Efficient synthesis of 3,4-dihydropyrimidin-2(1H)-ones over silica sulfuric acid as a reusable catalyst under solvent-free conditions

Article abstract of DOI:10.3987/COM-03-9837

3,4-Dihydropyrimidin-2(1H)-ones and their sulfur analogues are efficiently synthesized by the three-component condensation of β-dicarbonyl compounds, aromatic and aliphatic aldehydes, and urea or thiourea in the presence of catalytic amounts of silica sul

Full text of DOI:10.3987/COM-03-9837

HETEROCYCLES, Vol. 60, No. 11, 2003, pp. 2435 - 2440
Received, 24th June, 2003, Accepted, 11th September, 2003, Published online, 16th September, 2003
EFFICIENT SYNTHESIS OF
3,4-DIHYDROPYRIMIDIN-2(1H)-ONES OVER
SILICA SULFURIC ACID AS A REUSABLE
CATALYST UNDER SOLVENT-FREE CONDITIONS
a,
b
c
Peyman Salehi, * Minoo Dabiri, Mohammad Ali Zolfigol, and Mohammad Ali
Bodaghi Fard
b
a.Department of Phytochemistry, Aromatic and Medicinal Plants and Drug
Research Institute, Shahid Beheshti University, Evin, Tehran, P.O.Box 19835-389,
Iran, E-mail: p-salehi@cc.sbu.ac.ir, Fax:+98-21-2418679
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
Abstract- 3,4-Dihydropyrimidin-2(1H)-ones and their sulfur analogues are
efficiently synthesized by the three-component condensation of β-dicarbonyl
compounds, aromatic and aliphatic aldehydes, and urea or thiourea in the
presence of catalytic amounts of silica sulfuric acid under solvent-free conditions
in high yields. The catalyst is recyclable and can be used several times without
any decrease in the products yields.
1
,2
The Biginelli reaction was first reported more than a century ago and recently has been reviewed.
Dihydropyrimidinones (DHPMs), the products of Biginelli reaction, and their derivatives have attracted
considerable interest in recent times because of the interesting pharmacological properties, such as
3
efficacy as calcium channel modulators and α1a-adreno acceptor-selective antagonists; antihypertensive
4
agents and neuropeptide Y (NPY) antagonists. Also the anti-HIV activity in some marine natural
5
products containing the DHMPs skeleton, such as the alkaloid batzalladine B, is observed. Therefore, the
discovery of milder and practical routes for the synthesis of dihydropyrimidinones by the Biginelli
reaction continues to attract the attention of scientists.
The simple method reported by Biginelli involving three-component condensation reaction often suffers
from low yields, practically in cases of aliphatic and some substituted aromatic aldehydes.
Several improved procedures for the preparation of DHPMs have recently been reported, either by
6
-10
modification of the classical one-pot Biginelli approach itself,
or by the development of novel, but
1
1
more complex multi-step strategies. However, in spite of their potential utility, some of the newer
reported methods also suffer from drawbacks such as long reaction times, unsatisfactory yields,

6
,12-17
cumbersome product isolation procedures and environmental contamination.
Moreover some of the
6
,11d,15,17
methods are only practical for aromatic aldehydes.
Recently, we reported the preparation of silica sulfuric acid and some of its applications in synthetic
1
8
methodology. In an effort we reported the efficient synthesis of dihydropyrimidinones in solution using
1
9
20
silica sulfuric acid as catalyst. According to our experience in solvent-free reactions, we decided to
improve the reaction conditions by conducting three-component Biginelli condensation in the absence of
solvent. Here we report another remarkable catalytic activity of silica sulfuric acid for the one-pot
solvent-free synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones (Scheme 1).
R1
O
O
O
X
H
R3
+
Silica Sulfuric Acid
Solvent-Free
N
R1-CHO
+
R2
R3
NH2
H N
2
R2
N
X
X=O,S
h, 60oC
2
H
1(a-a')
2
3
4(a-a')
Scheme 1
We started to optimize the conditions by examining the reaction involving benzaldehyde, urea and ethyl
1
2
3
acetoacetate to afford the DHPM (4a) (R =Ph, R =Me, R =OEt, X=O). A 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. Entry 7 describes the yields of
five consecutive condensations leading to 4a under solvent-free conditions. In these experiments the
product was isolated by filtration and washing the solid residues with ethyl acetate, and the remaining
catalyst was reused for new runs. No decrease in the yield was observed demonstrating that silica sulfuric
acid can be recycled as catalyst in a Biginelli condensation with zero-discharge to the environment. Entry
8
shows the catalytic effect of silica sulfuric acid in the Biginelli reaction.
Table 2 shows the generality of the present protocol, which equally effective for urea and thiourea, and
also for aromatic and aliphatic aldehydes. Under these conditions, the reactions time shortened
1
9
significantly in comparison with similar reactions performed in solution.
Several aromatic aldehydes containing electron-donating or electron-withdrawing groups were examined
under the optimized conditions. In all cases the reactions with β-dicarbonyl compounds proceeded
o
smoothly within 2 h at 60 C to give the corresponding dihydropyrimidinones in high yields (Table 2).
One of the outstanding advantages of this method is its efficiency for conversion of aliphatic aldehydes
into their corresponding DHPMs in good yields (Table 2, Entries 12, 13). Satisfactory yields of 4l and
o
4
m were obtained at 100 C after 2 h.

Table 1. Reaction of benzaldehyde, ethyl acetoacetate and urea
under different conditions
a
Entry
Solvent
Catalyst
Yield(%)
1
2
CHCl
THF
3
Silica sulfuric acid
“
35
77
3
4
5
6
7
8
EtOH
“
91
CH
3
CN
“
91
Toluene
“
90
H
2
O
“
“
15
96,94,94,95,93
56
b
d
c
None
None
None
a
b
c
d
Refluxed for 6 h.
o
6
0 C for 2 h.
Catalyst was reused for five runs.
o
1
00 C for 2 h.
A wide variety of different groups in β-dicarbonyl compounds were tolerated in this procedure. Ethyl
acetoacetate, methyl acetoacetate, ethyl benzoylacetate and acetylacetone were used satisfactorily as the
model compounds. Thiourea was also used with similar success to provide the corresponding
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
2
1
development of anticancer drugs, was obtained in 90% yield (Table 2, Entry 25).
In conclusion the present procedure provides an efficient and improved modification of the Biginelli
reaction. In addition to its simplicity, milder reaction conditions, stability and recyclability of the reagent,
shorter reaction periods, higher yields and ease of work-up, the method enjoys the chemical and
2
2
environmental advantages of solvent-free reactions.
EXPERIMENTAL
All of the products are known compounds and characterized by comparison of their spectroscopic data
1
(
IR, H NMR) and melting points with those reported in the literature. Melting points were obtained in
open capillaries on an Electrothermal 9200 melting point apparatus and are not corrected. Silica sulfuric
18a
acid was prepared according to our reported procedure. Progresses of the reactions were followed by
dissolving a sample in ethyl acetate and monitoring on precoated TLC aluminum sheets (eluent: hexane/
ether: 1/1 ). Yields refer to isolated products.

Table 2. Synthesis of dihydropyrimidin-ones and thiones (DHPMs) by the condensation of aldehydes,
β-dicarbonyls and urea or thiourea catalyzed by silica sulfuric acid under solvent-free conditions
b
o
Yield
Mp( C)
a
1
2
3
Entry DHPM
R
R
R
X
(
%)
96
92
93
94
94
90
93
91
89
93
Found
203-205
210-213
208-210
202-204
181-183
224-226
168-170
260-262
203-205
176-178
230-232
153-154
152-154
154-156
210-213
205-209
190-193
238-240
256-258
230-232
170-172
Reported
6
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
C
6
H
5
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
202-204
6
4-O
4-Cl-C
4-MeO-C
4-F-C
3-O N-C
3-HO-C
2-MeO-C
2-O N-C
3,4-(MeO)
-CH=CH
n-Pr
n-C
2
N-C
6
H
4
208-211
6
6
H
4
213-215
6
6
H
4
201-203
6
6
H
4
185-186
1
1d
2
6
H
4
226-227
1
4
4g
4h
4i
6
H
4
164-166
2
3
6
H
4
262
1
1
1
7
2
3
2
6
H
4
206-208
176-177
232-235
157-158
151-152
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
4j
2 6 3
-C H
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
4k
4l
C
6
H
5
92
c
24
12
6
83
c
4m
4n
4o
4p
4q
4r
4s
6 13
H
80
d
C
6
H
5
5
6
C
6
H
5
90
157-159
209-212
204-207
192-194
235-237
6
6
6
6
C
6
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
95
97
96
91
96
89
83
91
95
93
90
95
93
4-Cl-C
H
4
4-MeO-C
6
H
4
4-O N-C H
2
6
4
1
3
2,4-(Cl)
2
-C
6
H
3
254-255
8
4t
6 5
C H
233-236
1
4
4u
4v
4w
4x
4y
4z
4a´
4-MeO-C
6
H
4
Me
168-170
1
3
4-O
2
N-C
6
H
4
Me
228(decomp)
210-212
204-206
182
230(decomp)
1
6
C
6
H
5
OEt
OEt
OEt
OEt
Me
208-210
1
1c
3-O
3-HO-C
4-MeO-C
2
N-C
6
H
4
S
206-207
184-186
150-152
2
5
6
6
H
4
S
1
6
H
4
S
155-156
2
6
C
6
H
5
S
182-184(decomp) 185(decomp)
a
1
Products were characterized by comparison of their spectroscopic data ( H-NMR and IR) and mps with those reported in the
literature.
b
o
Isolated yield (60 C, 2 h).
The reaction was performed at 100 C for 2 h.
c
o
d
o
The reaction was performed at 100 C for 3 h.

General Procedure for the Synthesis of DHPMs
+
Urea or thiourea (3 mmol) was grinded with silica sulfuric acid (0.23 g, equal to 0.6 mmol H ). Then
aldehyde (2 mmol) and β-dicarbonyl compound (2 mmol) were added to the mixture and the whole was
o
heated at 60 C for 2 h. The mixture was washed with cold water (20 mL) to remove the excess of urea
and filtered. The remaining solid material was washed with hot ethyl acetate (30 mL). The filtrate was
concentrated and the solid product was recrystallized from ethyl acetate/n-hexane or ethanol.
ACKNOWLEDGMENT
We are grateful to Shahid Beheshti University Research Council for financial support of this work.
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