SiO2-NaHSO4 as an efficient reusable heterogeneous catalyst for the one-pot three-component synthesis of octahydro-quinazolin-2,5- diones in Water

Article abstract of DOI:10.1016/S1872-2067(11)60366-5

An environmentally benign method for the synthesis of octahydro-quinazolin- 2,5-diones by the reaction of aromatic aldehydes, dimedone, and urea in the presence of SiO₂-NaHSO₄ is reported. SiO ₂-NaHSO₄ acts as a

Full text of DOI:10.1016/S1872-2067(11)60366-5

CHINESE JOURNAL OF CATALYSIS
Volume 33, Issue 4, 2012
Online English edition of the Chinese language journal
Cite this article as: Chin. J. Catal., 2012, 33: 677–680.
ARTICLE
SiO2-NaHSO4 as an Efficient Reusable Heterogeneous
Catalyst for the One-Pot Three-Component Synthesis of
Octahydro-quinazolin-2,5-diones in Water
Sadeq Hamood Saleh AZZAM1, Aisha SIDDEKHA2, Aatika NIZAM1, Mohamed Afzal PASHA*
1Department of Studies in Chemistry, Central College Campus, Bangalore University, Bengaluru-560001, India
2Department of Chemistry, Smt. V. H. D. Central Institute of Home Science, Bangalore-560 001, India
Abstract: An environmentally benign method for the synthesis of octahydro-quinazolin-2,5-diones by the reaction of aromatic aldehydes,
dimedone, and urea in the presence of SiO2-NaHSO4 is reported. SiO2-NaHSO4 acts as an efficient, mild, and recyclable heterogeneous
catalyst to give excellent yields within a short reaction time in water at 60–80 ꢀC.
Key words: octahydro-quinazolin-2,5-dione; aromatic aldehyde; dimedone; urea; water
Multicomponent reactions (MCRs) are very important for
the construction of many heterocyclic compounds [1] and this
strategy has been used effectively in the synthesis of many
biologically active substances and natural products [2]. The
synthesis of octahydro-quinazolin-2,5-diones has attracted the
attention of chemists because of their highly potent antibacte-
rial activity against many kinds of bacteria including Staphy-
lococcus aureus, Escherichia coli and Pseudomonas aerugi-
nosa [3]. Furthermore, they have demonstrated calcium an-
tagonist activity [4–6]. Several methods have been reported for
the synthesis of octahydro-quinazolin-2,5-diones from aro-
matic aldehydes, dimedone, and urea, involving the use of
catalysts such as NH4VO3 [7], TMSCl [8], Nafion-H [9], conc.
H2SO4 [10], conc. HCl [11], heteropolyacids [12–13], bakers’
yeast [14], and ionic liquids [15,16]. They can also be synthe-
erogeneous catalyst for the synthesis of octahydro-quinazolin-
2,5-diones from aromatic aldehydes, dimedone, and urea,
providing the product in excellent yields in a water solvent at
temperature in the range of 60–80°C. The catalyst can be easily
recovered and reused several times with good efficiency.
1 Experimental
1.1 Preparation of the catalyst
SiO2-NaHSO4 catalyst was prepared by the reported method
[18]. Silica gel (15 g, 100–200 mesh) was added to a mag-
netically stirred solution of NaHSO4.H2O (6.9 g, 50 mmol) in
distilled water (100 ml) at 25 °C over a 30 min period. The
mixture was stirred for a further 30 min allowing for the so-
dium bisulfate to adsorb onto the surface of the silica gel. The
water was removed in vacuo to give a powder which was dried
in an oven at 120 °C for 2–3 h.
sized via
a Biginelli multicomponent reaction using
cyclo-ꢀ-diketones [17]. Many of the reported methods suffer
from one or more disadvantages including harsh reaction con-
ditions, long reaction times, poor yields, and the use of haz-
ardous and expensive catalysts with limited reusability.
1.2 Synthesis of octahydro-quinazolin-2,5-diones
Herein, we have attempted to develop a clean and environ-
ment friendly approach to the synthesis of octahy-
dro-quinazolin-2,5-diones with high yields using SiO2-Na-
HSO4 as a catalyst. SiO2-NaHSO4 acts as highly efficient het-
All reactions were carried out in a 50 ml RB flask in water.
During a general procedure (Scheme 1), a mixture of dimedone
(1 mmol), urea (1.2 mmol), SiO2-NaHSO4 (0.1 g), and water
Received 16 October 2011. Accepted 6 January 2012.
*Corresponding author. Tel: +91-80-22961337; Fax: +91-80-22961331; E-mail: m_af_pasha@ymail.com
Copyright © 2012, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier BV. All rights reserved.
DOI: 10.1016/S1872-2067(11)60366-5

Sadeq Hamood Saleh AZZAM et al. / Chinese Journal of Catalysis, 2012, 33: 677–680
R
O
O
CHO
O
SiO2-NaHSO4
NH
+
+
H2N
NH2
H2O/Stirring
60ꢀ80 oC
1ꢀ2 h
R
O
O
N
H
4aꢀ4i
1aꢀ1i
3
2
R = -H, -OMe, -Cl, -OH, -NO2, -2-OMe, -N(CH3)2, -[4-OH, 3-OMe]
Scheme 1. Synthesis of octahydro-quinazolin-2,5-diones from aromatic aldehydes, dimedone, and urea catalyzed by SiO2-NaHSO4.
(10 ml) was taken in a 50 ml round bottom flask and heated at
60–80 °C for 30 min. An aromatic aldehyde (1 mmol) was then
added and heating was continued with stirring for a period of
time. Ethyl acetate (10 ml) was then added and the solid cata-
lyst filtered from the mixture, washed with chloroform, and
recycled. The filtrate was evaporated to give the crude product
which was recrystallized from methanol-water (2:1) to afford
the pure product.
During the course of the reaction, the product formation was
monitored by thin layer chromatography (TLC) analysis and
compared with the authentic samples. Melting points were
determined on a RAAGA system (Chennai, India). Infrared (IR)
spectra were recorded on a Shimadzu FT-IR-8400s spectro-
photometer from KBr discs. The 1H and 13C NMR spectra were
recorded from DMSO-d6 solvent on 400 and 100 MHz Bruker
instruments, respectively. Elemental analysis was done using a
vario MICRO CHN analyzer.
2 Results and discussion
2.1 Catalytic performance of SiO2-NaHSO4
Recently, SiO2-NaHSO4 catalyzed organic reactions have
gained much attention, because of their commercial availability,
moisture stability, and recyclability. A literature survey re-
vealed that the use of SiO2-NaHSO4 for the synthesis of xan-
thenediones [19], ꢀ-enaminones, and 2-methylquinolin-4(1H)-
ones [20]. Furthermore, SiO2-NaHSO4 has been used in the
protection of aldehydes with 2-mercaptoethanol [18]. In a
continuation of our work into the synthesis of biologically
active heterocyclic compounds using readily available, inex-
pensive, and environment friendly catalysts [21–26], herein we
are report the synthesis of octahydro-quinazolin-2,5-diones by
the one-pot multi-component reaction of aromatic aldehydes,
dimedone, and urea using SiO2-NaHSO4 as an efficient catalyst
in water. We have found that SiO2-NaHSO4 catalyzes the reac-
tion between aromatic aldehydes, dimedone, and urea in an
aqueous medium efficiently to afford the desired products in
excellent yield within 1–2 h. The catalyst can be easily pre-
pared [18] and safely handled, making the method more ad-
vantageous over other conventional methods and catalysts.
The efficiency of SiO2-NaHSO4 as a catalyst for the syn-
thesis of the model compound 7,7-dimethyl-4-phenyl-4,6,7,8-
tetrahydro-1H,3H-quinazoline-2,5-dione (4a), was compared
with that of other catalysts reported in the literature (Table 1). It
is clear from this table that SiO2-NaHSO4 is an efficient,
cost-effective, and environmentally benign catalyst which
could be useful in the synthesis of a series of octahy-
dro-quinazolin-2,5-diones. From a practical perspective, the
catalyst can be easily prepared from readily available reagents
and can also be recycled.
4-(2-hydroxyphenyl)-7,7-dimethyl-3,4,7,8-tetrahydroquinaz
oline-2,5(1H,6H)-dione (4b). Mp 184–186 °C. IR (KBr, cm–1):
ꢀ 498 (br), 3298 (br), 2954 (s), 1705 (s), 1654 (s), 1610 (vs),
1
1463 (w), 1350 (s), 1220 (s). H NMR (400 MHz, CDCl3 +
DMSO-d6): ꢁ 0.98 (s, 6H, 2Me), 2.1(s, 2H, CH2), 2.3 (s, 2H,
CH2), 3.4 (s, 1H, OH), 5.3 (s, 1H, CH), 6.9–7.3 (m, 4H, Ph), 9.8
(br, 2H, 2NH). 13C NMR (100MHz, CDCl3 + DMSO-d6): ꢁ
196.6 (C=O), 5.3 (NC=O),150.6 (NC=C), 129.6, 126.8, 124.4,
118.2, 115.8, 112.7 (all ArC), 112.7 (OC-C=C), 51.6 (C-NH),
48 (CH2), 32.5 (CH2), 32.3 (>C<), 29.8, 28.7(CH3). Anal.
Calcd for C16H18N2O3: C, 67.1328; H, 6.29; N, 9.79. Found: C,
67.20; H, 6.29; N, 9.83.
4-(3,4-dimethoxyphenyl)-7,7-dimethyl-3,4,7,8-tetrahydroq
uinazoline-2,5(1H,6H)-dione (4g). Mp 154–156 °C. IR (KBr,
cm–1): ꢀ 3433 (br), 3228 (br), 2954 (s), 1705 (s), 1668(s), 1615
(vs), 1498 (s), 1400 (s), 1244 (s), 1135 (vs), 1022 (s). 1H NMR
(400 MHz, CDCl3 + DMSO-d6): ꢁ 0.99 (s, 6H, 2Me), 2.3 (s, 2H,
CH2), 2.4 (s, 2H, CH2), 3.6 (s, 3H, CH3), 3.7 (s, 3H, CH3), 5.7 (s,
1H, CH), 6.5–6.8 (m, 3H, Ph), 9.8 (br, 2H, 2NH). 13C NMR
(100MHz, CDCl3 + DMSO-d6): ꢁ 195.5 (C=O) , 177.7(NC=O),
148.6 (NC=C), 146.3, 138.8, 119.7, 115.6, 112.3, 111.9 (all
ArC), 111.9 (OC-C=C), 56.4 (O-CH3), 55.8 (O-CH3), 51.3
(C-NH), 48 (CH2), 31.9 (CH2), 30.7 (>C<), 30.5, 27.9 (CH3).
Anal. Calcd for C18H23N2O4: C, 65.256, H, 6.94, N,
Table 1 Comparison of the efficiency of SiO2-NaHSO4 with other cata-
lysts for the synthesis of 4a
Catalyst
TMSCl
Time (h)
1.5
Yield (%)
Ref.
[8]
[16]
[10]
[11]
—
93
91
85
—
95
Ionic liquids
conc. H2SO4
conc. HCl
SiO2-NaHSO4
2.5
3.0
6.5
1.5
8.45. Found: C, 65.32, H, 6.97, N, 8.43.

Sadeq Hamood Saleh AZZAM et al. / Chinese Journal of Catalysis, 2012, 33: 677–680
Table 2 Synthesis of octahydro-quinazolin-2,5-diones catalyzed by SiO2-NaHSO4
Melting point (oC)
Aldehyde
Producta
Time (h)
Yieldb (%)
Reported
290–292
—
>300
192–194
284
298–300
—
302–304
231–232
Found
C6H5CHO 1a
2-OH-C6H4CHO 1b
4-Cl-C6H4CHO 1c
3-OMe,4-OH-C6H3CHO 1d
4-OMe-C6H4CHO 1e
3-NO2-C6H4CHO 1f
3,4-(OCH3)2C6H3CHO 1g
4-NO2-C6H4CHO 1h
4-N(CH3)2C6H4CHO 1i
4a
4bc
4c
4d
4e
1.5
1.0
1.5
1.0
2.0
2.0
1.0
2.0
1.5
95
88
90
85
92
85
95
90
90
292–295
184–186
297
189–191
278–280
297
154–156
296–298
229
4f
4gc
4h
4i
1
aAll the products are known and were characterized by IR (KBr) spectral analysis. Products 4a, 4b, 4c, 4g, and 4i were also characterized by H NMR
spectral analysis and by comparing on TLC with the samples prepared by reported methods.
bIsolated yield.
c4b and 4g are new compounds and were also characterized by 13C NMR and CHN analyses.
In order to optimize the reaction conditions, reactions be-
tween benzaldehyde, dimedone, and urea in the presence of
catalytic amounts of SiO2-NaHSO4 were conducted under
various reaction conditions including the ‘grinding’of the solid
reagents and catalyst in a mortar and pestle, heating of the
reaction mixture on a preheated hot plate at 120 °C without
solvent and by stirring in water at 60–80 °C. It was found that
grinding of the reactants and the catalyst did not afford the
product in good yield. Similarly, heating the materials neat on a
hot-plate at 120 °C provided only a moderate increase in yield,
whereas, stirring in water at 60–80 °C was found to be ideal for
the present reaction.
was added to the reaction mixture and the catalyst was filtered
and washed with chloroform, ready for further use. This proc-
ess of recycling was completed four times (with washing every
time). From Fig. 1 it can be seen that, in the first two runs, the
activity remained the same. After two runs, however, the ac-
tivity started decreasing, which may be due to the degradation
of the catalyst under mechanical stirring and heating. The
yields for the four runs were found to be 93%, 91%, 85%, and
75%, respectively.
2.2 Mechanism
In a typical experiment, dimedone, urea, SiO2-NaHSO4, and
water were taken in a 50 ml RB flask and the mixture was
heated in an oil bath at 60–80 °C for 30 min. Benzaldehyde was
then added and the heating was continued with stirring until 4a
was obtained in maximum yield (typically 1.5 h for a 95%
yield). In order to illustrate the versatility of the present method,
a variety of aromatic aldehydes were treated with dimedone
and urea. The results of the study are presented in Table 2. The
products obtained were characterized by spectral and elemental
analysis.
A plausible mechanism for the formation of 7,7-dimethyl-4-
aryl-4,6,7,8-tetrahydro-1H,3H-quinazoline-2,5-dione is pre-
sented in Scheme 2. The activation of dimedone may take place
by the protonation of one of the oxygens by the catalyst. A
nucleophilic reaction may then occur between activated di-
..
: :
..
O
O
:
:
O
NH2
S
H
+
..
H
N
O
O
..
O
HO
H
+
H
The possibility of recycling the catalyst was then examined.
After completion of the reaction (1.5 h), ethyl acetate (10 ml)
NH2
S = Silica-NaHSO4
H
ꢀ
H2N
+
H+
B
+
H
O
O
Ar
..
O
:
:
O
H
100
80
60
40
20
0
H
NH2
NH2
+
B
O
N
H
I
N
H
OH
Ar
O
II
..
O
:
:
O
Ar
H
+
NH
NH2
B
+
N
H
N
H
O
O
1
2
3
4
III
Cycle
Scheme 2.
A plausible mechanism for the formation of 7,7-di-
Fig. 1. Reusability of SiO2-NaHSO4 in the synthesis of 4a.
methyl-4-aryl-4,6,7,8-tetrahydro-1H,3H-quinazoline-2,5-dione.

Sadeq Hamood Saleh AZZAM et al. / Chinese Journal of Catalysis, 2012, 33: 677–680
5
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medone and urea resulting in the formation of intermediate (I)
which may lose a molecule of water to give intermediate (II).
Intermediate (II) may then attack the activated aldehyde
forming intermediate (III), which may undergo cyclization
through an internal nucleophilic attack to form 7,7-dimethyl-
4-aryl-4,6,7,8-tetrahydro-1H,3H-quinazoline-2,5-dione,
as
8
9
shown in the scheme (Scheme 2).
3 Conclusions
10 Hassani Z, Islami M R, Kalantari M. Bioorg Med Chem Lett,
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SiO2-NaHSO4 is a heterogeneous, easy to prepare, inexpen-
sive, and efficiently catalyst for the synthesis of octahy-
dro-quinazolin-2,5-diones. The advantages offered by this
method include simple reaction condition, short reaction time,
involvement of an environment friendly procedure, ease of
product isolation, excellent yields, and reusability of the cata-
lyst. To the best of our knowledge, this method is the first
reported procedure for the synthesis of tetrahydro-1H,3H-
quinazoline-2,5-dione molecules using a heterogeneous recy-
clable catalyst.
11 Sarac S, Yarim M, Ertan M, Kilic F S, Erol K. Pharmazie,
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The authors would like to acknowledge the SIF Department,
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