An efficient synthesis of multi-substituted 3,4-Dihydropyrimidin-2(1H)- ones/thiones under solvent-free microwave irradiation using alumina sulfuric acid

Article abstract of DOI:10.1080/10426500802083182

A new and efficient method for the synthesis of multi-substituted dihydropyrimidinone derivatives or their sulfur analogs has been developed under solvent-free microwave irradiation conditions in the presence of alumina sulfuric acid (Al₂O₃-SO₃H) as an environmentally friendly heterogeneous recyclable catalyst, in high yields and short reaction time.

Full text of DOI:10.1080/10426500802083182

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An Efficient Synthesis of
Multi-Substituted 3,4-
Dihydropyrimidin-2(1H)-ones/
thiones Under Solvent-Free
Microwave Irradiation Using
Alumina Sulfuric Acid
a
a
Hamid Reza Shaterian , Asghar Hosseinian
&
a
Majid Ghashang
a
Department of Chemistry, Faculty of Sciences,
University of Sistan and Baluchestan, Zahedan, Iran
Version of record first published: 19 Dec 2008.
To cite this article: Hamid Reza Shaterian, Asghar Hosseinian & Majid Ghashang
(2008): An Efficient Synthesis of Multi-Substituted 3,4-Dihydropyrimidin-2(1H)-
ones/thiones Under Solvent-Free Microwave Irradiation Using Alumina Sulfuric Acid,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:1, 197-205
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Phosphorus, Sulfur, and Silicon, 184:197–205, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802083182
An Efficient Synthesis of Multi-Substituted
3
,4-Dihydropyrimidin-2(1H)-ones/thiones Under
Solvent-Free Microwave Irradiation Using Alumina
Sulfuric Acid
Hamid Reza Shaterian, Asghar Hosseinian,
and Majid Ghashang
Department of Chemistry, Faculty of Sciences, University of Sistan and
Baluchestan, Zahedan, Iran
A new and efficient method for the synthesis of multi-substituted dihydropyrim-
idinone derivatives or their sulfur analogs has been developed under solvent-free
microwave irradiation conditions in the presence of alumina sulfuric acid (Al2O3-
SO3H) as an environmentally friendly heterogeneous recyclable catalyst, in high
yields and short reaction time.
Keywords Biginelli reaction; dihydropyrimidinone/thione; heterogeneous catalyst;
microwave; multi-component reaction; solvent-free
INTRODUCTION
Dihydropyrimidinones (DHPMs) and their derivatives have attracted
interest in medicinal chemistry, as they exhibit a wide range of biologi-
1
cal, pharmacological, and therapeutic properties. DHPMs can serve as
2
the integral backbones of several calcium channel blockers. They are
also reported to have antibacterial, antiviral, antitumor, antiinflamma-
3
tory, α-1a-antagonist, and neuropeptide Y (NPY) antagonist activities.
Recently, structurally simple DHPM derivatives have emerged as a mi-
totic kinesin Eg5 motor protein inhibitor for the development of anti-
4
cancer drugs. Furthermore, the dihydropyrimidinone moiety in batzel-
ladine alkaloids A and B inhibit the binding of HIV envelope protein
gp-120 to human CD4 cells, so that they are potential compounds in
Received 3 March 2008; accepted 27 March 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
197

198
H. R. Shaterian et al.
5
AIDS therapy. In addition, the antioxidant activity of this ring system
has been reported for retarding a variety of human diseases, including
6
diabetes and various neurodegenerative diseases.
The classical Biginelli reaction of an aldehyde, 1,3-dicarbonyl, and
urea or thiourea requires strongly acidic conditions with relatively low
7
yields, high reaction times, and harsh conditions. In order to improve
the efficiency of Biginelli reaction, many Lewis and Brønsted catalysts,
8
9
such as chlorotrimethylsilane, ferric chloride/tetraethyl orthosilicate,
1
0
11
ruthenium(III) chloride, N-bromosuccinimide, ferric and nickel
chloride hexahydrates, ammonium chloride, polystyrenesulfonic
acid (PSSA), Yb(III)-resin and polymer-supported scavengers, ZrCl4
or ZrOCl2, vanadium(III) chloride, sulfonic acid functionalized
silica, ion exchange resins, Ziegler–Natta, PW, PMo, SiW,
chloroacetic acid, ferric chloride and boric acid, iron(III) triflu-
oroacetate and trifluoromethanesulfonate, sulphamic acid, alky-
lammonium and alkylimidazolium perhaloborates, phosphates, and
1
2
13
1
4
15
1
6
17
1
8
19
20
21
2
2
23
2
4
25
aluminates, 1,1,3,3-tetrametylguanidinium trifluoroacetate,27 and
LaCl3-graphite28 have been developed. However, many of these meth-
ods are not green, as they use toxic chemicals, have low yields and very
long reaction times, and also use heavy metallic salts that pollution
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, introducing clean processes and utilizing eco-
friendly and green catalysts that can be simply recycled at the end
of reactions have been under constant attention. The demand for an
environmentally benign procedure with a heterogeneous and reusable
catalyst prompted us to develop a safe alternate method for the syn-
thesis of DHPMs as biologically important compounds in the presence
of Al2O3-SO3H as catalyst (Scheme 1).
26
This catalyst is safe, easy to handle, environmentally benign,
presents fewer disposal problems, and is stable in reaction media. Alu-
mina sulfuric acid was prepared according to the preparation of silica
2
9
sulfuric acid. It has been used in some organic reactions, such as
O
R1
Al O -SO H (Cat)
H N
2
3
3
O
O
2
R2
NH
1
+
+
X
R CHO
R2
R3
Solvent-free,
Microwave irradiation
H N
R3
2
N
H
X
1
2
R =Aryl, Alkyl
R = OEt, OMe, Me
X=O, S
3
R = Et, Me, Ph
SCHEME 1

Efficient Synthesis of Multi-Substituted 3,4-Dihydropyrimidin-2(1H)-ones/thiones 199
esterification of carboxylic acids30a 0abnd synthesis of keto- and ald-
oximes in Beckman rearrangement.3
RESULTS AND DISCUSSION
In order to be able to carry out Biginelli condensation in a more efficient
way that minimizes time, microwave power irradiation, and the amount
of catalyst, the reaction of benzaldehyde, ethyl acetoacetate, and urea
was selected as a model. The best result was obtained by carrying
out the reaction with 1:1.2:1.5 molar ratios of aldehyde, 1,3-dicarbonyl
compound, urea and 15 mol% of Al2O3-SO3H at 180W microwave power
in solvent-free conditions.
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 analogs.
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 and methyl/ethyl acetoacetate, or acetylacetone in the pres-
ence of catalytic amount of Al2O3-SO3H (15 mol %) gave the correspond-
ing 3,4-dihydropyrimidin-2(1H)-ones without the formation of any side
products, in high to excellent yields (Table I, Entries 1–5, 11–15, and
2
0–23). Under the optimized reaction conditions, by using thiourea in
place of urea, aldehydes were transformed to their corresponding 3,4-
dihydropyrimidin-2(1H)-thiones in high yield (Table I, Entries 6–10,
1
6–19, and 24–33), which are also of interest for their biological activi-
ties. The aliphatic aldehydes, which are known to be less reactive under
conventional Biginelli reaction conditions, also reacted smoothly to af-
ford high yields (Table I, Entries 5 and 15). This protocol significantly
improves the yields of Biginelli products, and the reaction was carried
out under solvent-free conditions without using any toxic solvents that
pollute the environment.
The suggested mechanism of the Al2O3-SO3H–catalyzed transfor-
mation is shown in Scheme 2. The first step in the mechanism is the
condensation between the aldehyde and urea/thiourea, with some sim-
ilarities to Mannich condensation. The acyl imine intermediate gen-
erated acts as an electrophile for the nucleophilic addition of the keto
enol ether, and the carbonyl ketone of the resulting adduct undergoes
condensation with the urea NH2 to give the cyclized Biginelli product.
In conclusion, we have described a rapid and highly effi-
cient method for the green synthesis of multi-substituted 3,4-
dihydropyrimidinones/thiones using reusable alumina sulfuric acid as

200
H. R. Shaterian et al.
TABLE I Al
2
O
3
-SO
3
H–Catalyzed Synthesis of 3,4-Dihydropyrimidin-
2
(1H)-ones/thiones Under Solvent-Free Microwave Irradiation
Conditions
Time (min)
/Yield (%)
R1
R2
R3
X
a
m.p C (lit. m.p)
◦
ref
Entry
1
1
2
2
2
1
1
2
2
2
1
2
1
2
2
2
6
3
0
0
2
6
6
7
0
2
3
2
3
2
2
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
C6H5
4-ClC6H4
1-Naphthyl
Ph CH CH
(CH3)2CH
C6H5
3-ClC6H4
4-NO2C6H4
3-MeOC6H4
4-HOC6H4
C6H5
2,4-Cl2C6H3
3-NO2C6H4
4-MeC6H4
(CH3)2CH
C6H5
3-NO2C6H4
4-HOC6H4
4- (Me)2NC6H4
C6H5
3-ClC6H4
4-NO2C6H4
4-MeOC6H4
C6H5
2-ClC6H4
3-ClC6H4
4-FC6H4
4-NO2C6H4
C6H5
4-MeOC6H4
C6H5
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5O C6H5
C2H5O C6H5
CH3O
CH3O
CH3O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
O
O
O
O
O
S
S
S
S
S
O
O
O
O
O
S
S
S
S
O
O
O
O
S
S
S
S
S
S
S
S
S
S
2 / 88
1.5 / 93
2 / 79
2.5 / 80
3 / 72
2.5 / 80
1.5 / 81
2.5 / 83
1.5 / 74
2 / 87
1.5 / 79
1.5 / 82
2.5 / 74
1.5 /89
3 / 69
1.5 / 84
2.5 / 68
1 / 92
1.5 / 90
0.5 / 91
1 / 87
1.5 / 80
1 / 93
1 / 91
205–207 (205–206)
211–213 (209–211)
255–257 (256–258)
232–234 (230–232)
195–197 (196–197)
206–207 (206–207)
196–198 (192–196)
108–110 (107–108)
150–152 (150–152)
194–196 (193–195)
210–212 (207–209)
252–254 (252–253)
276–278 (279–280)
208–210 (210–213)
215–217 (217–218)
221–223 (221–222)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
25
5
237–239 (237)
226–228 (227)
2
2
2
1
0
6
6
7
152–154 (152–153)
234–236 (235–236)
233–235 (229–231)
2
230(dec) (229(dec))
177–179 (175–178)
216–217 (214–215)
173–174 (173–174)
244–246 (243–245)
209–211 (209–212)
207–209 (207–209)
179–181 (183–185)
147–149 (151–152)
166–168 (168–169)
183–185 (183–185)
200–202 (201–203)
27
16
16
16
26
26
16
16
23
23
23
1.5 / 89
1 / 86
0.5/ 93
1.5 / 81
2 / 74
1.5 / 80
1.5 / 80
1.5 / 86
2 / 67
C2H5
C2H5
C2H5
2-ClC6H4
3-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,
8–28
IR, and NMR spectra with authentic samples.
a catalyst under heterogeneous catalysis conditions and also under
solvent-free microwave irradiation reaction conditions. With such suc-
cessful results, this convenient and efficient protocol should provide
a superior alternative to the existing methods because of its fast and

Efficient Synthesis of Multi-Substituted 3,4-Dihydropyrimidin-2(1H)-ones/thiones 201
X
X
CHO
+
H N
2
N
Al O -SO H
2
3
3
X
H N
2
NH2
-H O
2
H
X
O
O
Al O -SO H
2
3
3
R2
R3
X
X
Al O -SO H
2
3
3
O
X
OH
H N
NH
O
O
H N
2
NH
2
R2
R3
R3
H
X
X
R2
-
H O
2
HN
O
NH
R3
X
R2
SCHEME 2
clean reactions and high yields. Furthermore, its simple work-up proce-
dure will make the present method a useful and important for Biginelli
synthesis.
EXPERIMENTAL
All reagents were purchased from Merck and Aldrich and were used
without further purification. All yields refer to isolated products after
purification. Products were characterized by comparison with authentic
1
samples and by spectral data (IR, H NMR spectra). The NMR spectra
were recorded on a Bruker Avance DPX 500 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.

202
H. R. Shaterian et al.
Preparation of Alumina Sulfuric Acid
The idea for synthesis of alumina sulfuric acid is based on the prepara-
tion of silica sulfuric acid that it was first synthesized by Zolfigol29 as
following procedure.
A 500 mL suction flask was used. It was equipped with a con-
stant pressure-dropping funnel containing chlorosulfonic acid (14 mL,
2
10 mmol) and a gas inlet tube for conducting HCl gas over adsorb-
ing solution, e.g., water. Charged alumina (51 g, 510 mmol) was placed
into it. Chlorosulfonic acid was added dropwise over a period of 30 min
at room temperature. HCl gas evolved from the reaction vessel imme-
diately. After the addition was complete, the mixture was shaken for
6
0 min. A white solid alumina sulfuric acid (0.2 g, 0.6 mmol) of 67.0 g
+
was obtained. The amount of H in the alumina sulfuric acid was de-
termined by acid-base titration according to the reaction in Equation 1.
ꢀ
⊕
Al2O3 − SO3H + H2O −→ Al2O3 − SO + H3O
(1)
3
+
The librated H3O was titrated by standard NaOH, and the amount of
+
H
in alumina sulfuric acid was calculated (0.2 g of alumina sulfuric
acid equal to 0.6 mmol).
Typical Experimental Procedure for the One-Pot Preparation of
5
-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-
(1H)-one
2
A mixture of benzaldehyde (10 mmol), ethyl acetoacetate (12 mmol),
+
urea (15 mmol), and Al2O3-SO3H (0.5 g, 1.5 mmol H ) was placed in
a microwave oven (Samsung, model KE300R) and heated at 180 W
for the appropriate time. See Table I. After completion of the reac-
tion as indicated by TLC, the resulting solidified mixture was di-
luted with ethyl acetate (5 mL), and the catalyst was separated by
simple filtration and washed with ethyl acetate (2 × 5 mL). The fil-
trate obtained was washed with water (2 × 10 mL) and dried over
anhydrous MgSO4. Evaporation of the solvent under reduced pres-
sure yielded crude product, which was purified by recrystallization
with ethanol to afford pure 5-(ethoxycarbonyl)-6-methyl-4-phenyl-3,4-
1
dihydropyrimidin-2(1H)-one in 88% yield (Table I, Entry 1); H NMR
(
5
DMSO-d6, 300 MHz): δ = 9.21 (s, 1H), 7.76 (s, 1H), 7.42–7.27 (m, 5H),
.19 (d, J= 2.7 Hz, 1H), 4.02 (q, J= 7,2 Hz, 2H), 2.29 (s, 3H), 1.12 (t,
−1
J= 7,2 Hz, 3H) ppm; IR (KBr, cm ): 3250, 2940, 2900, 1720, 1690,
1
630, 1210, 750.
Similarly, other aldehydes were reacted with urea/thiourea
and β-dicarbonyl compounds to obtain the corresponding

Efficient Synthesis of Multi-Substituted 3,4-Dihydropyrimidin-2(1H)-ones/thiones 203
3
,4-dihydropyrimidin-2(1H)-ones/thiones. The Biginelli pure prod-
uct(s) was characterized by comparison of their physical data with
those of authentic samples. The spectral data of some representative
products are given below.
5
-(Ethoxycarbonyl)-6-methyl-4(4-chlorophenyl)-3,4-
dihydropyrimidin-2(1H)-one (Table I, Entry 2)
1
H NMR (DMSO-d6, 300 MHz): δ = 9.27 (s, 1H), 7.78 (s, 1H), 7.38 (d,
J= 8.5 Hz, 2H), 7.25 (d, J= 8.5 Hz, 2H), 5.14 (d, J= 3.6Hz, 1H), 3.53 (s,
−1
3
1
H), 2.25 (s, 3H) ppm; IR (KBr, Cm ): 3243, 3238, 3114, 2950, 2875,
702, 1645, 840.
5
-(Ethoxycarbonyl)-6-methyl-4(naphthalen-1-yl)-3,4-
dihydropyrimidin-2(1H)-one (Table I, Entry 3)
1
H NMR (DMSO-d6, 300 MHz): δ = 9.28 (s, 1H), 8.31 (d, J= 7.9 Hz,
1H), 7.95 (m, 2H), 7.78 (s, 1H), 7.55 (m, 4H), 6.09 (d, J= 2.7 Hz, 1H),
.82 (q, J= 7.03 Hz, 2H), 2.39 (s, 3H), 0.83 (t, J= 7.03 Hz, 3H) ppm; IR
3
−1
(KBr, cm ): 3423, 3252, 2978, 1701, 1596.
5
-(Ethoxycarbonyl)-6-methyl-4(cinnamyl)-3,4-
dihydropyrimidin-2(1H)-one (Table I, Entry 4)
1
H NMR (DMSO-d6, 300 MHz): δ = 9.13 (s, 1H), 7.54 (s, 1H), 7.19-
7.40 (m, 5H), 6.35 (d, J= 15.9, 1H), 6.18 (dd, J = 15.9, 15.5 Hz, 1H),
.72 (dd, J= 5.5, 3.4 Hz, 1H), 3.06 (q, J= 7,2 Hz, 2H), 2.20 (s, 3H), 1.18
4
(
t, J= 7,2 Hz, 3H) ppm; IR (KBr, cm−1): 3246, 2979, 1704, 1650.
5
-(Methoxycarbonyl)-6-methyl-4-(2,4-dichlorophenyl)-3,4-
dihydropyrimidin-2(1H)-one (Table I, Entry 12)
1
H NMR (DMSO-d6, 300 MHz): δ = 9.34 (s, 1 H), 7.77 (s, 1H), 7.58 (s,
1
H), 7.34 (d, J= 8.4 Hz, 1H), 7.30 (d, J= 8.4 Hz), 5.60 (s, 1H), 3.48 (s,
1
−
3
H), 2.57 (s, 3H) ppm; IR (KBr, cm ): 3362, 1697, 1647, 845, 820.
5
-(Methoxycarbonyl)-6-methyl-4-(4-(N,N-
dimethylamino)phenyl)-3,4-dihydropyrimidin-2(1H)-thione
1
H NMR (DMSO-d6, 300 MHz): 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
−1
(
s, 6H), 2.30 (s, 3H) ppm; IR (KBr, cm ): 3280, 3185, 2928, 1710, 1651.
REFERENCES
[1] (a) C. O. Kappe, Acc. Chem. Res., 33, 879 (2000); (b) C. O. Kappe, Tetrahedron, 49,
6937 (1993); (c) C. O. Kappe, Eur. J. Med. Chem., 35, 1043 (2000).

204
H. R. Shaterian et al.
[
2] (a) K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd, S. Moreland, A. Hedberg,
and B. C. O’Reilly, J. Med. Chem., 34, 806 (1991); (b) G. C. Rovnyak, K. S. Atwal, A.
Hedberg, S. D. Kimball, S. Moreland, J. Z. Gougoutas, B. C. O’Reilly, J. Schwartz,
and M. F. Malley, J. Med. Chem., 35, 3254 (1992); (c) G. J. Grover, S. Dzwonczyk,
D. M. McMullen, D. E. Normandin, C. S. Parham, P. G. Sleph, and S. J. Moreland,
Cardiovasc. Pharmacol., 26, 289 (1995).
[
3] (a) D. Nagarathnam, S. W. Miao, B. Lagu, G. Chiu, J. Fang, T. G. M. Dhar, J. Zhang,
S. Tyagarajan, M. R. Marzabadi, F. Q. Zhang, W. C. Wong, W. Y. Sun, D. Tian, J.
M. Wetzel, C. Forray, R. S. L. Chang, T. P. Broten, R. W. Ransom, T. W. Schorn,
T. B. Chen, S. O’Malley, P. Kling, K. Schneck, R. Benedesky, C. M. Harrell, K. P.
Vyas and C. Gluchowski, J. Med. Chem., 42, 4764 (1999); (b) T. G. Murali Dhar, D.
Nagarathnam, M. R. Marzabadi, B. Lagu, W. C. Wong, G. Chiu, S. Tyagarajan, S. W.
Miao, F. Zhang, W. Sun, D. Tian, Q. Shen, J. Zhang, J. M. Wetzel, C. Forray, R. S. L.
Chang, T. P. Broten, T. W. Schorn, T. B. Chen, S. O’Malley, R. Ransom, K. Schneck,
R. Bendesky, C. M. Harrell, K. P. Vyas, K. Zhang, J. Gilbert, D. J. Pettibone, M. A.
Patane, M. G. Bock, R. M. Freidinger, and C. Gluchowski, J. Med. Chem., 42, 4778
(1999); (c) J. C. Barrow, P. G. Nantermet, H. G. Selnick, K. L. Glass, K. E. Rittle,
K. F. Gilbert, T. G. Steele, C. F. Homnick, R. M. Freidinger, R. W. Ransom, P. Kling,
D. Reis, T. P. Broten, T. W. Schorn, R. S. L. Chang, S. S. O’Malley, T. V. Olah, J. D.
Ellis, A. Barrish, K. Kassahun, P. Leppert, D. Nagarathnam, and C. Forray, J. Med.
Chem., 43, 2703 (2000).
[
4] (a) T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King, S. L. Schreiber, and T. J.
Mitchison, Science, 286, 971 (1999); (b) S. J. Haggarty, T. U. Mayer, D. T. Miyamoto,
R. Fathi, R. W. King, T. J. Mitchison, and S. L. Schreiber, Chem. Biol., 7, 275 (2000).
5] (a) K. S. Atwal, G. C. Rovnyak, S. D. Kimball, D. M. Floyd, S. Mereland, B. N.
Swanson, D. Z. Gougoutas, J. Schewartz, K. M. Smillie, and M. F. Malley, J. Med.
Chem., 33, 2629 (1990); (b) K. S. Atwal, G. C. Rovnyak, B. C. O’Reilly, and J.
Schewartz, J. Org. Chem., 54, 5898 (1989).
[
[
6] (a) J. J. Haddad, Free Radical Biol. Med., 33, 907 (2002); (b) H. A. Stefani, C. B.
Oliveira, R. B. Almeida, C. M. P. Pereira, R. C. Braga, R. Cella, V. C. Borges, L.
Savegnago, and C. W. Nogueira, Eur. J. Med. Chem., 41, 513 (2006).
7] P. Biginelli, Gazz. Chim. Ital., 23, 360 (1893).
[
[
8] S. V. Ryabukhin, A. S. Plaskon, E. N. Ostapchuk, D. M. Volochnyuk, and A. A.
Tolmachev, Synthesis, 417 (2007).
[
9] I. Cepanec, M. Litvi c´ , A. Bartolin cˇ i c´ , and M. Lovri c´ , Tetrahedron, 61, 4275 (2005).
[10] J. H. Schauble, E. A. Trauffer, P. P. Deshpande, and R. D. Evans, Synthesis, 1333
(2005).
[
[
[
[
[
[
11] H. Hazarkhani and B. Karimi, Synthesis, 1239 (2004).
12] J. Lu and Y. Bai, Synthesis, 466 (2002).
13] A. Shaabani, A. Bazgir, and F. Teimouri, Tetrahedron Lett., 44, 857 (2003).
14] V. Polshettiwar and R. S. Varma, Tetrahedron Lett., 48, 7343 (2007).
15] A. Dondoni and A. Massi, Tetrahedron Lett., 42, 7975 (2001).
16] J. C. Rodriguez-Dominguez, D. Bernardi, and G. Kirsch, Tetrahedron Lett., 48, 5777
(
2007).
17] G. Sabitha, G. S. K. K. Reddy, K. B. Reddy, and J. S. Yadav, Tetrahedron Lett., 44,
497 (2003).
[
6
[18] R. Gupta, S. Paul, and R. Gupta, J. Mol. Catal. A: Chem., 266, 50 (2007).
[19] J. K. Joseph, S. L. Jain, and B. Sain, J. Mol. Catal. A: Chem., 247, 99 (2006).
[20] A. Kumar and R. A. Maurya, J. Mol. Catal. A: Chem., 272, 53 (2007).
[21] E. Rafiee and H. Jafari, Bioorg. Med. Chem. Lett., 16, 2463 (2006).

Efficient Synthesis of Multi-Substituted 3,4-Dihydropyrimidin-2(1H)-ones/thiones 205
[22] Y. Yu, D. Liu, C. Liu, and G. Luo, Bioorg. Med. Chem. Lett., 17, 3508 (2007).
[23] I. S. Zorkun, S. Sarac, S. Celebib, and K. Erol, Bioorg. Med. Chem., 14, 8582(2006).
[24] H. Adibi, H. A. Samimi, and M. Beygzadeh, Catal. Commun., 8, 2119 (2007).
[25] S. A. Kotharkar, M. R. Jadhav, R. R. Nagawade, S. S. Bahekar, and D. B. Shinde,
Lett. Org. Chem., 2, 662 (2005).
[26] E. S. Putilova, G. V. Kryshtal, G. M. Zhdankina, N. A. Troitskii, and S. G. Zlotin,
Russ. J. Org. Chem., 41, 512 (2005).
[27] A. Shaabani and A. Rahmati, Catal. Lett., 100, 3 (2005).
[28] H. Khabazzadeh, K. Saidi, and H. Sheibani, Bioorg. Med. Chem. Lett., 18, 278
(2008).
[29] M. A. Zolfigol, Tetrahedron, 57, 9509 (2001).
[30] (a) H. Sharghi, M. Hosseini-Sarvari, and R. Eskandari, J. Chem. Res., 488 (2005);
(
b) M. Hosseini-Sarvari and H. Sharghi, J. Chem. Res., 205 (2006).