Bronsted reusable acidic ionic liquids catalyzed Biginelli reaction under solvent-free conditions

Article abstract of DOI:10.1080/10426507.2012.710676

2-Pyrrolidonium hydrogensulfate, N-methyl-2-pyrrolidonium hydrogensulfate, and N-methyl-2-pyrrolidonium dihydrogenphosphate as Bronsted reusable acidic ionic liquids (ILs) catalyzed the preparation of 3,4-dihydropyrimidin- 2(1H)-one (thione) derivatives f

Full text of DOI:10.1080/10426507.2012.710676

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Phosphorus, Sulfur, and Silicon and the
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BrØnsted Reusable Acidic Ionic Liquids
Catalyzed Biginelli Reaction under
Solvent-Free Conditions
Hamid Reza Shaterian a & Morteza Aghakhanizadeh a
a Department of Chemistry, Faculty of Sciences , University of Sistan
and Baluchestan , Zahedan , Iran
Published online: 22 Jul 2013.
To cite this article: Hamid Reza Shaterian & Morteza Aghakhanizadeh (2013) BrØnsted Reusable Acidic
Ionic Liquids Catalyzed Biginelli Reaction under Solvent-Free Conditions, Phosphorus, Sulfur, and
Silicon and the Related Elements, 188:8, 1064-1070, DOI: 10.1080/10426507.2012.710676
To link to this article: http://dx.doi.org/10.1080/10426507.2012.710676
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Phosphorus, Sulfur, and Silicon, 188:1064–1070, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.710676
BRØNSTED REUSABLE ACIDIC IONIC LIQUIDS
CATALYZED BIGINELLI REACTION UNDER SOLVENT-FREE
CONDITIONS
Hamid Reza Shaterian and Morteza Aghakhanizadeh
Department of Chemistry, Faculty of Sciences, University of Sistan and
Baluchestan, Zahedan, Iran
GRAPHICAL ABSTRACT
Z
O
X
O
O
RO
NH
Z
Ionic Liquids (Catalyst)
60oC, Solvent-Free
+
H2N
+
NH2
X=O,S
CHO
RO
CH3
R= Et, Me
H3C
N
X
H
Z = H, Cl, Br, OH, NO2, MeO, Me, (Me)2N
Ionic Liquids = [Hnhp][HSO4], [NMP][HSO4], and [NMP][H2PO4]
Abstract 2-Pyrrolidonium hydrogensulfate, N-methyl-2-pyrrolidonium hydrogensulfate, and
N-methyl-2-pyrrolidonium dihydrogenphosphate as Brønsted reusable acidic ionic liquids
(ILs) catalyzed the preparation of 3,4-dihydropyrimidin-2(1H)-one (thione) derivatives from
ethyl/methyl acetoacetate, urea/thiourea, and aromatic aldehydes under thermal solvent-free
conditions.
Keywords Biginelli reaction; ionic liquid; catalyst; solvent-free; aldehyde
INTRODUCTION
The Biginelli reaction was developed by Pietro Biginelli in 1891.1 It is a multiple-
component chemical reaction that creates 3,4-dihydropyrimidine-2-(1H)-ones (DHPMs)
from ethyl acetoacetate, urea, and aryl aldehyde.1 The reaction can be catalyzed by Brønsted
acids and/or by Lewis acids.2 DHPMs are pharmacologically important compounds be-
cause of the promising biological activities including antiviral, antibacterial, antitumor,
and antihypertensive agents.3,4 Furthermore, these compounds have emerged as the integral
backbones of several calcium channel blockers.3–5
Received 4 May 2012; accepted 6 July 2012.
The authors are thankful to the University of Sistan and Baluchestan Research Council for the partial support
of this research.
Address correspondence to Hamid Reza Shaterian, Department of Chemistry, Faculty of Sciences, University
of Sistan and Baluchestan, PO Box: 98135-674, Zahedan, Iran. E-mail: hrshaterian@chem.usb.ac.ir
1064

3,4-DIHYDROPYRIMIDIN-2(1H)-ONES (THIONES)
1065
O
O
O
H
H
H
HSO4
N
N
N
HSO4
H2PO4
CH3
CH3
H
[NMP][H2PO4]
[Hnhp][HSO4]
[NMP][HSO4]
Figure 1 The structure of [Hnhp][HSO4], [NMP][HSO4], and [NMP][H2PO4].
Ionic liquids (ILs) are emerging as effective promoters and solvents for green chemi-
cal reactions.6 One of the most important advantages of ILs is the behavior of solvophobic
interactions that generate an internal pressure, which promotes the association of the chem-
ical reactants and reagents and also shows an acceleration of MCRs in comparison to
conventional solvents.7 Brønsted acidic ILs (BAILs) have been deemed promising alter-
natives for acid-catalyzed reactions and play a dual solvent–catalyst role in a variety of
reactions.7,8
Dihydropyrimidines have been synthesized using various ILs as catalyst such
as [Hmim]HSO4-NaNO3,9 [C4mim][HSO4],10 tri-(2-hydroxyethyl) ammonium acetate,11
BMImSac,12 and [bmim][FeCl4].13 In continuation of our research on new synthetic
methods in organic synthesis,14,15 we developed the Biginelli reaction with three BAILs
such as 2-pyrrolidonium hydrogensulfate ([Hnhp][HSO4]), N-methyl-2-pyrrolidonium
hydrogensulfate ([NMP][HSO4]), and N-methyl-2-pyrrolidonium dihydrogenphosphate
([NMP][H2PO4]) (Figure 1) as catalysts (Scheme 1).
Z
O
X
O
O
RO
NH
Z
Ionic Liquids (Catalyst)
60oC, Solvent-Free
+
H2N
+
NH2
X=O,S
CHO
RO
CH3
R= Et, Me
H3C
N
X
H
Z = H, Cl, Br, OH, NO2, MeO, Me, (Me)2N
Ionic Liquids = [Hnhp][HSO4], [NMP][HSO4], and [NMP][H2PO4]
Scheme 1 The preparation of 3,4-dihydropyrimidin-2(1H)-one (thione) derivatives.
RESULTS AND DISCUSSION
In order to carry out the Biginelli condensation in a more efficient way, the reaction
of ethyl acetoacetate (1.5 mmol), urea (1.1 mmol), and benzaldehyde (1.0 mmol) was
selected as a model system under thermal solvent-free conditions to find optimization con-
ditions. The preparation of 5-(ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-
◦
2(1H)-one was studied at different reaction temperatures (25, 60, 80, and 100 C) and
different amounts of acidic ILs as catalyst (5, 10, 15, 20, 25, and 30 mol%) (Table 1). The

1066
H. R. SHATERIAN AND M. AGHAKHANIZADEH
Table 1 Optimization of the amount of the acidic ILs, 2-pyrrolidonium hydrogensulfate (IL1), N-methyl-2-
pyrrolidonium hydrogensulfate (IL2), and N-methyl-2-pyrrolidonium dihydrogenphosphate (IL3), as catalysts
at different temperatures in the reaction of ethyl acetoacetate (1.5 mmol), urea (1.1 mmol), and benzaldehyde
(1 mmol) under solvent-free conditions
Time (min)
IL2
Yield (%)a
IL2
Catalyst
(mol%)
Temperature
(◦C)
Entry
IL1
IL3
IL1
IL3
1
2
3
4
5
6
7
8
–
5
100
100
100
100
100
100
100
25
60
9
7
6
5
60
10
9
8
6
8
9
42
8
10
60
13
12
11
13
12
8
58
11
9
–
–
–
85
87
89
90
90
93
18
83
79
78
84
88
88
92
92
15
85
85
78
80
83
86
89
91
25
80
83
10
15
20
25
30
5
7
10
48
12
11
9
10
5
5
60
80
aYields refer to isolated pure products.
best result was obtained by using 5 mol% of [Hnhp][HSO4], 5 mol% of [NMP][HSO4],
and 5 mol% of [NMP][H2PO4] at 60 ◦C (Table 1).
Using these optimized reaction conditions, the scope and efficiency of the procedure
was explored for the synthesis of a wide variety of substituted 3,4-dihydropyrimidin-2(1H)-
ones (thiones). As shown in Table 2, aromatic aldehydes with both electron-withdrawing and
electron-donating substituents reacted efficiently with urea (thiourea) and methyl/ethyl ace-
toacetate in the presence of a catalytic amount of [Hnhp][HSO4] (5 mol%) or [NMP][HSO4]
(5 mol%) or [NMP][H2PO4] (5 mol%), forming the corresponding 3,4-dihydropyrimidin-
2(1H)-ones (thiones) without the formation of any side products, in good to high yields. We
also used aliphatic aldehydes such as n-heptanal and n-octanal instead of benzaldehydes
in the mentioned reactions. Experimental observation showed us that all the starting reac-
tants were intact after 12 h without formation of any desired products and also byproducts
(Table 2, Entries 22 and 23).
The suggested mechanism was presented according to the proposed mechanism in
the literature.9,10,15 The ILs catalyzed this transformation. In the cyclic catalytic mechanism
(Scheme 2), the first step is the condensation between the aldehyde (1) and urea/thiourea
(2), with some similarities to Mannich condensation and formation of acyl imine. The
acyl imine (3) was activated with protonation in the presence of acidic ILs and afforded
the intermediate (4). Then, the intermediate (4) reacted with CH acid of methyl/ethyl
acetoacetate (5) and produced the intermediate (6). Subsequently, the ketone functional
group undergoes condensation with the NH2 of urea (thiourea) to give the cyclized Biginelli
product.
We also compared the results of the present ILs with other catalysts reported in the
literature such as [Hmim]HSO4-NaNO3,9 [C4mim][HSO4],10 tri-(2-hydroxyethyl) ammo-
nium acetate,11 Al(HSO4)3,14 and Al2O3-SO3H,14 for synthesis of 3,4-dihydropyrimidine-
2-(1H)-ones (Table 3). Table 3 clearly demonstrates that 2-pyrrolidonium hydrogensulfate,
N-methyl-2-pyrrolidonium hydrogensulfate, and N-methyl-2-pyrrolidonium dihydrogen-
phosphate are effective catalysts in terms of reaction time and yield of obtained product
relative to other reported catalysts.

3,4-DIHYDROPYRIMIDIN-2(1H)-ONES (THIONES)
1067
Table 2 Preparation of 3,4-dihydropyrimidine-2-(1H)-ones (thiones)
Time (min)
Yield (%)a
Entry
Aldehyde
R
X
IL1
IL2
IL3 IL1 IL2 IL3
M.p. (◦C)/Lit.M.p.[ref]
1
2
3
4
5
6
7
8
C6H5CHO
Et
Et
Et
Et
Et
Et
Et
O
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
S
S
O
O
12
6
39
7
12
14
8
26
6
8
7
27
8
15
12
9
23
5
9
9
9
8
11 83
83
43 75
89
18 66
30 84
85
86
80
91
72
82
88
76
88
84
92
85
87
58
72
92
82
61
82
85
79
80
82
76
85
75
75
90
78
84
79
86
87
85
62
81
201–203/[203–205][14]
207–209 /[206–208][9]
207–208/[207–208][9]
214–216/[214–215][9]
227–230/[227–229][11]
215/[214–217] [9]
228–230/[230–232][9]
237/[238–240][10]
235–236/[236–238] [9]
210–212/[211–212][10]
210/[210–212][10]
4-O2NC6H4CHO
4-CH3OC6H4CHO
4-ClC6H4CHO
4-HOC6H4CHO
4-CH3C6H4CHO
3-O2NC6H4CHO
7
8
9
86
38 80
86
3,4-(CH3O)2C6H3CHO Me
9
4-O2NC6H4CHO
C6H5CHO
4-BrC6H4CHO
2-BrC6H4CHO
4-ClC6H4CHO
C6H5CHO
4-O2NC6H4CHO
4-HOC6H4CHO
3-CH3OC6H4CHO
C6H5CHO
3-O2NC6H4CHO
4-HOC6H4CHO
4-(Me2N)C6H4CHO
n-Heptanal
Me
Me
Me
Me
Me
Et
Et
Et
Et
Me
Me
Me
Me
Et
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
10
8
6
12 65
10 89
8
8
83
82
220/[220–222][10]
206–207/[206–208][10]
204/[205–207] [14]
7
120 120 120 55
58
95
55
40
78 112 89
59 73 85
63 78
108/[108–110] [14]
90 194–195/[194–196] [14]
87
60
86
88
76
153–154/[150–152][14]
219–220/[221–223][14]
234–236/[237–239][14]
226/[226–228][14]
120 120 120 58
46
72
58
43
67
49
52 80
62 90
42 78
150–152/[152–154][14]
720 720 720
720 720 720
No reaction
No reaction
n-Octanal
Et
aYield refers to isolated pure product. The molar ration of the starting reactants was chosen as: methyl/ethyl
acetoacetate (1.5 mmol), urea/thiourea (1.1 mmol), and benzaldehyde (1 mmol); the reaction was carried out in
an oil bath at 60 ◦C. All known products have been reported in the literature and they were characterized by
comparing their melting point and IR and NMR spectra with authentic samples.9-11,14
In green organic synthesis, the recovery of the catalysts is more important. Thus, the
reusability of the ILs as catalysts was studied. After the completion of the reaction, the
mixture was cooled to r.t. and water (5 mL) was added to the reaction mixture. The IL was
dissolved in water, and filtered for separation of the crude product. The separated product
was washed twice with water (2 × 5 mL). To recover the ILs, water-containing ILs was
evaporated, and the remaining viscous liquid was washed with CH2Cl2 (5 mL) and dried
under reduced pressure. The recovered ILs were tested for studying their catalytic activity
in the subsequent run without adding the fresh catalyst. The ILs were tested for 5 runs. It
was seen that the ILs, as catalysts, displayed very good reusability without any considerable
loss of their activities.
EXPERIMENTAL
All reagents were purchased from Merck (Darmstadt, Germany) and Aldrich (St.
Louis, MO) and used without further purification. All yields refer to isolated products after
purification. 2-Pyrrolidonium hydrogensulfate,16 N-methyl-2-pyrrolidonium hydrogensul-
fate,17 and N-methyl-2-pyrrolidonium dihydrogenphosphate18 were prepared according
to the literature procedure. The NMR spectra were recorded on a Bruker Avance DPX

1068
H. R. SHATERIAN AND M. AGHAKHANIZADEH
Table 3 Comparison of the results of 2-pyrrolidonium hydrogensulfate, N-methyl-2-pyrrolidonium hydrogen-
sulfate, and N-methyl-2-pyrrolidonium dihydrogenphosphate with other catalysts reported in the literature for
synthesis of 3,4-dihydropyrimidine-2-(1H)-ones
Entry
Catalyst
Conditions
80 ◦C
Time (min) Yield (%)a
Ref
9
1
2
3
[Hmim]HSO4-NaNO3
(40 mol%)
[C4mim][HSO4] (10 mol%)
180
5
94
80
88
Microwave irradiation
(150 W)/140 ◦C
90 ◦C
10
11
Tri-(2-hydroxyethyl)-
ammonium acetate,
(62 mol%)
360
Microwave irradiation
(200 W)/90 ◦C
100 ◦C
4
90
5
6
7
8
9
Al(HSO4)3 (10 mol%)
Al2O3-SO3H (15 mol%)
[Hnhp][HSO4] (5 mol%)
[NMP][HSO4] (5 mol%)
[NMP][H2PO4] (5 mol%)
35
126
12
8
11
79
88
83
85
80
14
14
120 ◦C
Solvent-Free, 60 ◦C
Solvent-Free, 60 ◦C
Solvent-Free, 60 ◦C
This work
This work
This work
aBased on the reaction of ethyl acetoacetate, urea, and benzaldehyde.
O
O
H
HO S O
O
N
H
O
X
H2O
Z
H
+
H2N
NH2
(2)
Z
(1)
N
Z
H2N
X
(3)
O
X
O
H
RO
N
NH2
O
H
HO S O
O
O
CH3
N
H2O
H
(6)
X
H
NH2
N
Z
O
RO
H3C
NH
N
X
O
O
(4)
H
Product
RO
CH3
(5)
Scheme 2 The proposed mechanism for 2-pyrrolidonium hydrogensulfate as selected ILs that catalyzed the
preparation of 3,4-dihydropyrimidin-2(1H)-one (thione) derivatives.

3,4-DIHYDROPYRIMIDIN-2(1H)-ONES (THIONES)
1069
Figure 2 Reusability of ILs as catalysts. (Color figure available online).
300 MHz instrument (Germany). The spectra were measured in DMSO-d6 relative to TMS
(0.00 ppm). Melting points were determined in open capillaries with a BUCHI 510 melting
point apparatus. Thin-layer chromatography (TLC) was performed on silica-gel Poly Gram
SIL G/UV 254 plates.
General Procedure for the Synthesis of 3,4-dihydropyrimidin-2(1H)-one
(thione)
A stirred mixture of ethyl/methyl acetoacetate (1.5 mmol), aromatic aldehyde
(1 mmol), and urea (thiourea) (1.1 mmol) and 2-pyrrolidonium hydrogensulfate (0.009 g,
5 mol%, 0.05 mmol) or N-methyl-2-pyrrolidonium hydrogensulfate (0.0098 g, 5 mol%,
0.05 mmol) or N-methyl-2-pyrrolidonium d◦ihydrogenphosphate (0.0098 g, 5 mol%,
0.05 mmol) was reacted in an oil bath at 60 C for the appropriate time (Table 2). Af-
ter completion of the reaction, it was cooled to r.t. Then, water (5 mL) was added to the
mixture. The IL was dissolved in water, and filtered for separation of the crude product.
The separated product was washed twice with water (2 × 5 mL). The solid product was
purified by recrystallization procedure in ethanol. To recover the ILs, after the isolation of
insoluble products, water-containing IL was evaporated, and the remaining viscous liquid
was washed with CH2Cl2 (5 mL) and dried under reduced pressure.
All known products have been reported in the literature and they were characterized
by comparing their mp, IR, and NMR spectra with authentic samples.9–11,14
CONCLUSIONS
We have described a rapid and highly efficient method for the green synthesis of mul-
tisubstituted 3,4-dihydropyrimidine-2-(1H)-ones (thiones) using Brønsted reusable acidic
ILs as catalysts under homogeneous catalysis and also thermal solvent-free reaction condi-
tions. With such successful results, this convenient and efficient protocol should provide a
superior alternative to the existing methods because of its fast and clean reactions and high
yields. Furthermore, its simple workup procedure will make the present method useful and
important for Biginelli synthesis.

1070
H. R. SHATERIAN AND M. AGHAKHANIZADEH
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