An efficient one pot-three component cyclocondensation in the synthesis of 2-(2-chloroquinolin-3-yl)-2,3-dihydroquinazolin-4(1H)-ones: Potential antitumor agents

Article abstract of DOI:10.1007/s11164-011-0301-3

Montmorillonite K10 efficiently catalyzed a one pot-three component cyclocondensation of isatoic anhydride, NH₄OAc and aromatic/heteroaromatic aldehydes under ambient conditions to produce the corresponding 2-substituted-2,3-dihydroquinazolin-4(1H)-ones in good yields. The 2-(2-chloroquinolin-3-yl)-2,3-dihydroquinazolin-4(1H)-ones 3a-d were screened for their antitumor activity against Ehrlich Ascites Carcinoma tumor cells

Full text of DOI:10.1007/s11164-011-0301-3

Res Chem Intermed (2011) 37:919–927
DOI 10.1007/s11164-011-0301-3
An efficient one pot–three component
cyclocondensation in the synthesis of 2-(2-
chloroquinolin-3-yl)-2,3-dihydroquinazolin-4(1H)-ones:
potential antitumor agents
•
Selvaraj Mohana Roopan F. Nawaz Khan
•
•
Jong Sung Jin R. Senthil Kumar
Received: 3 January 2011 / Accepted: 11 March 2011 / Published online: 29 March 2011
Ó Springer Science+Business Media B.V. 2011
Abstract Montmorillonite K10 efficiently catalyzed a one pot–three component
cyclocondensation of isatoic anhydride, NH4OAc and aromatic/heteroaromatic
aldehydes under ambient conditions to produce the corresponding 2-substituted-2,3-
dihydroquinazolin-4(1H)-ones in good yields. The 2-(2-chloroquinolin-3-yl)-2,3-
dihydroquinazolin-4(1H)-ones 3a–d were screened for their antitumor activity
against Ehrlich Ascites Carcinoma tumor cells
Keywords Montmorillonite K10 Á Dihydroquinazolin-4(1H)-one Á Antitumor
studies
Introduction
The use of solid supported reagents has received considerable importance in recent
years in organic synthesis due to their ease of handling, reaction rates, greater
selectivity, simple work-up and recoverability of catalysts [1–3]. We have
previously successfully utilized the montmorillonite K-10 clay for the reduction
of 2-chloro-quinoline-3-carbaldehyde [2] and also for the syntheses of quinazolin-
4(3H)-ones from anthranilic acid and amides under solvent-free condition [3].
S. M. Roopan Á F. Nawaz Khan (&)
Organic & Medicinal Chemistry Research Laboratory, Organic Chemistry Division,
School of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
e-mail: nawaz_f@yahoo.co.in
F. Nawaz Khan Á J. S. Jin
Division of High Technology Materials Research, Busan Center,
Korea Basic Science Institute (KBSI), Busan 618 230, Korea
R. Senthil Kumar
Swamy Vivekanandha College of Pharmacy, Elayampalayam,
Tiruchengodu Taluk, Namakkal District 637 205, Tamil Nadu, India
123

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S. M. Roopan et al.
The efficiency of montmorillonite K10 catalysis in organic synthesis has been
demonstrated with their advantages of high atom efficiency, simplified isolation of
product, and easy recovery and recyclables of the catalysts [4–6]. Montmorillonites
¨
have both Bronsted and Lewis acid sites and, when exchanged with cations having a
high charge density, such as protons, they produce highly active catalysts for acid-
catalyzed reactions [7]. The use of inexpensive clays as a solid source of protons in
a number of industrially significant reactions are of greater interest [8].
Heterocyclic chemistry occupiesan important place in organic chemistry research
worldwide [9–12] and forms the basis of many pharmaceutical, agrochemical and
veterinary products. Especially, quinazolinone and its synthetic analogues have been
found to exhibit a broad spectrum of biological activities, including antituberculos
[13], anti-inflammatory [14], anticancer [15], antibacterial and antifungal [16].
Several methods have been reported for the synthesis of 2,3-dihydroquinazoli-
nones [17–19]. However, they suffer from lengthy procedures and/or low yields and
vigorous conditions [17–19]. Methods for the selective synthesis of 2,3-dihydro-
quinazolin-4(1H)-ones have not been explored before. Thus, developing versatile
approaches to synthesize 2,3-dihydroquinazolin-4(1H)-ones still remains a highly
desired goal in organic synthesis.
Recently, we successfully applied montmorillonite K10 in several reactions [2,
3]. These clays can be regarded simply as solid acids that act as heterogeneous
catalysts, with all the advantages resulting from the easy removal of the catalyst
from the product [2, 3]. As a result of our great interest in clay-catalyzed organic
reactions, here we report an efficient one pot synthesis of new 2-(2-chloroquinolin-
3-yl)-2,3-dihydroquinazolin-4(1H)-ones 3a–d by employing isatoic anhydride 1,
ammonium acetate and 2-chloroquinoline-3-carbaldehydes 2a–d, and the quinaz-
olinones 3a–d formed were screened and found to be potential antitumor agents.
Results and discussion
Initially, a mixture of isatoic anhydride 1, aromaticaldehyde 2, and ammonium
acetate in EtOH was stirred under reflux condition in the presence of a catalytic
amount of acidic alumina; the reaction produced the desired product in 45% of yield
(Table 1, entry 5). After screening the catalysts, such as silica get, bentonite,
montmorillonite KSF, basic alumina, acidic alumina, and montmorillonite K10, it
was found that montmorillonite K10 was the best catalyst for the synthesis of
2,3-dihydroquinazolin-4(1H)-ones in a shorter time and higher yield (Table 1,
Entry 6) in comparision to the reaction carried out in the absence of the catalyst,
(Table 2, entry 1). Montmorillonite K10 proved to be superior among all the
catalysts screened in this transformation.
It should be noted that 10 mg of montmorillonite K10 was efficient to catalyze
the reaction, and any increase in the amount of catalyst did not improve the yield
significantly (Table 2, Entries 6–8). The reusability of the catalyst by recovering the
montmorillonite K10 after the reaction was screened in new runs and it was found
that the catalyst could be reused several times without any decrease in the product
yield. The recyclability of the catalyst was investigated using a model reaction of
123

An efficient one pot–three component cyclocondensation
921
Table 1 Screening of the catalyst
O
O
O
+
- NH
O
O
4
NH
O
+
Cl
N
a
N
H
N
H
O
Cl
N
2a
3a
1
Entry
Catalyst
Time (h)
Product 3a
1
2
3
4
5
6
a
Silica gel
[2
[2
[2
[2
1
NRb
NRb
NRb
NRb
45%
88%
Bentonite
Montmorillonite KSF
Basic alumina
Acidic alumina
Montmorillonite K10
0.5
Reactions were carried out with 1 mmol of each 1, 2a and 1.2 mmol of ammonium acetate, 5 mL of
EtOH, and 10 mg catalyst, refluxed at 70 °C for the specified time period
b
NR No reaction
Table 2 Optimization of the
reaction
Entry
Refluxing at 70 °C under ethanol mediuma
Montmorillonite
K10 (mg)
Time (r)
Yield (%)
1
2
3
4
5
6
7
8
None
2
[5
1
40
52
58
62
73
88
89
89
4
1
6
1
8
0.5
0.5
0.5
0.5
10
12
14
a
1 mmol of each 1, 2a and
1.2 mmol of NH4OAc, 5 mL
EtOH
ammonium acetate with isatoic anhydride 1 and 2-chloroquinoline-3-carbaldehyde
3a. The catalyst can be removed from the organic phase by removing the ethanol
under vacuum then washing with fresh EtOH and drying at 80 °C for 1 h. Then, it
was utilized in second run of the reaction process. It was noticed that the use of
recycled catalyst in subsequent experiments gave almost similar yields. Thus, the
catalyst is not leached.
The role of montmorillonite K10 in the formation of 2-substituted-2,3-
dihydroquinazolin-4(1H)-ones 3 is illustrated in Fig. 1. The first step may involve
the condensation of isatoic anhydride 1 with ammonium acetate, with the liberation
123

922
S. M. Roopan et al.
O
O
O
CHO
R
NH4OAc
CO2
NH2
2
O
NH2
NH2
EtOH
N
R
N
H
O
II
1
I
MK10
O
OH
NH
MK10
O
MK10
1,5-H+ transfer
NH
NH
N
H
3
R
N
R
N
R
MK10
IV
III
Fig. 1 Role of montmorillonite K10 in the synthesis of 2-heterosubstituted-2,3-dihydroquinazolin-
4(3H)-ones
O
O
O
+
- NH
O
4
NH
O
+
R
O
R
N
H
MK-10, EtOH, reflux
N
H
O
3
2
1
Scheme 1 Synthesis of 2-substituted-2,3-dihydroquinazolin-4(3H)-one (3a–h)
of anthranilamide I which in turn led to intermediate II by the condensation of
I and heteroaldehydes 2 promoted by montmorillonite K10. The amide group of
intermediate II is then tautomerized in the presence of montmorillonite K10, and
simultaneously the imine group of intermediate II gets activated by montmorillonite
K10 resulting in intermediate IV by intramolecule nucleophilic attack of the amide
nitrogen on imine carbon. Subsequently, 2,3-dihydroquinazolin-4(1H)-ones 3 could
be formed by a 1,5-proton transfer. The isatoic anhydride 1, aromaticaldehydes 2
and ammonium acetate (used as the source of ammonia) in the presence of
montmorillonite K10, EtOH under reflux condition led to the 2-substituted 2,3-
dihydroquinazoline-4(1H)-ones 3a–h in good yields (Scheme 1). The optimization
of the reaction is shown in Table 2 and the results are summarized in Table 3.
In order to investigate the scope of this reaction, a variety of substituted aromatic
aldehydes 3a–h was utilized in this reaction (Table 3, entries 1–8). The results
suggest that, irrespective of heteroaryl or aromatic aldehydes, the reaction proceeds
well in the optimized conditions (Table 3, entries 1–8). The 2,3-dihydroquinazolin-
4(3H)-ones 3a–d were screened for their antitumor activity against Ehrlich Ascites
Carcinoma tumor cells. The result suggests that all compounds have lowest IC50
values compared to the standard 5-fluoro uracil (132.12 lg/mL) and hence
higher cytotoxicity effects on EAC tumor cell lines than the standard (Table 4).
123

An efficient one pot–three component cyclocondensation
923
Table 3 Synthesis of various 2-aryl-2,3-dihydroquinazolin-4(1H)-ones
O
O
O
+
- NH
O
4
NH
O
+
R
O
a
N
H
R
N
H
O
1
2
3
Entry
1
R 2/3
Products
Mp (°C)
Yield (%)b
3
3a
262
88
N
Cl
2
3
4
3b
3c
3d
258
265
274
72
N
N
N
Cl
83
92
Cl
Cl
5
6
3e
3f
21620
84
85
19321
H3CO
7
8
a
3g
3h
23320
82
87
20320
Cl
Reactions were carried out with 1 mmol of each 1, 2a and 1.2 mmol of ammonium acetate, 5 mL of
EtOH, and 10 mg of montmorillonite K-10 refluxed at 70 °C for 30 min
b
Isolated yields
123

924
S. M. Roopan et al.
Table 4 In vitro cytotoxic activity of newly synthesized compounds, 3a–d
Conc. (lg/mL)
% Cytotoxicity against EAC cella
3a
3b
3c
3d
500
250
125
62.5
31.25
IC50
a
94.7
82.3
78.2
72.4
68.6
22.77
96.4
91.8
77.3
62.6
60.4
25.86
100
86.4
72.3
69.4
40.8
30.4
76.59
84.6
70.8
61.4
48.3
50.00
Standard (5-fluorouracil) = 132.12 lg/mL
The cytotoxicity order of synthesized compounds is as follows: 3a[3b[3c[3d[
Standard.
In summary, a green chemical methodology has been proposed for the
construction of biologically active 2-heterosubstituted-2,3-dihydroquinazolin-
4(3H)-ones 3a–d. Present methodology offers very attractive features such as
reduced reaction times, higher yields and economic viability of the catalyst. To the
best of our knowledge, this is the first time an efficient method for 2,3-
dihydroquinazolin-4(3H)-ones by using montmorillonite K10 has been reported.
The catalyst can be recovered and reused with no change in the yield and catalytic
activity.
Experimental section
Solvents and reagents were commercially sourced and used without further
purification or preparation. Montmorillonite K-10 catalyst having the surface area of
250 m2/g was purchased from Sigma-Aldrich, Bangalore, India. Thin-layered
chromatography (TLC) was performed on preparative plates of silica gel (S.D. fine).
Visualization was made with an iodine charmber. Column chromatography was
performed by using silica gel (60–120 mesh). Melting points were taken on Elchem
microprocessor-based DT apparatus in open capillary tubes. IR spectra were
obtained on a Nucon infrared spectrophotometer using KBr pellets. The NMR
spectra were recorded on a Bruker-500 MHz spectrometer using TMS as internal
standard (chemical shifts d in ppm). Mass was recorded on Finnigan Mat 8230 mass
spectrometer.
2-Subsituted-2,3-dihydroquinazolin-4(3H)-ones (3)
General procedure
Isatoic anhydride 1 (1 mmol), aromatic aldehyde 2 (1 mmol), ammonium acetate
(1.2 mmol) and montmorillonite K10 (10 mg) were added to ethanol (5 mL). The
123

An efficient one pot–three component cyclocondensation
925
mixture was stirred at 70 °C for 30 min as indicated in Table 2. The progress of the
reaction was monitored by TLC. After completion, the reaction mixture was then
allowed to cool to room temperature and water (20 mL) was added. The
corresponding solid product was obtained through simple filtering, and recrystal-
lized from ethanol. Spectral data of the newly synthesized unreported compounds
3a–d are given below
1
3a: Pale yellow solid: mp 262 °C; H NMR (500 MHz, DMSO-d6):d = 8.64
(1H, s), 8.34 (1H, s, -NH-CO), 7.96–7.94 (1H, d, J 8), 7.71 (2H, t, J 6.5), 7.56
(1H, t, J 7.5), 7.30 (1H, t, J 7), 7.15 (1H, s, -CH, quinazolinone ring),
6.81–6.75 (m, 2H), 6.26 (1H, s, -NH), 2.68 (3H, s, -CH3); 13C NMR(125 MHz,
DMSO-d6) d 164.0 (-C=O), 148.2, 148.0, 146.4, 138.8, 135.7, 134.0, 131.9,
131.7, 127.9, 127.8, 127.3, 126.7, 118.3, 115.4, 115.2, 64.5 (-CH, quinazoli-
none ring), 17.8 (-CH3). HRMS: m/z calcd for C18H14ClN3O, 271.0825; found
271.0821 M?.
O
NH
N
H
Cl
N
1
3b: Pale yellow solid: mp 258 °C; H NMR (500 MHz, DMSO-d6):d = 8.63
(1H, s), 8.32 (1H, s, -NH-CO), 8.03–8.02 (1H, d, J 8), 7.53–7.51 (1H, d, J 8), 7.29
(2H, t, J 7.5), 7.21–7.19 (1H, d, J 8), 7.14 (1H, s, -CH, quinazolinone ring),
6.84–6.76 (m, 2H), 6.23 (1H, s, -NH), 2.57 (3H, s, -CH3); 13C NMR(125 MHz,
DMSO-d6) d 164.1 (-C=O), 149.0, 148.1, 147.6, 142.2, 138.3, 133.9, 131.1,
130.2, 127.9, 126.8, 125.3, 118.2, 117.5, 115.5, 115.3, 64.6 (-CH, quinazolinone
ring), 21.9 (-CH3). HRMS: m/z calcd for C18H14ClN3O, 271.0825; found
271.0823 M?.
O
NH
N
H
Cl
N
1
3c: White solid: mp 265 °C; H NMR (500 MHz, DMSO-d6):d = 8.54 (1H, s),
8.34 (1H, s, -NH-CO), 7.89 (2H, t, J 4), 7.70 (2H, t, J 7.5), 7.31–7.28 (1H, m),
7.15 (1H, s, -CH, quinazolinone ring), 6.81–6.74 (m, 2H), 6.22 (1H, s, -NH), 2.53
(3H, s, -CH3); 13C NMR(125 MHz, DMSO-d6) d 164.0 (-C=O), 148.1, 147.9,
145.8, 137.8, 137.7, 134.0, 132.1, 127.9, 127.6, 127.5, 127.2, 118.2, 115.3, 115.2,
64.5 (-CH, quinazolinone ring), 21.5 (-CH3). HRMS: m/z calcd for C18H14ClN3O,
271.0825; found 271.0824 M?.
123

926
S. M. Roopan et al.
O
NH
N
H
Cl
N
1
3d: White solid: mp 274 °C; H NMR (400 MHz, DMSO-d6):d = 8.59 (1H, s),
8.32 (1H, s, -NH-CO), 7.88–7.86 (1H, d, J 8.32), 7.71–7.69 (1H, d, J 7.76), 7.53-
7.50 (1H, d, J 8.36), 7.29 (1H, t), 7.13 (1H, s -CH, quinazolinone ring), 6.79 (1H, t),
6.78–6.76 (1H, t), 6.24 (1H, s, -NH), 2.63 (3H, s, -CH3), 2.49 (3H, s, -CH3); 13
C
NMR(100 MHz, DMSO-d6) d 163.4 (-C=O), 147.5, 145.8, 139.1, 138.2, 133.4,
132.6, 130.2, 127.4, 125.1, 117.3, 114.8, 114.7, 63.9 (-CH, quinazolinone ring), 20.2
(-CH3), 12.9 (-CH3).
O
NH
N
H
Cl
N
In vitro cytotoxic activity against Ehrlich Ascites Cacinoma cell
General procedure
Cytotoxicity was assessed by incubating 1 9 106 EAC cells in 1 mL phosphate
buffer saline with varying concentrations of the complexes at 37 °C for 3 h in CO2
atmosphere ensured using a McIntosh field jar. The viability of the cells was
determined by the trypan blue exclusion method. EAC cells were obtained through
the courtesy of Amala Cancer Research Center, Trissur, India. They were
maintained by weekly intraperitoneal inoculation of 106 cells.
Newly synthesized compound 2,3-dihydroquinazolin-4(3H)-ones 3a–d were
screen for their antitumor activity against Ehrlich Ascites Carcinoma tumor cells.
The latter type of cells was used in this study because they are the only tumor cells
that grow in mice available in Egypt. The target compounds have not been reported
hitherto. A set of sterile test tubes was used, where 1 9 106 tumor cells/mL were
suspended in phosphate–buffered saline. Then, 100, 200, 300, 400 and 500 lg/mL
from the tested compound were added to the suspension and kept at 37 °C for 3 h.
Trypan blue dye exclusion test was then carried out to calculate the percentage of
nonviable cells. 5-Fluorouracil (132.12 lg/mL) was taken as a positive control. The
percentages of the non-viable cells were calculated by the following equation:
percentage of non-viable cells = (N/Nt) 9 100, where N is the number of non-
viable cells counted, and Nt is the total number of cells.
123

An efficient one pot–three component cyclocondensation
927
The test was repeated four times for each compound. The results are summarized
in Table 4.
Acknowledgments This work was supported by Department of Science & Technology Government of
India (Grant No. SR/FTP/CS-99/2006). We also acknowledge SAIF, IIT Madras, Chennai for providing
NMR and MS facility. The authors are grateful to the VIT University management for their generous
support and facilities.
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