An efficient and clean one-pot synthesis of 3,4-dihydropyrimidine-2(1H)- ones catalyzed by tungstate sulfuric acid in solvent-free conditions

Article abstract of DOI:10.1002/jhet.5570450438

(Chemical Equation Presented) Tungstate sulfuric acid catalyzes the three component condensation reaction of an aromatic aldehyde, urea and a β-ketoester under solvent-free conditions to afford the corresponding dihydropyrimidinones in high to excellent y

Full text of DOI:10.1002/jhet.5570450438

Jul-Aug 2008
1183
An Efficient and Clean One-pot Synthesis of 3,4-
Dihydropyrimidine-2(1H)-ones Catalyzed by Tungstate Sulfuric
Acid in Solvent-free Conditions
Masoud Nasr-Esfahani*, Bahador Karami, Morteza Montazerozohori, Karim Abdi
Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran,
E-Mail: manas@mail.yu.ac.ir
Received January 2, 2007
R1
O
O
O
O
H
Tungstate Sulfuric Acid
solvent-free
R2O
Me
N
R1CHO
OR2
Me
+
+
H2N
NH2
O
N
H
4
1
2
3
Tungstate sulfuric acid catalyzes the three component condensation reaction of an aromatic aldehyde,
urea and a ꢀ-ketoester under solvent-free conditions to afford the corresponding dihydropyrimidinones in
high to excellent yields at room temperature.
J. Heterocyclic Chem., 45, 1183 (2008).
INTRODUCTION
from available and inexpensive raw materials, under
environmentally harmless processes[13].
Dihydropyrimidinones belong to an important class of
heterocyclic compounds that have attracted organic
chemists due to pharmacological and biological
properties, such as antihypertensive activity, calcium
channel blocking, alpha-1a-antagonism, neuropeptide
Y(NPY) antagonism, antitumor, antibacterial, and anti-
inflammatory activity [1–4]. Recently, the batzelladine
alkaloids containing the dihydropyrimidin-one-5-
carboxylate core have been found to be potent HIV-gp-
120-CD4 inhibitors [5]. Due to the importance of these
compounds as synthons in organic synthesis, many
synthetic methods for preparing such compounds have
been developed based on the Biginelli reaction [6].
However, there are several disadvantages associated
with the reported methodologies including unsatisfactory
yields, long conversion times, difficult handling of
reagents, toxic and inflammable organic solvents, and
incompatibility with other functional groups in the
molecules that limit these methods to small-scale
synthesis. Thus, developments of facile and environ-
mentally friendly synthetic methods for preparation of
the dihydropyrimidinones are yet demanded. Also in
view of the pharmaceutical importance of these
compounds, many improved catalytic methods have
been developed [7-11].
Today, substitution of homogenous reagents or
catalysts by heterogeneous ones is an active field both in
chemical industries and in laboratorial synthetic methods.
This is due to some advantages such as simplification in
handling, reduction of corrosion, green chemistry point of
view, avoidance of byproducts, easy and clean reaction
and simple work-up. Regarding the wide application of
acids as reagents or catalysts in organic chemistry,
preparation of a new inorganic solid acid can be useful in
this direction. Recently silica sulfuric acid and Nafion-H®
[14] have been used for a wide variety of reactions [15].
In continuation of above and our studies [16] on the
application of inorganic solid acid, we found that
anhydrous sodium tungstate reacts with chlorosulfonic
acid (1:2 mole ratio) to give tungstate sulfuric acid I. The
reaction is performed easy, clean and without any work-
up (Scheme 1). It is to be noted that there is no gas
production during the reaction.
Scheme 1
O
O
+
ONa
2 ClSO3H
HO3SO
OSO H
+
3
NaO
2 NaCl
W
O
W
O
It is well known in the protocol of green chemistry that
its main objective is to perform reactions under
solventless conditions using heterogeneous catalysts, in
order to generate environmentally friendly chemical
transformations [12]. In addition, it is important to note
that an ideal synthesis is considered as one in which a
target molecule is produced quantitatively in one step,
I
In continuation of our programme on utility of tungstate
sulfuric acid (I) in organic reactions, herein we were
interested to examine it as proton source in the synthesis
of dihydropyrimidinones.

1184
M. Nasr-Esfahani, M. Montazerozohori, B. Karami, K. Abdi
Vol 45
RESULTS AND DISCUSSION
excellent yields (Entries 1-23). It is noteworthy that acid-
sensitive substrates such as cinnamaldehyde also
proceeded well to give the dihydropyrimidinones without
any side products (Entry 17). However, aliphatic
aldehydes such as butanal as observed previously are
quite resistant to our reaction conditions [7d].
In this work [17], we wish to report an efficient and
convenient procedure for the synthesis of dihydropyrimi-
dinones from the alkyl or aryl aldehydes using tungstate
sulfuric acid as catalyst (Scheme 2).
To use of tungstate sulfuric acid in large-scale synthesis
especially in chemical laboratory, a typical reaction was
performed for synthesis of 4j with ten fold amounts of
reactants and catalyst with respect to one mentioned in the
experimental section. The result showed that the yield of
91% in these conditions is comparable with that one in
Table 1.
Scheme 2
R1
O
O
O
O
Tungstate Sulfuric Acid
H
O
R2O
R1CHO
N
+
+
OR2 H2N
solvent-free
NH2
Me
N
H
Me
To achieve the reaction efficiency of recovered catalyst,
the reaction mixture of 4j was treated by hot ethanol for 5
minutes and then filtered and washed with hot ethanol twice
to give tungstate sulfuric acid. The recovered acid was used
again for synthesis of 4j that lead to the yield of 85%.
In conclusion, we have found an efficient, inexpensive
reagent and straightforward procedure for one-pot
synthesis of dihydropyrimidinones using tungstate
sulfuric acid as catalyst. Also it was found that the
performance of the catalytic system is greatly facilitated
when used without solvents, important from the view-
point of green chemistry. Moreover, nonhygroscopic and
inexpensive for this transformation are other advantages
of this procedure.
Two parallel reaction series, one according to classical
Biginelli reaction (method B) and another in our
conditions (method A) were designed. As shown in Table
1, the product yields were low (29-76%) after 18 h, when
the reactions were carried out with HCl (aq.) alone (as
classical Biginelli reaction) whereas the same reactions in
the presence of tungstate sulfuric acid gave high to
excellent yields (89-97%) after 5-20 minutes under
solvent free conditions.
We extended these reaction conditions to a series of
alkyl or aryl aldehydes under solvent free conditions.
Both aromatic aldehydes bearing either activating or
deactivating groups reacted well with ꢀ- ketoesters to
yield the corresponding dihydropyrimidinones in high to
Table 1
Synthesis of dihydropyrimidinones catalyzed with tungstate sulfuric acid under solvent-free conditions.
Entry
DHPM
R1
R2
Yield(%)a
Bc
Mp
Found
(˚C)
Ab
96
95
96
90
89
94
92
90
94
97
94
95
93
90
95
91
90
92
95
92
94
92
93
25
Reported
209-2116c
206-2086c
2036a
150-1526d
220-2226d
192-1946c
236-2376c
192-1946f
254-2556f
202-2036c
215-2166c
1706e
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4x
4r
4s
C6H5
4-Cl-C6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
40
57
-
-
-
29
44
-
210-211
205-207
201-202
150-153
221-222
193-194
235-237
193-194
252-254
201-203
214-216
170-171
176-178
232-233
202-203
207-208
231-234
226-227
247-249
184-186
165-167
195-198
255-257
153-155
4-CH3-C6H4
3,4-(CH3O)2-C6H3
4-OH-3-CH3O-C6H3
4-CH3O-C6H4
4-NO2-C6H4
4-F-C6H4
2,4-(Cl)2-C6H3
C6H5-
4-Cl-C6H4
4-CH3-C6H4
3,4-(CH3O)2-C6H3
4-OH-3-CH3O-C6H3
4-CH3O-C6H4
4-NO2-C6H4
C6H5-CH=CH
3-NO2-C6H4
2,4-(Cl)2-C6H3
4-F-C6H4
9
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
76
56
-
-
176-1776e
231-2326c
201-2026c
208-2096c
232-2356f
227-2286c
248-2506b
185-1866g
164-1666h
1976e
43
60
58
-
49
69
-
-
-
-
15
Et
Et
Et
Et
Et
Et
4t
4u
4v
4w
4q
3-OH-C6H4
4-Br-C6H4
4-N(CH3)2-C6H4
CH3(CH2)2
256-2586b
152-1546b
a Isolated yields;b Method A: new reaction conditions in solvent-free (cat. tungstate sulfuric acid, 5-20 min);cMethod B: classical
Biginelli conditions (cat. HCl in EtOH, reflux 18h).

Jul-Aug 2008
An efficient and clean one-pot synthesis of 3,4-Dihydropyrimidine-2-(1H)-ones
1185
[2] (a) Kappe, C.O.; Fabian, W. M. F.; Semones, M. A.
Tetrahedron 1997, 53, 2803; (b) Hu, E. H.; Sidler, D. R.; Dolling, U. H.
J. Org. Chem. 1998, 63, 3454.
[3] Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Moreland, S.; Hedberg, A.; O’Reilly, B. C. J. Med. Chem. 1991, 34,
806.
[4] Grover, G. J.; Dzwonczyk, S.; McMullen, D. M.; Normadin,
D. E.; Sleph, P. G.; Moreland, S. J.; Parham, C. S. J. Cardiovasc.
Pharmacol. 1995, 26, 289.
EXPERIMENTAL
All chemicals were purchased from Merck, Fluka and Sigma-
Aldrich chemical companies. The reactions were monitored by
TLC. The products were isolated and identified by comparison
of their physical and spectral data with authentic samples. IR
spectra were recorded on FT-IR JASCO-680, the 1H-NMR
spectra were obtained on a Brüker-instrument DPX-300 MHz
and melting points were determined on
Electrothermal (BI 9300) apparatus.
a
Barnstead
[5] (a) Overman, L.E.; Rabinowitz, M.H.; Renhowe, P.A. J. Am.
Chem. Soc. 1995, 117, 2657; (b) Snider, B.; Shi, Z. J. Org. Chem. 1993,
58, 3828.
Preparation of tungstate sulfuric acid (I). Anhydrous
sodium tungstate was prepared by drying of sodium tungstate
dihydrate (Na2WO4. 2H2O, MW = 329.86) in the oven at 200°C
for 4 hours. To 0.2 mol of chlorosulfonic acid (23.30 g, 13.31
mL) in 250 mL round bottom flask in the ice-bath, 0.1 mol
(29.38 g) anhydrous sodium tungstate was added gradually with
stirring. After the completion of addition of anhydrous sodium
tungstate, the reaction mixture was shaken for 1 h. Then 50 mL
of cold water was added to the reaction mixture and stirred for
10 minutes. The mixture was filtered and a yellowish-white
solid of tungstate sulfuric acid, 40.2 g (98%), m.p. 285°C (dec.)
was obtained. Characterstic IR bands (KBr, cm-1): 3600-2200
(OH, bs), 1240-1140 (S=O, bs), 1060 (S-O, m), 1005 (S-O,m),
880-840 (W=O, m), 450 (W-O, m) [16].
[6] (a) Fan, X.; Zhang, X.; Zhang, Y. J. Chem. Res.(S) 2002,
436; (b) Lu, J.; Bai, Y. Synthesis 2002, 466; (c) Jin, T.; Zhang, S.; Guo,
J.; Li, T. J. Chem. Res. (S) 2002, 37; (d) Mitra, A. K.; Banerjee, K.
Synlett. 2003, 1509; (e) Reddy, K. R.; Reddy, C. V.; Mahesh, M.; Raju,
P. V. K.; Reddy, V. V. N. Tetrahedron Lett. 2003, 44, 8173; (f) Ma, Y.;
Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65, 3864; (g) Hu, E.
H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem. 1998, 63, 3454; (h) Ranu,
B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65, 6270.
[7] (a) Khodaei, M. M.; Khosropour, A. R.; Beygzadeh, M.
Synth. Commun. 2004, 34, 1551. (b) Tu, S.; Fang, F.; Zhu, S.; Li, T.;
Zhang, X.; Zhuang, Q. Synlett 2004, 537. (c) Gohain, M.; Prajapati, D.;
Sandhu, J. S. Synlett 2004, 235. (d) Bose, D. S.; Kumar, R. K.; Fatima,
L. Synlett 2004, 279. (e) Wang, Z.-T.; Xu, L.-W.; Xia, C.-G.; Wang, H.-
Q. Tetrahedron Lett. 2004, 45, 7951.
[8] (a) Reddy, G. S. K. K.; Srinivas Reddy, Ch.; Yadav, J. S.;
Sabitha, G. Synlett 2003, 858. (b) Varala, R.; Alam, M. M.; Adapa, S. R.
Synlett 2003, 67. (c) Reddy, K. R.; Reddy, C. V.; Mahesh, M.; Raju, P.
V. K.; Reddy, V. V. N. Tetrahedron Lett. 2003, 44, 8173. (d) Tu, S.;
Fang, F.; Miao, C.; Jiang, H.; Feng, Y.; Shi, D.; Wang, X. Tetrahedron
Lett. 2003, 44, 6153.
[9] (a) Paraskar, A. S.; DewKar, G. K.; Sudalai, A.; Tetrahedron
Lett. 2003, 44, 3305. (b) Subhas Bose, D.; Fatima, L.; Mereyala, H. B. J.
Org. Chem. 2003, 68, 587.
[10] Reddy, Ch. V.; Mahesh, M.; Raju, P. V. K.; Babu, T. R.;
Reddy, V. V. N. Tetrahedron Lett. 2002, 43, 2657.
[11] (a) Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron
Lett. 2000, 41, 9075. (b) Kappe, C. O. J. Org. Chem. 1997, 62, 7201.
[12] Anastas, P. T.; Williamson, T. C. Green Chemistry, Frontiers
in Benign Chemical Syntheses and Processes, Oxford University Press,
1998.
Typical procedure for the preparation of 5-(Ethoxy-
carbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-
one (4j).
A mixture of benzaldehyde (1 mmol), ethyl-
acetoacetate (1 mmol), urea (1.5 mmol) and tungstate sulfuric
acid (1 mmol) in a mortar was prepared. The mixture was
ground with a pestle for 10 minutes. After completion of the
reaction as monitored by TLC, 5 mL of ethanol was added to the
reaction mixture, stirred and heated for 5 minutes. The reaction
mixture was filtered and washed with hot ethanol. The hot
filtrate was poured onto crushed ice, the solid product collected
by filtration and washed with cold ethanol and a mixture of
ethanol-water. The solid product was recrystalized from ethanol.
The products were characterized by IR, 1H-NMR and via
comparison of their melting points with the reported ones.
5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrim-
idin-2(1H)-one (4j). IR (KBr), ꢀ (cm-1): 3232, 3104, 2936,
[13] Wender, P. A.; Handy, S. L.; Wright, D. L. Chem. Ind. 1997,
765.
1
1718, 1696, 1598, 1216 cm-1; H NMR (CDCl3), ꢁ (ppm): 8.15
[14] (a) Zolfigol, M. A. Tetrahedron 2001, 57, 9509; (b) Olah, G.
A.; Molhotra, R.; Narang, S. C. J. Org. Chem. 1978, 43, 4628.
[15] (a) Zolfigol, M. A.; Shirin, F.; Ghorbani Choghamarani, A.;
Mohammadpoor-Baltork, I. Green Chem. 2002, 4, 562; (b) Zolfigol, M.
A.; Bamoniri, A. Synlett 2002, 1621; (c) Shirini, F.; Zolfigol, M. A.;
Mohammadi, K. Bull. Korean Chem. Soc. 2004, 25, 325.
[16] (a) Karami, B.; Montazerozohori, M.; Habibi, M. H. Bull.
Korean Chem. Soc. 2005, 26, 1125; (b) Karami, B.; Montazerozohori,
M.; Karimipour, G. R.; Habibi, M. H. Bull. Korean Chem. Soc. 2005, 26,
1431; (c) Karami, B.; Montazerozohori, M.; Habibi, M. H.; Zolfigol M.
A.; Heterocyclic Commun. 2005, 11, 513; (d) Karami B.;
Montazerozohori M.; Habibi, M. H. Phosphorus Sulphur silicon and
related elements 2006 181, 2825.
(1H, s), 7.1-7.35 (5H, m), 6.15 (1H, s), 5.42 (1H, s), 4.10 (2H,
q), 2.34 (3H, s), 1.25 (3H, t); MP = 201-203 ° C ( Lit. [6c] 202-
203 ° C)
Acknowledgement. We are thankful to the Yasouj University
for partial support of this work.
REFERENCES
[1] (a) Atwal, K.S.; Rovnyak, G.C.; O’Reilly, B.C.;Schwartz, J.
J. Org. Chem. 1989, 54, 5898; (b) Rovnyak, G.C.; Kimball, S.D.; Beyer,
B.; Cucinotta, G.; Dimarco, J.D.; Gougoutas, J.; Hedberg, A.; Malley,
M.; McCarthy, J.P.; Zhang, R.; Moreland, S. J. Med. Chem. 1995, 38,
119.
[17] Nasr-Esfahani, M.; Khosropour, A. R. Bull. Korean Chem.
Soc. 2005, 26, 1331.