Environmentally friendly preparation of 3,4-dihydropyrimidin-2(1H)-thiones catalyzed by Al(H2PO4)3

Article abstract of DOI:10.1080/10426500802080576

An efficient, facile, simple, and green synthetic protocol for the Biginelli reaction has been developed for the preparation of 3,4-dihydropyrimidin-2(1H)-thione derivatives under thermal and microwave irradiation, solvent-free conditions, in the presence

Full text of DOI:10.1080/10426500802080576

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Phosphorus, Sulfur, and Silicon
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Environmentally Friendly
Preparation of 3,4-
Dihydropyrimidin-2(1H)-
thiones Catalyzed by
Al(H2PO4)3
Hamid Reza Shaterian a , Asghar Hosseinian a &
Majid Ghashang a
a Department of Chemistry, Faculty of Sciences ,
University of Sistan and Baluchestan , Zahedan , Iran
Published online: 19 Dec 2008.
To cite this article: Hamid Reza Shaterian , Asghar Hosseinian & Majid Ghashang
(2008) Environmentally Friendly Preparation of 3,4-Dihydropyrimidin-2(1H)-thiones
Catalyzed by Al(H2PO4)3 , Phosphorus, Sulfur, and Silicon and the Related Elements,
184:1, 126-134, DOI: 10.1080/10426500802080576
To link to this article: http://dx.doi.org/10.1080/10426500802080576
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Phosphorus, Sulfur, and Silicon, 184:126–134, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802080576
Environmentally Friendly Preparation of
3,4-Dihydropyrimidin-2(1H)-thiones Catalyzed
by Al(H2PO4)3
Hamid Reza Shaterian, Asghar Hosseinian,
and Majid Ghashang
Department of Chemistry, Faculty of Sciences, University of Sistan and
Baluchestan, Zahedan, Iran
An efficient, facile, simple, and green synthetic protocol for the Biginelli reaction has
been developed for the preparation of 3,4-dihydropyrimidin-2(1H)-thione deriva-
tives under thermal and microwave irradiation, solvent-free conditions, in the
presence of aluminum hydrogen phosphate, Al(H2PO4)3, as an environmentally
friendly heterogeneous recyclable catalyst, in high to excellent yields and short re-
action time. In addition, the catalyst could be easily recovered from the reaction
mixture by simple filtration and reused several times without any loss of activity.
Keywords Al(H2PO4)3; Biginelli reaction; 3,4-dihydropyrimidin-2(1H)-thione; hetero-
geneous catalyst; multicomponent reaction
INTRODUCTION
Dihydropyrimidinones (DHPMs) and their derivatives have attracted
interest in medicinal chemistry, because they exhibit a wide range of bi-
ological, pharmacological and therapeutic properties.1 The dihydropy-
rimidinones (DHPMs) can serve as the integral backbones of several
calcium channel blockers.2 They are also reported to have antibacte-
rial, antiviral, antitumor, antiinflammatory, α-1a-antagonist, and neu-
ropeptide Y (NPY) antagonist activities.3 Recently, structurally simple
DHPM derivatives have emerged as a mitotic kinesin Eg5 motor pro-
tein inhibitor for the development of anticancer drugs.4 Furthermore,
the dihydropyrimidinone moiety in batzelladine alkaloids A and B in-
hibit the binding of HIV envelope protein gp-120 to human CD4 cells,
Received 16 January 2008; accepted 19 February 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, P. O. Box 98135-674, Zahedan, Iran.
E-mail: hrshaterian@hamoon.usb.ac.ir
126

Preparation of 3,4-Dihydropyrimidin-2(1H)-thiones
127
so that they are potential compounds in AIDS therapy.5 In addition,
the antioxidant activity of this ring system has been reported for re-
tarding a variety of human diseases, including diabetes and various
neurodegenerative diseases.6
The classical Biginelli reaction of an aldehyde, 1,3-dicarbonyl,
and urea or thiourea requires strongly acidic conditions with rel-
atively low yields, high reaction times, and harsh conditions.7
In order to improve the efficiency of the Biginelli reaction, sev-
eral Lewis and Brønsted catalysts, such as chlorotrimethylsilane,8
ferric chloride/tetraethyl orthosilicate,9 ruthenium(III) chloride,10
N-bromosuccinimide,11 ferric and nickel chloride hexahydrates,12
ammonium chloride,13 polystyrenesulfonic acid (PSSA),14 Yb(III)-
resin and polymer-supported scavengers,15 ZrCl4 or ZrOCl2,16 vana-
dium(III) chloride,17 sulfonic acid functionalized silica,18 ion ex-
change resins,19 Ziegler–Natta,20 PW, PMo, SiW,21 chloroacetic
acid,22 ferric chloride and boric acid,23 iron(III) trifluoroacetate
and trifluoromethanesulfonate,24 sulphamic acid,25 alkylammonium
and alkylimidazolium perhaloborates, phosphates, aluminates,26
1,1,3,3-tetrametylguanidinium trifluoroacetate,27 and ZnBr2 using α-
(benzotriazolyl)alkyl urea derivatives28 have been developed. However,
many of these methods are not environmentally sound in that they are
toxic chemicals, have low yields and very long reaction times, and use
heavy metallic salts that pollute the environment. Hence, there is a
clear need for a simple and practical methodology for the synthesis
of this useful class of molecules on a large scale. Therefore, introduc-
ing clean processes and utilizing ecofriendly and green catalysts that
can be simply recycled at the end of reactions have been under con-
stant attention. The demand for an environmentally benign procedure
with heterogeneous and reusable catalyst, prompted us to develop a
safe alternate method for the synthesis of 3,4-dihydropyrimidin-2(1H)-
thione derivatives in the presence of Al(H2PO4)3 as a solid acid catalyst
(Scheme 1).
R1
Al(H2PO4)3
(Cat)
H2N
H2N
CHO
+
O
O
O
S
+
R1
Method A, B
R2
R3
R2
NH
R3
N
S
R1= H, Cl, NO2,
OMe, OH, N(Me)2, F
R2= OEt, OMe, Me
R3= Me, Et
H
Method A : Solvent free, thermal conditions
Method B : Solvent free, Microwave irradiation
SCHEME 1

128
H. R. Shaterian et al.
This catalyst is safe, easy to handle, environmentally benign,
presents fewer disposal problems, and is stable in reaction media.
Al(H2PO4)3 has been used as catalyst for nitration of organic com-
pounds with nitric acid.29
RESULTS AND DISCUSSION
In order to carry out the Biginelli condensation in a more efficient
way that minimizes the time, temperature, and amount of catalyst, the
reaction of benzaldehyde, ethyl acetoacetate, and thiourea was selected
as model to investigate the effects of the catalyst at different reaction
temperatures (70, 100, and 120◦C) and tdiffering amounts of catalyst (8,
16, 31, and 39 mol%) for method A and the different power of microwave
irradiation (180 and 300 W) and the different amount of catalyst (16
and 31 mol%) for method B. The best result was obtained by carrying
out the reaction with 1:1.2:1.5 molar ratios of aldehyde, 1,3-dicarbonyl
compound, thiourea, and 16 mol% of Al(H2PO4)3 at 120◦C (Method A)
or 31 mol% of Al(H2PO4)3 at 180 W microwave power (Method B) in
solvent-free conditions (Table I).
Using these optimized reaction conditions, the scope and efficiency
of these procedures were explored for the synthesis of a wide variety
TABLE I Synthesis of Ethyl 1,2,3,4-Tetrahydro-6-methyl-4-phenyl-2-
thioxopyrimidine-5-carboxylate from the Reaction of Benzaldehyde,
Ethylacetoacetate, and Thiourea Using Different Quantities of
Al(H2PO4)3 as Catalyst
Method Aa
Time (min)/
Yield(%)b
Method Ba
Time (min)/
Yield (%)b
Catalyst
(Mol %)
MW
Power (W)
Entry
T (◦C)
1
2
3
4
5
6
7
8
9
39
31
16
8
16
16
16
31
31
120
120
120
120
100
70
–
–
–
–
–
–
–
–
19/95
22/90
25/92
38/78
60/85
95/50
–
–
–
–
–
–
–
–
300
300
180
20/76
10/75
20/82
–
–
aMolar ratio: benzaldehyde (1 mmol), ethylacetoacetate (1.2 mmol), and thiourea
(1.5 mmol).
bYields refer to the isolated pure product.

Preparation of 3,4-Dihydropyrimidin-2(1H)-thiones
129
TABLE II Al(H2PO4)3 Catalyzed Synthesis of 3,4-Dihydropyrimidin-
2(1H)-thiones Under Solvent-Free Thermal and Microwave
Irradiation Conditions
Method A
Method B
Time (min)/
Yield (%)a
Time (min)/
Yield (%)a
Entry
R1
R2
R3
[lit. Yield (%)]ref
m.p.◦C (lit m.p)ref
1
2
3
4
5
6
7
8
H
3-Cl
C2H5O CH3 25/(88–92)b [56]16 20/(78–82)b 206–207(206–207)16
C2H5O CH3
40/85 [60.1]16
60/75 [91]27
50/84 [82]20
45/65 [79]22
50/90 [83]22
45/78 [90]25
40/70 [88]25
30/92 [70]20
20/95 [83]16
50/86 [90.1]16
30/89 [89]16
25/90 [89]26
45/81 [74]26
45/80 [30.4]23
20/80
20/65
20/83
20/68
20/91
20/72
20/63
20/83
15/90
15/89
15/84
15/86
15/74
20/81
20/72
20/56
196–198(192–196)16
108–110(107–108)27
150–152(150–152)20
194–196(193–195)22
221–223(221–222)22
237–239(237)25
4-NO2 C2H5O CH3
3-MeO C2H5O CH3
4-HO
H
3-NO2
4-HO
4-(Me)2N CH3O CH3
H
2-Cl
3-Cl
4-F
4-NO2
H
C2H5O CH3
CH3O CH3
CH3O CH3
CH3O CH3
226–228(227)25
9
152–154(152–153)20
216–217(214–215)16
173–174 (173–174)16
244–246(243–245)16
209–211(209–212)26
207–209 (207–209)26
166–168 (168–169)23
161–162 (161–163)23
200–202 (201–203)23
10
11
12
13
14
15
16
17
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3O C2H5
4-Cl
3-NO2
CH3O C2H5 40/75 [25.87]23
CH3O C2H5 60/60 [16.06]23
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.14−27
bYield after the fifth recovery of the catalyst.
of substituted 3,4-dihydropyrimidin-2(1H)-thiones, and the results are
summarized in Table II.
As shown in Table II, aromatic aldehydes with both electron-
withdrawing and electron-donating substituents reacted efficiently
with thiourea and methyl/ethyl acetoacetate, acetylacetone, or methyl
propionylacetate afforded to the corresponding 3,4-dihydropyrimidin-
2(1H)-thiones without the formation of any side products, in high to
excellent yields (Table II, Entries 1–17). This protocol significantly im-
proves the yields of Biginelli products, and the reaction was carried out
under solvent-free conditions without using any toxic solvents.
In a typical experiment, after a period of time that the reaction was
completed, the mixture was diluted with ethyl acetate and the hetero-
geneous catalyst was recovered. In every experiment, the entirety of the
catalyst was easily recovered from the reaction mixture. The reusability

130
H. R. Shaterian et al.
TABLE III Comparison Results of Al(H2PO4)3 with Other Catalysts
Reported in the Literature
Conditions
Method A
(Catalyst)
Conditions
Method B
Time/Yield (%) (Catalyst)
Entry CatalystRef
Time/Yield (%)
1
2
3
4
Al(H2PO4)3
Solvent-free/
20–60 min/ Solvent-free/ 15–20 min/56–91
120◦C (16 mol%)
60–95
180 W
(31 mol %)
–
NH4Cl13 Solvent-free/100◦C
3 h/78–88
(40 mol%)
–
PSSA14
–
–
Solvent-free/ 20 min/86–88
100 W
(20 mol%)
Chloroacetic Solvent-free/90◦C
acid22
(10 mol%)
3 h/79–87
–
–
of the catalysts is one of the most important benefits that makes them
useful for commercial applications. Thus the recovery and reusability
of aluminum hydrogen phosphate, Al(H2PO4)3, was investigated. The
separated catalyst can be reused after washing with ethyl acetate and
drying at 100◦C. The reusability of the catalyst was checked by using
the reaction of benzaldehyde, ethyl acetoacetate, and thiourea in the
presence of Al(H2PO4)3 under thermal and microwave conditions. The
results indicate that the catalyst can be used five times without any
loss of activity (Table II, Entry 1).
To show the merit of the present work in comparison with re-
ported results in the literature, we compared results of Al(H2PO4)3
with ammonium chloride,13 polystyrenesulfonic acid (PSSA),14 and
chloroacetic acid22 in the synthesis of 3,4-dihydropyrimidin-2(1H)-
thione compounds. As shown in Table III, Al(H2PO4)3 can act as ef-
fective catalyst with respect to reaction times, yields, and the obtained
products.
CONCLUSION
In conclusion, we have developed a simple, cost-effective, and green pro-
cedure for the synthesis of 3,4-dihydropyrimidin-2(1H)-thione deriva-
tives using recyclable Al(H2PO4)3 catalyst under heterogeneous catal-
ysis conditions. Furthermore, the solvent-free microwave irradiation
and thermal conditions, high yield of products, short reaction time,
ease of work-up, compatibility with various functional groups, and the
ecologically clean procedure will make the present method a useful

Preparation of 3,4-Dihydropyrimidin-2(1H)-thiones
131
FIGURE 1 The reusability of Al(H2PO4)3 in the reaction of benzaldehyde,
ethyl acetoacetate, and thiourea under thermal (Method A) and microwave
(Method B) conditions.
and important addition to the present methodologies for the Biginelli
synthesis.
EXPERIMENTAL
All reagents were purchased from Merck and Aldrich and used without
further purification. All yields refer to isolated products after purifica-
tion. Products were characterized by comparison with authentic sam-
1
ples and by spectroscopy data (IR, H NMR). The NMR spectra were
recorded on a Bruker Avance DEX 300 MHz instrument. The spectra
were measured in DMSO-d6 relative to TMS (0.00 ppm). IR spectra
were recorded on a JASCO FT-IR 460plus spectrophotometer. Melting
points were determined in open capillaries with a BUCHI 510. TLC
was performed on silica-gel PolyGram SIL G/UV 254 plates.
Preparation of Al(H2PO4)3
The catalyst was prepared by taking a mixture of alumina (neutral)
and concentrated phosphoric acid (88%) in a silica boat maintaining the

132
H. R. Shaterian et al.
molar ratio of alumina: H3PO4 as 1:3 and heating at 200–220◦C on a hot
sand bath. The mixture was stirred at the stipulated temperature until
the swampy mass solidified and then the temperature was reduced
to around 100◦C. The whole was then placed in a vacuum desiccator
and cooled to ambient temperature. The catalyst thus prepared was
finally transferred and stored in an airtight sample vial. The catalyst
has been reported previously in the literature, and was characterized
by comparison of IR spectroscopy and the powder XRD with known
samples.29 The IR spectrum and powder XRD pattern matched well
with the literature.
Typical Experimental Procedure for the One-Pot Preparation of
5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-thione
A mixture of benzaldehyde (1 mmol), ethyl acetoacetate (1.2 mmol),
thiourea (1.5 mmol), and Al(H2PO4)3 (16 mol % for method A or
31 mol% for method B) was stirred at 120◦C (Method A) or the mix-
ture was inserted in a microwave oven (Samsung, model KE300R) and
heated at 180 W (Method B) for the appropriate time (Table II). After
completion of the reaction as indicated by TLC, the resulting solidi-
fied mixture was diluted with ethyl acetate (5 mL) and the catalyst
was separated by simple filtration and washed by ethyl acetate (2 ×
5 mL). The filtrate obtained was washed with water (2 × 10 mL) and
dried over anhydrous MgSO4. Evaporation of the solvent under reduced
pressure yielded crude product, which was purified by recrytallization
with ethanol to afford pure product in 92% and 82% yields for methods
A and B, respectively.
5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-thione (Table II, Entry 1)
1H NMR: δ = 9.19 (s, 1H), 7.73 (s, 1H), 7.22 (m, 5H), 5.14 (d, J= 3.6
Hz, 1H), 3.40 (q, J= 6.9 Hz, 2H), 2.24 (s, 3H), 1.09 (t, J= 6.9 Hz, 3H)
ppm; IR (KBr, cm−1): 2940, 1980, 1940, 1810, 1650, 1240, 1050, 790.
The spectral data of some representative products are given below:
5-(Methoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-thione (Table II, Entry 6)
1H NMR: δ = 10.37 (s, 1H), 9.68 (s, 1H), 7.21–7.37 (m, 4H), 5.18 (s,
1H), 3.55 (s, 3H), 2.30 (s, 3H) ppm; IR (KBr, cm−1): 3340, 1662, 1600,
1566.

Preparation of 3,4-Dihydropyrimidin-2(1H)-thiones
133
5-(Methoxycarbonyl)-6-methyl-4-(4-(dimethylamino)phenyl)-
3,4-dihydropyrimidin-2(1H)-thione (Table II, Entry 9)
1H NMR: δ = 9.95 (s, 1H), 9.30 (s, 1H), 7.16 (d, J= 9.1 Hz, 2H), 6.62
(d, J= 9.1 Hz, 2H), 5.13 (s, 1H), 3.60 (s, 3H), 2.92 (s, 6H), 2.30 (s, 3H)
ppm; IR (KBr, cm−1): 3280, 3185, 2928, 1710, 1651.
5-Acetyl-6-methyl-4(2-chlorophenyl)-3,4-dihydropyrimidin-
2(1H)-thione (Table II, Entry 11)
1H NMR: δ = 10.36 (s, 1H), 9.65 (d, J= 2.5 Hz, 1H), 7.48– 7.44 (m,
1H), 7.35–7.31 (m, 2H), 7.27–7.26 (m, 1H), 5.70 (d, J= 5 Hz, 1H), 2.38
(s, 3H), 2.12 (s, 3H) ppm; IR (KBr, cm−1): 3252, 1710, 1659, 855.
5-Acetyl-6-methyl-4(4-fluorophenyl)-3,4-dihydropyrimidin-
2(1H)-thione (Table II, Entry 13)
1H NMR: δ = 10.35 (s, 1H), 9.75 (s, 1H), 8.20 (d, J= 7.5 Hz, 2H), 7.55
(d, J= 7.5 Hz, 2H), 5.40 (d, J= 7.4 Hz, 1H), 2.35 (s, 3H), 2.25 (s, 3H)
ppm; IR (KBr, cm−1): 3288, 3144, 2896, 2765, 1697, 1637.
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