Silica sulfuric acid: An efficient and reusable catalyst for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/S0040-4039(03)00436-2

Silica sulfuric acid efficiently catalyzes the three-component Biginelli reaction between an aldehyde, a β-dicarbonyl compound and urea or thiourea in refluxing ethanol to afford the corresponding dihydropyrimidinones in high yields. The catalyst is reusa

Full text of DOI:10.1016/S0040-4039(03)00436-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2889–2891
Silica sulfuric acid: an efficient and reusable catalyst for the
one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones
a,
b
c
b
Peyman Salehi, * Minoo Dabiri, Mohammad Ali Zolfigol and Mohammad Ali Bodaghi Fard
a
Department of Phytochemistry, Aromatic and Medicinal Plants and Drug Research Institute, Shahid Beheshti University, Evin,
Tehran 1983963113, Iran
b
Department of Chemistry, Faculty of Science, Shahid Beheshti University, Evin, Tehran 1983963113, Iran
c
Department of Chemistry, Faculty of Science, Bu-Ali Sina University, Hamadan 65174, Iran
Received 7 December 2002; revised 1 February 2003; accepted 14 February 2003
Abstract—Silica sulfuric acid efficiently catalyzes the three-component Biginelli reaction between an aldehyde, a b-dicarbonyl
compound and urea or thiourea in refluxing ethanol to afford the corresponding dihydropyrimidinones in high yields. The catalyst
is reusable and can be applied several times without any decrease in the yield of the reactions. © 2003 Elsevier Science Ltd. All
rights reserved.
5
3
,4-Dihydropyrimidin-2(1H)-ones and their sulfur ana-
The Biginelli reaction has been reviewed. Several
improved protocols for the preparation of DHPMs have
logs (DHPMs) have been reported to possess diverse
pharmacological activities such as antiviral, antibacterial
and antihypertensive activity, as well as efficacy as
calcium channel modulators and a -antagonists. The
biological activity of some alkaloids isolated recently has
recently been reported, either by modification of the
1
6–10
classical one-pot condensation approach itself,
or by
2
the development of novel, but more complex, multi-step
1
a
11
strategies. However, some of the newer reported meth-
ods also suffer from drawbacks such as unsatisfactory
yields, cumbersome product isolation procedures and
Moreover some of the
methods are only practical for aromatic alde-
3
also been attributed to the dihydropyrimidinone moiety.
6,12–17
The simple and direct method for the synthesis of
DHPMs reported by Biginelli in 1893 involves the
one-pot condensation of an aldehyde, a b-ketoester and
environmental pollution.
6,11d,15,17
hydes.
Therefore, a need still exists for versatile,
4
a urea under strongly acidic conditions. However, this
simple and environmentally friendly processes whereby
DHPMs may be formed under milder and practical
conditions.
method suffers from low yields especially in the cases of
aliphatic and some substituted aromatic aldehydes.
Scheme 1.
Keywords: Biginelli reaction; silica sulfuric acid; dihydropyrimidinones; catalysis; solid phase.
*
Corresponding author.
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00436-2

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P. Salehi et al. / Tetrahedron Letters 44 (2003) 2889–2891
Table 1. Reaction of benzaldehyde, ethyl acetoacetate and
summary of the results obtained is provided in Table 1.
Entries 1–6 show the effect of various solvents on the
yield of the reaction. Although acetonitrile and toluene
afforded the product in high yields, we chose ethanol for
its cheapness and environmental acceptability. Entry 3
describes the yields of five consecutive condensations
leading to 4a. In these experiments the product was
isolated by filtration and washing the solid residues with
ethyl acetate, the remaining catalyst being reloaded with
fresh reagents for further runs. No decrease in the yield
was observed demonstrating that silica sulfuric acid can
be reused as a catalyst in Biginelli condensations. Entry
urea under different conditions
Entry
Solventa
Catalyst
Yield (%)
1
2
3
4
5
6
7
CHCl3
THF
Silica sulfuric acid
Silica sulfuric acid
Silica sulfuric acid
Silica sulfuric acid
Silica sulfuric acid
Silica sulfuric acid
None
35
77
b
C H OH
91, 92, 90, 93, 90
2
5
CH CN
91
90
15
26
3
Toluene
H O
2
c
C H OH
2
5
a
Refluxed for 6 h.
The same catalyst was used for each of the five runs.
Refluxed for 24 h.
7
shows the catalytic effect of silica sulfuric acid in the
three-component condensation of benzaldehyde, urea
and ethyl acetoacetate.
b
c
Recently, we reported the preparation of silica sulfuric
acid as a stable acidic reagent and showed its catalytic
activity in synthetic methodology. Here we wish to
report the ability of this reagent as a reusable catalyst
for the one-pot synthesis of 3,4-dihydropyrimidin-
The reactions proceeded smoothly in refluxing ethanol
and were completed within 6 h. Table 2 shows the
generality of the present protocol, which is equally
effective for urea or thiourea, and also for aromatic and
aliphatic aldehydes. Under these conditions, the yields
were significantly better in comparison with the classical
Biginelli procedure.
1
8
2(1H)-ones and -thiones in high yields (Scheme 1).
We started to study the three-component Biginelli con-
densation catalyzed by silica sulfuric acid by examining
the conditions required for the reaction involving benz-
aldehyde, urea and ethyl acetoacetate to afford the
Several aromatic aldehydes carrying either electron-
releasing or electron-withdrawing substituents in the
ortho, meta and para positions afforded high yields of
the products. An important feature of this procedure is
1
2
3
DHPM 4a (R =Ph, R =Me, R =OEt, X=O). A
Table 2. Synthesis of dihydropyrimidin-ones and -thiones (DHPMs) by the condensation of aldehydes, b-dicarbonyls and
urea or thiourea catalyzed by silica sulfuric acid in ethanol
Entry
DHPMa
R1
R2
R3
X
Yield (%)b
Mp (°C)
Reported
Found
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
C H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
Me
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
91
94
95
95
92
93
93
92
87
94
90
86
84
87
96
94
95
95
96
87
86
92
93
91
92
84
93
206
202–2046
208–2116
6
5
4-O N-C H
209–212
209–212
205–207
182–184
227–229
167–170
259–260
208–210
175–177
230–232
154
152–154
155–157
210–212
203–205
189–192
233–235
252–253
229–231
170–172
229 (dec)
209–211
203–205
183–184
153–155
183 (dec)
2
6
4
6
4-Cl-C H
4-CH O-C H
4-F-C H
213–215
6
4
201–2036
185–1866
226–2271
3
6
4
4
6
4
1d
4
3-O N-C H
2
6
4
1
3-HO-C H
2-CH O-C H
164–166
6
4
26220
3
6
1
7
2-O N-C H
206–208
2
6
4
12
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4j
4k
4l
3,4-(CH O) -C H
3
178
3
2
6
232–2351
3
1
2
C H -CH=CH
6
5
2
n-C H
157–158
3
7
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4y
4z
4a%
n-C H
151–1521
6
13
C H
C H
157–1596
6
5
5
6
5
6
C H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
209–212
6
4-Cl-C H
4-CH O-C H
204–2076
6
4
6
192–194
3
6
4
4-O N-C H
4
235–2376
254–2551
233–2368
2
6
3
2,4-(Cl) -C H
2
6
3
C H
6
5
4-CH O-C H
Me
Me
168–17014
3
6
4
13
4-O N-C H
230 (dec)
2
6
4
4
208–2101
6
C H
OEt
OEt
OEt
OEt
Me
6
5
1
1c
3-O N-C H
S
S
S
S
206–207
2
6
184–1862
2
6
3-HO-C H
4-CH O-C H
C H
6
6
4
1
150–152
3
6
4
185 (dec)23
5
a
1
Products were characterized by comparison of their spectroscopic data ( H NMR and IR) and mps with those reported in the literature.
Isolated yield.
b

P. Salehi et al. / Tetrahedron Letters 44 (2003) 2889–2891
2891
the survival of a variety of functional groups such as
ethers, nitro groups, hydroxy groups, halides, etc. under
the reaction conditions. Another advantage of this
method is its efficiency for the high yield synthesis of
DHPMs from aliphatic aldehydes.
Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland,
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corresponding
3,4-dihydropyrimidin-2(1H)-thiones
which are also of interest with regard to their biological
activities. For example monastrol 4y, a mitotic kinesin
Eg5 motor protein inhibitor and a potential new lead
for the development of anticancer drugs, was obtained
6. Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem.
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1
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in a 92% yield (Table 2, entry 25).
9
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In conclusion, the present procedure provides an
efficient and improved modification of the Biginelli
reaction. Mild reaction conditions, ease of workup,
high yields, and stability and recyclability of the reagent
are features of this new procedure. Moreover, this
method has the ability to tolerate a wide variety of
substituents in all three components. The results are
reproducible and the reactions can be carried out on a
gram scale.
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General procedure for the synthesis of DHPMs
2
A mixture of the aldehyde (2 mmol), the b-dicarbonyl
compound (2 mmol), urea or thiourea (3 mmol) and
6
+
silica sulfuric acid (0.23 g, equal to 0.6 mmol H ) in
ethanol (10 ml) was refluxed for 6 h. After completion
of the reaction, the solvent was evaporated under
reduced pressure. The solid mixture was washed with
cold water (20 ml) to remove the excess of urea or
thiourea and then filtered. The remaining solid material
was washed with hot ethyl acetate (30 ml). The filtrate
was concentrated and the solid product was recrystal-
lized from ethyl acetate/n-hexane or ethanol.
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Acknowledgements
We are grateful to Shahid Beheshti University Research
Council for partial support of this work.
1
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