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Scientia Iranica C (2013) 20 (3), 549554

Sharif University of Technology


Scientia Iranica
Transactions C: Chemistry and Chemical Engineering
www.sciencedirect.com

Calcium oxide nanoparticles catalyzed one-step multicomponent


synthesis of highly substituted pyridines in aqueous ethanol media
J. Safaei-Ghomi a, , M.A. Ghasemzadeh a , M. Mehrabi b
a
b

Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, P.O. Box 87317-51167, Islamic Republic of Iran
Institute of Nano Science and Nano Technology, University of Kashan, Kashan, P. O. Box. 8731751167, Islamic Republic of Iran

Received 27 April 2012; revised 29 September 2012; accepted 23 December 2012

KEYWORDS
Multicomponent reactions;
Nanoparticles;
Calcium oxide;
Poly functionalized
pyridines;
Heterogeneous catalyst;
One-pot.

Abstract An efficient one-pot three-component condensation of aldehydes, thiols and malononitrile


has been developed in the presence of calcium oxide nanoparticles. Highly substituted pyridines as
privileged medicinal scaffolds have been efficiently prepared via carboncarbon and carbonheteroatom
bond formation. This method provides a novel and improved approach for the synthesis of 2-amino-4-aryl3,5-dicyano-6-sulfanylpyridines in terms of excellent yields, short reaction times, reusability and little
catalyst loading.
2013 Sharif University of Technology. Production and hosting by Elsevier B.V.
Open access under CC BY-NC-ND license.

1. Introduction
Multicomponent reactions (MCRs) are special types of synthetically useful organic reactions, in which three or more
various substrates react to give a final product in a one-pot
procedure [1]. Clearly, for multi-step synthetic pathways, a
number of reactions and purification steps are the most important criteria for the efficiency and ability of the process, and
should be as low as possible [2]. MCRs are powerful devices in
novel drug discovery procedures and allow the fast, automated
and high-throughput generation of organic compounds [3]. The
formation of CN, CO and CS bonds by MCRs is usual in numerous compounds with pharmaceutical, biological and material properties [4].
Because of significant biological and physiological activities, synthesis of pyridines has attracted much attention

Corresponding author. Tel.: +98 361 5912385; fax: +98 361 5912397.
E-mail address: safaei@kashanu.ac.ir (J. Safaei-Ghomi).
Peer review under responsibility of Sharif University of Technology.

in recent years [57]. Polyfunctionalized pyridine derivatives, known as medicinally privileged scaffolds, can inhibit
MAPK-activated PK-26 [8] and modulate androgen receptor
functions [9]. Among them, 2-amino-3,5-dicyano-6-sulfanyl
pyridines, in particular serve as a privileged scaffold due to
their potential therapeutic applications in the treatment of urinary incontinence [10], HBF infections [11], Creutzfeldt-Jacob
disease, Parkinsons disease, hypoxia/ischemia, asthma, kidney disease, epilepsy and cancer [1214]. Also, a 2-amino3,5-dicyano-6-sulfanyl pyridines skeleton is often used as an
anti-prion [15], anti-hepatitis B virus and anti-bacterial [16].
Consequently, synthesis of highly functionalized pyridine
derivatives, with the aim of developing new drug molecules,
has been an active area of research. Recently, much attention has been paid to the development of new methodologies for the preparation of pyridines. The synthetic routes for
preparation of substituted pyridines, mainly, are the Mannich
reaction of iminium salts and aldehydes [17], azaelectrocyclization of azatrienes [18], conversion of ketene dithioacetals
to substituted pyridines [19], reaction of 3-siloxy-1-aza1,3-butadiens and 2H-1,4-oxazinones with acetylenes [20],
conversion of conjugated oximes under Vilsmeier conditions [21], cycloisomerization of 3-azadienynes [22], VilsmeierHaack reaction of -hydroxyketenedithioacetals [23], and
the Diels-Alder cycloadditions of oximinosulfonates [24]. One

1026-3098 2013 Sharif University of Technology. Production and hosting by Elsevier B.V. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.scient.2012.12.037

550

J. Safaei-Ghomi et al. / Scientia Iranica, Transactions C: Chemistry and Chemical Engineering 20 (2013) 549554

Scheme 1: Synthesis of highly substituted pyridine derivatives catalyzed by


CaO nanoparticles.

of the most attractive ways for the synthesis of these


compounds involves the cyclocondensation of aldehydes,
malononitrile and thiols. Generally, this method has been
carried out under basic conditions using various bases, such as:
Et3 N, DABCO, piperidine, morpholine, thiomorpholine, pyrrolidine, N,N-DIPEA, pyridine, 2,4,6-collidine, DMAP, aniline,
N-methylaniline, N,N-dimethylaniline and N,N-diethylaniline
[25,26]. The preparation of pyridines has been reported in
the presence of [bmim]OH [27], KF/alumina [28], DBU [29],
TBAH [30], ZnCl2 [31], microporous molecular sieves [32] and
boric acid [33]. Moreover, some heterogeneous nanocatalysts,
such as silica nanoparticles [34] and magnesium oxide nanoparticles [35], have been used in the synthesis of poly functionalized pyridine derivatives.
The last decade has witnessed enormous development in
the field of nanoscience and nanotechnology. Several reports
show the amazing level of the performance of nanoparticles
as catalysts in terms of selectivity, reactivity and improved
yields of products. In addition, the high surface-to-volume ratio
of nanoparticles provides a larger number of active sites per
unit area, in comparison with their heterogeneous counter sites
[36,37].
Among various nanoparticles, calcium oxide nanoparticles
have received considerable attention because of their unusual
properties and potential applications in diverse fields [38].
Calcium oxide (CaO), in particular, being cheap, has a high
basicity, and is non-corrosive, economically benign and easy
to handle compared to homogeneous base catalysts. Also, they
require only mild reaction conditions to produce high yields of
products in short reaction times, in comparison with traditional
catalysts, and can also be recycled [3941]. Recently, calcium
oxide nanoparticles were used as an active catalyst in many
chemical transformations such as: adsorption of Cr (VI) from
aqueous solutions [42], transesterification of sun flower oil [43],
removal of toxic heavy metal ions in water [44], artificial
photosynthesis [45] and transesterification of palm oil [46].
In accordance with the above mentioned significance of
nanoparticles in catalysis, and the importance of highly
substituted pyridines as privileged medicinal scaffolds, herein,
we wish to report a novel, green and mild method for the
synthesis of 2-amino-3,5-dicyano-6-sulfanyl pyridines 4 via
multicomponent coupling of aldehydes 1, malononitrile 2 and
thiols 3, using CaO nanoparticles (CaO NPs) in aqueous ethanol
media (Scheme 1). Calcium oxide nanoparticles, as an efficient,
non-explosive, eco-friendly, non-volatile, recyclable and easy to
handle catalyst, can be used in the catalysis of many organic
transformations.
2. Experimental
2.1. Material and methods
Chemicals were purchased from the Sigma-Aldrich and
Merck in high purity. All the materials were of commercial
reagent grade and were used without further purification.
Calcium oxide nanoparticles were prepared in accordance with

the procedure reported by Tang et al. [47]. All melting points


are uncorrected and were determined in capillary tubes on a
Boetius melting point microscope. 1 H NMR and 13 C NMR spectra
were obtained on a Bruker 400 MHz spectrometer, with CDCl3
as the solvent. Using tetramethylsilane (TMS) as an internal
standard, the chemical shift values are in . The FT-IR spectrum
was recorded on a Magna-IR, spectrometer, 550 Nicolet, in
KBr pellets, in the range of 4004000 cm1 . The elemental
analyses (C, H, N) were obtained from a Carlo ERBA Model EA
1108 analyzer. Powder X-ray diffraction (XRD) was carried out
on a Philips diffractometer of the Xpert Company with mono
chromatized Cu K radiation ( = 1.5406 ). The microscopic
morphology of products was visualized by SEM (LEO 1455VP).
2.2. Preparation of CaO nanoparticles
NaOH (1 g) was added to a mixture of ethylene glycol (12 ml)
and Ca(NO3 )2 . 4H2 O (6 g) and the solution stirred vigorously
at room temperature for 10 min; the gel solution was kept
about 5 h at static state. Afterwards, it was washed using
water and dried under vacuum drying. Finally, the prepared CaO
nanoparticles were calcinated at 700 C for 3 h.
2.3. Typical procedure for the sysnthesis of 2-amino-3,5-dicyano6-sulfanyl pyridines (4a4o)
To a mixture of aldehyde (1 mmol), malononitrile (0.145 g,
2.2 mmol), in 2.5 mL ethanol and 2.5 mL of water, was added
CaO nanoparticles (0.01 g, 0.2 mmol, 20 mmol%), and the
reaction mixture was stirred for 10 min at 50 C. Then, the
desired thiol (1 mmol) was added and the solution was refluxed.
Progress of the reaction was continuously monitored by TLC.
When the reaction was complete, the mixture was cooled to
room temperature and then was centrifuged to separate the
catalyst. The solvent was evaporated under vacuum and the
solid obtained was recrystallised from EtOH to afford pure
pyridines.
2.4. Spectral data of the new products
2-Amino-4-(3-hydroxyphenyl)-6-(phenylsulfanyl)-3,
5-pyridinedicarbonitrile (4d)
White solid; mp 265 C; IR (KBr) v : 3445, 3366, 3211, 2213,
1622, 1575, 1536, 1483, 1255, cm1 ; 1 H NMR (CDCl3 , 400 MHz)
: 5.42 (s, 2H, NH2 ), 7.05 (s, 1H, Ar-H), 7.237.25 (m, 3H, ArH), 7.487.53 (m, 3H, Ar-H), 7.577.59 (m, 2H, Ar-H), 10.51 (bs,
1H, OH); 13 C NMR (CDCl3 , 100 MHz) : 87.8, 94.2, 113.1, 115.3,
127.2, 129.1, 129.8, 130.7, 132.1, 133.5, 134.1, 135.8, 136.6,
157.1, 161.8, 164.5, 168.2.; Anal. Calcd for C19 H12 N4 OS : C,
66.26; H, 3.5; N, 16.27%. Found: C, 66.52; H, 3.42; N, 16.08%.
2-Amino-4-(4-methylphenyl)-6-(4-methylphenylsulfanyl)3,5-pyridinedicarbonitrile (4l)
Colorless solid; mp 222C; IR (KBr) v : 3442, 3357, 3198,
2211, 1616, 1572, 1533, 1481, 1252, cm1 ; 1 H NMR (CDCl3 ,
400 MHz) : 2.41 (s, 3H, CH3 ), 2.11 (s, 3H, CH3 ), 5.44 (s, 2H,
NH2 ), 7.257.36 (m, 4H, Ar-H), 7.417.59 (m, 4H, Ar-H); 13 C
NMR (CDCl3 , 100 MHz) : 15.7, 17.1, 86.1, 96.3, 114.2, 115.5,
126.6, 129.1, 129.2, 129.7, 130.1, 131.4, 131.8, 134.6, 135.2,
136.1, 156.2, 158.9, 167.6.; Anal. Calcd for C21 H16 N4 S : C, 70.76;
H, 4.52;, 15.72%. Found: C, 70.52; H, 4.65; N, 15.84%.
2-Amino-4-(4-nitrophenyl)-6-(4-methylphenylsulfanyl)-3,
5-pyridinedicarbonitrile (4n)
Yellow solid; mp 301C; IR (KBr) v : 3472, 3332, 3218, 2215,
1626, 1541, 1509, 13.44, 1262, cm1 ; 1 H NMR (CDCl3 , 400 MHz)

J. Safaei-Ghomi et al. / Scientia Iranica, Transactions C: Chemistry and Chemical Engineering 20 (2013) 549554

551

Figure 1: SEM images of CaO NPs.

Figure 2: The XRD patern of CaO nanoparticles.

: 2.40 (s, 3H, CH3 ), 5.50 (s, 2H, NH2 ), 7.267.28 (d, J = 7.8 Hz,
2H, Ar-H), 7.437.45 (d, J = 8 Hz, 2H, Ar-H), 7.667.68 (d, J =
7.8 Hz, 2H, Ar-H), 8.39-8.41 (d, J = 8 Hz, 2H, Ar-H); 13 C NMR
(CDCl3 , 100 MHz) : 18.9, 86.8, 96.2, 115.1, 116.9, 125.3, 131.3,
132.9, 134.1, 134.9, 135.5, 136.2, 137.3, 156.1, 158.2, 165.1.;
Anal. Calcd for C20 H13 N5 O2 S : C, 62.01; H, 3.38; N, 18.08%.
Found: C, 61.85; H, 3.26; N, 18.16%.
2-Amino-4-(4-cyanophenyl)-6-(4-methylphenylsulfanyl)3,5-pyridinedicarbonitrile (4o)
White solid; mp 272 C; IR (KBr) v : 3479, 3352, 3215, 2218,
1634, 1551, 1498, 1256, cm1 ; 1 H NMR (CDCl3 , 400 MHz) :
2.41 (s, 3H, CH3 ), 5.50 (s, 2H, NH2 ), 7.287.30 (d, J = 8 Hz, 2H,
Ar-H), 7.377.51 (m, 4H, Ar-H), 7.717.73 (d, J = 8 Hz, 2H, ArH); 13 C NMR (CDCl3 , 100 MHz) : 87.2, 94.5, 114.9, 115.8, 128.1,
130.5, 131.5, 133.8, 134.1, 134.4, 135.7, 136.5, 155.4, 156.3,
165.1.; Anal. Calcd for C21 H13 N5 S : C, 68.65; H, 3.57; N, 19.06%.
Found: C: 68.78; H, 3.44; N, 18.95%.
3. Results and discussion
Initially, in order to investigate the morphology and particle
size of prepared CaO nanoparticles, a SEM image of CaO NPs is
presented in Figure 1. These results show that spherical calcium
oxide nanoparticles were obtained with particle size 3040 nm
using the thermal-decomposition method.
The XRD pattern of CaO nanoparticles has been shown in
Figure 2. All reflection peaks in Figure 2 can be readily indexed
to a pure cubic phase of CaO with a Fm-3m space group (JCDPS
No. 77-2376). The crystallite size diameter (D) of the CaO NPs
has been calculated by the DebyeScherrer equation (D =
K/ cos ), where FWHM (full-width at half-maximum or
half-width) is in radian and is the position of the maximum
of the diffraction peak. K is the so-called shape factor, which
usually takes a value of about 0.9, and is the X-ray wavelength
(1.5406 for Cu K ). The average crystallite size of CaO has been
found to be 35 nm.

Figure 3: FT-IR spectrum of CaO nanoparticles.

Scheme 2: The model reaction for the preparation of poly functionalized


pyridines.

Figure 3 shows the FT-IR spectrum of CaO nanoparticles.


The broad peak at 3431 cm1 can be attributed to the
(OH) stretching vibration. These peaks indicate the presence of
physisorbed water linked to nanoparticles.
In continuation of this research, the reaction conditions were
optimized on the basis of the catalyst, solvent and reactants for
carboncarbon and carbonheteroatom bond formation. To test
the efficiency of the catalytic activity, we chose to focus our
initial studies on the cyclization reaction of aldehydes, thiols
and malononitrile in the presence of different nanocatalysts
such as CuO, Mn3 O4 , MgO, NiO, SiO2 , CaO and also in the
presence of regular CaO. Therefore, we run the model reaction
using benzaldehyde, thiophenol and malononitrile, by the use
of each catalyst separately (Scheme 2).
As a result of these experiments, we found that CaO NPs is
the most effective catalyst, in comparison with other catalysts,
in this cyclization reaction. The increased catalytic activity of
CaO nanoparticles over the commercially available bulk CaO
is attributed to the higher surface area of nanomaterials. So,
we run the model reaction using calcium oxide nanoparticles
(Table 1), Also, the optimum ratio of the catalyst was 20 mol%
CaO NPs, and increasing this amount did not a show significant
change in the yield and time of the reaction. Several reports
dealing with the role of the CaO NPs show highly effective

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J. Safaei-Ghomi et al. / Scientia Iranica, Transactions C: Chemistry and Chemical Engineering 20 (2013) 549554
Table 2: One-pot synthesis of 2-Amino-4-phenyl-6-(phenylsulfanyl)-3,5pyridinedicarbonitrile (4a) in various solvents.a
Entrry
1
2
3
4
5

Toluene
Acetonitrile
Ethanol
Water
Water/Ethanol
a
b

Figure 4: Recoverability of CaO nanoparticles.

Table
1:
Preparation
of
2-Amino-4-phenyl-6-(phenylsulfanyl)
-3,5-pyridinedicarbonitrile (4a) in different catalysts.a
Entrry
1
2
3
4
5
6
7

Catalyst
CuO NPs
Mn3 O4 NPs
MgO NPs
NiO NPs
SiO2 NPs
CaO NPs
CaO bulk

Time (min)
140
150
130
140
180
100
260

Yields
(%)b
60
55
70
65
40
85
40

a
1 mmol of benzaldehyde, 2.2 mmol of malononitrile and 1 mmol of
thiophenol under reflux conditions.
b
Isolated yields.

catalytic behavior, because of surface properties, including


acidity by Ca2+ and basicity by O2 , in which, the interaction
of these ions with reactants leads to accelerating the reaction
conditions.
The significant results of Table 1 are related to the reactivity
of catalytic nanoparticles, which is largely determined by the
energy of surface atoms, and which can be easily gauged by
the number of neighboring atoms by the bonding modes and
accompanying energies of small molecules to be transformed
on the nanoparticle surface.
During the optimization of reaction conditions, we run the
model reaction using CaO nanoparticles in various solvents.
The results in Table 2 show that a mixture of water/ethanol
is the most effective solvent for this multicomponent reaction.
This is not surprising, in view of the fact that the hydrogen

Solvent

Time (min)
240
180
120
140
100

Yields
(%)b
35
50
70
60
85

Reflux conditions.
Isolated yields.

bonding between water/ethanol and substrate can promote the


nucleophilic attack of the reactants.
In order to establish the optimum ratio of reactants, the
model reaction was carried out several times in the presence
of calcium oxide nanoparticles. The best results were obtained
when benzaldehyde, malononitrile and thiophenol were employed as substrates in a 1:2.2:1 ratio. To study the scope of
this procedure, we next used a diversity of aldehydes and thiols to investigate three component reactions under the optimized conditions. We observed that electron-withdrawing
groups, such as NO2 , Cl and Br, reacted with malononitrile very
smoothly in the beginning of the reaction, which resulted to
produce 2-amino-3,5-dicarbonitrile-6-thio-pyridines in short
reaction times. In addition, the reaction of sterically hindered
aldehydes was performed slowly in comparison with unhindered aldehydes. The results are summarized in Table 3.
3.1. Catalyst recovery
After completion of the process, the calcium oxide nanoparticles were separated by centrifuge, were then washed three to
four times with water and ethyl acetate and dried in an oven
overnight at 80 C. The separated catalyst was used several
times with a slightly decreased activity, as shown in Figure 4.
This slight reactivity is related to the trace solubility of calcium
oxide in solvent.
The characterization of the CaO NPs, before and after reuse
three times, showed the same particle size by the SEM image
(Figure 5). Interestingly, the shape and size of the nanoparticles
almost remained unchanged after recovery.
4. Conclusion
In summary, an efficient, facile and economical method for
the preparation of poly functionalized pyridine derivatives has

Figure 5: SEM images of CaO NPs after three times reuse.

J. Safaei-Ghomi et al. / Scientia Iranica, Transactions C: Chemistry and Chemical Engineering 20 (2013) 549554

553

Table 3: One-pot synthesis of poly functionalized pyridines catalyzed by CaO nanoparticles.


Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

Ar
Ph
m-MeC6 H4
p-MeC6 H4
m-HOC6 H4
p-HOC6 H4
p-MeOC6 H4
m-O2 NC6 H4
p-O2 NC6 H4
p-ClC6 H4
p-BrC6 H4
Ph
p-MeC6 H4
p-MeOC6 H4
p-O2 NC6 H4
p-NCC6 H4

Ar
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-MeC6 H4
p-MeC6 H4
p-MeC6 H4
p-MeC6 H4
p-MeC6 H4

Product
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o

been developed using CaO NPs as a catalyst in green media.


The products were obtained in excellent yields and the reaction
times were significantly low. The present protocol represents
a simple and remarkable method for the three-component
reactions of aldehydes, thiols and malononitrile, in order
to synthesize some 2-amino-3,5-dicyano-6-sulfanyl pyridine
derivatives in the presence of novel nano-scale materials.
Acknowledgments
The authors are grateful to the University of Kashan for
supporting this work with Grant No: 159196/X.
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Time (min)
100
120
140
130
145
150
110
85
80
90
110
115
130
80
95

Yield (%)
85
85
90
80
85
92
78
75
80
80
82
80
85
70
78

mp (C)
218220
277279
208210
265267
314316
240242
218220
288290
221223
254256
248250
222224
229231
301303
272274

Lit. mp (C)
(220221)29
(278280)29
(206207)32

(315317)32
(241244)29
(219220)29
(289290)32
(221222)32
(255257)29
(246249)35

(230233)35

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Javad Safaei-Ghomi received a B.S. degree in Chemistry from the University of


Kashan, Iran, in 1985, a M.S. degree in Organic Chemistry from the University
of Mazandaran, Babolsar, Iran, in 1988, and a Ph.D. degree in Organic Chemistry
from the University of Wollongong, Australia, in 1995. He is currently Professor
in the Department of Organic Chemistry at the University of Kashan, where
he is Head of the International Science Cooperation Office. His research
interests lie in: asymmetric synthesis of amino acids, extraction of essential oils,
antioxidant and antibacterial activity of the extracts and using nanoparticles in
multicomponent reactions.

Mohammad Ali Ghasemzadeh received B.S., M.S. and Ph.D. degrees in


Chemistry and Organic Chemistry from the University of Kashan, Iran, in 2005,
2008 and 2012, respectively. His research interests lie in nanoscience and
nanotechnology, application of nanoparticles as catalyst in multi-component
reactions and ionic liquids in organic synthesis.

Mohsen Mehrabi received a B.S. degree in Physics from the University of


Yasooj, Iran, in 2007, a M.S. degree in Nanotechnology and Nanoscience
from the University of Kashan, Iran, in 2010, and is now a Ph.D. student
in Laser Physics at Amirkabir University of Technology, Tehran, Iran. He is
currently a Lecturer at the Institute of Nanoscience and Nanotechnology
in the University of Kashan. His research interests lie in: nanoparticles
(synthesis and characterization) nanophotonic (thermo luminescence and
photo luminescence) and nanostructure solar cells.