Facile method for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones catalyzed by SiO2–H3PW12O40 in water

Article abstract of DOI:10.1007/s11164-016-2634-4

The 12-tungstophosphoric acid supported on silica gel (PW/SiO₂) exhibits excellent activity in the synthesis of 2,3-dihydroquinazolin-4(1H)-ones by cyclocondensation reaction of 2-aminobenzamide with carbonyl compounds in water under reflux conditions. The desired products have been obtained in short reaction times in high yields. Our method has been successfully applied for both aldehydes and ketones (aromatic and aliphatic). Easy recovery and reusable catalyst, easy work-up and avoidance of using harmful organic solvents are the major advantages of our method in comparison to existing methods.

Full text of DOI:10.1007/s11164-016-2634-4

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Res Chem Intermed
DOI 10.1007/s11164-016-2634-4
Facile method for the synthesis of 2,3-
dihydroquinazolin-4(1H)-ones catalyzed by SiO2–
H3PW12O40 in water
Heshmatollah Alinezhad1 Elham Soleymani1
•
•
Mahboobeh Zare2
Received: 2 February 2016 / Accepted: 29 June 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract The 12-tungstophosphoric acid supported on silica gel (PW/SiO2) exhi-
bits excellent activity in the synthesis of 2,3-dihydroquinazolin-4(1H)-ones by
cyclocondensation reaction of 2-aminobenzamide with carbonyl compounds in
water under reflux conditions. The desired products have been obtained in short
reaction times in high yields. Our method has been successfully applied for both
aldehydes and ketones (aromatic and aliphatic). Easy recovery and reusable catalyst,
easy work-up and avoidance of using harmful organic solvents are the major
advantages of our method in comparison to existing methods.
Keywords 2,3-Dihydroquinazolin-4(1H)-one Á SiO2–H3PW12O40
2-Aminobenzamide Á Heterogeneous catalyst
Á
Introduction
2,3-Dihydroquinazolineone-4(1H)-one is a class of heterocyclic compounds which
is found in various natural products [1–3]. They exhibit a broad range of
pharmacological activities such as antibacterial, anticancer, antitumor, analgesic,
antihypertonic, antidepressant, antihistamine, diuretic activities and plant growth
regulation ability [4–10]. They are also efficient in various cellular processes [11].
Therefore, the development of new methods for the synthesis of quinazolineas is of
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2634-
4) contains supplementary material, which is available to authorized users.
&
Heshmatollah Alinezhad
Heshmat@umz.ac.ir
1
2
Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar,
Iran
Faculty of Science and Herbs, Amol University of Special Modern Technologies, Amol, Iran
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H. Alinezhad et al.
great importance due to their potential biological and pharmaceutical activities.
These compounds can easily be oxidized to corresponding quinazoline-4(3H)-ones
by using KMnO4 and are useful as growth inhibitors against leukemia cells [11].
Several classical procedures have been developed to prepare these classes of
compounds. Among them, the condensation of 2-aminobenzamide with aldehydes
or ketones is the simplest and most direct method for the synthesis of 2,3-
dihydroquinazolin-4(1H)-ones. Various acid catalysts such as cerium(IV)ammo-
nium nitrate (CAN) [12], cellulose-SO3H [11], succinic acid [13], p-TSA [14],
nanocomposites [15], ionic liquid [16], Sc(OTf)3 [17], boric acid-functionalized
MCM-41 [18], ammonium chloride [19], ZrCl4 [20] b-cyclodextrin-SO3H [21],clay
[22], succinimide-N-sulfonic acid [23], lactic acid [24], L-proline nitrate [25], and
molecular sieve-supported lanthanum catalyst [26], as well as catalyst-free [27, 28]
have been utilized to accomplish this transformation. Some of these methods require
the use of organic solvents, expensive reagents, extended reaction times, and also
tedious work-up procedures. Moreover, most of them are only applied for either
aldehydes or ketones. Thus, the development of a simple, efficient, and high-
yielding method for synthesizing 2,3 dihydroquinazolin-4(1H)-ones from both
aldehydes and ketones is still in demand.
Heteropolyacids have numerous applications due to their super-acidic properties.
Among heteropolyacids, polytungstic acids are widely used in organic synthesis.
Non-toxicity, environmental compatibility, thermal stability, experimental simplic-
ity, low reducibility and ease of handling are the major advantages of polytungstic
acids that make them useful in organic synthesis [29–31]. Since heteropolyacids
have low surface area (8–10 m2/g), supporting them on acidic or neutral solids such
as silica improves the surface area and causes better accessibility of reactants to the
active sites. Supported 12-tungstophosphoric acid on silica gel has been used as an
effective catalyst for many organic reactions such as the synthesis of ß-acetamido
ketones [32], Friedel–Crafts reactions [33], Fries rearrangement [34] and Diels–
Alder reaction [35].
In the present study, we have reported an efficient synthesis with high-to-
excellent yields and simple workup of 2-substituted 2,3-dihydroquinazolin-4(1H)-
ones via cyclocondensation of o-aminobenzamide with different aldehydes and
ketones in the presence of SiO2–H3PW12O40 in water (Scheme 1). Adopting water
as the solvent is a better alternative. Organic reactions in water have attracted more
attention because water is cheap, abundant and environmentally benign.
O
CN
O
NH2
NH
SiO2-H3PW12O40
EtOH
NH2
N
H
CHO
CN
Scheme 1 Synthesis of 2,3-dihydroquinazolin-4(1H)-ones in water
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Facile method for the synthesis of 2,3-dihydroquinazolin-4…
Experimental
General procedure for preparation of 12-tungstophosphoric acid supported
on silica gel
The 12-tungstophosphoric acid supported on silica gel (PW/SiO2) was prepared by
mixing silica gel (1.50 g, Merck grade 60, 230–400 mesh) with a solution of
tungstophosphoric acid (0.50 g) in distilled water (10 mL). The resulting mixture
was stirred for 30 min and then water was removed in a rotary evaporator and the
solid powder was dried at 70 °C for 3 h [29].
General procedure for the preparation of 2,3-dihydroquinazolin-4(1H)-ones
catalyzed by SiO2–H3PW12O40
A stirred mixture of carbonyl compound (aromatic aldehyde and ketone (1 mmol),
aliphatic aldehyde and ketone (2 mmol)), 2-aminobenzamide (1 mmol) and PW/
SiO2 (50 mg) in water (5 mL) was refluxed for an appropriate time. After
Table 1 Optimization for the synthesis of 2,3-dihydroquinazolin-4(1H)-one
Entry Solvent
Temperature
(°C)
Catalyst
Amount of catalyst
(g)
Time
(min)
Yield
(%)b
1
2
3
4
5
6
EtOH
MeOH
THF
100
100
100
100
PW/SiO2
PW/SiO2
PW/SiO2
PW/SiO2
PW/SiO2
PW/SiO2
0.1
0.1
0.1
0.1
0.1
0.1
15
15
95
98
60
55
50
60
90
Dioxan
90
Acetonitril 100
90
Solvent-
free
100
120
7
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
100
80
PW/SiO2
PW/SiO2
PW/SiO2
PW/SiO2
PW/SiO2
PW/SiO2
PW/SiO2
PW/SiO2
PW/SiO2
H3PW12O40
H3PW12O40
0.1
15
190
240
315
420
60
98
98
98
98
95
98
98
98
65
10
30
40
8
0.1
9
60
0.1
10
11
12
13
14
15
16
17
18
40
0.1
25
0.1
100
100
100
100
100
100
100
0.3
0.2
30
0.05
0.025
0.007
0.015
0.05
12
180
180
180
420
SiO2
230–400
19
H2O
100
PW/SiO2
0
420
30
a
Reactions were carried out with 2-aminobenzamide (1 mmol), 4-cyanobenzaldehyde (1 mmol) and
water (5 ml)
b
Isolated yield
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H. Alinezhad et al.
completion of the reaction, as indicated by TLC (ethyl acetate:n-hexane, 3:2), the
reaction mixture was cooled to room temperature and water was removed by simple
filtration. Then, ethyl acetate (10 mL) was added to the mixture and the catalyst was
separated by filtration. Then ethyl acetate was removed under reduced pressure, and
crude solid product was purified by recrystallization from ethanol. For the other
carbonyl compounds, the reactions were performed in the presence of aqueous
CTAB solution (0.02 g/mL). A stirred mixture of carbonyl compound (1 mmol)
2-aminobenzamide (1 mmol) and PW/SiO2 (50 mg) in the presence of aqueous
CTAB solution (0.02 g/mL) was refluxed for an appropriate time. After completion
of the reaction, as indicated by TLC (ethyl acetate:n-hexane, 3:2), the reaction
mixture was cooled to room temperature, then ethyl acetate (5–10 mL) was added to
the mixture and the catalyst was filtered. To remove CTAB from the reaction
mixture, the organic and aqueous layers were separated with a separator funnel and
CTAB was removed from the aqueous layer. The organic product was isolated by
extraction with ethyl acetate. The ethyl acetate was dried (sodium sulfate) and then
evaporated under reduced pressure, and the products were purified further by
crystallization from ethanol, to afford the pure 2,3-dihydroquinazolin-4(1H)-ones
1
which were characterized by H NMR, 13CNMR, IR, CHN analysis, and melting
point, and compared with literature data.
Results and discussion
Initially, to optimize the reaction conditions, the effects of the solvent were
investigated using 2-aminobenzamide (1 mmol) and 4-cyanobenzaldehyde
(1 mmol) in the presence of SiO2–H3PW12O40 under reflux of the solvent as a
model (Table 1, entries 1–7). This reaction was observed to perform well in water
and methanol in comparison with the commonly used organic solvents such as
CH3OH, CH3CN, THF and dioxin (Table 1, entries 2 and 7). We have chosen water
as a solvent because it is in accordance with green chemistry. Then, we examined
varying the temperatures to improve the reaction conditions (Table 1, entries 7–11).
The results indicate that the reflux temperature is the best condition for this reaction.
In the next step, we studied the effect of the amount of catalyst on the conversion
rate of the reaction by varying the amount of the catalyst. The results are shown in
Table 1 (entries 12–15).
As shown from Table 1, the best results were obtained using 0.05 g of SiO2–
H3PW12O40 as the catalyst. We studied the effect of 12-tungstophosphoric acid
(H3PW12O40) and SiO2 (mesh 230–400) on the 2, 3-dihydroquinazolin-4(1H)-ones
formation (Table 1, entries 16–18). However, their catalytic activities were much
lower than SiO2–H3PW12O40. To understand the role of the catalyst, the reaction
was performed in its absence, when the desired product was isolated in only 30 %
yield after 7 h (Table 1, entry 19).
To explore the scope and limitation of this reaction, we extended the
cyclocondensation of 2-aminobenzamide with various carbonyl compounds
(Scheme 1) in the presence of SiO2–H3PW12O40 in water under reflux conditions
and the results are summarized in Table 2.
123