The efficient synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and their sulfur derivatives with H2SO4 immobilized on activated charcoal

Article abstract of DOI:10.1080/10426507.2011.631644

Various 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs) and their sulfur derivatives were efficiently synthesized by a one-pot cyclocondensation reaction of aromatic and aliphatic aldehydes, β-dicarbonyl compounds and urea (or thiourea) in the presence of sulfur

Full text of DOI:10.1080/10426507.2011.631644

This article was downloaded by: [McGill University Library]
On: 18 September 2012, At: 01:58
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
The Efficient Synthesis of 3,4-
Dihydropyrimidin-2-(1H)-Ones and
Their Sulfur Derivatives with H2SO4
Immobilized on Activated Charcoal
Karim Akbari Dilmaghani a , Behzad Zeynizadeh a & Hadi Parasajam a
a Department of Chemistry, Faculty of Science, Urmia University,
Urmia, Iran
Version of record first published: 31 Jan 2012.
To cite this article: Karim Akbari Dilmaghani, Behzad Zeynizadeh & Hadi Parasajam (2012): The
Efficient Synthesis of 3,4-Dihydropyrimidin-2-(1H)-Ones and Their Sulfur Derivatives with H2SO4
Immobilized on Activated Charcoal, Phosphorus, Sulfur, and Silicon and the Related Elements, 187:4,
544-553
To link to this article: http://dx.doi.org/10.1080/10426507.2011.631644
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 187:544–553, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.631644
THE EFFICIENT SYNTHESIS
OF 3,4-DIHYDROPYRIMIDIN-2-(1H)-ONES AND THEIR
SULFUR DERIVATIVES WITH H2SO4 IMMOBILIZED
ON ACTIVATED CHARCOAL
Karim Akbari Dilmaghani, Behzad Zeynizadeh,
and Hadi Parasajam
Department of Chemistry, Faculty of Science, Urmia University, Urmia, Iran
GRAPHICAL ABSTRACT
R
O
O
O
X
R: Aryl, aliphatic
R': OMe, OEt, Me
X: O, S
H2SO4/C (133% w/w)
n-hexane-CH 3CN
5−150 min, 81−97%
NH
R'
Me
RCHO
+
+
R'
H2N
NH2
X
N
H
Abstract
Various 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs) and their sulfur derivatives were effi-
ciently synthesized by a one-pot cyclocondensation reaction of aromatic and aliphatic alde-
hydes, β-dicarbonyl compounds and urea (or thiourea) in the presence of sulfuric acid im-
mobilized on activated charcoal (133% w/w). The reactions were carried out in refluxing
n-hexane-acetonitrile (2.5:0.5 mL) within 5–150 min to give 3,4-dihydropyrimidinones (or
thiones) in high to excellent yields (81–97%).
Keywords 3,4-Dihydropyrimidin-2(1H)-one; activated charcoal; H2SO4; Biginelli synthesis
INTRODUCTION
3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) and related compounds have attracted
a great deal of attention in organic and medicinal chemistry.1 This class of compounds
possesses a broad range of biological activities including antiviral, antitumor, antibacterial,
anti-inflammatory, antihypertensive, and potent calcium channel blockers.2 The classical
Biginelli synthesis of 3,4-dihydropyrimidinones was first reported in 1893 by a one-pot
cyclocondensation reaction of β-dicarbonyl compounds, aromatic aldehydes and urea
under strongly acidic conditions.3 However, this reaction suffers from harsh reaction
conditions, long reaction times and unsatisfactory yields. 3,4-Dihydropyrimidinones were
also prepared by complex multi-step strategies with higher overall yields, whereas they lack
the simplicity of one-pot protocol.4 A literature review shows that numerous homogeneous
as well as heterogeneous reagents have been devoted to a one-pot approach because of
Received 26 August 2011; accepted 10 October 2011.
Address correspondence to Behzad Zeynizadeh, Department of Chemistry, Faculty of Science, Urmia
University, Urmia, Iran. E-mail: bzeynizadeh@gmail.com
544

SYNTHESIS OF 3,4-DIHYDROPYRIMIDINONES
545
simplicity and high yields. FeCl3/Si(OEt)4,5 ZrCl4,6 ZrOCl2·8H2O,7 BiCl3,8 SnCl2·2H2O,9
InBr3,10 InCl3,11 LaCl3·7H2O,12 CeCl3·7H2O,13 CuCl2·2H2O,14 CaCl2,15 BF3·OEt2,16
I2,17 Mn(OAc)3·2H2O,18 NaIO4,19 NH4Cl,20 Cu(OTf)2,21 Bi(OTf)3,22 Fe(OTf)3 and
Fe(O2CCF3),23 Yb(OTf)3,24 B(OH)3,25 Al(HSO4)3,26 NaHSO4·H2O,27 H2SO4/SiO2
or Al2O3,28 silica sulfuric acid,29 MeSO3H/Al2O3,30 sulfated zirconia,31 p-TsOH,32
montmorillonite KSF,33 Envirocat EPZ10,34 dodecylphosphonic acid,35 H3PW12O40,36
H3PMo12O40,37 baker yeast,38 and ionic liquid39 are some of the reagents that have been
used for synthesis of 3,4-dihydropyrimidinones.
On the other hand, solid supports have become popular and have been used for im-
mobilization of various reagents. Heterogeneous catalyst/reagent systems derived by the
immobilization method have been found a lot of benefits relative to the homogeneous
ones. They have special characteristics such as ease of manipulation, rise in the selec-
tivity of reactions, decrease in the waste production, ability to support moisture-sensitive
reagents/catalysts, provide straightforward workup procedures and finally rendering more
attractive synthetic processes from both the environmental and the economic point of view,
in agreement with some parameters of the “ideal synthesis” presented by Wender.40 Nu-
merous articles have demonstrated the importance and applications of solid supports41 as
well as heterogeneous systems42 in organic synthesis. In this context, activated charcoal,
because of its high degree of micro-porosity (just one gram of activated carbon has a surface
area in excess of 500 m2 with 1500 m2 being readily achievable), provides a high surface
area and this situation makes it more desirable for academic and industrial applications.43
Recently, the immobilization of sulfuric acid on silica gel or alumina as an efficient
heterogeneous acidic reagent has been reported by our research group for the synthesis of
DHPMs and their sulfur analogs.28 Therefore, to continue our research program and due to
lack of information to investigate the influence of high micro-porosity of activated charcoal
on Biginelli synthesis of DHPMs (or thiones), we decided to study the combination system
of sulfuric acid and activated charcoal in catalysis of the titled reaction. Herein, we wish
to introduce a fast and efficient protocol for synthesis of DHPMs as well as their sulfur
analogs by a one-pot cyclocondensation reaction of aromatic and aliphatic aldehydes (1),
β-dicarbonyl compounds (2), and urea (or thiourea) (3) with sulfuric acid immobilized
on activated charcoal as a readily available heterogeneous acidic reagent in refluxing n-
hexane-CH3CN (Scheme 1).
R
O
O
O
X
R: Aryl, aliphatic
R': OMe, OEt, Me
X: O, S
H2SO4/Charcoal
NH
R'
RCHO
+
+
R'
H2N
NH2
n-Hexane-CH3CN
Me
X
N
H
1
2
3
4-61
Scheme 1
RESULTS AND DISCUSSION
Reaction conditions were preliminary optimized by the promotion of a one-pot cyclo-
condensation reaction of benzaldehyde, ethyl acetoacetate, and urea with the immobilized
sulfuric acid on activated charcoal to afford 3,4-dihydropyrimidinone (4). The effect of
various solvents, sulfuric acid alone and mass ratio of sulfuric acid to charcoal (w/w) were

546
K. A. DILMAGHANI ET AL.
Table 1 Synthesis of 3,4-dihydropyrimidin-2(1H)-one (4) with H2SO4 immobilized on activated charcoal under
different conditionsa
H2SO4
(g)
Charcoal
(g)
H2SO4/C
(% w/w)
Time
(min)
Conversionb
(%)
Entry
Solvent
n-Hexane (3 mL)
CH3CN (3 mL)
THF (3 mL)
1
2
3
4
5
6
7
8
9
0.3
0.3
0.3
0.3
0.3
0.3
0.2
0.35
0.4
0.5
—
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
—
360
60
60
80
120
90
60
45
35
30
12
30
20
100
100
100
100
100
67
117
133
167
H2O (3 mL)
n-hexane (3 mL)
5
100
100
30
100
100
100
n-hexane-CH3CN (2.5:0.5 mL)
n-hexane-CH3CN (2.5:0.5 mL)
n-hexane-CH3CN (2.5:0.5 mL)
n-hexane-CH3CN (2.5:0.5 mL)
n-hexane-CH3CN (2.5:0.5 mL)
10
aAll reactions were carried out with 1 mmol of benzaldehyde in a molar ratio of aldehyde:ethyl acetoacetate:urea
(1:1:1.2) under reflux conditions.
bConversions less than 100% were determined on the basis of recovered aldehyde.
studied in Table 1. The results showed that in the case of sulfuric acid alone, the reaction
remained incomplete after 360 min, with only 12% conversion, whereas the immobiliza-
tion of sulfuric acid on activated charcoal dramatically accelerated the rate of reaction
and consequently the reaction was completed within 30–120 min in refluxing n-hexane
or a mixture of n-hexane-CH3CN (Scheme 2). The results revealed that the reaction in a
mixture of n-hexane-CH3CN (2.5:0.5 mL) was faster than using n-hexane alone. Although
the effect of mixing acetonitrile and n-hexane in promotion of the titled reaction is not
clear, however, this could be due to less solubility of the produced dihydropyrimidinone (4)
in n-hexane and more solubility of the reaction components in part of CH3CN. Therefore,
using H2SO4/charcoal system (133% w/w, easily available by mixing 0.4 g H2SO4 98%
with 0.3 g activated charcoal) in refluxing n-hexane-CH3CN (2.5:0.5 mL) is the optimum
reaction conditions to afford the best yield of DHPM (4) from the reaction of benzalde-
hyde (1 mmol), ethyl acetoacetate (1 mmol), and urea (1.2 mmol) within 35 min (Table 1,
entry 9).
H2SO4/charcoal (133% w/w)
Ph
CHO
Et2OC
Me
n-Hexane-CH3CN, 35 min, 100%
NH
+
H2NCONH2
Me
N
H
O
H2SO4
O
CO2Me
n-Hexane, 360 min, 12%
4
Scheme 2
The synthetic utility of H2SO4/charcoal system (133% w/w) was further stud-
ied by the reaction of various aromatic and aliphatic aldehydes, β-dicarbonyl com-
pounds (ethyl/methyl acetoacetate and acetylacetone) and urea at the optimized conditions.
Table 2 summarizes the results of this investigation. As it is observed, all reactions were
carried out successfully in a mixture of n-hexane-CH3CN (2.5: 0.5 mL) within 5–120 min
to afford DHPMs (4–28) in high to excellent yields. Thiourea has also been used to provide

SYNTHESIS OF 3,4-DIHYDROPYRIMIDINONES
547
Table 2 Synthesis of 3,4-dihydropyrimidin-2-(1H)-ones with H2SO4 immobilized on activated charcoala
Yield
(%)b
M.p.(◦C)
Found
R
R’
X
DHPMs
Time (min)
Reported
C6H5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
4
5
6
7
8
35
14
30
5
95
90
85
92
88
94
95
89
92
91
87
95
91
88
94
93
87
85
92
90
92
91
95
85
90
202, 203
216, 217
250, 251
226, 227
208, 209
170, 171
201, 202
206, 207
246, 247
193, 194
243, 244
210, 211
253, 254
280, 281
234–236
203, 204
193, 194
171, 172
283–285
252–254
235, 236
171, 172
227, 228
250, 251
182, 183
200–20228
215–21830
249, 25012b
226, 22730
208–21130
170–17219
200–20130
207–20811
246–24821
194–19510
242–24410
209–21228
254–25529
279–28020
235–23728
204–20628
192–19428
—
2-ClC6H4
2,4-Cl2C6H3
3-NO2C6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
1-Naphthyl
CH3
17
40
40
50
40
30
15
60
70
30
10
120
50
40
25
12
120
7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
OEt
OEt
H
C6H5
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
2,4-Cl2C6H3
3-NO2C6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-OH-3-MeOC6H3
1-Naphthyl
CH3
283–2865
–
234–2365
—
4-MeC6H4
2-MeOC6H4
CH3
120
60
10
228–22919
—
Me
Me
—
aAll reactions were carried out with a molar ratio of aldehyde/β-dicarbonyl/urea (1:1:1.2) in the presence of
H2SO4/charcoal (133% w/w) system under refluxing n-hexane-CH3CN (2.5:0.5 mL).
bYields refer to isolated pure products.
sulfur analogs of 3,4-dihydropyrimidinones. Similarly, the reaction of substituted aromatic
and aliphatic aldehydes (1 mmol), β-dicarbonyl compounds (1 mmol) and thiourea (1.2
mmol) with the immobilized sulfuric acid on activated charcoal (133% w/w) in refluxing
n-hexane-CH3CN (2.5:0.5 mL) afforded 3,4-dihydropyrimidin-2(1H)-thiones (29–61) in
high to excellent yields (Table 3).
The important aspect of sulfuric acid-activated charcoal system in synthesis of 3,4-
dihydropyrimidinones (or thiones) is the tolerance of substituents including NO2, Br, Cl,
OH, OMe, and Me under the experimental conditions. In addition, aliphatic aldehydes
such as HCHO and CH3CHO as well as aromatic ones exhibited the high efficiency
at this synthetic protocol that is known to be less reactive under conventional Biginelli
reaction conditions (Table 2: DHPMs 13, 14, 25, and 28; Table 3: DHPMs 38, 50, and 61).
Moreover, in Tables 2 and 3, the influence of electron-donating and withdrawing groups of
the aromatic rings on the rate of reactions is easily observed in the time of reactions. For
example, Table 2 shows that in the case of substituted aromatic aldehydes, ethyl acetoacetate
and urea, electron-withdrawing groups such as 3- or 4-NO2 and 2,4-dichloro increase the
rate of Biginelli cyclocondensation reaction and vice versa electron-donating groups such
as 4-Me, 3-, or 4-OMe decrease the rate of reaction. Substituents such as hydrogen (in

548
K. A. DILMAGHANI ET AL.
Table 3 Synthesis of 3,4-dihydropyrimidin-2-(1H)-thiones with H2SO4 immobilized on activated charcoala
Yield
(%)b
M.p.(◦C)
Found
R
Rꢁ
X
DHPMs
Time (min)
Reported
C6H5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
s
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
120
90
50
14
130
35
150
15
140
20
120
70
20
130
60
75
130
30
15
30
120
10
150
120
25
110
25
96
87
90
91
97
90
85
95
88
92
82
88
89
90
82
91
92
96
89
86
81
90
96
82
87
87
95
90
92
97
88
89
95
206–208
112–114
170–172
110, 111
192, 193
199, 200
150–152
184, 185
199–201
174–176
227, 228
247, 248
193, 194
211, 212
255–257
185, 186
165, 166
222, 223
244, 245
257, 258
254, 255
198–200
219–221
273, 274
256–258
231–233
192, 193
182, 183
228, 229
250, 251
252, 253
232–234
192–194
206, 20728
2,4-Cl2C6H3
3-BrC6H4
4-NO2C6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
3-OHC6H4
1-Naphthyl
CH3
—
—
109–11139
192–19428
—
150–15211
184–18628
—
—
C6H5
228–22939
3-BrC6H4
3-NO2C6H4
3-MeOC6H4
2-MeOC6H4
4-MeOC6H3
4-MeC6H3
3-OHC6H3
4-OHC6H3
4-OH-3-MeOC6H3
1-Naphthyl
CH3
—
—
—
—
185–18639
—
—
—
—
—
—
C6H5
220–22239
3-BrC6H4
4-NO2C6H4
3-MeOC6H4
2-MeOC6H4
4-MeOC6H3
4-MeC6H3
3-OHC6H3
4-OHC6H3
4-OH-3-MeOC6H3
CH3
Me
Me
Me
Me
Me
Me
Me
Me
—
—
—
—
75
120
25
8
5
183–18445
—
—
—
—
—
s
s
s
s
Me
Me
15
aAll reactions were carried out with a molar ratio of aldehyde/β-dicarbonyl/thiourea (1:1:1.2) in the presence
of H2SO4/charcoal (133% w/w) system under refluxing n-hexane-CH3CN (2.5:0.5 mL).
bYields refer to isolated pure products.
benzaldehyde) and benzene ring (in 1-naphthaldehyde) exhibit the efficiency of electron-
donating groups similarly. In addition, the examinations with aliphatic aldehydes show
more rates than aromatic ones in Biginelli synthetic reaction. The results of a comparable
study in Tables 2 and 3 also show that the rate enhancement of 3,4-dihydropyrimidinones
synthesis is generally higher than 2-thioxo derivatives when the same aldehydes and β-
dicarbonyl compounds were used. This reveals that the nucleophilic activity of urea is
higher than thiourea under the experimental conditions.
Reusability of the catalyst at this synthetic method was studied by recovering of char-
coal immobilized sulfuric acid from the reaction mixture and then reusing it for the synthesis
of 3,4-dihydropyrimidinones (4) from the reaction of benzaldehyde, ethyl acetoacetate, and

SYNTHESIS OF 3,4-DIHYDROPYRIMIDINONES
549
urea in a mixture of n-hexane-CH3CN. The results showed that due to liberation and con-
sumption of some amount of sulfuric acid from the surface of charcoal in the reaction
mixture, the regenerated system did not show the original activity. However, when the re-
generated charcoal again is charged with sulfuric acid up to 133% w/w, the reagent system
shows the primary catalytic activity in synthesis of 3,4-dihydropyrimidinone (4).
Kappe, in 1997 using spectroscopic methods,44 demonstrated that the classical three-
component Biginelli synthesis of 3,4-dihydropyrimidinone from the reaction of an alde-
hyde, ethyl acetoacetate, and urea in the presence of strong Brønsted acidic catalyst (HCl)
exactly take places through the Folkers and Johnson proposed mechanism pathways in-
volving acid-catalyzed formation of N-acyliminium ion precursor of type 62 from the
preliminary condensation of an aldehyde and urea components as a key intermediate in
the rate determining step. Although the exact mechanism of sulfuric acid immobilized on
activated charcoal for the promotion of 3,4-dihydropyrimidinone synthesis is not clear,
however, we think that due to closer characteristics of sulfuric acid to hydrochloric acid
which was used in classical Biginelli reaction, the following mechanistic pathways could
play a role in catalysis of the titled reaction (Scheme 3).
R
-H2O/H+
OH
H
Et2OC
Me
-H+
Me
RCHO
H2NCONH2
+
R
NH2
O
NH
R
NH2
O
+
N
N
H
O
O H2N
-H2O
O
H
R: Aryl and alkyl
CO2Me
62
R
Et2OC
Me
NH
N
H
O
Scheme 3
As mentioned above, the promotion of 3,4-dihydropyrimidinone synthesis has been
reported by modified sulfuric acid systems such as NaHSO4·H2O,27 H2SO4 immobilized
on SiO2 or Al2O3,28 and silica sulfuric acid.29 So, in order to highlight the advantages
of H2SO4/charcoal system (133% w/w), we compared some of our results with those of
reported methods (Table 4). Comparison of the results shows that due to high micro-
porosity and surface area of activated charcoal, the immobilization of sulfuric acid on
charcoal exhibited the more rates and efficiency than the other protocols.
In summary, we have shown the high efficiency of sulfuric acid immobilized on
activated charcoal (133% w/w) as an inexpensive and heterogeneous acidic reagent to
promote the synthesis of DHPMs and their sulfur analogs in high to excellent yields. The
reactions were carried out by a one-pot cyclocondensation reaction of aromatic and aliphatic
aldehydes, β-dicarbonyl compounds and urea (or thiourea) in refluxing n-hexane-CH3CN
within 5–150 min. Therefore, the use of available low-cost reagents, synthesis of wide
spectrum of 3,4-dihydropyrimidinones (or thiones) from aromatic aldehydes especially
aliphatic ones, the tolerance of various functional groups and reusability of the recovered
charcoal are the main advantages that make this protocol a useful addition to the present
methodologies.

550

SYNTHESIS OF 3,4-DIHYDROPYRIMIDINONES
551
EXPERIMENTAL
General
All reagents and substrates were purchased from commercial sources with the best
quality and they were used without further purification. Activated charcoal was obtained
1
from Merck Company (Art No 102186). IR and H/13C NMR spectra were recorded
on Thermo Nicolet Nexus 670 FT-IR and 300 MHz Bruker spectrometers, respectively
(1H at 300MHz; 13C at 75MHz. The products were characterized by their spectra data
and comparison with the reported data in literature. Melting points were recorded on a
Philip Harris C4954718 apparatus. All yields refer to isolated pure products. Thin layer
chromatography (TLC) was applied for the purity determination of substrates, products,
and reaction monitoring over silica gel 60 F254 aluminum sheet.
Preparation of Sulfuric Acid Immobilized on Activated
Charcoal (133% w/w)
To a round-bottom flask (5 mL) equipped with a magnetic stirrer, activated charcoal
(0.3 g) and sulfuric acid (0.4 g, 98%) were added and the mixture was stirred vigorously
for 3 min to afford sulfuric acid immobilized on activated charcoal (133% w/w). FT-IR
(νmax/cm−1, KBr): 3400, 2610, 2488, 1713, 1633, 1286, 1176, 1069, 1008, 881, 851, 657,
578, 455. Figure S1 (Supplemental materials) shows the FT-IR spectrum of the catalyst.
General Procedure for Synthesis of DHPMs (Thiones) with Sulfuric Acid
Immobilized on Activated Charcoal
In a round-bottom flask (10 mL) equipped with a magnetic stirrer and condenser,
freshly prepared H2SO4/charcoal system (133% w/w), n-hexane (2.5 mL) and CH3CN
(0.5 mL) were added and the mixture was stirred for 1 min at room temperature. After
addition of the aldehyde (1 mmol), β-dicarbonyl compound (1 mmol) and urea/thiourea
(1.2 mmol) to the reaction mixture, stirring under reflux conditions was continued for the
appropriate time (Tables 2 and 3). The progress of the reaction was monitored by TLC.
When the reaction was complete, the mixture was cooled to room temperature and a sinter
glass funnel removed the residue charcoal. To the filtrate, aqueous NaHCO3 (10%, 5 mL)
was added and the mixture was extracted with EtOAc (3 × 15 mL). The combined extracts
were dried over anhydrous Na2SO4. Evaporation of the solvent and recrystallization of
the crude product in hot MeOH affords DHPMs or 2-thione (4–61) in 81–97% yield.
Spectroscopic data for the previously prepared products are provided as supplementary
data sheet.
ACKNOWLEDGMENT
The financial support of this work was gratefully acknowledged by the Research
Council of Urmia University.
REFERENCES
1. Kappe, C. O. Tetrahedron 1993, 49, 6937-6963.
2. (a) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879-888; (b) Kappe, C. O. Eur. J. Med. Chem.
2000, 35, 1043-1052; (c) Kappe, C. O.; Fabian, W. M. F.; Semones, M. A. Tetrahedron 1997,

552
K. A. DILMAGHANI ET AL.
53, 2803-2816; (d) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.;
Gougoutoy, J. Z.; O’Reilly, B. C.; Schwartz, J. J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254-
3263; (e) Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J. J. Org. Chem. 1989, 54,
5898-5907.
3. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360-416.
4. (a) Shutalev, A. D.; Kishko, E. A.; Sivova, N.; Kuznetsov, A. Y. Molecules 1998, 3, 100-106;
(b) Atwal, K. S.; O’Reilly, B. C.; Gougoutas, J. Z.; Malley, M. F. Heterocycles 1987, 26,
1189-1192; (c) O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185-1188.
5. Cepanec, I.; Litvic, M.; Bartolincic, A.; Lovric, M. Tetrahedron 2005, 61, 4275-4280.
6. Reddy, C. V.; Mahesh, M.; Raju, P. V. K.; Babu, T. R.; Narayana Reddy, V. V. Tetrahedron Lett.
2002, 43, 2657-2659.
7. Rodriguez-Dominguez, J. C.; Bernardi, D.; Kirsch, G. Tetrahedron Lett. 2007, 48, 5777-5780.
8. Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B. Synlett 2001, 863-865.
9. Russowsky, D.; Lopes, F. A.; da Silva, V. S. S.; Canto, K. F. S.; D’Oca, M. G. M.; Godoi, M. N.
J. Braz. Chem. Soc. 2004, 15, 165-169.
10. Fu, N. Y.; Yuan, Y. F.; Cao, Z.; Wang, S. W.; Wang, J. T.; Peppe, C. Tetrahedron 2002, 58,
4801-4807.
11. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65, 6270-6272.
12. (a) Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron Lett. 2000, 41, 9075-9078; (b) Li,
W.; Lu, J.; Ma, H. Chin. J. Appl. Chem. 2001, 18, 566-568.
13. Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003, 68, 587-590.
14. Gohain, M.; Prajapati, D.; Sandhu, J. S. Synlett 2004, 235-238.
15. Gangadasu, B.; Narender, P.; Raju, B. C.; Rao, V. J. Indian J. Chem. 2006, 45B, 1259-1263.
16. Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem. 1998, 63, 3454-3457.
17. Srinvas, K. V. N. S.; Das, B. Synthesis 2004, 2091-2093.
18. Kumar, K. A.; Kasthuraiah, M.; Reddy, C. S.; Reddy, C. D. Tetrahedron Lett. 2001, 42, 7873-
7875.
19. Jing, X.; Li, Z.; Pan, X.; Shi, Y.; Yan, C. J. Iran. Chem. Soc. 2009, 6, 514-518.
20. Shaabani, A.; Bazgir, A.; Teimouri, F. Tetrahedron Lett. 2003, 44, 857-859.
21. Paraskar, A. S.; Dewkar, G. K.; Sudalai, A. Tetrahedron Lett. 2003, 44, 3305-3308.
22. Varala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 67-70.
23. Adibi, H.; Samimi, H. A.; Beygzadeh, M. Catal. Commun. 2007, 8, 2119-2124.
24. Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65, 3864.
25. Tu, S.; Fang, F.; Miao, C.; Jiang, H.; Feng, Y.; Shi, D.; Wang, X. Tetrahedron Lett. 2003, 44,
6153-6155.
26. Khodaei, M. M.; Salehi, P.; Zolfigol, M. A.; Sirouszadeh, S. Pol. J. Chem. 2004, 78, 385-388.
27. Zeynizadeh, B.; Dilmaghani, K. A.; Yari, M. Phosphorus, Sulfur, Silicon Relat. Elem. 2009, 184,
2465-2471.
28. Dilmaghani, K. A.; Zeynizadeh, B.; Yari, M. Phosphorus, Sulfur, Silicon Relat. Elem. 2009, 184,
1722-1728.
29. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Bodaghi Fard, M. A. Tetrahedron Lett. 2003, 44, 2889-
2891.
30. Sharghi, H.; Jokar, M. Synth. Commun. 2009, 39, 958-979.
31. Kumar, D.; Sundaree, M. S.; Mishra, B. G. Chem. Lett. 2006, 35, 1074-1075.
32. Jin, T.; Zhange, S.; Li, T. Synth. Commun. 2002, 32, 1847-1851.
33. Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G. Tetrahedron Lett. 1999, 40, 3465-3468.
34. Lee, K. Y.; Ko, K. Y. Bull. Korean Chem. Soc. 2004, 25, 1929-1931.
35. Ghassamipour, S.; Sardarian, A. R. J. Iran. Chem. Soc. 2010, 7, 237-242.
36. Heravi, M. M.; Derikvand, F.; Bamoharram, F. F. J. Mol. Catal. A: Chem. 2005, 242, 173-175.
37. Heravi, M. M.; Bakhtiari, K.; Bamoharram, F. F. Catal. Commun. 2006, 7, 373-376.
38. Kumar, A.; Maurya, R. A. Tetrahedron Lett. 2007, 48, 4569-4571.
39. Shaabani, A.; Rahmati, A. Catal. Lett. 2005, 100, 177-179.
40. Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. (London) 1997, 765-769.

SYNTHESIS OF 3,4-DIHYDROPYRIMIDINONES
553
41. (a) Clark, J. H.; Kybett, A. P.; Macquarrie, D. J. Supported Reagents: Preparation, Analysis,
and Applications, Wiley-VCH: Weinheim, 1992; (b) Clark, J. H.; Rhodes, C. N. Clean Synthesis
Using Porous Inorganic Solid Catalysts and Supported Reagents, Royal Society of Chemistry:
Cambridge, 2000; (c) Drewry, D. H.; Coe, D. M.; Poon, S. Med. Res. Rev. 1999, 19, 97-
148; (d) Bhattacharyya, S. Curr. Opin. Drug Discov. Devel. 2004, 7, 752-764; (e) Sherrington,
D. C. Kybett, A. P. Supported Catalysts and Their Applications, Royal Society of Chemistry:
Cambridge, 2001; (f) Ranu, B. C.; Bhadra, S.; Saha, D. Curr. Org. Synth. 2011, 8, 146-171;
(g) Chang, Y.; Bae, C. Curr. Org. Synth. 2011, 8, 208-236.
42. (a) Smith, G. V.; Notheisz, F. Heterogeneous Catalysis in Organic Chemistry, Academic Press,
New York, 1999; (b) Sheldon, R. A.; van Bekkum, H. Fine Chemicals Through Heterogeneous
Catalysis, Wiley-VCH: Weinheim, 2001; (c) Thomas, J. M.; Thomas, W. J. Principles and
Practice of Heterogeneous Catalysis, Wiley-VCH: Weinheim, 2005; (d) Santen, R. A.; Neurock,
M. Molecular Heterogeneous Catalysis: A Conceptual and Computational Approach, Wiley-
VCH: Weinheim, 2006; (e) Hagen, J. Industrial Catalysis: A Practical Approach, 2nd ed.;
Wiley-VCH: Weinheim, 2006; (f) Rothenberg, G. Catalysis: Concepts and Green Applications,
Wiley-VCH: Weinheim, 2008.
43. (a) Activated Carbon, http://en.wikipedia.org/wiki/Activated carbon (accessed October 7, 2011);
(b) Paquette, L. A. Encyclopedia of Reagents for Organic Synthesis, 2nd ed.; Wiley: New York,
2009.
44. (a) Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55, 3784-3791; (b) Kappe, O. C. J. Org.
Chem. 1997, 62, 7201-7204; (c) Hu, E. H.; Slider, D. R.; Dolling, U. H. J. Org. Chem. 1998, 63,
3454-3457; (d) Cepanec, I.; Litvic, M.; Filipan-Litivic, M.; Grungold, I. Tetrahedron 2007, 63,
11822-11827.
45. Foroughifar, N.; Mobinikhaledi, A.; Fathinejad Jirandehi, H.; Memar, S. Phosphorus, Sulfur
Silicon Relat. Elem. 2003, 178, 1269-1276.