22% Co/CeO2-ZrO2-catalyzed synthesis of 1,2,3,4-tetrahydro-2-pyrimidinones and -thiones

Article abstract of DOI:10.2174/157017812802850159

Three-component condensation reaction of an aldehyde with β-ketoester and urea or thiourea in acetonitrile to afford the dihydropyrimidinones and thions (DHPMs) in the presence of 22% Co/CeO₂-ZrO₂ nano fine particle as a novel, reusable and green catalyst is reported. Utilizing of 22% Co/CeO₂-ZrO₂ nano fine particle catalyst also offers a cleaner process in that it can be reused and will not bring additional pollutants into the "environment" that is agreeable green chemistry point of view.

Full text of DOI:10.2174/157017812802850159

580
Letters in Organic Chemistry, 2012, 9, 580-584
22% Co/CeO2-ZrO2-catalyzed Synthesis of 1, 2, 3, 4-tetrahydro-2-
pyrimidinones and -thiones
Hajar Biklariana, Farahnaz K. Behbahani*a and Zahra Fakhroueianb
aDepartment of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran
bInstitute of Petroleum Engineering, P.O. Box: 11155-4563, Tehran University, Tehran, Iran
Received January 10, 2012: Revised March 12, 2012: Accepted June 07, 2012
Abstract: Three-component condensation reaction of an aldehyde with ꢀ-ketoester and urea or thiourea in acetonitrile to
afford the dihydropyrimidinones and thions (DHPMs) in the presence of 22% Co/CeO2-ZrO2 nano fine particle as a novel,
reusable and green catalyst is reported. Utilizing of 22% Co/CeO2-ZrO2 nano fine particle catalyst also offers a cleaner
process in that it can be reused and will not bring additional pollutants into the “environment” that is agreeable green
chemistry point of view.
Keywords: 22% Co/CeO2-ZrO2, aldehydes, dihydropyrimidinones.
INTRODUCTION
long reaction times, unsatisfactory yields, incompatibility
with other functional groups and involve difficult product
isolation procedures. Thus, there is still a need for a simple
and general procedure for one-pot synthesis of dihydro-
pyrimidinones and thiones under mild conditions.
Functionalized 3,4-dihydropyrimidin-2(1H) ones and
their sulfur analogs represent a class of heterocyclic system
that has attracted a considerable interest of organic and me-
dicinal chemists due to interesting pharmacological and
structural [1] profiles such as antiviral, antibacterial, antitu-
mor, anti-inflammatory properties [2], as antihypertensive
agents as well as calcium channel blockers, and ꢁ-1a-
antagonists and neuropeptide antagonists [3]. The biological
activity of some recently isolated alkaloids has also been
attributed to the presence of dihydropyrimidinone moiety
[4]. The most important of them are Batzelladine alkaloids
which have been found to be potent HIV gp-120-CD4 inhibi-
tors [5]. The most simple procedure for the synthesis of di-
hydropyrimidinones reported by Biginelli in 1893, involves
the acid-catalyzed condensation of a, ꢀ-ketoester with aro-
matic aldehyde derivatives and urea/thiourea [6]. Several
Owed to importing of these pharmacological compounds,
the synthesis of unprecedented DHPMs is also demanded.
Therefore, in connection with our research using green and
nano catalyst in organic reaction [8] and expansion of our
study on multi component synthesis [9], herein, we are inter-
ested to report a simple and green method for the preparation
of
authentic
and
unknown
1,2,3,4-tetrahydro-2-
pyrimidinones and -thiones in high yields from the reaction
of various aldehydes, benzyl, ethyl and methyl acetoacetate,
urea and thiourea in the presence of catalytic amount of 22%
Co/CeO2-ZrO2 nano fine particles refluxing acetonitrile
(Scheme 1).
R'O
O
R
O
X
O
O
R'O
NH
22% Co/CeO2-ZrO2
MeCN
+
H
R
+
H2N
NH2
Me
N
H
X
Me
R'= Me, Et, Bn
X= O, S
Scheme 1.
methods with catalysts, reagents and others techniques in
organic synthesis [7] are also reported. However, some of
them are associated with expensive and toxic reagent, stio-
chiometric amounts of catalysts, strongly acidic conditions,
RESULTS AND DISCUSSION
The reaction conditions (solvent, temperature, and cata-
lyst amount) were studied to optimize this procedure. At
first, a model reaction was chosen for the synthesis of 5-
ethoxy carbonyl-4-phenyl-6-methyl-3, 4-dihydropyrimidin-
2(1H) one (4a). For this purpose, we carried out the model
reaction under solvent-free conditions at room temperature
*Address correspondence to this author at the Department of Chemistry,
Karaj Branch, Islamic Azad University, Karaj, Iran; Tel: +98 0261 4418145;
Fax: +98 0261 4418156; E-mail: Farahnazkargar@yahoo.com
0
and at 100 C, but the product resulted on a trace. Then the
effect of water, ethanol and acetonitrile was examined in the
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Synthesis of 1, 2, 3, 4-Tetrahydro-2-Pyrimidinones and –thiones
Letters in Organic Chemistry, 2012, Vol. 9, No. 8
581
Table 1. Effect of Temperature and Varying the Solvent on the Yield of 4a.
Entry
Solvent
Temp. (°C)
Yield%
1
2
3
5
free
H2O
r.t./100
trace/15
30/45
50/ reflux
50/ reflux
50/ reflux
EtOH
CH3CN
55/60
78/93
Table 2. 22%Co/CeO2-ZrO2 Nano Fine Particles Catalyzed Synthesis of Dihydropyrimidinones and Thiones.
MP(ꢀC)
Entry
R1
Product
R2
X
Time(h)
Yield(%)
Found
Reported[Ref.]
1
2
Ph-
4a
4b
4c
4d
4e
4f
Et
Et
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
2.0
2.0
2.5
7.0
6.0
5.0
2.5
3.0
4.0
4.0
4.0
6.0
5.0
6.0
5.0
2.0
2.0
2.5
2.0
6.0
2.5
4.0
5.0
3.0
2.0
3.0
3.0
6.0
2.0
3.0
5.0
93
92
85
90
92
88
86
93
85
90
91
93
88
84
95
93
90
96
88
93
84
87
88
90
95
92
95
91
87
85
92
202–205
209–211
206-208
224-226
198-202
253-260
199-204
230–234
195-199
232-238
215-217
189–194
269–272
228-232
185–189
198-202
185–190
155-158
204-208
189-193
185-190
200-204
198-201
155-162
195-198
188-191
172-174
195
206-207 [11]
210-212 [12]
207-208.5 [11]
226-227.5 [11]
226-227 [13]
258-259 [11]
212 [11]
4-Cl-C6H4
3
4-NO2-C6H4
3-NO2-C6H4
4-OCH3-C6H4
2-OCH3-C6H4
4-CH3-C6H4
4-Me2N-C6H4
4-Br-C6H4
Et
4
Et
5
Et
6
Et
7
4g
4h
4i
Et
8
Et
251-252 [14]
199 [15]
9
Et
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
a28
a29
a30
a31
4-OH-C6H4
2-Cl-C6H4
4j
Et
198–200 [14]
220-223 [16]
194-95 [17]
273-275 [18]
235-237 [11]
190-192 [13]
203-205 [19]
190-192 [14]
152-154 [13]
206-208 [20]
193-194 [14]
192-194 [21]
212-214 [20]
209-210 [21]
152-155 [12]
186-187 [18]
199-200 [22]
169-171 [18]
[ New]
4k
4l
Et
2-Pyridyl
Et
3-NO2-C6H4
4-NO2-C6H4
4-OCH3-C6H4
4-Cl-C6H4
4m
4n
4o
4p
4q
4r
Me
Me
Me
Me
Et
Ph-
4-OCH3-C6H4
2-HO-C6H4
4-OH-C6H4
4-CH3-C6H4
3,4-diOMe-C6H3
4-Me2N-C6H4
4-Me2N-C6H4
4-OCH3-C6H4
2-OCH3-C6H4
Ph-
Et
S
4s
Et
S
4t
Et
S
4u
4v
4w
4x
4y
4z
4a'
4b'
4c'
4e'
4f'
Et
S
Et
S
Et
S
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
S
O
O
O
O
O
S
Ph-CH=CH
2,4-diCl-C6H3
4-NO2-C6H4
2,4-diCl-C6H3
160
[ New]
215
[ New]
S
203-206
[ New]
model reaction under heating conditions. The best result was
obtained in acetonitrile under reflux condition.
this reaction. To establish the scope of these novel synthesis
protocols, variety of aldehydes were subjected under the
optimized reaction conditions. Both electron poor and rich
aryl aldehydes gave excellent yields (Table 2). The method
is not applicable to aliphatic aldehydes.
The 0.02 g of catalyst was optimized for 1mmol of alde-
hyde in the model reaction. Using excess of catalyst (0.1 g),
did not show further increasing in yield. To study the effect
of catalyst, the model reaction was carried out in the absence
of catalyst in refluxing acetonitrile, but the reaction rate was
very low. Clearly, the catalyst is an affecting component for
Four compounds are also new dihydropyrimidinone and
thione derivatives (entries 28-31, Table 2). Their physical
and spectroscopic data of the known product were in good

582 Letters in Organic Chemistry, 2012, Vol. 9, No. 8
Behbahani et al.
Table 3. The Various Catalysts that were Used in One-Pot Three Component Synthesis of 4a.
Ref.
Yield (%)
Time(h)
Mol% or g
Catalyst
14
18
90
90
4
3
10
40
ZrCl4
NH4Cl
21
91
3
10
TiCl4-MgCl2.4CH3OH
HCOOH⁄MW
TBAB
20
92.31
96
0.06
0.6
22
15
0.33
3
25
23
1.5
13
75
20-100
0.3g
0.35-0.50
0.25g
10
SbCl3
26
94
PPE
15
96
N-butyl-N,N-dimethyl-ꢀ-phenylethylammonium bromide
24
96
Nafion-NR-50
InBr3
25
98
7
26
97
0.75
6
5-10
5
TaBr5
27
77.8
92
Sr(NO3)2
LiBr
29
3
10
30
70
10
0.15
0.8
40
PPh3
31
87
0.5-1.0
0.02g
Fe(ClO4)3
22%Co/CeO2-ZrO2
This work
92
adaptable conditions with those of authentic samples and
new derivative compounds having been shown in experi-
mental section. The reusability of the catalyst was also stud-
ied. At the end of the reaction, the product was filtered off,
washed by diethyl ether, and dried at 40 °C. Then the cata-
lyst was subjected for three runs. After three runs, the cata-
lytic activity of the catalyst was almost the same as those of
the freshly used catalysts (93, 91, 90% yields, entry 1, Table
5). Small size of the catalyst also indicates a large external
surface area which causes its improved catalytic perform-
ance. However, this interesting nano catalyst has previously
shown high catalytic activity in (POM) or syngas reactions
[10].
time. After that, they were thoroughly washed with distilled
water several times to remove any potassium impurity and
then initially air-dried for 48h, followed by drying at 100-
120˚C for 6h. This material was finally calcined at 800-
850˚C in an aerobic environment to get the final nanocatalyst
product [10].
Spectra Data of the Catalyst
XRD pattern of 22% Co over the CeO2-ZrO2 as support
Powder X-ray diffraction (XRD) analysis of the catalysts
was carried out by PW1840-philips with Cu K ꢀ radiation.
Fig. (1) shows XRD patterns of nanospherical catalysts after
calcination at 800-850°C. 22%Co indicates Ce0.75Zr0.25O2
cubic structure with crystallite size of 32nm. This data is in
accordance with the preparation of nanocatalyst.
To show the merits of this catalytic method, the results of
the formation of 4a (Entry 1, Table 2) were compared with
previously reported catalytic methods. The advantages of our
method are evident regarding the catalyst amount and high
yield which are very important in chemical industry espe-
cially when it is combined with easy separation.
SEM Image of Typical 22%Co Nanoparticale
SEM image for nanoparticle 22% Co over the ZrO2-CeO2
mixed oxide after calcination has shown morphology and
homogeneous spherical nanoparticle in Fig. (2).
EXPERIMENTAL
The Synthesis of Dihydropyrimidinones
The Synthesis of Nano Fine 22% Co/ ZrO2CeO2 Catalyst
by Co-Precipitation Method
In a two-neck flask, ethyl acetoacetate (5 mmol), alde-
hyde (5 mmol), urea (10 mmol) and acetonitrile (5 ml) were
heated under reflux condition for indicated times in the
Table 2. The progress of the reaction was monitored by TLC.
Upon completion of the reaction, acetonitrile was evaporated
and boiling ethanol (40 ml) was added. At once, the catalyst
was filtered off and the product was recovered at ambient
temperature. For more purification, the solid residue recrys-
tallized using ethanol and dihydropyrimidine derivatives was
obtained in high yields.
0.8 mole Ce (NO3)3.6H2O, 0.2 mole ZrOCl2.8H2O solu-
tion and Co(NO3)2.6H2O were dissolved in the mixture of
distilled water, isopropyl alcohol and tylose (hydroxyl ethyl
cellulose) as a dispersant, and the resulting solution was
transferred to a round- bottom flask, to this solution, an
aqueous solution of 20% KOH (w/w) was added drop-wise
at 80°C with constant stirring to attain an alkaline pH of 9-10
at 80°C. The precipitate was digested at 80-90°C for suitable

Synthesis of 1, 2, 3, 4-Tetrahydro-2-Pyrimidinones and –thiones
Letters in Organic Chemistry, 2012, Vol. 9, No. 8
583
1H, CH), 5.02– 4.93 (m, 2H, CH2Ph), 2.36 (s, 3H, CH3). 13
C
NMR: ꢁ(ppm) 174.5, 167.2, 158.8, 140.9, 133.7, 130.2,
126.8, 141.2, 68.9, 45.5, 15.6 C19H16Cl2N2O3 GC/MS(M+):
390. Eln. Anal. C, 55.91; H, 3.66; Cl, 17.41; N, 6.83.
5-benzyloxycarbonyl-6-methyl-4-(4-nitrophenyl)-3,4-
dihydropyrimidin-2(1H)-thione (30): Mp 215°C; IR
(KBr): ꢀ [cm-1]3280, 3182, 3087, 1733, 1607, 1567, 1518,
1
1451, 1439, 1384, 1349, 1320. H NMR (DMSO-d6, 300
MHz): ꢁH 2.25 (s, 3H, CH3), 4.99 and 5.04 (d, 2H, OCH2),
5.32 (s, 1H, CH), 6.83–7.27 (9H, m, arom.), 7.68 (1H, s,
NH), 9.21 (1H, s, NH). 13C NMR: ꢁ (ppm) 174.5, 167.2,
158.8, 149.3, 141.2, 129.0, 127.2, 120.9, 106.0, 68.9, 54.6,
5.6; C19H17N3O4S GC/MS: 383 (M+); Eln. Anal C, 59.32; H,
4.26; N, 10.74.
Fig. (1). XRD pattern 22% Co/ZrO2CeO2 nanoparticles catalysts.
5-benzyloxycarbonyl-6-methyl-4-(2,4-dicholoro-
phenyl) -3,4dihydropyrimidin-2(1H)- thione (31): Mp
203-206°C; IR (KBr): ꢀ [cm-1] 3285, 3030, 1692, 1638,
1584, 1567, 1463, 1372, 1312. 1H NMR (300 MHz, DMSO)
ꢁ(ppm) 10.44 (s, 1H, NH), 9.62 (s, 1H, NH), 6.98-7.50(m,
8H, arom), 5.61 (s, 1H, CH), 5.05(d, 1H, CH2), 4.92 (d, 1H,
CH2), 2.31 (s, 3H, CH3). 13C NMR: ꢁ(ppm) 173.5, 167.2,
157.8, 140.9, 133.6, 130.2, 126.5, 141.2, 68.9, 45.5, 15.6
C19H16Cl2N2O2S GC/MS(M+): 406. Eln. Anal. C, 55.66; H,
3.49; Cl, 16.93; N, 6.68.
Recyclability of the Catalyst
The reusability of the catalyst was also studied. At the
end of the reaction, the catalyst was removed by filtration
and washed with diethyl ether. The recycled catalyst could
be subjected to a second or even another reaction. In the case
of the model reaction, after three runs the catalytic activity of
the catalyst was almost the same as that of the freshly used
catalyst (Table 4).
Fig. (2). SEM image and morphology of 22% Co nanoparticle cata-
lyst.
Physical and Spectra Data for New Compounds
(E)-5-benzyloxycarbonyl-6-methyl-4-styryl-3,4-
dihydropyrimidin-2(1H)-one (28): Mp 195°C; IR (KBr): ꢀ
[cm-1]3245, 3110, 3028, 2960, 1711, 1648, 1459, 1436,
1385, 1332, 1311.1H NMR (DMSO-d6, 300 MHz): ꢁ(ppm)
9.21(s, 1H, NH), 7.55(s, 1H, NH), 7.21-7.38(m, 10H, arom),
6.32(dd, 1H, CH=CH), 6.13-.21(dd, 1H, CH=CH), 5.08 (d,
1H, CH2) 5.19 (d, 1H, CH2), 4.75(s, 1H, CH), 2.20 (s, 3H,
CH3). 13C NMR: ꢁ (ppm) 15.0, 48.9, 68.9, 108.2, 126.4,
128.7, 135.2, 141.2, 145.8, 150.3, 167.2. C21H20N2O3
GC/MS(M+): 348.147. Eln. Anal. C, 72.10; H, 5.59; N, 7.94.
CONCLUSION
In conclusion, we have described a simple modification
of the Biginelli dihydropyrimidinone and thion synthesis and
developed four unprecedented DHPMs 22% Co/CeO2-ZrO2-
catalyzed as a novel catalyst in refluxing acetonitrile. High
yields of the products, mild reaction conditions and simple
procedure make this protocol complementary to the existing
methods. Further, the catalyst can be easily recovered and
reused without a considerable loss in its activity that is
adopted from green chemistry point of view. Another impor-
tant aspect of this procedure is survival of a variety of func-
tional groups such as NO2, Cl, OH, OMe, N, N-dimethyl, 2-
pridyl and cinnamyl under the reaction conditions.
5-benzyloxycarbonyl-6-methyl-4-(2,4-dicholoro-
phenyl)-3,4-dihydropyrimidin-2(1H)-one (29): Mp 160°C
IR (KBr): ꢀ [cm-1]3442,3301, 3067, 3034, 2974, 1718,
1656, 1590, 1547, 1498, 1470, 1456, 1377. 1HNMR
(DMSO-d6, 300 MHz) 9.23 (1H, s, NH), 7.25 (s, 1H, NH),
7.30–7.24 (m, 4H, arom.), 7.17–6.88 (m, 5H, arom.), 5.58 (s,
Table 4. Reusability of the Catalyst was Examined by the Model Reaction at 2.0 h.
Entry
Run(s)
RCHO
Yield (%)
1
2
3
4
Fresh
1st
Benzaldehyde
93
90
90
88
"
"
"
2nd
3th

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Behbahani et al.
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CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flicts of interest.
ACKNOWLEDGEMENTS
[15]
Declared none.
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