ZnO Nanoparticles: A mild and efficient reusable catalyst for the one-pot synthesis of 4-amino-5-pyrimidinecarbonitriles under aqueous conditions

Article abstract of DOI:10.1080/00397910903219385

An efficient method for the synthesis of 4-amino-5-pyrimidinecarbonitriles by three-component reaction of malononitrile, aldehydes, and N-unsubstituted amidines, under aqueous conditions, using ZnO nanoparticles as catalyst is reported. The catalyst exhibited remarkable activity and is recyclable. Copyright

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ZnO Nanoparticles: A Mild and
Efficient Reusable Catalyst for the
One-Pot Synthesis of 4-Amino-5-
pyrimidinecarbonitriles Under Aqueous
Conditions
a
a
a
Rahim Hekmatshoar , Ghodsieh Nanva Kenary , Sodeh Sadjadi
&
a
Yahya S. Beheshtiha
a
Department of Chemistry, School of Science, Alzahra University,
Vanak, Tehran, Iran
Version of record first published: 08 Jun 2010.
To cite this article: Rahim Hekmatshoar , Ghodsieh Nanva Kenary , Sodeh Sadjadi & Yahya S.
Beheshtiha (2010): ZnO Nanoparticles: A Mild and Efficient Reusable Catalyst for the One-Pot
Synthesis of 4-Amino-5-pyrimidinecarbonitriles Under Aqueous Conditions, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:13, 2007-2013
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1
Synthetic Communications , 40: 2007–2013, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903219385
ZnO NANOPARTICLES: A MILD AND EFFICIENT
REUSABLE CATALYST FOR THE ONE-POT SYNTHESIS
OF 4-AMINO-5-PYRIMIDINECARBONITRILES UNDER
AQUEOUS CONDITIONS
Rahim Hekmatshoar, Ghodsieh Nanva Kenary, Sodeh Sadjadi,
and Yahya S. Beheshtiha
Department of Chemistry, School of Science, Alzahra University, Vanak,
Tehran, Iran
An efficient method for the synthesis of 4-amino-5-pyrimidinecarbonitriles by
three-component reaction of malononitrile, aldehydes, and N-unsubstituted amidines, under
aqueous conditions, using ZnO nanoparticles as catalyst is reported. The catalyst exhibited
remarkable activity and is recyclable.
Keywords: Aldehydes; amidines; 4-amino-5-pyrimidinecarbonitriles; malononitrile; ZnO nanoparticles
INTRODUCTION
Heterocyclic compounds occur widely in nature and are essential to life.
Nitrogen-containing heterocyclic molecules constitute the largest portion of chemical
entities, which are part of many natural products, fine chemicals, and biologically
[
1]
active pharmaceuticals that are vital for enhancing the quality of life.
Pyrimidine is one of the most popular N-heteroaromatic compounds incorpo-
rated into the structures of many pharmaceuticals. Some such compounds
[3]
[2]
are analgesics, antihypertensives, antipyretics, and anti-inflammatory drugs.
[5]
Pyrimidines occur in some pesticides, herbicides, and plant growth regulators.
[4]
The organic reactions in aqueous media have attracted much attention in syn-
thetic organic chemistry, not only because water is one of the most abundant, cheap-
est, and environmentally friendly solvents but also because water exhibits unique
reactivity and selectivity, different from those obtained in conventional organic sol-
vents. Novel reactivity as well as selectivity that cannot be attained in conventional
[
6]
organic solvents are challenging goals in aqueous chemistry. The significant
enhancement in the rate of reaction has been attributed to hydrophobic packing, sol-
[
vent polarity, hydration, and hydrogen bonding. Thus, the use of water instead of
7]
[
8]
organic solvents an essential component of sustainable chemistry.
Received March 1, 2009.
Address correspondence to Rahim Hekmatshoar, Department of Chemistry, School of Science,
Alzahra University, Vanak, Tehran, Iran. E-mail: rhekmatus@yahoo.com
2
007

2008
R. HEKMATSHOAR ET AL.
Scheme 1. Synthesis of 4-amino-5-pyrimidinecarbonitriles.
ZnO, a wide-band-gap semiconductor with large excitation binding energy,
possesses unique properties.
[9,10]
The size and morphology of ZnO nanoparticles
have great influences on their performances. Because the properties of nanomaterials
depend on their size and shape, new synthetic strategies in which the size and shape
[
11]
of nanostructures can be easily tailored are important.
With the aim to develop more efficient synthetic processes, reduce the number
of separate reaction steps, and minimize by-products, and in continuation of our
[
12]
recent interest in the construction of heterocyclic scaffolds,
practical, inexpensive method for the preparation of 2-amino-5-pyrimidinecarboni-
we herein describe a
triles 4 via multicomponent reactions of aldehydes 1, malononitrile 2, and amidines
3
in the presence of ZnO nanoparticles (Scheme 1).
Our catalytic strategy was first evaluated by treating benzaldehyde and malo-
nonitrile with guanidinum carbonate in water for 15 min at room temperature using
catalytic amounts (10 mol%) of ZnO. This reaction successfully afforded the desired
4
-amino-5- pyrimidinecarbonitrile in 93% yield. Without ZnO nanoparticles, the
same reaction generated only 25% of 4-amino-5-pyrimidinecarbonitrile over the
same period of time.
To investigate the advantageous role of water as a solvent for this method, com-
parative reactions were carried out in other solvents. The reaction of benzaldehyde,
guanidinum carbonate, and malononitrile was carried out in CHCl and CH Cl
2
3
2
under similar reaction conditions where it furnished the 2,4-diamino-6-phenyl-5-
pyrimidinecarbonitrile 4b in yields of only 48 and 53%, respectively. When the same
reaction was carried out in more polar solvents such as tetrahydrofuran (THF), MeCN,
and EtOH under identical conditions, 4b was obtained in yields of 68, 73, and 78%,
respectively (Table 1). It is remarkable that the reaction carried out in water afforded
a
Table 1. Solvent effect for synthesis of 4-amino-5-pyrimidinecarbonitrile
Entry
Solvent
CH Cl
THF
Time (min)
Yield (%)
1
2
3
4
5
6
2
2
60
30
60
30
30
15
53
68
48
78
73
93
CHCl
EtOH
MeCN
3
2
H O
a
Reaction conditions: benzaldehyde 1 (1 mmol), malononitrile 2 (1 mmol), guanidinum
O, room temperature.
carbonate 3 (1 mmol), and ZnO nanoparticles (10 mol%), H
2

4
-AMINO-5-PYRIMIDINECARBONITRILES
2009
Table 2. Comparison between ZnO nanoparticles, bulk ZnO, Al
catalysts in the reaction of benzaldehyde, malononitrile, and guanidinum carbonate
2 3 2 3
O , and basic Al O
a
Time
(min)
Amount of
catalyst (mmol)
Yield
(%)
Entry
Catalyst
1
2
3
4
ZnO nanoparticle
Bulk ZnO
15
30
15
30
(0.1 mmol)
(0.5 mmol)
(0.3 mmol)
(0.5 mmol)
93
73
85
78
2 3
Basic Al O
Al O
2
3
a
Reaction conditions: benzaldehyde 1 (1 mmol), malononitrile 2 (1 mmol), guanidinum
O, room temperature.
carbonate 3 (1 mmol), and ZnO nanoparticles (10 mol%), H
2
2
,4-diamino-6-phenyl-5-pyrimidinecarbonitrile 4b in excellent yield (93%), which is
significantly more than those obtained for the volatile=toxic=polar organic solvents.
The role of water as the reaction medium and its mechanism are still not clear.
Recently, it has been reported that some organic molecules can react on the surface
of water. Often a very strong enhancement of reaction rates was noticed in this case,
particularly when at least one component involved in this reaction bore a polar
group, enabling some degree of solubility. The significant enhancement in the rate
of reaction has been attributed to hydrophobic packing, solvent polarity, hydration,
[13]
and hydrogen bonding.
The ZnO nanoparticle catalyst was studied along with other known solid base
catalysts using the reaction of benzaldehyde, malononitrile, and guanidinum carbon-
ate in 5 mL of water as a model system for the synthesis of the corresponding
4
results show that the three-component reactions catalyzed by basic Al O and
-amino-5-pyrimidinecarbonitrile. The results are summarized in Table 2. The
2
3
Al O proceed over longer reaction times and afford moderate product yields. The
2
3
size of ZnO plays an important role in terms of yields and reaction times. Changing
the size of the particles from nanoparticles to bulk resulted in a drop in the catalytic
activity. It is interesting to note that the ZnO nanoparticle catalyst catalyzes the
present reaction in excellent yield within a shorter reaction time than the other solid
base catalysts. It appears that the basicity of the catalyst plays a prominent role.
The generality of this process was demonstrated by the wide range of substi-
tuted aldehydes and N-unsubstituted amidines to synthesize the corresponding
products in good to excellent yields (Table 3). The results in Table 3 indicate that
a
Table 3. Synthesis of 4-amino-5-pyrimidinecarbonitriles
0
ꢀ
[13]
Entry
R
R
Yield (%)
Mp ( C) Observed (lit.)
a
b
c
d
e
f
C
C
6
6
H
5
Ph
NH
Ph
98
93
91
96
93
98
212 (212)
230 (228–230)
208–210 (210)
130 (130)
H
5
2
2
2
4-MeC
4-MeC
6
H
4
4
6
H
NH
Ph
4-ClC
4-ClC
6
H
4
221–222 (222)
231 (229–231)
6
H
4
NH
a
Reaction conditions: benzaldehyde 1 (1 mmol), malononitrile 2 (1 mmol), N-unsubstituted amidines
O, room temperature, 15 min.
3
(1 mmol), and ZnO nanoparticles (10 mol%), H
2

2010
R. HEKMATSHOAR ET AL.
Scheme 2. Plausible reaction mechanism.
the aromatic aldehydes bearing different functional groups such as chloro, nitro,
methyl, or methoxy groups were able to undergo the condensation reaction.
A mechanism for the reaction is outlined in Scheme 2. The reaction occurs via
initial formation of the cyano olefin 3 from the condensation of aryl aldehyde 1 and
malononitrile 2. The second step is followed by Michael addition, cycloaddition, iso-
merization, and aromatization to afford the 4-amino-5-pyrimidinecarbonitriles 5.
Intermediate 4 is not stable and is easily oxidized by air to produce compound 5.
The insolubility of the catalyst ZnO in different organic solvents and water
provided an easy method for its separation from the product. Recycling experiments
were performed using the ZnO nanoparticle catalyst for the synthesis of
2
,4-diamino-6-phenyl-5-pyrimidinecarbonitrile 4b. These recycling experiments show
that the ZnO nanoparticle catalyst catalyzes the reaction with consistent activity
even after four cycles. Infrared (IR) spectra of the resulting solids indicate that the
catalyst can be recovered without structural degradation (Fig. 1).
Figure 1. IR spectrum of nanosized ZnO before (a) and after (b) use.

4
-AMINO-5-PYRIMIDINECARBONITRILES
2011
Table 4. Synthesis of 4b under different reaction conditions
Time
(min)
Yield
(%)
Entry
Method
Catalyst
Solvent
Solvent-free
Solvent-free
1
2
Microwave-assisted
Sodium acetate
Without a catalyst
5
70
52
74
90
73
78
93
[13]
conditions
Microwave-assisted
10
[13]
conditions
Microwave-assisted
3
4
5
6
7
Sodium acetate
Triethylamine
Toluene
1.5
0.5
0.5
360
15
[13]
conditions
Microwave-assisted
Toluene
[13]
conditions
Microwave-assisted
Sodium acetate
Sodium acetate
ZnO nanoparticles
Water
[13]
conditions
[13]
Reflux
Water=ethanol
(1:1)
Water
Stirrer at room
temperature
Note. All reactions were carried out at 300 W of microwave irradiation.
Finally, the efficacy of the present method for the synthesis of 4b was compared
[13]
with other reported procedures (Table 4). It revealed that ZnO nanoparticle is an
efficient, environmentally benign catalyst in the synthesis of 2,4-diamino-6-phenyl-
5
-pyrimidinecarbonitrile.
In conclusion, we have reported here in several noteworthy features of a new
catalyst for the synthesis of 4-amino-5-pyrimidinecarbonitriles through the
three-component reaction of malononitrile, aldehydes, and N-unsubstituted ami-
dines using ZnO nanoparticles. This protocol offers many attractive features such
as reduced reaction times, greater yields, and economic viability of the catalyst.
The reaction proceeds under aqueous conditions. Isolation of the catalyst is easily
achieved, and the catalyst is recoverable and can be used in several runs without loss
of catalytic activity. This makes the method economic, benign, simple, and
convenient for the synthesis of 4-amino-5-pyrimidinecarbonitriles.
EXPERIMENTAL
Preparation of Zno Nanoparticles
Zinc nitrate (4.05 g) was added to a beaker containing 28 ml saturated
NH HCO solution, and 14 ml ammonia (28 wt%) was gradually dropped into the
4
3
beaker under magnetic stirring at room temperature. The reaction was run until zinc
nitrate was dissolved completely, and the obtained solution was then added into four
times its volume of distilled water. The reaction was carried out under magnetic stir-
ꢀ
ꢀ
ring at 60 C for 1 h. The precursor was separated by centrifugation, dried at 60 C
ꢀ
for 12 h, and finally calcined at 450 C for 3 h in ambient oxygen. The morphology
and size distribution of ZnO nanoparticles were determined by scanning electron
micrography (SEM) (Fig. 2).

2012
R. HEKMATSHOAR ET AL.
Figure 2. Scanning electron micrograph of nanosized ZnO particles.
General Procedure for the Preparation of 4-Amino-5-
pyrimidinecarbonitriles
A mixture of aldehyde 1 (1 mmol), malononitrile 2 (1 mmol), amidine hydro-
chloride or guanidinum carbonate (1 mmol), and ZnO nanoparticles (0.1 mmol) in
H2O (5 mL) was stirred for 15 min [the progress of the reaction was monitored by
thin-layer chromatography (TLC) using n-hexane=ethyl acetate as an eluent (2:3)].
Upon completion of the reaction, the reaction mixture was filtered to isolate the solid
product. Then the solid product was diluted with chloroform, and the catalyst
was removed by simple centrifugation (the catalyst is not soluble in chloroform).
After evaporation of solvent, more purification was obtained by recrystallization
from ethanol.
Spectral data of 4-amino-5-pyrimidinecarbonitriles described in this article are
14]
the same as those reported in a previously published paper.
[
Reusing the Catalyst
After completing the model reaction, the catalyst was separated by centrifuga-
ꢀ
tion, washed three times with 10 ml of chloroform, dried at 120 C for 1 h, and
subjected to a second run of the reaction.
ACKNOWLEDGMENT
The authors are thankful to the Alzahra Research Council for partial financial
support.

4
-AMINO-5-PYRIMIDINECARBONITRILES
2013
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