Melamine trisulfonic acid: A new, efficient and recyclable catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones in the absence of solvent

Article abstract of DOI:10.1016/j.cclet.2010.10.033

Melamine trisulfonic acid (MTSA) can be used as an efficient and recyclable catalyst for the promotion of the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/ thiones (DHPMs) in the absence of solvent. All reactions were performed at 80 °C in good to high yi

Full text of DOI:10.1016/j.cclet.2010.10.033

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 318–321
www.elsevier.com/locate/cclet
Melamine trisulfonic acid: A new, efficient and recyclable catalyst
for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones in
the absence of solvent
b
a
Farhad Shirini a, , Mohammad Ali Zolfigol , Jalal Albadi
*
a Department of Chemistry, College of Science, University of Guilan, Rasht 41335, Islamic Republic of Iran
b College of Chemistry, Bu-Ali Sina University, Hamadan, Islamic Republic of Iran
Received 1 July 2010
Available online 22 December 2010
Abstract
Melamine trisulfonic acid (MTSA) can be used as an efficient and recyclable catalyst for the promotion of the synthesis of 3,4-
dihydropyrimidin-2(1H)-ones/thiones (DHPMs) in the absence of solvent. All reactions were performed at 80 8C in good to high
yields.
# 2010 Farhad Shirini. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Melamine trisulfonic acid; 3,4-Dihydropyrimidin-2(1H)-ones/thiones; Biginelli reaction; Aldehydes; Solvent-free reactions
In recent years, the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones has attracted the attention of many
organic chemists. This attention can be attributed to their wide range therapeutical and pharmacological properties,
such as antiviral, antitumor, antibacterial, and anti-inflammatory properties [1]. Also, some of them have been
successfully used as calcium channel blockers, antihypertensive agents, and a1a-antagonists [2]. In addition, several
alkaloids containing the dihydropyrimidine core unit, exhibiting interesting biological properties, have been isolated
from marine sources [3–5]. Among these the crambine [3] and batzelladine alkaloids [4] were found to be potent
HIVgp-120-CD4 inhibitor.
In 1893, Biginelli reported the first synthesis of 3,4-dihydropyrimidin-2(1H)-ones, via a one-pot three component
condensation of an aldehyde, a b-ketoester and urea [6]. In spite of the importance of the reported method, it suffers
from long reaction times, acidic reaction conditions, low yields of the products particularly in the case of substituted
aldehydes and loss of sensitive functional groups during the reaction. This problem has led to the development of
multi-step synthetic approaches for the synthesis of DHPMs. These methods however afford better yields of the
desired products, but lack the simplicity of the original one-step synthesis [7].
In order to improve the efficiency of Biginelli reaction, a variety of catalysts have been reported which of them
H4PMo11VO40 [8], Dowex-50W [9], H3PW12O40/SiO2 [10], MgBr2 [11], polymer-supported 4-aminoformoyl-
diphenylammonium triflate [12], NaHSO4/SiO2 [13], FeCl3 [14], ZrCl4 [15], Cu(OTf)2 [16], Bi(OTf)3 [17],
* Corresponding author.
E-mail address: shirini@guilan.ac.ir (F. Shirini).
1001-8417/$ – see front matter # 2010 Farhad Shirini. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.10.033

F. Shirini et al. / Chinese Chemical Letters 22 (2011) 318–321
319
yutterbium triflate [18], NH2SO3H [19], 12-molbdophosphoric acid [20], natural HEU type zeolite [21], Sr(OTf)2 [22],
covalently anchored sulfonic acid onto silica [23], ZrOCl2Á8H2O [24], silica triflate [25], Fe(HSO4)3 [26], TCICA [27],
PPh3 [28], CaF2 [29], [bmim]BF4-immobilized Cu(II) acetylacetonate [30], and [bmim][FeCl4] [31] are examples.
However, in spite of their potential utility, the practical application of most of these reagents suffers from
disadvantages such as the use of expensive or less easily available reagents, vigorous reaction conditions, long reaction
times, high temperatures, unsatisfactory yields and tedious manipulations to isolate the products. Therefore, the
discovery of an inexpensive, facile and efficient reagent for the preparation of DHPMs under mild conditions is an
active ongoing research topic.
1. Experimental
Chemicals were purchased form Fluka, Merck and Aldrich Chemical Companies. All yields refer to the isolated
products. The purity determination of the substrate and reaction monitoring were accompanied by thin-layer
chromatography (TLC) on a silica-gel polygram SILG/UV 254 plates. The IR spectra were recorded on a PerkinElmer
781 Spectrophotometer. In all the cases the 1H NMR spectra were recorded with Bruker Avance 300 MHz instrument.
Chemical shifts are reported in parts per million in CDCl3 with tetramethylsilane as an internal standard. 13C NMR
data were collected on Bruker Avance 75 MHz instrument.
1.1. General procedure for the preparation of 3,4-dihydropyrimidin-2(1H)-ones/thiones
A mixture of aldehyde (1 mmol), b-ketoester (1 mmol), urea or thiourea (1 mmol) and MTSA (0.05 mmol, 0.02 g)
was heated in an oil bath (80 8C) for the appropriate time (Table 1). The reaction was monitored by TLC. On
completion, 5 mL of ethyl acetate was added to the mixture and filtered. The catalyst was washed with ethyl acetate
and dried; the recovered catalyst can be used for two reactions again. The solvent was evaporated from the organic
Table 1
Synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones in the absence of solvent.a,b
Entry
R1
R2
X
Time (min)
Yield (%)
M.P. (8C)
Found
Reported
1
2
Ph
Et
O
O
O
O
O
O
O
O
S
8 (9, 9)c
92 (90, 87)c
204–206
213–216
209–211
227–228
209–211
212–214
200–202
209–211
205–206
167–169
181–183
191–194
205–207
210–213
204–206
190–192
209–210
220–222
–
202–204 [28]
216–218 [19]
210–212 [21]
226–227 [19]
212–214 [22]
215–216 [28]
202–204 [28]
208–210 [22]
208–209 [22]
168–169 [34]
192–194 [12]
192–196 [34]
206–207 [22]
209–212 [22]
204–207 [22]
192–194 [21]
202–204 [21]
221–222 [35]
–
2-Cl–Ph
4-Cl–Ph
3-NO2–Ph
4-NO2–Ph
4-Me–Ph
4-MeO–Ph
2-Furyl
Et
14
91
3
Et
10
89
4
Et
22
90
5
Et
13
8 (8, 10)c
86
92 (90, 90)c
6
Et
7
Et
5
93
8
Et
12
13
18
16
14
24
9
90
9
Ph
Et
90
10
11
12
13
14
15
16
17
18
19
20
21
2-Cl–Ph
4-Cl–Ph
3-Cl–Ph
3-NO2–Ph
Ph
Et
S
87
Et
S
91
Et
S
88
Et
S
86
Me
Me
Me
Me
Me
Et
O
O
O
O
S
90
4-Cl–Ph
4-MeO–Ph
2-Furyl
11
7
94
92
14
9
85
Ph
92
CH3(CH2)3
PhCH2CH2
4-Cl–Ph + PhCH2CH2
O
O
O
45
30
12
0
Et
0
–
–
Et
100d + 0d
–
–
a
Products were characterized by their physical constants, comparison with authentic samples, IR and NMR spectroscopy.
b
c
d
Isolated yield.
Results obtained using recycled catalyst.
Conversion.

[()TD$FIG]
320
F. Shirini et al. / Chinese Chemical Letters 22 (2011) 318–321
O
R1
O
O
X
MTSA
R2 O
NH
R1CHO +
R1= Aryl
+
Me
OR2
R2= Me, Et
H2N
NH2
Solvent-free, 80 O
C
Me
N
H
X
X= O, S
Scheme 1.
layer and the solid residue was washed with cold water, dried and recrystallized from ethanol to afford the
corresponding DHPMs in good to high yields.
2. Results and discussion
Recently, we have reported the preparation of melamine trisulfonic acid (MTSA) and its application in the
promotion of the chemoselective methoxymethylation of alcohols and acetylation of alcohols, phenols and amines
[32,33]. In continuation of these studies, herein, we wish to report the applicability of this reagent in the promotion of
the preparation of DHPMs via three-component Biginelli reaction (Scheme 1).
At first, for the optimization of the reaction conditions, the condensation of benzaldehyde, ethyl acetoacetate and
urea was investigated under solvent-free conditions. The best result was achieved by caring out the reaction of
benzaldehyde, ethyl acetoacetate and urea (with 1:1: mol ratio) in the presence of 0.05 mmol of MTSA at 80 8C for
8 min under solvent-free conditions (Table 1, entry 1). Other aromatic aldehydes, containing both electron-donating
and electron-withdrawing groups, and heteroaromatic aldehydes were also reacted under the same reaction conditions
to produce the corresponding DHPMs in good to high yields (Table 1). Methyl acetoacetate and thiourea were also
used with similar success to provide the corresponding 3,4-dihydropyrimidin-2(1H)-thiones. Aliphatic aldehydes
remain intact under the same reaction conditions (Table 1, entries 19 and 20). Therefore, the method can be useful for
the chemoselective Biginelli condensation of aromatic aldehydes in the presence of aliphatic ones (Table 1, entry 21).
Our investigation showed that MTSA is reusable for three times (Table 1, entries 1 and 6). The same IR spectra of
the reagent were obtained before and after its use in the reactions, which demonstrate the stability of its comparison.
A plausible mechanism of the reaction is shown in Scheme 2 based on the literature [22], our observations and
obtained results.
The priority of this method to some of the previously reported ones, is shown by the comparison of the obtained
results in Table 2 [21–23,28].
In conclusion, we have described a novel and efficient method for the preparation of DHPMs catalyzed by MTSA,
as a newly prepared melamine based reagent, under solvent-free conditions. High yields of the products, short reaction
times, ease of the preparation and recyclability of the reagent, solvent-free nature of the reaction, chemoselectivity of
the reaction and easy work-up are among the other advantages of this method which make this procedure a useful
addition to the available methods.
[()TD$FIG]
O
S
N
N
HO
HN
O
Ar
OH
(MTSA)
X
ArCHO +
N
O
NH2
- H2O
H2N
NH2
H
X
O
O
Ar
O
Ar
Ar
H
X
O
N
N
-H2O
Me
OR
RO
Me
NH
RO
Me
NH
O
S
HN
N
NH2
X
H
MTSA
O
O
N
H
X
NH2
Scheme 2.

F. Shirini et al. / Chinese Chemical Letters 22 (2011) 318–321
321
Table 2
Comparison of some of the results obtained by the present method (I) with some of those reported by natural HEU (II) [21], Sr(OTf)2 (III), covalrntly
anchored sulfonic acid onto silica (IV) [23], and PPh3 (V) [28].
Entry
R1
R2
X
Time (h)/yield (%)
(I)
(II)
(III)
(IV)
(V)
1
2
3
Ph
Et
Et
Et
O
O
O
0.13/92
0.1/93
5/75
5/75
5/76
4/97
–
8/90
7/92
–
10/70
10/58
–
4-MeO–Ph
Ph
0.15/90
4/93
Acknowledgment
We are thankful to the University of Guilan Research Council for the partial support of this work.
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