Granulated copper oxide nanocatalyst: A mild and efficient reusable catalyst for the one-pot synthesis of 4-amino-5-pyrimidinecarbonitriles under aqueous conditions

Article abstract of DOI:10.1007/s00706-011-0579-2

An efficient method for the synthesis of 4-amino-5-pyrimidinecarbonitriles by the three-component reaction of malononitrile, aldehydes, and N-unsubstituted amidines under aqueous conditions using CuO microspheres as catalyst is reported. The catalyst exhibited remarkable reusable activity. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-011-0579-2

Monatsh Chem (2011) 142:1163–1168
DOI 10.1007/s00706-011-0579-2
ORIGINAL PAPER
Granulated copper oxide nanocatalyst: a mild and efficient
reusable catalyst for the one-pot synthesis of 4-amino-5-
pyrimidinecarbonitriles under aqueous conditions
•
Seyed Javad Ahmadi Sodeh Sadjadi
•
Morteza Hosseinpour
Received: 18 February 2010 / Accepted: 12 July 2011 / Published online: 12 August 2011
Ó Springer-Verlag 2011
Abstract An efficient method for the synthesis of
4-amino-5-pyrimidinecarbonitriles by the three-component
reaction of malononitrile, aldehydes, and N-unsubstituted
amidines under aqueous conditions using CuO micro-
spheres as catalyst is reported. The catalyst exhibited
remarkable reusable activity.
most common N-heteroaromatic compounds incorporated
into the structures of many pharmaceuticals, including
analgesics [3], antihypertensives, antipyretics, and anti-
inflammatory drugs [4]. Pyrimidines also occur in some
pesticides [5], herbicides, and plant growth regulators [6].
Organic reactions in aqueous media have attracted much
attention in synthetic organic chemistry, not only because
water is the most abundant, cheap, and environmentally
friendly solvent but also because water exhibits unique
reactivity and selectivity, which are different from those
obtained in conventional organic solvents. Thus, elements
of novel reactivity as well as selectivity that cannot be
attained in conventional organic solvents are challenging
goals in aqueous chemistry [7]. The significant enhance-
ment in the rate of reaction has been attributed to
hydrophobic packing, solvent polarity, hydration, and
hydrogen bonding [8–10]. Thus, the use of water instead
of organic solvents has gained importance as an essen-
tial component of the development of sustainable
chemistry [11].
Keywords CuO microspheres ꢀ Malononitrile ꢀ
Aldehydes ꢀ Amidines ꢀ
4-Amino-5-pyrimidinecarbonitriles
Introduction
Heterocyclic compounds occur very widely in nature and
are essential to life. Nitrogen-containing heterocyclic
molecules constitute the largest portion of chemical enti-
ties, which are part of many natural products, fine
chemicals, and biologically active pharmaceuticals vital for
enhancing the quality of life [1, 2]. Pyrimidine is one of the
Very recently, the employment of nanocrystalline metal
oxides as catalysts in organic synthesis has attracted much
attention [12]. Nanocatalysts in general and nano metal
oxides in particular, despite having a greater chemical
reactivity, suffer from inappropriate physical forms that
make their practical applications often unfeasible or at least
formidable. Industrial processes, especially fixed bed
operations, often require casting of powdery nanocatalysts
into a granulated structure.
S. J. Ahmadi ꢀ S. Sadjadi (&)
Nuclear Fuel Cycle School,
Nuclear Science and Technology Research Institute,
End of North Karegar Ave., P.O. Box 1439951113,
Tehran, Iran
We herein describe a practical, inexpensive method for
the preparation of spherical granules of CuO catalyst. The
prepared catalysts were then used in the synthesis of
4-amino-5-pyrimidinecarbonitriles 4 via multi-component
reactions of aldehydes 1, malononitrile (2), and amidines 3
under aqueous conditions (Scheme 1).
e-mail: sadjadi.s.s@gmail.com
M. Hosseinpour
Department of Energy Engineering,
Sharif University of Technology,
Azadi Ave., P.O. Box 113658639, Tehran, Iran
123

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S. J. Ahmadi et al.
Scheme 1
R
NH
CN
N
CuO microspheres
H2O, rt
+
RCHO
+
NC
CN
R'
NH2
R'
N
NH2
1
2
3
4
R'= Ph, NH2
Results and discussion
Granulated copper oxide nanocatalyst was prepared via a
three-step procedure. In the first step, copper oxide nano-
particles were synthesized by hydrothermal decomposition
of copper nitrate under supercritical water conditions.
Then, they were immobilized in the polymeric matrix of
sodium alginate. High temperature calcination in an air
stream was the third step, which entirely removed the
carbonaceous materials and resulted in a pebble-type cat-
alyst of high porosity.
The X-ray diffraction (XRD) patterns of nano-sized and
bulk CuO are shown in Fig. 1. All XRD peaks are indexed
to the monoclinic crystal system of CuO. The average size
of the obtained CuO particles shown in Fig. 2 is 5 nm. The
crystallite size was also calculated by X-ray line-broaden-
ing analysis using the Scherrer equation: the average CuO
crystallite size was found to be 8 nm. The mean surface
area of the CuO catalyst was 32.457 m2 g-1 from Bru-
nauer–Emmett–Teller (BET) analysis.
Fig. 2 Transmission electron micrographs of CuO nanoparticles
The first step in the synthesis of CuO microspheres was
preparation of the aqueous CuO nanoparticle suspension.
Fig. 3 Schematic diagram of the apparatus for preparation of
granulated CuO microspheres
Fabrication of the microspheres (MSs) was then effected by
mixing of the CuO suspension with sodium alginate solu-
tion, and dropwise injection of the obtained sol into BaCl2
solution through a 0.50-mm medical needle to gelify and
form microspheres (Fig. 3). The size of the droplets and
thus microspheres was adjusted by means of a pneumatic
Fig. 1 XRD patterns of CuO particles prepared under supercritical
conditions and bulk CuO
123

Granulated copper oxide nanocatalyst
1165
Table 1 Surface area of microspheres at different conditions
Entry
Temperature/°C
Time/h
BET/m2 g-1
MS1
MS2
MS3
600
700
800
6
6
6
18.74
9.16
5.65
Fig. 4 XRD patterns of CuO microspheres: a MS1, b MS2, c MS3
cutting system which provided an air stream blown around
the injecting needle.
Particles obtained by the dripping method were calcined
at different temperature [600 °C (MS1), 700 °C (MS2),
800 °C (MS3)]. With respect to particle morphology, the
calcination temperature played an important role in the
surface characteristics of the microspheres.
Table 1 presents the results of BET tests of the final
granulated products. Maximum surface area was shown by
MS1 that was calcined at the lowest temperature.
The XRD patterns of CuO microspheres are shown in
Fig. 4. All XRD peaks are indexed to the monoclinic
crystal system of CuO. The XRD pattern of the copper
oxide microspheres formed at 800 °C shows a relatively
sharp peak with the highest intensity as shown in Fig. 4.
This is mainly due to the growth of crystallite size.
Scanning electron microscope (SEM) images in
Fig. 5a–c show the size and morphology of different
microspheres that have undergone different thermal treat-
ments. The size of all microspheres is in the range of
300–500 lm.
Our catalytic strategy was first evaluated by treating
benzaldehyde and malononitrile with guanidinum carbon-
ate in water for 15 min at room temperature using
catalytic amounts (10 mol%) of CuO microspheres. This
reaction successfully afforded the desired 4-amino-5-pyr-
imidinecarbonitrile in moderate to good yield (78–93%).
Fig. 5 SEM images of a MS1, b MS2, c MS3 (scale bar 1 lm)
The size of CuO plays an important role in terms of
yields and reaction times. When the reaction was con-
ducted with bulk CuO, a poor yield of the product was
obtained (Table 2).
We compared the catalytic activity of CuO nanoparticles
with CuO microspheres (MS1, MS2, and MS3). The highest
yield was obtained with CuO nanoparticles and surprisingly
CuO microspheres (MS1) gave comparable yields to CuO
123

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S. J. Ahmadi et al.
The role of water as the reaction medium and its
mechanism are still not clear. Recently, it was 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 com-
ponent involved in this reaction bore a polar group,
enabling some degree of solubility [13].
Table 2 Synthesis of 2,4-diamino-6-phenyl-5-pyrimidinecarbonitrile
with different copper oxide catalysts
Entry
Catalyst
Time/min
Yield/%
1
2
3
4
5
CuO bulk
Nano-CuO
MS1
45
15
15
30
30
59
96
93
84
78
MS2
The generality of this process was demonstrated by the
wide range of substituted aldehydes and N-unsubstituted
amidines used to synthesize the corresponding products in
high to excellent yields (Table 4). The results in Table 4
indicate that aromatic aldehydes bearing different func-
tional groups such as chloro, nitro, methyl, or methoxy
were able to undergo the condensation reaction.
MS3
Reaction conditions: benzaldehyde (1 mmol), malononitrile
(1 mmol), guanidinum carbonate (1 mmol), and catalyst (10 mol%),
H2O, room temperature
nanoparticles (Table 2). The high surface area of the copper
oxides is supposed to be important for the catalytic perfor-
mance. Granulation of nanoparticles by the immobilization–
calcination method reduces the specific surface area from
32.5 to 18.74 m2 g-1, but the value of surface area is still
much larger than that of bulk CuO (0.49 m2 g-1).
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 malono-
nitrile. The second step is followed by Michael addition,
cycloaddition, isomerization, and aromatization of the
unstable intermediate via facile aerial oxidation to afford
the 4-amino-5-pyrimidinecarbonitriles 4.
Although it is possible to slightly increase the yield of the
reaction by using CuO nanoparticles, the CuO microsphere-
catalyzed reaction has the advantages of easy product
purification, efficient recycling of the catalyst, and mini-
mization of metal oxide traces in the product. Thus, we
chose CuO microspheres (MS1) as catalyst for this reaction.
To investigate the advantageous role of water as a sol-
vent for this method, comparative reactions were carried
out in other solvents. The reaction of benzaldehyde, gua-
nidinum carbonate, and malononitrile was carried out in
CHCl3 and CH2Cl2 under similar reaction conditions to
The insolubility of CuO microspheres in different
organic solvents and water provided an easy method for
their separation from the product. Recycling experiments
were performed using the CuO microsphere (MS1)
catalyst for the synthesis of 2,4-diamino-6-phenyl-5-pyr-
imidinecarbonitrile (4b). After each cycle, the catalyst was
recovered by simple filtration, washed with deionized
water and ethanol, and dried in vacuo. The recovered CuO
microspheres were used directly in the next cycle. The
recycling results are listed in Table 5 and show that the
catalyst was still highly efficient after the fifth cycle.
Finally, the efficiency of the present method for the syn-
thesis of 4b was compared with other reported procedures
(Table 6) [14]. CuO microspheres (MS1) are therefore an
efficient, environmentally benign catalyst in the synthesis of
2,4-diamino-6-phenyl-5-pyrimidinecarbonitrile.
furnish
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 other-
wise identical conditions, 4b was obtained in yields of 68,
73, and 78%, respectively (Table 3). It is remarkable that
the reaction carried out in water afforded 4b in excellent
yield (93%), which is significantly higher than those
obtained for the volatile/toxic/polar organic solvents.
Table 4 Synthesis of 4-amino-5-pyrimidinecarbonitriles 4
4
R
R0
Yield/% M.p./°C
98 212–213 212
229–230 228–230
Lit. m.p./°C [14]
Table 3 Solvent effect for synthesis of 2,4-diamino-6-phenyl-5-
pyrimidinecarbonitrile
a
b
c
d
e
f
C6H5
Ph
C6H5
NH2 93
Ph 91
NH2 96
Ph 93
NH2 98
Entry
Solvent
Time/min
Yield/%
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-BrC6H4
208–210 210
129–130 130
221–222 222
229–230 229–231
211–213 213
234–236 235–238
160–162 162
1
2
3
4
5
6
CH2Cl2
THF
60
30
60
30
30
15
53
68
48
78
73
93
CHCl3
EtOH
MeCN
H2O
g
h
i
Ph
Ph
82
88
86
4-Me2NC6H4 Ph
Reaction conditions: benzaldehyde (1 mmol), malononitrile
(1 mmol), guanidinum carbonate (1 mmol), and CuO microspheres
(MS1, 10 mol%), room temperature
Reaction conditions: aldehyde 1 (1 mmol), malononitrile (1 mmol),
N-unsubstituted amidines 3 (1 mmol), and CuO microspheres (MS1,
10 mol%), H2O, room temperature, 15 min
123

Granulated copper oxide nanocatalyst
1167
Scheme 2
NH
NH2
R
CN
N
R
CN
CN
R'
-H2O
HN
RCHO + NC
CN
N
Michael addition
R'
NH
1
2
3
R
N
R
CN
CN
-H2
N
R'
NH2
R'
N
NH2
4
Preparation of CuO took place in a stainless steel autoclave
that was able to endure a working temperature and pressure
of 550 °C and 610 atm. The concentration of Cu(NO3)2
was 0.05 mol dm-3, and the heating period was about 2 h.
Synthesis was carried out at 500 °C to accelerate the
hydrolysis reactions and thus shorten the fabrication per-
iod. In order to maintain the safety margin, the 200-cm3
stainless steel autoclave was loaded with only 60–80 cm3
of the solution.
Table 5 Recycling of CuO microspheres
Run
1
2
3
4
5
Time/min
Yield/%
15
93
15
91
20
86
23
83
27
81
In conclusion, we have reported herein several note-
worthy features of a new catalyst for the synthesis
of 4-amino-5-pyrimidinecarbonitriles through the three-
component reaction of malononitrile, aldehydes, and
N-unsubstituted amidines using CuO microspheres. This
protocol offers many attractive features such as reduced
reaction times, higher yields, and economic viability of the
catalyst. The reaction proceeds under aqueous conditions
and isolation of the catalyst is easily achieved. The catalyst
is recoverable and reusable in several runs without loss of
catalytic activity. This makes the method an economic,
benign, simple, and convenient process for the synthesis of
4-amino-5-pyrimidinecarbonitriles.
After removing from the furnace, the autoclave was
quenched with cold water and CuO nanoparticles were
recovered from the discharged solution by high speed
centrifugation at 14,000 rpm for about 60 min. The pro-
duced nanoparticles were then washed in the same
centrifuge with ultra-pure water three times, and then dried
at ambient temperature.
Preparation of granulated CuO microspheres
CuO nanoparticles (2 g) were dispersed in 5 cm3 deionized
water and the mixture was stirred to form an aqueous CuO
suspension, and the reaction mixture was exposed to
ultrasonic irradiation for 30 min. Then 14 cm3 of gelatin
aqueous solution (sodium alginate, 3.6 wt.%) was added
into the above solution, and the mixture was mechanically
stirred for 2 h. An alginate–CuO nanoparticle solution was
sprayed through a thin inner nozzle ([ = 0.5 mm) into a
Experimental
Batchwise supercritical hydrothermal synthesis of CuO
nanoparticles
Copper(II) nitrate trihydrate (Merck AG, for synthesis) was
used as the precursor for synthesis of nano copper oxide.
Table 6 Synthesis of 4b under different reaction conditions [14]
Entry
Method
Catalyst
Solvent
Time/min
Yield/%
1
2
3
4
5
6
7
Microwave-assisted conditions
Microwave-assisted conditions
Microwave-assisted conditions
Microwave-assisted conditions
Microwave-assisted conditions
Reflux
Sodium acetate
Without catalyst
Sodium acetate
Triethylamine
Solvent-free
Solvent-free
Toluene
5
70
52
74
90
73
78
93
10
1.5
0.5
0.5
360
15
Toluene
Sodium acetate
Sodium acetate
CuO microspheres (MS1)
Water
Water/ethanol (1:1)
Water
Stirring at room temperature
All reactions were carried out under 300-W microwave irradiation
123

1168
S. J. Ahmadi et al.
0.1 mol dm-3 barium chloride solution with pressured air
blown through an outer aperture in the nozzle (Fig. 3). The
resultant beads were allowed to stand in the solution for 3 h
at room temperature on a magnetic stirrer, and then they
were washed with pure water three times and eventually
dried at 400 °C for 10 h. The dried microspheres were
transferred into a muffle furnace and calcined at 600 °C
(MS1), 700 °C (MS2), and 800 °C (MS3) for 6 h to
decompose and burn all of the organic material.
mixture was filtered to isolate the solid product. The solid
product was dissolved in chloroform and the catalyst was
then removed by simple filtration. After evaporation of the
solvent, the products were purified by recrystallization
from ethanol.
The spectral data of 4-amino-5-pyrimidinecarbonitriles
described in this article agree with those reported in a
previously published paper [14].
Acknowldgements The authors are thankful to the Nuclear Science
and Technology Research Institute for partial financial support.
Characterization
The crystal structure of the prepared CuO nanoparticles
and final microspheres was analyzed by using Cu Ka
radiation (Philips PW 1800). The particle size and mor-
phology of the nanocrystalline particles were examined
using a transmission electron microscope (TEM, LEO
912AB). In the case of microspheres, a SEM (LEO1
455VP) was used for the same purpose. The surface area of
the CuO nanoparticles and the granular microspheres was
determined by the nitrogen adsorption BET method
(Quantachrome Instruments, Nova 2000e).
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General procedure for the preparation of 4-amino-5-
pyrimidinecarbonitriles
A
mixture of aldehyde 1 (1 mmol), malononitrile
(1 mmol), amidine hydrochloride or guanidinum carbonate
3 (1 mmol), and CuO microspheres (0.1 mmol) in 5 cm3
H2O was stirred for 15 min, the progress of the reaction
being monitored by TLC using n-hexane/ethyl acetate (2:3)
as eluent. Upon completion of the reaction, the reaction
123