Synthesis of 2,3-dihydroquinazolin-4(1H)-ones catalyzed by zirconium (IV) chloride as a mild and efficient catalyst

Article abstract of DOI:10.1016/j.cclet.2011.05.011

2,3-Dihydroquinazolin-4(1H)-ones have been synthesized in the high to excellent yields via condensation of 2-aminobenzamide with aldehydes and ketones in the presence of catalytic amount of ZrCl₄ in EtOH at room temperature. Mild reaction conditions, clean reaction media, simple workup and easy purification are advantages of this methodology.

Full text of DOI:10.1016/j.cclet.2011.05.011

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Chinese Chemical Letters 22 (2011) 1163–1166
www.elsevier.com/locate/cclet
Synthesis of 2,3-dihydroquinazolin-4(1H)-ones catalyzed by
zirconium (IV) chloride as a mild and efficient catalyst
*
Mohammad Abdollahi-Alibeik , Elahe Shabani
Department of Chemistry, Yazd University, Yazd 89195-741, Iran
Received 5 January 2011
Available online 20 July 2011
Abstract
2,3-Dihydroquinazolin-4(1H)-ones have been synthesized in the high to excellent yields via condensation of 2-aminobenzamide
with aldehydes and ketones in the presence of catalytic amount of ZrCl4 in EtOH at room temperature. Mild reaction conditions,
clean reaction media, simple workup and easy purification are advantages of this methodology.
# 2011 Mohammad Abdollahi-Alibeik. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 2,3-Dihydroquinazolin-4(1H)-one; ZrCl4; Catalysis; 2-Aminobenzamide
2,3-Dihydroquinazolin-4(1H)-ones are an important class of heterocyclic compounds that have been attracted
considerable attention. The natural quinazolinones and their synthetic analogous have been reported to possess a
wide range of pharmacological and biological activities including antimalarial [1], antibacterial [2], anticonvulsant
[3], anticancer [4] and antifungal [5] activities. Several methods for the synthesis of these compounds have been
reported. Among them, the general method includes condensation of aldehydes or ketones with 2-aminobenzamide
in the presence of acid catalysts, such as Sc(OTf)3 [6], NH4Cl [7], p-TsOH [8], CuCl2 [9] and [Bmim]PF6 [10].
Three-component reaction of isatoic anhydride, aldehyde and amine [10–14], reduction cyclization of o-
nitrobenzamides and orthoformate, aldehydes or ketones [15] and reduction of quinazolin-4(3H)-ones [16] are also
reported for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones. However, most of reported methods suffer from
some limitations such as long reaction times, harsh reaction conditions, low yields, tedious workup and multistep
reaction. Therefore, mild, simple and efficient processes for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones are
still in demands.
ZrCl4 is an air and moisture tolerant, readily available Lewis acid catalyst possessing low toxicity [LD50 (ZrCl4,
oral rat) = 1.688 mg kgÀ1] and ease and safety of handling. These salient features along with the strong coordinating
ability of Zr4+, makes it a potential catalyst [17,18]. ZrCl4 has already been used as catalyst for various organic
transformations [17–19].
In continuation of our previous work for the synthesis of pharmaceutically important heterocycles [20–22], herein,
we report the synthesis of 2,3-dihydroquinazolin-4(1H)-ones via the condensation reaction of 2-aminobenzamide with
aldehydes and ketones in the presence of catalytic amount of ZrCl4 in EtOH at room temperature (Scheme 1).
* Corresponding author.
E-mail address: abdollahi@yazduni.ac.ir (M. Abdollahi-Alibeik).
1001-8417/$ – see front matter # 2011 Mohammad Abdollahi-Alibeik. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.05.011

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M. Abdollahi-Alibeik, E. Shabani / Chinese Chemical Letters 22 (2011) 1163–1166
O
O
O
NH
NH
ZrCl4 (2 mol%)
EtOH, r.t
2
+
NH
N
H
2
2a-2k
3a-3k
1
Scheme 1.
Initially, the reaction condition was optimized in the reaction of 2-aminobenzamide and benzaldehyde as model
reaction. The results of optimization experiments were summarized in Table 1. Among all the solvents screened, EtOH
is the best. The model reaction was carried out in the presence of various amounts of ZrCl4 and in the terms of reaction
time and yield of the product, 2 mol% of the catalyst was selected as the best amount of the catalyst. It is noticeable
that, the reaction has shown the best time in the presence of 10 mol% ZrCl4, but the yield was low in this condition
because of production of byproduct. Water tolerant of the ZrCl4 in the reaction media was investigated by performing
the model reaction in the presence of 8 mol% HCl (the same equivalent of 2 mol% ZrCl4). The reaction was completed
after 15 min with 83% yield of products. Comparison of this result with result obtained in the presence of 2 mol%
ZrCl4 suggest that ZrCl4 has stability toward low amount of water and hydrolysis of ZrCl4 to HCl could not take place
in the presence of trace of water. This result can also suggest that the progress of hydrolysis is too slow in the presence
of low amount of water that does not have significant effect on the results of reaction. However, low yield of product
and presence of byproduct using 10 mol% ZrCl4 (Table 1, entry 1) may be due to hydrolysis of ZrCl4 to trace of HCl
due to the presence of higher amount of ZrCl4 in the reaction media.
Following the obtained results, the reaction of 2-aminobenzamide and benzaldehyde was carried out in the presence
of 2 mol% ZrCl4 in EtOH at room temperature and the corresponding 2,3-dihydroquinazolin-4(1H)-one was obtained
in 95% yield (Table 2, entry 1). The scope and generality of this method was investigated in the reaction of various
types of aldehydes with 2-aminobenzamide. Aldehydes with both electron-donating and electron-withdrawing
substituents were reacted with 2-aminobenzamide at the same reaction conditions and the corresponding 2-aryl-2,3-
dihydroquinazolin-4(1H)-ones were obtained in the 82–97% yields (Table 2, entries 2–8). 2-Furyl-2,3-
dihydroquinazolin-4(1H)-one was also obtained using 2-furaldehyde as starting material in good yield at short
reaction time. Cyclic ketones were also condensed with 2-aminobenzamide successfully and the corresponding 2,3-
dihydroquinazolin-4(1H)-one with spiro structure were obtained in good yields at short reaction times (Table 2, entries
10 and 11).
It is noteworthy that the reaction procedure is very clean without any undesirable side reaction. The workup and
purification procedure was also very simple. After completion of the reaction (monitored by TLC) cold water was
added to the reaction mixture and the precipitate was filtered. The crude products were obtained with very high purity.
Further purification was achieved by recrystallization from ethanol:water.
In conclusion, a new catalytic protocol to the synthesis of 2,3-dihydroquinazolin-4(1H)-ones has been developed.
This method offers several advantages, such as use of green solvent, simple workup and purification procedure without
use of any chromatographic method, mild reaction condition, use of inexpensive and commercially available starting
material and short reaction time.
Table 1
Reaction of 2-aminobenzamide with benzaldehyde in the presence of various amounts of ZrCl4 in various solvents.
Entry
ZrCl4 (mol%)
Solvent
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
10
5
EtOH
7
15
85
94
95
97
94
37
9
EtOH
2
EtOH
25
1
EtOH
120
25
2
MeOH
CH3CN
CH2Cl2
CHCl3
2
25
2
25
2
25
9
a
Isolated yields.

M. Abdollahi-Alibeik, E. Shabani / Chinese Chemical Letters 22 (2011) 1163–1166
1165
Table 2
Synthesis of 2,3-dihydroquinazolin-4(1H)-ones by the reaction of 2-aminobenzamide with aldehydes and ketones in the presence of 2 mol% ZrCl4.
Entry
1
Aldehyde or ketone (2)
Dihydroquinazoline (3)
Time (min)
25
Yielda (%)
95
O
CHO
NH
N
H
CHO
O
2
15
97
NH
Me
N
H
Me
O
3
4
CHO
15
37
93
91
NH
MeO
N
H
OMe
O
CHO
NH
Cl
N
H
Cl
O
5
6
CHO
40
89
96
NH
HO
N
H
OH
O
20b
CHO
NH
O2N
N
H
NO2
O
CHO
7
8
20b
87
82
NH
N
H
NO2
NO2
O
CHO
60
NH
Me2N
N
H
NMe2
O
9
10
11
9
20
50
87
92
80
O
CHO
NH
O
N
H
O
O
O
NH
N
H
O
NH
N
H
a
Isolated yields.
b
The reactions were performed at 50 8C.

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M. Abdollahi-Alibeik, E. Shabani / Chinese Chemical Letters 22 (2011) 1163–1166
1. Experimental
All of the chemicals were commercial products. Reagent grade solvent (E. Merck) were used without purification.
All melting points were obtained by Buchi B-540 apparatus. All reactions were monitored by TLC and all yields refer
1
to isolated products. H and 13C NMR spectra were recorded in CDCl3 and DMSO-d6 on a Bruker 500 MHz
spectrometer. Infrared spectra were recorded on a Bruker FT-IR Equinax-55 spectrophotometer.
1.1. General procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones
To a solution of 2-aminobezamide (1 mmol) and aldehyde or ketone (1 mmol) in EtOH (3 mL), ZrCl4 (4 mg,
2 mol%) was added. The mixture was stirred at room temperature for an appropriate time as indicated in Table 2. After
completion of the reaction, as indicated by TLC (ethyl acetate:n-hexane 1:1), the product was precipitated by addition
of 9 mL of water. Then the precipitate was filtered off and washed with extra water. Finally the crude product was
purified by recrystallization from EtOH and water to afford the corresponding 2,3-dihydroquinazolin-4(1H)-ones in
80–97% yield.
1.2. Physical and spectroscopic data for selected compound
2,3-Dihydro-2-phenylquinazolin-4(1H)-one (3a): White solid, mp 225–2278 C (Lit. [7] mp 218–2208 C); IR (neat)
cmÀ1 n: 3303, 3176, 3061, 1651, 1610, 1508, 1482; 1H NMR (500 MHz, DMSO-d6): d 5.76 (s, 1H, CH), 6.68 (t, 1H,
J = 7.4 Hz, ArH), 6.76 (d, 1H, J = 8.09 Hz, ArH), 7.10 (br s, 1H, NH), 7.25 (t, 1H, J = 7.3 Hz, ArH), 7.33–7.41 (m, 3H,
ArH), 7.50 (d, 2H, J = 7.44 Hz, ArH), 7.62 (d 1H, J = 7.7 Hz, ArH), 8.28 (br s, 1H, NH); 13C NMR (125.7 MHz, 1H-
decoupled): d 67.4, 115.2, 115.8, 117.9, 127.7, 128.2, 129.1, 129.3, 134.1, 142.5, 148.7, 164.4.
Acknowledgment
We are thankful to the Yazd University Research Council for partial support of this work.
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