Silica gel-supported polyphosphoric acid (PPA-SiO2) catalyzed one-pot multi-component synthesis of 3, 4-dihydropyrimidin-2(1H)-ones and -thiones: An efficient method for the Biginelli reaction

Article abstract of DOI:10.5012/bkcs.2011.32.2.656

A green and efficient method for the synthesis of 3, 4-dihydropyrimidin- 2(1H)-ones and -thiones through one-pot three-component reaction of ethyl acetoacetate, an aryl aldehyde, and urea or thiourea in acetonitrile using silica gel-supported polyphosphor

Full text of DOI:10.5012/bkcs.2011.32.2.656

6
56 Bull. Korean Chem. Soc. 2011, Vol. 32, No. 2
Mohsen Zeinali-Dastmalbaf et al.
DOI 10.5012/bkcs.2011.32.2.656
Silica Gel-Supported Polyphosphoric Acid (PPA-SiO
2
) Catalyzed One-Pot
Multi-Component Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones and -thiones:
An Efficient Method for the Biginelli Reaction
*
†
Mohsen Zeinali-Dastmalbaf, Abolghasem Davoodnia, Majid M. Heravi, Niloofar Tavakoli-Hoseini,
‡
Amir Khojastehnezhad, and Hassan Ali Zamani
Department of Chemistry, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
*
E-mail: adavoodnia@mshdiau.ac.ir
†
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
‡
Department of Applied Chemistry, Quchan Branch, Islamic Azad University, Quchan, Iran
Received November 13, 2010, Accepted December 18, 2010
A green and efficient method for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and -thiones through one-pot
three-component reaction of ethyl acetoacetate, an aryl aldehyde, and urea or thiourea in acetonitrile using silica
gel-supported polyphosphoric acid (PPA-SiO ) as catalyst is described. Compared to the classical Biginelli reaction
2
conditions, the present methodology offers several advantages such as high yields, relatively short reaction times,
mild reaction condition and a recyclable catalyst with a very easy work up.
Key Words: Biginelli reaction, Heterogeneous catalysis, PPA-SiO
2
, Multi-component reactions
Ar
Introduction
O
H
O
Ar
2
+
Multi-component reactions (MCRs) have emerged as an effi-
O
PPA-SiO2
CH3CN
cient and powerful tool in modern synthetic organic chemistry
because the synthesis of complex organic molecules from sim-
EtO
NH
EtO
NH2
Me
N
H
X
ple and readily available substrates can be achieved in a very
fast and efficient manner without the isolation of any intermedi-
Me
O
H N
X
2
1
3
4a-m
1-3
ate. MCRs contribute to the requirements of an environment-
ally friendly process by reducing the number of synthetic steps,
energy consumption and waste production. Therefore, the dis-
covery for new MCRs and improving the already known MCRs
are of considerable interest.
Scheme 1. Biginelli reaction catalyzed by PPA-SiO
2
Recently, solid-supported reagents, such as silica gel-support-
ed acids, have gained considerable interest in organic synthesis
because of their unique properties of the reagents such as high
efficiency due to more surface area, more stability and reus-
Dihydropyrimidinones and -thiones have attracted consider-
able interest recently because of their wide range of biological
activities such as antibacterial, antitumor, anticancer, and anti-
22-24
ability, low toxicity, greater selectivity and ease of handling.
4-6
inflammatory properties. Also, Functionalized dihydropyri-7
Although, the catalytic applications of silica supported reagents
for organic synthesis have been established, to the best of our
knowledge, there is no report in the literature on the use of
midinones have been used as potent calcium channel blockers
8
and antihypertensive agents. The first procedure for the syn-
thesis of dihydropyrimidinones reported by Biginelli in 1893,
involves acid catalyzed one-pot three-component condensation
of β-dicarbonyl compounds with an aromatic aldehyde and urea
PPA-SiO
2
in Biginelli reaction.
Due to our interest in the synthesis of heterocyclic com-
25-29
pounds,
applications of reusable catalysts in organic reactions,
we reported the PPA-SiO catalyzed synthesis of 3,4-dihydro-
and in continuation of our previous works on the
9
30-39
derivatives. A major drawback to Biginelli’s original reactions,
herein
10
however, was poor to moderate yields. There are several im-
proved methods for the synthesis of dihydropyrimidinones and
2
pyrimidin-2(1H)-ones and -thiones (Scheme 1).
-
thiones using various Brønsted acid and Lewis acid catalysts
11
12
13
14
19
such as alcoholic HCl, dry acetic acid, boric acid, p-TsOH,
silica sulfuric acid, La(OTf) , Sr(OTf) , Fe(ClO ) , InBr ,
3 2 4 3 3
InCl
Experimental
15
16
17
18
2
0
21
3
, and Bi(OTf)
3
. However, many of these methods are
All chemicals were commercially available and used without
associated with expensive and highly acidic catalysts, long re-
action times, unsatisfactory yields, and difficult product isol-
ation. Therefore, the development of simple, efficient, clean,
high-yielding, and environmentally friendly approaches using
new catalysts for the synthesis of these compounds is an im-
portant task for organic chemists.
further purification. The PPA-SiO was prepared according to
2
40
the literature. Melting points were recorded on an electro-
thermal type 9100 melting point apparatus. The IR spectra were
obtained on a 4300 Shimadzu spectrophotometer as KBr disks.
1
The H NMR (500 MHz) spectra were recorded on Bruker
DRX500 spectrometer.

2
PPA-SiO Catalyzed Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones and -thiones Bull. Korean Chem. Soc. 2011, Vol. 32, No. 2 657
General Procedure forthe Synthesis of 3,4-Dihydropyrimi-
din-2(1H)-ones and-thiones 4a-mUsing PPA-SiO as Catalyst.
A mixture of ethyl acetoacetate 1 (5 mmol), aryl aldehyde 2
5 mmol), urea or thiourea 3 (6 mmol), and PPA-SiO (0.3 g)
mmol) in the presence of PPA-SiO was heated in different
2
2
solvents and under solvent-free conditions (Table 1). As can be
seen from Table 1, the shortest time and best yield was achieved
in acetonitrile (entry 6). The efficiency of the reaction is mainly
effected by the amount of the catalyst. No product could be de-
tected in the absence of this catalyst even after 3 hours (entry 1),
(
2
as catalyst in acetonitrile (15 mL) was heated under reflux for
the appropriate time. The progress of the reaction was monitor-
ed by TLC. After completion of the reaction, the catalyst was
filtered under hot condition. After cooling the fiterate, the pre-
cipitated solid was filtered and recrystallized from ethyl acetate/
n-hexane to give compounds 4a-min good to excellent yields.
while good results were obtained in the presence of PPA-SiO .
2
The optimal amount of the catalyst was 0.3 g (entry 6), the higher
amount of the catalyst did not increase the yield noticeably
(entry 7).
1
The structures of the products were confirmed by H NMR, IR
In order to evaluate the generality of this model reaction we
then prepared a range of 3,4-dihydropyrimidin-2(1H)-ones and
-thiones under the optimized reaction conditions. In all cases,
aromatic aldehydes with substituents carrying either electron-
donating or electron-withdrawing groups reacted successfully
and gave the expected products in good to excellent yields in
relatively short reaction times. The kind of aldehyde has no
significant effect on the reaction. The results are shown in
Table 2.
spectra and comparison with authentic samples prepared by
15,17,18
reported methods.
Recycling and Reusing of the Catalyst. The catalyst was
o
recovered by filtration, dried at 100 C under vacuum for 2 h
and reused in another reaction. The catalyst could be reused at
least three times with only slight reduction in the catalytic
activity of the catalyst.
Results and Discussion
Reusability of the catalyst was also investigated. For this
purpose, the same model reaction was again studied under the
optimized conditions. After completion of the reaction, the ca-
For our investigations, PPA-SiO was prepared according
2
40
to the literature procedure. Initially, in order to optimize the
reaction conditions, the synthesis of compound 4b was used
as a model reaction. Therefore, a mixture of ethyl acetoacetate
Table 2. PPA-SiO
2
catalyzed synthesis of 3,4-dihydropyrimidin-
a
2
(1H)-ones and -thiones 4a-m
(
5 mmol), 4-chlorobenzaldehyde (5 mmol), and thiourea (6
o
mp ( C)
Time Yields
Entry Ar
X Comp.
b
(
min) (%)
Found
Reported
Table 1. Synthesis of compound 4b in the presence of PPA-SiO
catalyst in different solvents
2
as
a
18
1
2
3
4
5
6
7
8
9
C
4-ClC
3-HOC
4-HOC
4-CH
6
H
5
S
S
S
S
S
O
O
O
O
O
O
O
O
4a
4b
4c
4d
4e
4f
4g
4h
4i
30
45
45
45
60
60
45
45
30
45
45
45
45
85
92
84
91
73
88
76
77
71
94
87
79
83
206-208 209-211
185-187 191-195
181-183 183-184
198-200 202-203
154-156 155-156
210-211 201-204
214-216 214-217
169-171 167-170
231-233 237-238
214-216 202-204
219-220 215-217
215-217 225-228
208-210 205-209
1
1
1
8
5
7
6
H
4
Catalyst
T
( C)
Time
(min)
Yield
b
(%)
Entry
Solvent
o
6
H
H
4
(
g)
6
4
1
2
3
4
5
6
7
8
9
None
0.1
0.2
0.25
0.3
0.3
0.4
0.1
0.2
0.3
0.4
0.1
0.2
0.3
0.4
0.1
0.2
0.3
0.3
0.4
0.1
0.2
0.3
0.4
CH
CH
CH
CH
CH
CH
CH
CHCl
CHCl
CHCl
CHCl
EtOH
EtOH
EtOH
EtOH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
100
180
60
60
60
60
45
60
60
60
60
60
60
60
60
60
60
60
45
60
60
60
60
60
60
None
53
56
79
92
92
93
35
46
60
62
41
52
73
72
44
59
83
88
88
37
42
50
51
18
18
18
15
17
18
18
18
18
3
OC
6
H
4
C
6
H
5
4-ClC
3-HOC
4-HOC
6
H
4
6
H
H
4
6
4
1
0 4-CH
1 4-CH
2 3-NO
3 4-NO
3
OC
6
H
4
4j
4k
4l
1
1
1
3
C
6
H
H
H
4
3
3
3
3
2
C
C
6
4
2
6
4
4m
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
a
5
mmol ethyl acetoacetate, 5 mmol aryl aldehyde, 6 mmol urea or thiourea,
b
and 0.3 g PPA-SiO
2
in acetonitrile under reflux. The yields were calcul-
ated base on aryl aldehyde and refer to the pure isolated product.
92
89
87
1
00
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
80
6
0
0
4
Solvent-free
Solvent-free
Solvent-free
Solvent-free
100
100
100
20
0
1
2
3
a
5
mmol ethyl acetoacetate, 5 mmol 4-chlorobenzaldehyde, 6 mmol thio-
b
Reaction cycles
Figure 1. Reusability of PPA-SiO for model reaction.
urea. The yields were calculated based on 4-chlorobenzaldehyde and refer
to the pure isolated product.
2

658 Bull. Korean Chem. Soc. 2011, Vol. 32, No. 2
Mohsen Zeinali-Dastmalbaf et al.
talyst was filtered under hot condition, dried and reused for the
same reaction process. As shown in Fig. 1, the catalyst could
be reused at least three times with only slight reduction in the
catalytic activity of the catalyst.
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In conclusion, we have developed an efficient, mild, and
green method for the synthesis of dihydropyrimidin-2(1H)-ones
and -thiones through one-pot three-component reaction of ethyl
acetoacetate, an aryl aldehyde, and urea or thiourea in aceto-
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