Al(HSO4)3 and Al2O3-SO 3H as efficient catalysts for modified preparation of 3,4-dihydropyrimidin-2 (1H)-ones/thiones

Article abstract of DOI:10.1080/10426500802454144

An environmentally friendly procedure for the preparation of dihydropyrimidinone derivatives or their sulfur analogues under thermal solvent-free conditions in the presence of aluminium hydrogen sulfate [Al(HSO₄)₃] and alumina sulfur

Full text of DOI:10.1080/10426500802454144

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Al(HSO4)3 and Al2O3-SO3H
as Efficient Catalysts for
Modified Preparation of 3,4-
Dihydropyrimidin-2 (1H)-ones/
thiones
Hamid Reza Shaterian a , Asghar Hosseinian a , Majid
Ghashang a , Fahimeh Khorami a & Neda Karimpoor a
a Department of Chemistry, Faculty of Sciences,
University of Sistan and Baluchestan, Zahedan, Iran
Version of record first published: 04 Sep 2009.
To cite this article: Hamid Reza Shaterian, Asghar Hosseinian, Majid Ghashang,
Fahimeh Khorami & Neda Karimpoor (2009): Al(HSO4)3 and Al2O3-SO3H as Efficient
Catalysts for Modified Preparation of 3,4-Dihydropyrimidin-2 (1H)-ones/thiones,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:9, 2333-2338
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Phosphorus, Sulfur, and Silicon, 184:2333–2338, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802454144
Al(HSO4)3 and Al2O3-SO3H as Efficient Catalysts
for Modified Preparation of 3,4-Dihydropyrimidin-2
(1H)-ones/thiones
Hamid Reza Shaterian, Asghar Hosseinian, Majid
Ghashang, Fahimeh Khorami, and Neda Karimpoor
Department of Chemistry, Faculty of Sciences, University of Sistan and
Baluchestan, Zahedan, Iran
An environmentally friendly procedure for the preparation of dihydropyrimidinone
derivatives or their sulfur analogues under thermal solvent-free conditions in the
presence of aluminium hydrogen sulfate [Al(HSO ) ] and alumina sulfuric acid
4 3
(Al O -SO H) as heterogeneous catalysts was developed.
2
3
3
Keywords Aluminium hydrogen sulfate; alumina sulfuric acid; Biginelli reaction; 3,4-
dihydropyrimidin-2(1H)-ones/thiones
INTRODUCTION
Dihydropyrimidinones (DHPMs) and their derivatives have attracted
interest in medicinal chemistry because they exhibit a wide range of
biological, pharmacological, and therapeutic properties.1 DHPMs can
serve as the integral backbones of several calcium channel blockers.2
They are also reported to have antibacterial, antioxidant, antiviral, an-
titumor, anti-inflammatory, α-1a-antagonist, and neuropeptide Y (NPY)
antagonist activities.3–6
The classical Biginelli reaction of an aldehyde, 1,3-dicarbonyl, and
urea or thiourea requires strongly acidic conditions with relatively low
yields, high reaction times, and harsh conditions.7 In order to im-
prove the efficiency of Biginelli reaction, a number of catalysts have
been developed. These include ammonium chloride,8 ZrCl4 or ZrOCl2,9
Received 16 April 2008; accepted 12 August 2008.
We are thankful to the Sistan and Baluchestan University Research Council for
partial support of this work.
Address correspondence to Hamid Reza Shaterian, Department of Chemistry, Faculty
of Sciences, University of Sistan and Baluchestan, PO Box 98135-674, Zahedan, Iran.
E-mail: hrshaterian@hamoon.usb.ac.ir
2333

2334
H. R. Shaterian et al.
vanadium(III) chloride,10 chloroacetic acid,11 graphite-supported lan-
thanum chloride,12 alkylammonium and alkylimidazolium perhalob-
orates, phosphates, and aluminates,13 1,1,3,3-tetrametylguanidinium
trifluoroacetate,14 ferric chloride and boric acid,15 sulphamic acid,16
tetrabutyl ammonium hydrogensulfate,17 and polyphosphate ester
(PPE).18 However, many of these methods suffer from the draw-
backs inconsistent with green chemistry, such as the use of toxic
chemicals and heavy metals. Therefore utilization of clean processes
as well as eco-friendly and green catalysts has been a subject of
intense research. The demand for environmentally benign proce-
dures with heterogeneous catalysts prompted us to develop a safe
alternate method for the synthesis of dihydropyrimidinones (DH-
PMs) as biologically important compounds in the presence Al(HSO4)3
and alumina sulfuric acid (Al2O3-SO3H) as heterogeneous catalysts
(Scheme 1).
SCHEME 1 The synthesis of dihydropyrimidinones (DHPMs) in the presence
of aluminum hydrogen sulfate and alumina sulfuric acid as catalysts.
In this research, Al(HSO4)3 and alumina sulfuric acid (Al2O3-SO3H)
as heterogeneous solid acid catalysts deserve special mention. These
catalysts are safe, easy to handle, environmentally benign, and present
fewer disposal problems. Al(HSO4)139 and alumina sulfuric acid (0.2 g of
alumina sulfuric acid equal to 0.6 mmol H+)20 were prepared according
to the reported procedures.
RESULTS AND DISCUSSION
In order to be able to carry out Biginelli condensation in a more efficient
way and minimizing the time, temperature, and amount of the catalyst,
the reaction of benzaldehyde, ethyl acetoacetate, and urea was selected
as a model system to investigate the effects of the catalyst at different
reaction temperatures (50, 60, 100, and 120◦C) and different amounts of
catalyst (5, 10, 15, 20, 25, and 30 mol%). The best result was obtained
by carrying out the reaction with 1:1.2:1.5 molar ratios of aldehyde,

Al(HSO ) and Al O -SO H as Efficient Catalysts
4 3
2335
2
3
3
1,3-dicarbonyl compound, urea and 10 mol% of Al(HSO4)3 at 100◦C
under thermal solvent-free conditions. We also used alumina sulfuric
acid (Al2O3-SO3H) as catalyst in the model system to find optimization
conditions at the same molar ratios. The best result was obtained by
using 15 mol% of Al2O3-SO3H at 120◦C.
Using these optimized reaction conditions, the scope and efficiency
of these procedures were explored for the synthesis of a wide variety of
substituted 3,4-dihydropyrimidin-2(1H)-ones or their sulfur analogues.
The results are summarized in Table I.
As shown in Table I, aromatic aldehydes with both electron-
withdrawing and electron-donating substituents reacted efficiently
with urea/thiourea and methyl/ethyl acetoacetate or acetylacetone in
the presence of a catalytic amount of Al(HSO4)3 (10 mol %) or Al2O3-
SO3H (15 mol%), forming the corresponding 3,4-dihydropyrimidin-
2(1H)-ones/thiones without the formation of any side products, in good
to high yields (Table I).
TABLE I Synthesis of 3,4-Dihydropyrimidin- 2(1H)-ones/thiones
Al(HSO4)3 Al2O3-SO3H
Time (min)/
Time (h)/
Entry
R1
R2
X
Yield (%)a
Yield (%)a
mp◦C (lit mp◦C )
1
2
3
4
5
6
7
8
C6H5
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
CH3O
CH3O
CH3O
CH3O
CH3O
O
O
O
S
S
S
S
S
O
O
S
S
S
S
O
S
S
S
S
S
35/79
55/90
150/55
30/80
110/83
90/79
100/76
50/60
20/92
15/74
10/87
30/86
10/77
110/67
20/90
15/91
40/82
15/80
25/92
25/74
2.1/88
1.6/94
3.3/69
2.7/81
1.5/81
2.5/83
1.7/73
2.1/75
1.7/85
2.7/74
1.8/84
2.7/68
1.1/81
1.5/70
0.6/93
1.1/93
1.6/88
1.1/87
0.7/93
1.6/81
203–205 (200–202)8
210–212 (209–211)8
195–197 (196–197)11
205–207 (205–206)8
196–198 (192–196)9
108–110 (107–108)14
150–152 (150–152)12
194–196 (193–195)11
252–254 (252–253)11
276–278 (279–280)8
221–223 (221–222)11
237–239 (237)16
4-ClC6H4
(CH3)2CH
C6H5
3-ClC6H4
4-NO2C6H4
3-OMeC6H4
4-HOC6H4
2,4-Cl2C6H3
3-NO2C6H4
C6H5
3-NO2C6H4
4-HOC6H4
4-(Me)2NC6H4 CH3O
C6H5
C6H5
9
10
11
12
13
14
15
16
17
18
19
20
226–228 (227)16
152–154 (152–153)12
234–236 (232–235)8
216–217 (214–215)9
173–174 (173–174)9
244–246 (243–245)9
209–211 (209–212)13
207–209 (207–209)13
CH3
CH3
CH3
CH3
CH3
CH3
2-ClC6H4
3-ClC6H4
4-FC6H4
4-NO2C6H4
aYields refer to the pure isolated products. All known products have been reported
previously in the literature and were characterized by comparison of melting points,
and IR and NMR spectra with authentic samples.8−18

2336
H. R. Shaterian et al.
TABLE II Comparison of the Results of Al(HSO4)3 and Al2O3-SO3H
with Other Catalysts Reported in the Literature
Entry
Catalyst (mol %)
Conditions (molar ratio)a
Time/Yield (%)
1
2
3
4
5
6
Al(HSO4)3 (10)
Al2O3-SO3H(15)
NH4Cl (40)
ZrOCl2.8H2O (15)
VCl3 (10)
Solvent-free/100◦C (1/1.2/1.5)
Solvent-free/120 ◦C (1/1.2/1.5)
Solvent-free/100◦C (1/1/1.5)
Solvent-free/90–100◦C (1/1/1.3)
CH3CN/Reflux (1/1/1.5)
10–150 min/55–92
0.6–3.3 h/68–94
3 h/42–92
30–180 min/40–99
2 h/65–96
Chloroacetic acid (10)
Solvent-free/90 ◦C (1/1.1/1.5)
3 h/47–98
aThe molar ratio of aldehyde/1,3-dicarbonyl compounds/urea or thiourea.
To show the merit of the present work in comparison with reported
results in the literature, we compared results of aluminium hydrogen
sulfate and alumina sulfuric acid with ammonium chloride,8 ZrOCl2,9
vanadium(III) chloride,10 and chloroacetic acid11 in the synthesis of
Biginelli compounds. As shown in Table II, Al(HSO4)3 and Al2O3-SO3H
can act as effective catalysts with respect to reaction times, yields, and
the obtained products.
In conclusion, we have developed a simple, cost-effective, and green
procedure for the synthesis of 3,4-dihydropyrimidinones/thiones using
aluminium hydrogen sulfate and alumina sulfuric acid as heteroge-
neous catalysts under thermal solvent-free conditions.
EXPERIMENTAL
All reagents were purchased from Merck and Aldrich and used with-
out further purification. All yields refer to isolated products after pu-
rification. Products were characterized by comparison with authentic
samples and by spectroscopy data (IR and 1H NMR spectra). The NMR
spectra were recorded on a Bruker Avance DPX 300 MHz instrument.
Mass spectra were recorded on an Agilent Technologies 5973 network
mass selective detector (MSD) operating at an ionization potential of 70
eV. Melting points were determined in open capillaries with a BUCHI
510 melting point apparatus. TLC was performed on silica-gel polygram
SIL G/UV 254 plates.
Typical Experimental Procedure for the One-Pot Preparation
of 5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-one
A mixture of benzaldehyde (4 mmol), ethyl acetoacetate (4.8 mmol),
urea (6 mmol), and Al(HSO4)3 (0.4 mmol) at 100◦C or Al2O3-SO3H

Al(HSO ) and Al O -SO H as Efficient Catalysts
4 3
2337
2
3
3
(0.2 g, 0.6 mmol H+) at 120 ◦C was stirred in an oil bath for the appropri-
ate time (Table I). After completion of the reaction as indicated by TLC,
the resulting solidified mixture was diluted with ethyl acetate (5 mL),
and the catalyst was separated by simple filtration and washed with
ethyl acetate (2 × 5 mL). The filtrate obtained was washed with water
(2 × 10 mL) and dried over anhydrous MgSO4. Evaporation of the sol-
vent under reduced pressure yielded crude product, which was purified
by recrystallization with ethanol to afford pure 5-(Ethoxycarbonyl)-6-
methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (Table I, Entry 1).
The desired pure products were characterized by comparison of
their physical data with those of known 3,4-dihydropyrimidin-2(1H)-
ones/thiones, which are reported in the litrature.8–18
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