Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide

Article abstract of DOI:10.1080/00397910802592874

A simple, efficient and practical procedure for the Biginelli reaction using zinc oxid (ZnO) as a novel and reusable catalyst is described under solvent-free conditions in high yields. The use of this agent is characterized by remarkable reactivity, moder

Full text of DOI:10.1080/00397910802592874

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Highly Efficient Solvent-
Free Synthesis of
Dihydropyrimidinones
Catalyzed by Zinc Oxide
Kiumars Bahrami a b , Mohammad Mehdi Khodaei a b
& Azita Farrokhi a
a Department of Chemistry, Razi University,
Kermanshah, Iran
b Nanoscience and Nanotechnology Research Center
(NNRC), Razi University, Kermanshah, Iran
Version of record first published: 15 Apr 2009.
To cite this article: Kiumars Bahrami, Mohammad Mehdi Khodaei & Azita Farrokhi
(2009): Highly Efficient Solvent-Free Synthesis of Dihydropyrimidinones Catalyzed
by Zinc Oxide, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:10, 1801-1808
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Synthetic Communications1, 39: 1801–1808, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802592874
Highly Efficient Solvent-Free Synthesis of
Dihydropyrimidinones Catalyzed by Zinc Oxide
Kiumars Bahrami,1,2 Mohammad Mehdi Khodaei,1,2
and Azita Farrokhi1
1Department of Chemistry, Razi University, Kermanshah, Iran
2Nanoscience and Nanotechnology Research Center (NNRC),
Razi University, Kermanshah, Iran
Abstract: A simple, efficient and practical procedure for the Biginelli reaction
using zinc oxid (ZnO) as a novel and reusable catalyst is described under
solvent-free conditions in high yields. The use of this agent is characterized by
remarkable reactivity, moderate costs, low toxicity and simple work up procedures.
Keywords: Cyclocondensation, solvent-free, 1,2,3,4-tetrahydropyrimidine, zinc oxide
INTRODUCTION
The demand for structural diversification in compound libraries for
screening in drug discovery is the driving force behind the development
of new methodologies and structural motifs. The cyclocondensation of
acetoacetic esters with aromatic aldehydes and (thio)urea, known as
the Biginelli reaction, has attracted considerable attention in recent years.
The resulting 1,2,3,4-tetrahydropyrimidine derivatives have been shown
to possess a variety of interesting pharmacological properties.[1] Conse-
quently, synthesis of the heterocyclic nucleus contained in such
compounds has gained importance. Many synthetic methods for the
synthesis of this heterocyclic scaffold are now available.[2–14] Some of
them are really very fascinating from a synthetic chemist’s point. Despite
Received September 11, 2008.
Address correspondence to Kiumars Bahrami, Department of Chemistry, Razi
University, Kermanshah 67149, Iran. E-mail: kbahrami2@hotmail.com
1801

1802
K. Bahrami, M. M. Khodaei, and A. Farrokhi
Scheme 1. ZnO-catalyzed Biginelli reaction.
their tremendous success, however, some drawbacks still remain. For
example, some of the catalysts are expensive, complex, or unavailable,
and organic solvents are always used.
With the increase of environmental consciousness in chemical
research and industry, the solvent-free Biginelli reaction has attracted
much attention and received good results recently.[8,15,16] Herein we
report a general and practical route for the preparation of 3,4-dihydro-
pyrimidin-2-(1H)-ones using zinc oxide as a mild and reusable catalyst
(Scheme 1).
Zinc oxide (ZnO), a very inexpensive and easily available Lewis acid
catalyst, has been widely used in organic reactions, but it has not been
carefully studied as a catalyst in the Biginelli condensation until now,
except for a few mentions in the literature.[17]
To be able to carry out such a Biginelli condensation in a more
efficient way, minimizing the time, temperature, and amount of catalyst,
we performed a set of preliminary experiments on benzaldehyde as model
substrate, ethyl acetoacetate, and urea in the presence of different
amounts of zinc oxide under solvent-free conditions at 80ꢀC.
Table 1. Effect of increasing amount of ZnO on the preparation
of 3,4-dihydropyrimidin-2-(1H)-onesa
Entry
ZnO (mmol)
Yield (%)b
1
2
3c
4
0.05
0.1
0.125
0.25
43
75
97, 95, 92
98
aReaction conditions: The reactions were performed with
benzaldehyde (1 mmol), ethyl acetoacetate (1.3 mmol), and urea
(1.5 mmol) for 19 min at 80ꢀC under solvent-free conditions.
bIsolated yield.
cCatalyst was recycled three times.

Solvent-Free Synthesis of Dihydropyrimidinones
1803
The results are depicted in Table 1. As shown, a ratio of 1:1.3:
1.5:0.125 benzaldehye=1,3-dicarbonyl=urea=ZnO was found to be opti-
mal for the preparation of 3,4-dihydropyrimidin-2-(1H)-ones. The best
conversion was obtained when the reaction was run at 80ꢀC. An
increase in the reaction temperature and time did not improve the yields
significantly.
Although acetonitrile and ethanol were found to be effective, consid-
ering stringent environmental regulations, solvent-free reactions are
desired. Therefore, we intended the Biginelli reaction to be under solvent-
free conditions. The activity of the recycled catalyst was also examined
under the optimized conditions, and the desired product was obtained
in 97, 95, and 92% yields after one to three runs, respectively (Table 1,
entry 3).
Table 2. Zinc oxide–catalyzed synthesis of dihydropyrimidinones under
solvent-free conditions
Entry
R
R0
X
Time (min)
Yield (%)a,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
C6H5
4-MeC6H4
4-OHC6H4
4-NO2C6H4
4-NMe2C6H4
4-MeOC6H4
4-ClC6H4
CH3
CH3CH2CH2
4-MeC6H4
4-NO2C6H4
4-MeOC6H4
4-ClC6H4
C6H5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
Me
O
O
O
O
O
O
O
O
O
S
S
S
S
S
O
S
O
O
O
S
19
15
12
11
20
15
12
17
18
24
16
20
14
35
8
97
96
94
95
95
98
95
75
60
96
96
95
95
98
97
97
95
96
94
96
96
95
4-FC6H4
4-ClC6H4
4-MeOC5H4
4-NO2C6H4
4-FC6H4
C6H5
2-ClC6H4
4-MeOC6H4
10
10
6
8
8
Me
Me
Me
Me
S
S
11
18
Me
aThe products were characterized by comparison of their spectroscopic and
physical data with authentic samples synthesized by reported procedures.
bYields refer to pure isolated products.

1804
K. Bahrami, M. M. Khodaei, and A. Farrokhi
To extend the scope of the reaction and to generalize the procedure,
we investigated the reactions of a series of aromatic aldehydes with
(thio)urea and 3-oxo esters or acetylacetone under the optimized reaction
conditions. In all cases studied, the three-component reaction proceeded
smoothly to give the corresponding 3,4-dihydropyrimidin-2(1H)-ones in
satisfactory yields. Aromatic aldehydes carrying either electron-donating
or electron-withdrawing substituents reacted efficiently and gave excellent
yields. Even for aliphatic aldehydes, which usually show extremely poor
yields in the Biginelli reaction, 75% and 60% yields of the corresponding
dihydropyrimidin-2(1H)-ones 8 and 9 could be obtained. In addition,
thiourea were also used with similar success to provide the corresponding
3,4-dihydropyrimidin-2(1H)-thiones (Table 2).
A comparison of the catalytic efficiency of ZnO with selected
previously known catalysts is shown in Table 3 to demonstrate that the
present protocol is indeed superior to several of the other protocols.
In conclusion, we have described a new and simple modification
of the Biginelli reaction using inexpensive ZnO as a catalyst in solvent-
free conditions. The method offers several advantages including catalyst
recyclability, excellent yields, environmentally friendly procedure, short
reaction times, simple work up procedure, and easy isolation, which
make it a useful process for the synthesis of dihydropyrimidiones as
well as the thio-derivatives. Hence, it is a useful addition to the existing
methods.
Table 3. Comparison of protocols for the synthesis of dihydropyrimidin-2-(1H)
ones
Entry
1
Reagent=catalyst
Time
Yield (%)
ZnO
19 min
1 h
3 h
30 min
15 min
3 h
50 min
15 min
7 min
45 min
12 min
8 h
97
93
92
90
96
86
97
98
84
92
95
95
95
H3PMo12O40=CH3CN=80ꢀC[18]
ClCH2COOH=solvent-free=90ꢀC[19]
Cu(BF4)2ꢁxH2O=solvent-free=rt[20]
ZnO
2
6
7
ClCH2COOH=solvent-free=90ꢀC[19]
H3PW12O40=SiO2=CH3CN=80ꢀC[21]
ZnO
CH3COOH=MW[22]
HBF4=solvent-free=45ꢀC[23]
ZnO
TCCAa=Ethnol=reflux[24]
HPVMo11=EtOH=80ꢀC[25]
6 h
aTrichloroisocyanuric acid.

Solvent-Free Synthesis of Dihydropyrimidinones
EXPERIMENTAL
1805
Zinc oxide as well as urea, thiourea, b-dicarbonyls, and all the aldehydes
employed and substrates are commercial products (Merck) and were used
without further purification. Melting points were determined in a capil-
1
lary tube and are not corrected. H NMR and 13C NMR spectra were
recorded on a Bruker-200 NMR spectrometer using tetramethylsilane
(TMS) as internal standard.
General Procedures for One-Pot Preparation of 3,4-Dihydropyrimidiones
or Its Derivatives Using ZnO as a Catalyst
A mixture of aldehyde (1 mmol), b-dicarbonyl (1.3 mmol), urea or
thiourea (1.5 mmol), and ZnO (0.125 mmol, 0.01 g) was heated at 80ꢀC
under stirring for the time indicated in Table 2. Then, ethanol (15 mL)
was added to the reaction mixture, and it was stirred for 5 min at
80ꢀC. The reaction mixture was filtered to remove the catalyst, and the
filtrate was poured into cold water. The solid was suction filtered, washed
with cold water (20 mL ꢂ 2), filtered, and recrystallized from ethyl
acetate=n-hexane to afford pure product.
All products are known compounds and characterized easily by
comparison with authentic samples, except compounds 19, 21, and 22
(Table 2), whose spectral and analytical data are furnished.
Compound 19
Solid, mp 220ꢀC; 1H NMR (200 MHz, DMSO-d6): d ¼ 9.23 (br, 1H), 7.86
(br, 1H), 7.11–7.31 (m, 5H), 5.26 (d, J ¼ 3.48 Hz, 1H), 2.29 (s, COCH3)
2.12 (s, CH3); 13C NMR (50 MHz, DMSO-d6): d ¼ 195, 152.48, 148.73,
128.92, 128.76, 115.86, 115.44, 110.08, 53.48, 30.80, 19.37. Anal. calcd.
for C13H13N2O2F: C, 62.9; H, 5.3; N, 11.3. Found: C, 62.8; H, 5.4; N, 11.5.
Compound 21
1
Solid, mp 118ꢀC; H NMR (200 MHz, DMSO-d6): d ¼ 10.31 (br, 1H),
9.60 (br, 1H), 7.18–7.34 (m, 3H), 7.39–7.44 (m, 1H), 5.65 (d, J ¼ 3.72 Hz,
1H), 2.32 (s, COCH3), 2.07 (s, CH3); 13C NMR (50 MHz, DMSO-d6):
d ¼ 195, 174.34, 145.33, 140.16, 132.29, 130.16, 129.52, 128.36, 110.15,
52, 30.72, 18.60. Anal. calcd. for C13H13N2SOCl: C, 55.6; H, 4.7; N,
10.0; S, 11.42. Found: C, 55.4; H, 4.8; N, 9.8; S, 11.5.

1806
K. Bahrami, M. M. Khodaei, and A. Farrokhi
Compound 22
1
Solid, mp 173ꢀC; H NMR (200 MHz, DMSO-d6): d ¼ 10.30 (br, 1H),
9.75 (br, 1H), 7.20 (d, J ¼ 8.41 Hz, 2H), 6.95 (d, J ¼ 8.41 Hz, 2H), 5.27
(d, J ¼ 3.72 Hz, 1H), 3.86 (s, OCH3), 2.40 (s, COCH3) 2.17 (s, CH3);
13C NMR (50 MHz, DMSO-d6): d ¼ 195.25, 174.15, 159.12, 144.63,
135.42, 128.21, 114.34, 110.79, 55.46, 53.67, 30.63, 18.55. Anal. calcd.
for C14H16N2SO: C, 60.8; H, 5.8; N, 10.1; S, 11.6. Found: C, 60.6; H,
6.0; N, 10.3; S, 11.5.
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