction of 4-nitrobenzaldehyde
(1 mmol), 2.2 mmol of malononitrile and 1 mmol of thiophenol
as a model reaction. Meanwhile, we investigated the reaction of
salicylaldehydes, thiols and 2 equiv. of malononitrile in the
presence of different catalysts for the synthesis of chromeno
[2,3-b]pyridines. As given in Table 2, the solvent has a great
effect on the acceleration of the reactions. Several reactions
dicyano-6-sulfanyl pyridines using SnO nanoparticles as an
efficient and reusable heterogeneous catalyst under reux
conditions in ethanol (Scheme 1). A number of methods have
been developed for the synthesis of chromeno[2,3-b]pyridines
and 2-amino-3,5-dicyano-6-sulfanyl pyridines using MCRs in
the presence of few catalysts such as Et3N (under reux condi-
tions in ethanol),33 K2CO3 (EtOH:H2O, reux).34
2. Results and discussion
The rst step entails the synthesis of highly stable SnO nano-
particles. The catalyst was prepared by co-precipitation tech-
nique and microwave radiation. For more investigation of the
inuence of microwave irradiation in this reaction, the
synthesis of SnO nanoparticle was compared in two times. The
precipitate dispersed in water kept under irradiation of micro-
wave for 18 min and 12 min (Microwave power was maintained
at 600 W). Particle size of SnO nanoparticles, was investigated
by XRD pattern. The crystallite size diameter (D) of the SnO
nanoparticles has been calculated by Debye–Scherrer equation
(D ¼ Kl/b cos q), where FWHM (full-width at half-maximum or
half-width) is in radians and q is the position of the maximum
of diffraction peak, K is the so-called shape factor, which usually
takes a value about 0.9, and l is the X-ray wavelength. Crystallite Fig. 3 SEM image of the SnO nanoparticles.
Fig. 2 XRD pattern of the SnO nanoparticles.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 50668–50677 | 50669

View Article Online
RSC Advances
Paper
were scrutinized using various solvents such as EtOH, CH3CN, oxides or salts can be determined with the help of a very weak
water, DMF and CHCl3. The best results were obtained under basic molecule which is only adsorbed on Lewis centres very
reux conditions in ethanol and found that the reaction gave weakly. The surface of a metal oxide consists of ordered arrays
satisfying results in the presence of SnO nanoparticles at 6 of acid–base centres. The cationic metal centres act as Lewis
mol% which gave excellent yields of products (Tables 1 and 2). acid sites while the anionic oxygen centres act as Lewis bases.
The polarity, dipole moment, polarizability and hydrogen The strong solid acids or bases usually give higher activities in
bonding of a solvent determine what type of compounds it is condensation reactions. We propose that SnO NPs have highly
able to dissolve. In this reaction, the use of polar solvents effective catalytic behaviour because of the surface properties
favours the reaction mechanism. The catalyst showed best that include Sn2+ as acid and O2ꢀ as base that accelerate the
activity in ethanol compared to other organic solvents such as reaction rate. These complementary interactions between
DMF, CH3CN, and CHCl3. The dielectric constant of solvents reactants and catalyst lead to an increase in the rate of reaction.
was listed in Table 2. The ethanol with dielectric constant 24.5 Size of prepared SnO nanoparticles in the presence of micro-
carried out reactions in good to excellent yields. Therefore, the wave was reduced until 28 nm, and specic surface area was
use of polar solvents with moderate dielectric constant favours
the condensation reactions. Also, the activity and stability of the
SnO nanoparticles and those metal oxides in ethanol is
Table 3 Effect of different size of the catalyst for the synthesis
6-sulfanyl pyridinesa (5) and chromenopyridinesb
maximum compared to other solvents. The model reactions was
carried out in the presence of various catalysts such as metal
oxide (MgO, CaO, CuO, ZrO2, SnO) and InCl3, CuCl, SnCl2 and
CuSO4. When the reaction was carried out using CuO, MgO and
SnO NPs as the catalyst, the product could be obtained in
moderate to good yield. The acidity or basicity of those metal
Time 5a/6a
(min)
Yieldc 5a/6a
(%)
Entry
Catalyst
Surface area
1
2
3
4
SnO bulk
0.93 m2 gꢀ1
35 m2 gꢀ1
190/120
99/54
106/65
116/73
63/56
92/88
89/85
83/81
SnO 28 nm
SnO 40 nm
SnO 82 nm
29.9 m2 gꢀ1
16.2 m2 gꢀ1
Table 1 Optimization for the synthesis 6-sulfanyl pyridinesa (5) and
chromenopyridinesb (6) by various catalysts in ethanol under reflux
conditions
a
1 mmol of 4-nitrobenzaldehyde, 2.2 mmol of malononitrile and
b
1 mmol of thiophenol. Salicyladehyde (1.5 mmol), malononitrile
(3 mmol) and benzenethiol (1.5 mmol). c Isolated yields.
Entry
Catalyst
(mol%)
Yieldsc 5a/6a (%)
1
2
3
4
5
6
7
8
—
MgO
CuCl
CuO
InCl3
ZrO2
CaO
CuSO4
SnCl2
SnO NPs
SnO NPs
SnO NPs
—
15
10
10
5
10
5
10
10
3
20/17
55/44
42/32
40/22
24/27
49/33
54/38
30/18
40/35
82/79
92/88
92/89
9
10
11
12
6
9
a
1 mmol of 4-nitrobenzaldehyde, 2.2 mmol of malononitrile and 1
Fig. 4 Reusability of SnO nanoparticles catalyst for the preparation of
5e and 6a.
b
mmol of thiophenol. Salicyladehyde (1.5 mmol), malononitrile (3
mmol) and benzenethiol (1.5 mmol). c Isolated yields.
Table 2 Synthesis of 6-sulfanyl pyridinesa (5) and chromenopyridinesb
(6) using different solvents with SnO NPs (6 mol%)
Dielectric
constant
Time 5a/6a
(min)
Yieldsc 5a/6a
(%)
Entry
Solvent
1
2
3
4
5
6
H2O (80 ꢁC)
z80
37.5
38
4.81
z24.5
24.5
200/140
150/100
160/110
260/180
130/98
99/54
55/42
70/64
65/60
31/38
69/60
92/88
CH3CN (reux)
DMF (reux)
CHCl3 (reux)
EtOH (45 ꢁC)
EtOH (reux)
a
1 mmol of 4-nitrobenzaldehyde, 2.2 mmol of malononitrile and 1
b
mmol of thiophenol. Salicyladehyde (1.5 mmol), malononitrile (3
mmol) and benzenethiol (1.5 mmol). c Isolated yields.
Fig. 5 SEM of SnO nanoparticles.
50670 | RSC Adv., 2014, 4, 50668–50677
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 4 Synthesis of 2-amino-3,5-dicyano-6-sulfanyl pyridines and chromeno[2,3-b]pyridines using SnO nanoparticles
Entry
Aldehyde
Thiols
Product of 5a–l and 6a–f
Time (min)
Yielda (%)
M.P ꢁ
C
1
110
84
229–231 (ref. 26)
2
125
83
240–242 (ref. 26)
3
4
132
141
79
80
218–220 (ref. 26)
237–239 (ref. 26)
5
99
92
301–303 (ref. 26)
6
103
89
248–250 (ref. 26)
7
115
81
278–280 (ref. 36)
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 50668–50677 | 50671

View Article Online
RSC Advances
Paper
Table 4 (Contd.)
Entry
Aldehyde
Thiols
Product of 5a–l and 6a–f
Time (min)
Yielda (%)
M.P ꢁ
C
8
112
85
206–207 (ref. 37)
9
100
142
98
89
79
92
221–222 (ref. 37)
315–317 (ref. 37)
289–290 (ref. 37)
10
11
12
104
85
255–257 (ref. 36)
13
14
54
57
88
85
220–222 (ref. 34)
223–225 (ref. 34)
50672 | RSC Adv., 2014, 4, 50668–50677
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 4 (Contd.)
Entry
15
Aldehyde
Thiols
Product of 5a–l and 6a–f
Time (min)
Yielda (%)
M.P ꢁ
C
62
80
173–175
16
17
63
56
81
83
200–202
206–208 (ref. 27)
18
57
85
225–227 (ref. 27)
a
Isolated yields.
increased about 35 m2 gꢀ1. Table 3 shows that the inuence of before and aer reaction. We believe that, this is also the
particles size on the activity of the SnO nanoparticles in the possible reason for the extreme stability of the SnO nano-
synthesis of 6-sulfanyl pyridines and chromenopyridines. As particles presented herein.
expected, the increased surface area due to small particle size
To study the scope of this reaction, we next utilized various
increased reactivity of catalyst. This factor is responsible for the aldehydes and thiols in four-component reactions under reux
accessibility of the substrate molecules on the catalyst surface. conditions in ethanol (Table 4).
However, the activity of solid catalysts is inuenced by the acid–
As represented in Table 4, these products precipitate from
base properties and many other factors such as geometric reuxing ethanolic solutions and are isolated by easy
structure (particularly pore structure), the distribution of sites ltration.
and the polarity of the surface sites.28
The proposed mechanism for the preparation of 2-amino-
We also investigated recycling of the SnO NPs as catalyst 3,5-dicyano-6-sulfanyl pyridines is shown in Scheme 2. Initially,
under reux conditions in ethanol. The results showed that we assumed that the reaction occurs via a Knoevenagel
SnO NPs can be reused several times without noticeable loss condensation between malononitrile and aldehyde. Then, the
of catalytic activity (yields 92 to 86%) (Fig. 4). The catalyst subsequent Michael-type addition of the second molecule of
could be reused for ve times with a minimal loss of activity. malononitrile to the Knoevenagel adduct and thiolate addition
Perhaps, activity of SnO NPs is decreased by the number of to C^N of the adduct and cyclization to dihydropyridine which
the regeneration. The morphology and particle size of SnO upon aromatization and oxidation (air) under the reaction
nanoparticle was investigated by scanning electron micros- conditions leads to pyridine. In this mechanism the SnO NPs
copy (SEM) before use and aer reuse of ve times with act as Lewis solid acid and activate the C]O group for better
images shown in Fig. 5. The SEM of SnO nanoparticles before reaction with nucleophiles.
and aer the reaction showed identical shape. Interestingly,
A possible mechanism for the formation of chromeno[2,3-
the morphology of the nanoparticles remained unchanged b]pyridines is shown in Scheme 3. Thus, salicylaldehyde
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 50668–50677 | 50673

View Article Online
RSC Advances
Paper
3. Experimental
3.1. Chemicals and apparatus
All reagents and solvents were purchased from Merck (Ger-
many) and Aldrich and used without further purication.
Melting points were determined on Electro thermal 9200.1H
NMR and 13C NMR spectra were recorded with a Bruker Avance-
400 MHz. NMR spectra were obtained in CDCl3 and DMSO-d6
solution and are reported as parts per million (ppm) downeld
from tetramethylsilane as internal standard. The IR spectra
were recorded on FT-IR Magna 550 apparatus using with KBr
plates. EIMS (70 eV) was performed by Finnigan-MAT-8430
mass spectrometer in m/z. The elemental analyses (C. H. N) of
the samples were performed using a LECO CHNS 923 analyser.
Surface area was determined by nitrogen adsorption measure-
ment (Micrometrics ASAP-2000). Powder X-ray diffraction (XRD)
of SnO nanoparticles was carried out on a Philips diffractometer
of X'pert Company with monochromatized Cu Ka radiation (l ¼
Scheme 2 Possible mechanism of the one-pot reaction for the
preparation of 2-amino-3,5-dicyano-6-sulfanyl pyridines.
˚
1.5406 A). Microscopic morphology was visualized by SEM (LEO
1455VP).
3.2. Preparation of SnO nanoparticles
Tin oxide nanoparticles were prepared according to the proce-
dure reported in the literature.35 A 100 ml aqueous solution of
10ꢀ2 M is prepared by dissolving 0.225 g of tin(II) chloride
(SnCl2$2H2O) in dilute HCl. The solution was continuously
stirred and diluted NH4OH was added drop-wise to obtain a
precipitate. The solution pH increased to 5. The precipitate was
washed several times to remove excess ions. The precipitate
dispersed in water kept under irradiation of microwave for 18
min. The sample is characterised by X-ray diffraction (XRD) and
scanning electron microscopy (SEM).
3.3. General procedure for the preparation of 2-amino-3,5-
dicyano-6-sulfanyl pyridines
Scheme 3 Proposed reaction pathway for the synthesis of chromeno
[2,3-b]pyridines.
SnO nanoparticles (6 mol%) were added to a mixture of alde-
hyde (1 mmol) and malononitrile (2.2 mmol) in 5 mL ethanol
and the reaction mixture was stirred for 10 min at 60 ꢁC. Then,
the desired thiol (1 mmol) was added to the solution and the
solution was reuxed. Progress of the reaction was continuously
monitored by thin-layer chromatography. When the reaction
was completed, the mixture was cooled to room temperature
and centrifuged to separate the catalyst. The solvent was evap-
orated under vacuum and the solid obtained was recrystallized
from ethanol to afford the pure pyridines. The products were
characterized by IR, NMR analysis and elemental analysis.
reacts with 1 equiv. of malononitrile to form iminochromene
H. This compound undergoes addition with thiophenol to
afford phenylsulfanylchromene I. Finally, when I is treated
with another equivalent of malononitrile, chromenopyridine
P forms in good to excellent yield. Also, the in the present
reaction SnO NPs may play as Lewis solid acids. The
increased surface area due to small particle size increased
reactivity. So, we were encouraged to use SnO NPs in the
following optimization of the reaction conditions.
This exible and nano-catalytic procedure showed good
recyclability and provides cleaner condensation reaction in a
short reaction time and excellent yields. Nanoparticles
exhibit good catalytic activity due to their large surface area
and active sites which are mainly responsible for their cata-
lytic activity. These advances have opened the door for the
design of fresh nanocatalysts for particular applications in
synthetic chemistry.
3.4. General procedure for the preparation of chromeno[2,3-
b]pyridines
To a mixture of a selected salicylaldehyde (1.5 mmol), malo-
nonitrile (3 mmol) and a desired thiol (1.5 mmol) in 5 mL of
anhydrous ethanol was added SnO NPs (6 mmol%). The
resulting mixture was reuxed for 50–60 min and then allowed
to cool to room temperature. The formed precipitate was iso-
lated by ltration. The product was dissolved in DMF (3 mL) and
50674 | RSC Adv., 2014, 4, 50668–50677
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
the catalyst was ltered. Then, 4 mL water was added to the 7.8, 2H, Ar-H), 7.66–7.68 (d, J ¼ 7.6, 2H, Ar-H), 8.39–8.41 (d, J ¼
ltrate which resulted in the crystallization of the product. The 7.8, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d (ppm) 18.9, 86.8,
resulting crystalline structure was ltered and dried with a 96.2, 115.1, 116.9, 125.3, 131.3132.9, 134.1, 134.9, 135.5, 136.2,
vacuum pump. The structures of the products were fully 137.3, 156.1, 158.2165.1. MS (EI, 70 eV): m/z 387 (M+), anal. calcd
1
established on the basis of their H NMR, 13C NMR and FT-IR for C20H13N5O2S: C, 62.01; H, 3.38; N, 18.08%. Found: C, 61.83;
spectra.
H, 3.26; N, 18.15%.
2-Amino-4-phenyl-6-(p-tolylthio)pyridine-3,5-dicarbonitrile
(5f). Yellow solid, mp 248–250 ꢁC; FT-IR (KBr): (vmax/cmꢀ1):
3446, 3314, 2219, 1627, 1522; H NMR (400 MHz, DMSO-d6): d
3.5. Spectral data
1
2-Amino-4-(4-methoxyphenyl)-6-(p-tolylthio)pyridine-3,5- (ppm) 2.34 (s, 3H, CH3), 7.27 (d, J ¼ 7.9, 2H, Ar-H), 7.45 (d, 2H, J
dicarbonitrile (5a). Yellow solid, mp 229–231 ꢁC; FT-IR (KBr): ¼ 7.9, Ar-H), 7.49 (m, 5H, Ar-H), 7.80 (s, 2H, NH2); 13C NMR (100
1
(vmax/cmꢀ1): 3462, 3332, 2218, 1632, 1544; H NMR (400 MHz, MHz, DMSO-d6): d (ppm) 21.4, 87.2, 95.7, 114.8, 115.2, 123.5,
CDCl3): d (ppm) 2.43 (s, 3H, CH3), 3.88 (s, 3H, OCH3), 5.47 (s, 128.4, 129.9, 130.1, 130.9, 133.2, 135.6, 140.3, 158.3, 159.3,
2H, NH2), 7.04–7.06 (d, 2H, J ¼ 8 Hz, Ar-H), 7.28 (d, 2H, Ar-H), 169.5, MS (EI, 70 eV): m/z 342 (M+), HR MS calc. for C20H14N4S:
7.42 (d, 2H, J ¼ 7.8 Hz, ArH), 7.51–7.53 (d, 2H, J ¼ 8 Hz, ArH); 13
C
342.0939; found: 342.0949; anal. calcd for C20H14N4S: C, 70.15;
NMR (100 MHz, CDCl3): d (ppm) 21.4, 55.6, 87.1, 94.8, 114.3, H, 4.12; N, 16.36%. Found: C, 70.09; H, 4.21; N, 16.31%.
115.6, 124.1, 126.1, 130.3, 130.4, 135.3, 139.7, 158.2, 160.2,
161.2, 165.1, 167.4; MS (EI, 70 eV): m/z 372 (M+), anal. calcd for (5g). Colorless solid; mp 278–280 ꢁC, IR (KBr) (vmax/cmꢀ1): 3420,
21H16N4OS: C, 67.72; H, 4.33; N, 15.04%. Found: C, 67.62; H, 3339, 3219, 2214, 1621; 1H NMR (400 MHz, DMSO-d6): d (ppm) d
2-Amino-6-(phenylthio)-4-m-tolylpyridine-3,5-dicarbonitrile
C
4.39; N, 15.14%.
2.44 (s, 3H), 7.32–7.74 (m, 6H), 7.45–7.55 (m, 3H) 7.63 (s, 2H,
2-Amino-4-(4-methoxyphenyl)-6-(phenylthio)pyridine-3,5- NH2); 13C NMR (100 MHz, DMSO-d6): d (ppm) 15.1, 87.6, 94.1,
dicarbonitrile (5b). Yellow solid, mp 240–242 ꢁC; FT-IR (KBr): 115.9, 116.0, 126.0, 128.1, 129.7, 130.1, 130.3, 130.5, 131.3,
(vmax/cmꢀ1): 3438, 3329, 2217, 1640, 1545; H NMR (400 MHz, 132.2, 133.5, 135.6, 142.7, 158.6, 160.6. MS (EI, 70 eV): m/z 342
1
CDCl3): d (ppm) 3.86 (s, 3H, OCH3), 6.81 (s, 2H, NH2), 7.04 (d, (M+), anal. calcd for C20H14N4S: C, 70.15; H, 4.12; N, 16.36%.
2H, J ¼ 7.6 Hz, Ar-H), 7.42–7.51 (m, 5H, Ar-H), 7.54 (d, 2H, J ¼ Found: C, 70.18; H, 4.15; N, 16.32%.
7.6 Hz, Ar-H); 13C NMR (100 MHz, CDCl3): d (ppm) 55.5, 86.3,
2-Amino-6-phenylsulfanyl-4-p-tolyl-pyridine-3,5-dicarbonitrile
93.6, 114.2, 115.6, 129.3, 129.6, 130.8, 131.1, 133.2, 135.7, 157.6, (5h). Colourless solid, mp 206–207 ꢁC, IR (KBr) (vmax/cmꢀ1): 3441,
158.9, 159.9, 161.4, 166.9; MS (EI, 70 eV): m/z 358 (M+), anal. 3339, 3216, 2214, 1627, 1544, 1522, 1265; 1H NMR (400 MHz,
calcd for C20H14N4OS: C, 67.02, H, 3.94; N, 15.63%. Found: C, DMSO-d6): d (ppm) 2.52 (s, 3H), 7.33–7.75 (m, 6H), 7.46–7.55 (m,
67.11; H, 3.85; N, 15.52%.
3H), 7.63 (s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6): d (ppm)
2-Amino-4-(3-nitrophenyl)-6-(phenylsulfanyl)-3,5-pyridine 14.9, 87.6, 94.1, 115.9, 116.0, 126.0, 126.2, 128.1, 129.7, 130.1,
dicarbonitrile (5c). Yellow solid, mp 218–220 ꢁC; FT-IR (KBr): 130.3, 130.5, 135.6, 142.7, 158.6, 160.6. MS (EI, 70 eV): m/z 342
(vmax/cmꢀ1): 3447, 3315, 2218, 1626, 1523, 1349; H NMR (400 (M+), anal. calcd for C20H14N4S: C, 70.15; H, 4.12; N, 16.36%.
1
MHz, CDCl3): d (ppm) 5.38 (s, 2H, NH2), 7.50–7.57 (m, 5H, Ar-H), Found: C, 70.17; H, 4.18; H, 16.39%.
7.38–7.72 (m, 3H, Ar-H), 8.44 (s, 1H, ArH); 13C NMR (100 MHz,
2-Amino-4-(4-chlorophenyl)-6-phenylsulfanylpyridine-3,5-
CDCl3): d (ppm) 87.4, 95.9, 114.8, 115.2, 127.1, 128.4, 129.3, dicarbonitrile (5i). Colourless solid, mp 221–222 ꢁC, IR (KBr)
129.9, 131.2, 133.2, 135.8, 136.1, 137.2, 158.4, 159.3, 164.1, (vmax/cmꢀ1): 3487, 3344, 3222, 2926, 2214, 1633, 1545; 1H NMR
169.5; MS (EI, 70 eV): m/z 373 (M+), HR MS calc. for (400 MHz, DMSO-d6): d (ppm) 7.45–7.50 (m, 3H, Ar-H), 7.57 (d,
C
C
19H11N5O2S: 373.0633, found: 373.0631; anal. calcd for 2H, J ¼ 8.0 Hz, Ar-H), 7.59 (d, 2H, J ¼ 8.0 Hz, Ar-H), 7.64 (d, 2H, J
19H11N5O2S: C, 61.12; H, 2.97; N, 18.76%. Found: C, 61.21; H, ¼ 8.0 Hz, Ar-H) 7.83 (s, 2H, NH2); 13C NMR (100 MHz, DMSO-
2.91; N, 18.68%.
d6): d (ppm) 87.5, 93.7, 115.2, 115.5, 127.3, 129.2, 129.5, 129.8,
2-Amino-4-(4-chlorophenyl)-6-((4-methoxybenzyl)thio)-3,5- 130.8, 133.1, 135.2, 135.7, 157.8, 159.9, 166.6. MS (EI, 70 eV): m/z
pyridinedicarbonitrile (5d). Yellow solid, mp 237–239 ꢁC; FT-IR 362 (M+), HRMS m/z (ESI) calcd for C19H12N4SCl (M + H)+
(KBr): (vmax/cmꢀ1): 3322, 2214, 1626, 1543, 1482, 1243; 1H NMR 363.0471, found 363.0481. Anal. calcd for C19H11ClN4S: C,
(400 MHz, DMSO-d6): d (ppm) 3.71 (s, 3H, OCH3), 4.43 (s, 2H, 62.89; H, 3.06; N, 15.44%. Found: C, 62.85; H, 3.11; N, 15.48%.
CH2), 6.84–6.86 (d, J ¼ 8.4, 2H, Ar-H), 7.41–7.43 (d, J ¼ 8.2, 2H,
2-Amino-4-(4-hydroxy-phenyl)-6-phenylsulfanyl-pyridine-3,5-
Ar-H), 7.54–7.56 (d, J ¼ 8.4, 2H, Ar-H), 7.61–7.63 (d, J ¼ 8.2, 2H, dicarbonitrile (5j). Colourless solid, mp 315–317 ꢁC, IR (KBr)
Ar-H), 8.06 (s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6): d (ppm) (vmax/cmꢀ1): 3648, 3498, 3367, 3237, 2222, 2217, 1632; 1H NMR
33.3, 55.5, 86.3, 93.6, 114.2, 114.9, 115.6, 129.3, 129.6, 130.8, (400 MHz, DMSO-d6): d (ppm) d 6.94 (d, J ¼ 8.5 Hz, 2H), 7.39 (d, J
131.1, 133.2, 135.7, 157.6, 158.9, 159.9, 169.8; MS (EI, 70 eV): m/z ¼ 8.5 Hz, 2H), 7.52 (m, 3H), 7.60 (m, 2H), 7.69 (s, 2H), 10.05 (bs,
406 (M+), anal. calcd for C21H15ClN4OS: C, 61.99; H, 3.72; N, 1H, OH); 13C NMR (100 MHz, DMSO-d6): d (ppm) 93.7, 96.9,
13.77%. Found: C, 61.83; H, 3.80; N, 13.86%.
115.6, 115.9, 116.0, 124.5, 127.5, 129.8, 130.1, 130.7, 135.2,
2-Amino-4-(4-nitrophenyl)-6-(p-tolylthio)pyridine-3,5-dicar- 159.1, 159.8, 160.3, 166.5; MS (EI, 70 eV): m/z 344 (M+), anal.
bonitrile (5e). Yellow solid, mp 301–303 ꢁC; FT-IR (KBr): calcd for C19H12N4OS: C, 66.26; H, 3.51; N, 16.27%. Found: C,
(vmax/cmꢀ1): 3472, 3332, 3218, 2215, 1626, 1541, 1509, 1344, 66.10; H, 3.62; N, 16.22%.
1262; 1H NMR (400 MHz, CDCl3): d (ppm) 2.40 (s, 3H, CH3), 5.50
2-Amino-4-(4-nitro-phenyl)-6-phenylsulfanyl-pyridine-3,5-
(s, 2H, NH2), 7.26–7.28 (d, J ¼ 7.6, 2H, Ar-H), 7.43–7.45 (d, J ¼ dicarbonitrile (5k). Colourless solid, mp 289–290 ꢁC, IR (KBr)
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 50668–50677 | 50675

View Article Online
RSC Advances
Paper
(vmax/cmꢀ1): 3407, 3328, 3235, 2228, 2214, 1645, 1555; 1H NMR Hz), 7.17 (t, 1H, J ¼ 8 Hz), 7.24 (s, 1H), 7.31 (t, 2H, J ¼ 8 Hz); 13
C
(400 MHz, DMSO-d6): d (ppm) 7.47–7.49 (m, 3H), 7.56–7.59 (m, NMR (100 MHz, DMSO-d6): d (ppm) 25.9, 36.03, 71.0, 87.9,
2H), 7.85 (d, J ¼ 8.5 Hz, 2H), 7.91 (s, 2H, NH2), 8.39 (d, J ¼ 8.5 107.8, 111.0, 116.5, 116.9, 129.0, 129.7, 133.8, 142.7, 149.4,
Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d (ppm) 87.2, 93.3, 151.2, 157.1, 160.03, 160.10. MS (EI, 70 eV): m/z 350 (M+), HRMS
114.9, 115.3, 124.2, 127.2, 129.8, 130.1, 130.5, 135.1, 140.5, m/z (ESI) calcd for C18H15N4O2S (M + H)+ 351.0915, found
148.9, 157.0, 159.8, 166.5; MS (EI, 70 eV): m/z 373 (M+), anal. 351.0913. Anal. calcd for C18H14N4O2S: C, 61.70; H, 4.03; N,
calcd for C19H11N5O2S: C, 61.12; H, 2.97; N, 18.76%. Found: C, 15.99%. Found C, 61.62; H, 4.10; N, 15.91%.
61.05; H, 2.78; N, 18.91%.
2,4-Diamino-5-(benzylthio)-7-bromo-5H-chromeno[2,3-b]-
2-Amino-4-(4-bromophenyl)-6-phenylsulphanylpyridine-3,5- pyridine-3-carbonitrile (6e). Yellow solid, mp 206–208 ꢁC, IR
dicarbonitrile (5l). Colourless solid, mp 255–257 ꢁC; IR (KBr) (KBr) (vmax/cmꢀ1): 3315, 3441, 2189, 1403, 1653; H NMR (400
1
(vmax/cmꢀ1): 3442, 3338, 3222, 2219, 1629, 1555, 1531, 1459; 1H MHz, DMSO-d6) d 4.06–4.45 (ABq, 2H, J ¼ 12 Hz), 4.67 (1H), 6.48
NMR (400 MHz, DMSO-d6): d (ppm) 7.54–7.62 (m, 5H), 7.80–7.82 (s, 1H), 6.88–6.90 (m, 5H), 7.37 (m, 6H); 13C NMR (100 MHz,
(m, 4H), 7.87 (s, 2H, NH2); 13C NMR (100 MHz, DMSO-d6): d DMSO-d6) d (ppm) 33.34, 35.78, 71.21 87.22, 116.46, 118.79,
(ppm) 85.6, 92.1, 113.5, 113.4, 120.6, 125.9, 127.1, 128.0, 129.5, 120.90, 121.60, 124.41, 128.60, 129.79, 131.05, 137.53, 137.96,
131.9, 133.5, 134.3, 158.3, 159.8, 166.5; MS (EI, 70 eV): m/z 405 148.22, 152.75, 160.44, 160.80. MS (EI, 70 eV): m/z 439 (M+),
(M+), HRMS calc. for C19H11BrN4S: 405.9888, found: 405.9885. anal. calcd for C20H15N4OSBr: C, 54.68; H, 3.44; N, 12.75%.
Anal. calcd for C19H11BrN4S: C, 56.03; H, 2.72; N, 13.76%. Found C, 54.55; H, 3.52; N, 12.61%.
Found: C, 56.08; H, 2.78; N, 13.68%.
5-((Furan-2-yl)methylthio)-2,4-diamino-7-bromo-5H-chrom-
2,4-Diamino-5-phenylsulfanyl-5H-chromeno[2,3-b]pyridine- eno[2,3-b]pyridine-3-carbonitrile (6f). Yellow solid, mp 225–
1
3-carbonitrile (6a). Yellow solid, mp 220–222 ꢁC, IR (KBr) 227 C, IR (KBr) (vmax/cmꢀ1): 3311, 3442, 2194, 1404, 1655; H
ꢁ
(vmax/cmꢀ1): 3355, 3429, 2203, 1400–1623; H NMR (400 MHz, NMR (400 MHz, DMSO-d6) d 4.14–4.56 (ABq, 2H, J ¼ 12 Hz), 4.89
1
DMSO-d6): d 5.73 (s, 1H), 6.50 (2H, s), 6.74–6.78 (3H, m), 6.94 (s, (1H), 6.34 (s, 1H), 6.46 (d, J ¼ 8.3 Hz, 1H), 6.78–6.95 (m, 6H),
2H), 7.05–7.11 (3H, m), 7.15–7.30 (m, 3H); 13C NMR (100 MHz, 7.39 (d, 1H, J ¼ 9 Hz), 7.62 (d, 1H); 13C NMR (100 MHz, DMSO-
DMSO-d6): d (ppm) 43.12, 70.8, 86.90, 116.01, 116.5, 121.5, d6) d (ppm) 28.64, 36.31, 54.27, 84.86, 108.77, 111.49, 116.50,
123.9, 128.60, 128.64, 129.50, 129.70, 134.2, 137.7, 150.90, 118.87, 119.41, 124.14, 125.50, 131.12, 131.89, 143.26, 148.21,
156.40, 159.7, 160.90. MS (EI, 70 eV): m/z 346 (M+), HRMS m/z 150.72, 155.24, 160.5. MS (EI, 70 eV): m/z 427, 429 (M+), anal.
(ESI) calcd for C19H15N4OS (M + H)+ 347.0966, found 347.0958. calcd for C18H13N4O2SBr: C, 50.39; H, 3.05; N, 13.06%. Found C,
Anal. calcd for C19H14N4OS: C, 65.88; H, 4.074; N, 16.17%. 50.35; H, 2.97; N, 13.01%.
Found C, 65.82; H, 4.09; N, 16.07%.
2,4-Diamino-5-(4-methylphenylsulfanyl)-5H-chromeno[2,3-b]-
4. Conclusions
pyridine-3-carbonitrile (6b). Yellow solid, mp 223–225 ꢁC; IR
1
(KBr) (vmax/cmꢀ1): 3457, 3349, 2198, 1400–1623; H NMR (400 In conclusion, we have developed a exible, green and highly
MHz, DMSO-d6): d 2.19 (s, 3H), 5.66 (s, 1H), 6.46 (br s, 2H), 6.61 efficient protocol for the synthesis of chromeno[2,3-b]pyridines
(d, J ¼ 7.9 Hz, 2H), 6.79 (d, J ¼ 7.9 Hz, 1H), 6.90 (m, 4H), 7.11; (d, J and 2-amino-3,5-dicyano-6-sulfanyl pyridines using SnO nano-
¼ 6.8 Hz, 1H), 7.19 (d, J ¼ 7.3 Hz, 2H); 13C NMR (100 MHz, particles under reux conditions in ethanol. These heterocyclic
DMSO-d6): d (ppm) 21.2, 43.11, 70.8, 86.3, 115.7, 116.4, 121.8, compounds will provide promising candidates for chemical
123.6, 127.0, 128.2, 128.6, 129.8, 136.9, 138.3, 151.33, 156.3, biology and drug discovery. The advantages offered by this
160.08, 160.25 MS (EI, 70 eV): m/z 360 (M+), HR MS ESI [M + H]+ method include, easy workup, the employment of a cost-effec-
calcd for C20H17N4OS 361.1123; found 361.1132. Anal. calcd for tive catalyst, short reaction times, excellent yields and the use of
C20H16N4OS: C, 66.64; H, 4.47; N, 15.54%. Found C, 66.59; H, ethanol as a solvent that is considered to be relatively environ-
4.51; N, 15.48%.
mentally benign.
2,4-Diamino-5(benzylthio)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile (6c). Yellow solid, mp 175–177 ꢁC; IR (KBr)
Acknowledgements
1
(vmax/cmꢀ1): 3377, 3439, 2200, 1400, 1605; H NMR (400 MHz,
DMSO-d6): d 3.49 (ABq, 2H, J ¼ 12 Hz), 5.48 (1H), 6.55 (bs, 2H), The authors acknowledge a reviewer who provided helpful
6.83 (bs, 2H), 7.03–7.21 (m, 7H), 7.33 (m, 2H); 13C NMR (100 insights. The authors are grateful to University of Kashan for
MHz, DMSO-d6): d (ppm) 35.02, 44.01, 70.90, 87.01, 117.6, 118.3, supporting this work by Grant no.: 159196/XXI.
119.3, 122.8, 124.2, 124.3, 129.6, 133.2, 133.3, 136.6, 143.7,
152.9, 159.9, 160.2. MS (EI, 70 eV): m/z 360 (M+), HRMS m/z (ESI)
References
calcd for C20H17N4OS (M + H)+ 361.1123, found 361.1129. Anal.
calcd for C20H16N4OS: C, 66.64; H, 4.47; N, 15.54%. Found C,
66.48; H, 4.58; N, 15.39%.
1 S. B. Levy, M. N. Alekshun, B. L. Podlogar, K. Ohemeng,
A. K. Verma, T. Warchol, B. Bhatia, T. Bowser and
M. Grier, Substituted benzoimidazole compounds as
transcription factor-modulating compounds useful as anti-
infectives, US Patent Appl. 2005124678 A120050609, 2005.
2 M. T. Cocco, C. Congiu, V. Lilliu and V. Onnis, Bioorg. Med.
Chem., 2007, 15, 1859–1867.
5-((Furan-2-yl)methylthio)-2,4-diamino-5H-chromeno[2,3-b]-
pyridine-3-carbonitrile (6d). Yellow solid, mp 200–201 ꢁC; IR
1
(KBr) (vmax/cmꢀ1): 3386, 3440, 2203, 1397, 1612; H NMR (400
MHz, DMSO-d6): d 3.51 (ABq, 2H, J ¼ 12 Hz), 5.46 (1H), 5.99
(1H), 6.23 (s, 1H), 6.55 (bs, 2H), 6.79 (bs, 2H), 7.10 (d, 1H, J ¼ 8
50676 | RSC Adv., 2014, 4, 50668–50677
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
3 T. R. K. Reddy, R. Mutter, W. Heal, K. Guo, V. J. Gillet, S. Pratt 18 D. R. Anderson, S. Hegde, E. Reinhard, L. Gomez,
and B. Chen, J. Med. Chem., 2006, 49, 607–615.
W. F. Vernier, L. Lee, S. Liu, A. Sambandam, P. A. Snider
4 H. Harada, S. Watanuk, T. Takuwa, K. Kawaguchi,
and L. Masih, Bioorg. Med. Chem. Lett., 2005, 15, 1587–1590.
T. Okazaki, Y. Hirano and C. Saitoh, PCT Int. Appl. WO 19 J. A. Bristol, E. H. Gold, I. Gross, R. G. Lovey and J. F. Long, J.
Patent 2002006237 A1 20020124, 2002. Med. Chem., 1981, 24, 1010–1013.
5 T. Murata, M. Shimada, S. Sakakibara, T. Yoshino, 20 J.-P. Wan and Y. Liu, RSC Adv., 2012, 2, 9763–9777.
H. Kadono, T. Masuda, M. Shimazaki, T. Shintani, 21 M. S. Singh and S. Chowdhury, RSC Adv., 2012, 2, 4547–4592.
K. Fuchikami, K. Sakai, H. Inbe, K. Takeshita, T. Niki, 22 F. Yu, R. Huang, H. Ni, J. Fan, S. Yan and J. Lin, Green Chem.,
M. Umeda, K. B. Bacon, K. B. Ziegelbauer and
T. B. Lowinger, Bioorg. Med. Chem. Lett., 2003, 13, 913.
6 J. Deng, T. Sanchez, L. Q. Al-Mawsawi, R. Dayam, R. A. Yunes,
2013, 15, 453–462.
23 A. R. Kiasat and J. Davarpanah, J. Mol. Catal. A: Chem., 2013,
373, 46–54.
A. Garofalo, M. B. Bolger and N. Neamati, Bioorg. Med. 24 H. R. Shaterian, M. Ghashang and M. Feyzi, Appl. Catal., A,
Chem., 2007, 15, 4985. 2008, 345, 128–133.
7 H. Chen, W. Zhang, R. Tam and A. K. Raney, PCT Int. Appl. 25 M. Sridhar, B. C. Ramanaiah, C. Narsaiah, B. Mahesh,
WO2005058315 A1 20050630, 2005.
8 M. W. Beukers, L. C. W. Chang, J. K. F. D. Kunzel, T. Mulder-
M. Kumaraswamy, K. K. R. Mallu, V. M. Ankathi and
P. S. Rao, Tetrahedron Lett., 2009, 50, 3897–3900.
¨
Krieger, R. F. Spanjersberg, J. Brussee and A. P. Ijzerman, J. 26 J. Safaei-Ghomi and M. A. Ghasemzadeh, J. Sulfur Chem.,
Med. Chem., 2004, 47, 3707–3709. 2013, 34, 233–241.
9 L. C. W. Chang, J. K. Kunzel, T. Mulder-Krieger, 27 J. Safaei-Ghomi, M. Kiani, A. Ziarati and H. Shahbazi-Alavi, J.
R. F. Spanjersberg, S. F. Roerink, G. Van Den Hout, Sulfur Chem., 2014, 35, 450–457.
M. W. Beukers, J. Brussee and A. P. Ijzerman, J. Med. 28 K. Tanabe, Solid acids and bases, Academic Press, New York,
Chem., 2004, 48, 2045–2053. 1970.
10 B. B. Fredholm, A. P. Ijzerman, K. A. Jacobson and 29 M. Kidwai, A. Jain and S. Bhardwaj, Mol. Diversity, 2012, 16,
K.-N. Klotz, Pharmacol. Rev., 2001, 53, 527–552. 121–128.
11 S. K. Srivastava, R. P. Tripathi and R. Ramachandran, J. Biol. 30 S. Banerjee, A. Horn, H. Khatri and G. Sereda, Tetrahedron
Chem., 2005, 280, 30273–30281. Lett., 2011, 52, 1878–1881.
12 G. Kolokythas, N. Pouli, P. Marakos, H. Pratsinis and 31 A. Maleki, Tetrahedron, 2012, 68, 7827–7833.
¨
D. Kletsas, Eur. J. Med. Chem., 2006, 41, 71–79.
13 Y. Maruyama, K. Goto and M. Terasawa, Ger. Offen. DE
Patent 3010751 19810806, 1981.
14 M. A. Azuine, H. Tokuda, J. Takayasu, F. Enjyo,
T. Mukainaka, T. Konoshima, H. Nishino and G. Kapadia,
J. Pharmacol. Res., 2004, 49, 161–169.
15 S. Toshiro and W. Noriko, Eur. Pat. Appl. EP647445 A1
19950412, 1995.
16 Y. Ito, H. Kato, S. Yasuda, N. Kato, N. Iwasaki and
32 A. I. Ahmed, S. A. El-Hakam, M. A. A. Elghany and W. S. A. El-
Yazeed, Appl. Catal., A, 2011, 407, 40–48.
33 N. M. Evdokimov, A. S. Kireev, A. A. Yakovenko,
M. Y. Antipin, I. V. Magedov and A. Kornienko,
Tetrahedron Lett., 2006, 47, 9309–9312.
34 S. Mishra and R. Ghosh, Synth. Commun., 2012, 42, 2229–
2244.
35 M. H. M. Ara, P. Boroojerdian, Z. Javadi, S. Zahedi and
M. Morshadian, Micro Nano Lett., 2011, 6, 249–252.
H. Nishino, M. Takeshita, Jpn. Kokai Tokkyo Koho JP 36 R. Mamgain, R. Singh and D. S. Rawat, J. Heterocycl. Chem.,
06107664 A2 19940419, 1994. 2009, 46, 69–73.
17 K. Ukawa, T. Ishiguro, H. Kuriki and A. Nohara, Chem. 37 P. V. Shinde, V. B. Labade, B. B. Shingate and M. S. Shingare,
Pharm. Bull., 1985, 33, 4432–4437.
J. Mol. Catal. A: Chem., 2011, 336, 100–105.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 50668–50677 | 50677