Convenient and Scalable Synthesis of 2,3-Dihydroquinazolin-4(1 H)-one Derivatives and Their Anticancer Activities

Article abstract of DOI:10.1080/00397911.2015.1046555

An efficient and mild InBr3-catalyzed approach to synthesize 2,3-dihydroquinazolin-4(1H)-one derivatives (3a-3aa) has been developed. Notably, all the products were isolated by recrystallization and the reaction is accessible on a gram scale. Moreover, the reactions only require 10-60 min. All the synthesized compounds were evaluated for their in vitro anticancer activity against four human cancer cell lines.

Full text of DOI:10.1080/00397911.2015.1046555

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A Convenient and Scalable Synthesis of 2,3-
Dihydroquinazolin-4(1H)-one Derivatives and Their
Anticancer Activity
Lingayya Rajakaa, Nageshwar Rao Penumatia, K. Nagaiaha, Poornachandra Yb & Ganesh
Kumar Cb
a Organic and Biomolecular Chemistry Division, CSIR - Indian Institute of Chemical
Technology, Hyderabad, India
b Medicinal Chemistry and Pharmacology Division, CSIR -Indian Institute of Chemical
Technology, Hyderabad, India
Accepted author version posted online: 08 Jun 2015.
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To cite this article: Lingayya Rajaka, Nageshwar Rao Penumati, K. Nagaiah, Poornachandra Y & Ganesh Kumar C (2015): A
Convenient and Scalable Synthesis of 2,3-Dihydroquinazolin-4(1H)-one Derivatives and Their Anticancer Activity, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry
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A Convenient and Scalable Synthesis of 2,3-Dihydroquinazolin-4(1H)-one
Derivatives and their Anticancer Activity
Lingayya Rajaka1, Nageshwar Rao Penumati1, K. Nagaiah1, Poornachandra Y2, Ganesh
Kumar C2
1Organic and Biomolecular Chemistry Division, CSIR - Indian Institute of Chemical
Technology, Hyderabad, India, 2Medicinal Chemistry and Pharmacology Division, CSIR
-Indian Institute of Chemical Technology, Hyderabad, India
Corresponding author: E-mail: nagaiah@iict.res.in, nagasaisrikari@gmail.com
Abstract
An efficient and mild InBr3 – catalyzed approach to synthesize 2,3-dihydroquinazolin-
4(1H)-one derivatives (3a-3aa) has been developed. Notably, all the products were
isolated by recrystallization and the reaction is accessible on a gram scale. Moreover, the
reactions only require 10-60 min. All the synthesized compounds were evaluated for their
in vitro anticancer activity against four human cancer cell lines.
KEYWORDS: Aromatic aldehydes, Cyclocondensation, Indium(III) bromide, 2,3-
dihydroquinazolin-4(1H)-ones, Anticancer activity
INTRODUCTION
1

Cancer is a systemic disease characterized by uncontrolled growth of abnormal cells and
a leading cause of fatality worldwide. It continues to be a major threat to human health [1]
In 2012, cancer caused death lead to 8.2 million people worldwide [2]. In the past few
.
decades many efforts have been made for the treatment of cancer, but the success towards
the treatment of cancer remains a challenge. Therefore, there is an increasing demand for
the discovery of new antitumor agents, which should be highly potent, selective and less
toxic.
2,3-Dihydroquinazolin-4(1H)-one derivatives are an important class of fused N-
containing heterocycles with various biological, medicinal, and pharmacological
activities such as antitumor[3], antibiotic[4], antifungal[5], analgesic[6], diuretic[7],
antifertility[8], antidepressant[9], antihistaminic[10], vasodilating[11], and antifibrillatory
agent[12]. In addition, these compounds can act as potent tubulin inhibitors with promising
anti-proliferative activity against several human cancer cell lines[13]. Additionally, they
can act analogous to the antimitotic agent colchicine[14]. On the other hand,
dihydroquinazolinones can easily be oxidized to their quinazolin-4(3H)-one analogues[15]
,
which are themselves more important and bioactive N-based heterocyclic compounds[16]
occuring in several natural products such as rutaecarpine and lutonin A[17]. As a
consequence of this biological significance, the 2,3-dihydroquinazolin-4(1H)-one frame
work is described as a privileged scaffold for drug design. Some examples of diverse
commercial pharmaceuticals and natural products with quinazolinone core skeleton are
,
shown in the Figure 1 [18]
.
2

Several methods have been reported in literature for the synthesis of 2,3-
dihydroquinazolin-4(1H)-one derivatives, some of them suffer from harsh reaction
conditions, excess catalyst loading, prolonged time, hazardous and expensive catalyst[19]
Therefore, there is still a demand for simple, efficient and easy work-up method.
.
Over the past few years, indium(III) salts have emerged as an efficient, mild Lewis acid
catalysts for various organic transformations, due to its advantages such as relatively low
toxicity, higher stability in H2O, operational simplicity, strong tolerance towards
functional groups and substances containing N- and O-atoms[20]. Herein, we describe the
synthesis of 2,3- dihydroquinazolin-4(1H)-one derivatives using 0.5 mol % InBr3 as
catalyst under mild conditions in ≤60 min.
RESULTS AND DISCUSSION
Chemistry
At the outset, we carried out the cyclocondensation reaction between 2-
aminobenzanilide (1a) and benzaldehyde (2a) in MeCN at room temperature with altered
catalyst loading and their results are summarized in Table 1. Without any catalyst, the
yield was poor even after longer time, but at reflux temperature moderate yields were
obtained (Table 1, entries 1, 2 and 3). Under low catalyst loading conditions the reaction
time was increased (Table 1, entries 4-6). It was found that 0.5 mol % of InBr3 efficiently
catalyzed the reaction, which was completed in 60 min with excellent yield (Table 1,
entry 7) and upon increasing catalyst loading did not show any significant change in the
reaction (Table 1, entries 8 and 9). Further investigation of the In(III) catalyst precursors
3

revealed that the best result was achieved with InBr3 (Table 1, entries 10 and 11). With
other catalysts, such as FeBr3 (74 %), CuBr2 (67 %), and ZnCl2 (77 %) less satisfactory
results were obtained (Table 1, entries 12-14).
To determine the effect of solvents, we carried out our reaction in different solvent
systems as depicted in Table 1. In all the solvents screened, it was found that MeCN was
the most suitable one for this reaction. In H2O, the reaction does not proceed at room
temperature, whereas at reflux, it proceeds well but requires a long reaction time, due to
the poor solubility of the starting materials in H2O.
With these optimized conditions in hand, we extended the scope of our method by
synthesizing an array of 2,3-dihydroquinazolin-4(1H)-one derivatives bearing either
electron-donating or electron-withdrawing groups on the aromatic ring (Table 2). The
cyclization of 2-aminobenzanilide (1a) with aromatic aldehyde having no substituent
such as benzaldehyde, and 1-naphthaldehyde afforded 3a and 3l, respectively, with
excellent yield (Table 2, entries 1 and 12). The presence of an electron-withdrawing CN
group, as well as Me, iPr, MeO, F, Br, and Ph in para-positition of aryl ring, is well
tolerated in synthesizing dihydroquinazolinones with excellent yields. We further
elaborate the scope of our method to study 2,4-; 3,4-disubstituted and 3,4,5-trisubstituted
benzaldehydes. It is evident from Table 2 that disubstituted and trisubstituted
benzaldehydes are well tolerated substrates under the optimized reaction conditions.
4

Following the results we proceeded to highlight the efficiency of our catalytic system
in synthesizing 2,3-dihydroquinazolinone derivates by reacting 5-chloro substituted 2-
aminobenzamide with aromatic aldehydes bearing electron-donating and electron-
withdrawing substituents to form a corresponding products 3m-3y (Table 2) with
excellent yields. The electronic effects have no significant impact on the reaction rate and
time. Further, aliphatic aldehydes were tested in the reaction, corresponding products
were isolated in good yields (Table 2, entries 26 and 27). Finally, the reaction is
accessible on a high scale (10 mmol of 2-aminobenzanilide and benzaldehyde) requiring
only 60 min to achieve excellent conversion (92%).
Thus we have synthesized a series of 2,3-dihydroquinazolin-4(1H)-one derivates
1
(3a-3aa) in excellent yields. The structures of all the products were confirmed by H-
NMR, 13C-NMR, IR, Ms and HRMS. The data of the known products were found to be in
good agreement with those reported in the literature. The HRMS analysis of 3a shows a
(M+H)+ peak at m/z = 301.13271 as C20H17ON2, and (M+Na)+ peak at m/z = 323.11462 as
C20H16ON2Na, which matches the expected 2,3-diphenyl-2,3-dihydroquinazolin-4(1H)-
one. Spectral data of 1H- and 13C-NMR of the molecule are in good accord with its
structure.
Based on the relevant literature,[19c] a plausible mechanism was proposed to account for
the InBr3 catalyzed reaction (Figure 2). First, condensation of I with aldehyde promoted
by InBr3, affords an imine intermediate II [15]. The part of amide in intermediate II could
be converted into tautomer in the presence of InBr3. Meanwhile, the part of imine in
5

intermediate III could be activated by InBr3. Thus, intermediate III could be converted to
intermediate IV by intramoleculer nucleophilic attack of the amide nitrogen on activated
imine carbon. Finally, 2,3-dihydroquinazolin-4(1H)-ones (V) could be formed by a 1,5-
proton transfer of IV.
BIOLOGICAL EVALUATION
Anticancer Activity
Synthesized compounds were evaluated for their in vitro cytotoxicity against four
different human cancer cell lines, i.e., lung cancer (A549), breast cancer (MCF7),
cervical cancer (HeLa), and prostate cancer (DU145) by previously reported MTT assay
[21] performed in a 96 well plate. Doxorubicin is one of the most effective antitumor agent
and used as a reference drug in this study. Results of in vitro anticancer activity were
compared with that of reference drug and the results are reported in Table 3. Compounds
3x, 3o, 3u and 3n exhibited promising cytotoxicity against all the four tested cancer cell
lines. It was observed that the presence of different substituents like 1-naphthyl, and
isopropyl, bromo, methyl on phenyl ring in the 2,3-dihydroquinazolin-4(1H)-one moiety
contributed towards cytotoxicity against tested cell lines. Further, the compounds 3p, 3q,
3v, 3w, 3y and 3k containing both electron-donating as well as electron-withdrawing
groups on phenyl ring of the 2,3-dihydroquinazolin-4(1H)-one moiety exhibited good
cytotoxicity against the human breast cancer cell line, MCF7 and prostate cancer cell
line, DU145, while the compound 3m showed good cytotoxicity towards A549 and HeLa
cancer cell lines. Moreover, the other compounds showed moderate cytotoxicity against
the tested cell lines. The parameter expressed in terms of IC50 which corresponds to the
6

concentration required for 50% inhibition of cell viability. The IC50 values (in µM) were
expressed as the means ± SD of three independent experiments.
CONCLUSIONS
In summary, a series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a-3aa) were
synthesized by using 0.5 mol % InBr3 as catalyst. The protocol demonstrated a concise,
efficient, mild and facile condition favouring short reaction time, safe experimental
procedures, and practically free of chromatographic separation. Synthesized compounds
was assessed for their in vitro cytotoxicity against lung cancer (A549), breast cancer
(MCF7), cervical cancer (HeLa) and prostate cancer (DU145) cell lines. The in vitro
assay results showed that the compounds 3x, 3o, 3u and 3n exhibited promising
cytotoxicity against all the four human cancer cell lines. Further the compounds 3p, 3q,
3v, 3w, 3y and 3k showed good activity against MCF7 and DU145 cancer cell lines,
while compound 3m showed good cytotoxicity towards A549 and HeLa cancer cell lines.
Based on these preliminary results, further mechanism of action of compounds and SAR
studies under progress will be reported in due course.
EXPERIMENTAL
General Procedure For Synthesis Of 2,3-Dihydroquinazolin-4(1H)-Ones (3a-3aa)
Indiumtribromde (0.5 mol %) was added to a solution of 2-amino benzanilide or 2-
amino-5-chloro benzamide (1 mmol) and desired aldehydes (1 mmol) in acetonitrile
(3mL). The mixture was stirred at room temperature for the specified period of time. The
progress of the reaction was monitored by TLC. After completion of reaction, solvent
7

was evaporated at reduced pressure, and solid was partitioned between ethyl acetate (15.0
mL) and water (15.0 mL), and transferred to a separatory funnel. The organic layer was
washed with water, and brine, dried over anhydrous Na2SO4 (s) and concentrated in
vacuo. The residue was purified by recrystallization from CH2Cl2/Hexane to afford the
corresponding pure 2,3-dihydroquinazolin-4(1H)-ones (3a-3aa) as solids with excellent
yields.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGMENTS
We thank the Director of CSIR-Indian Institute of Chemical Technology for the generous
support and CSIR, New Delhi for funding through the programme ORIGIN XII FYP
(CSC-0108). R. L. thanks CSIR, New Delhi for the Research Fellowship.
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10

Table 1. Cyclocondensation reaction of 2-aminobenzanilide with benzaldehyde under
different reaction conditionsa
Entry Catalyst (mol %) Solvent
Time
24 h
12 h
12 h
12 h
7 h
Yieldb (%)
1
None
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
12
23
32
58
66
78
94
95
95
86
89
74
67
77
88
2c
3d
4
None
None
InBr3 (0.05)
InBr3 (0.1)
InBr3 (0.25)
InBr3 (0.5)
InBr3 (1)
5
6
3 h
7
1 h
8
1 h
9
InBr3 (2)
1 h
10
11
12
13
14
15
InCl3 (0.5)
In(OTf)3 (0.5)
FeBr3 (0.5)
CuBr2 (0.5)
ZnCl2 (0.5)
InBr3 (0.5)
1 h
1 h
4 h
6 h
5 h
MeCN/H2o( 2 h
1:1)
16
InBr3 (0.5)
H2O
12 h
0
11

17d
18
19
20
21
22
23
InBr3 (0.5)
InBr3 (0.5)
InBr3 (0.5)
InBr3 (0.5)
InBr3 (0.5)
InBr3 (0.5)
InBr3 (0.5)
H2O
12 h
2 h
4 h
3 h
2 h
4 h
5 h
58
80
78
81
83
82
81
DCM
DMF
DCE
DMSO
THF
MeOH
aReaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), Catalyst (0.5 mol %), in a solvent
(3.0 mL). bYield of isolated products (average of two runs). c The reaction was run at 50
°C. dThe reaction was run at 100 °C
12

a
Table 2. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones in the presence of InBr3
Entry X R1 R2
Time (min) Product Yieldb (%)
1
H
H
H
H
H
H
H
H
H
H
H
H
Ph C6H5
60
40
94
96
97
98
95
96
96
94
97
96
93
94
97
95
96
98
96
95
3a
3b
3c
3d
3e
3f
2
Ph 4-MeC6H4
3
Ph 4- IsopropylC6H4 50
4
Ph 4- MeOC6H4
10
30
5
Ph 3,4-(MeO)2C6H3
6
Ph 3,4,5-(MeO)3C6H2 30
7
Ph 4 – FC6H4
45
60
60
60
60
60
60
30
3g
3h
3i
8
Ph 2,4- diClC6H3
Ph 4 – BrC6H4
Ph 4 – PhC6H4
Ph 4 – CNC6H4
Ph 1 - Naphthyl
9
10
11
12
13
14
15
16
17
18
3j
3k
3l
Cl H C6H5
3m
3n
3o
3p
3q
3r
Cl H 4 – MeC6H4
Cl H 4- IsopropylC6H4 40
Cl H 4- MeOC6H4
10
20
Cl H 3,4-(MeO)2C6H3
Cl H 3,4,5-(MeO)3C6H2 30
13

19
20
21
22
23
24
25
26
27
Cl H 4 - FC6H4
50
60
50
40
60
60
60
60
60
94
93
96
95
93
95
94
75
79
3s
Cl H 2,4- diClC6H3
Cl H 4 – BrC6H4
Cl H 4 – PhC6H4
Cl H 4 – CNC6H4
Cl H 1 - Naphthyl
Cl H 4 – NO2C6H4
3t
3u
3v
3w
3x
3y
3z
H
H
Ph Butyl
Ph Pentyl
3aá
aReaction conditions: 1 ( 1.0 mmol), 2 (1.0 mmol), InBr3 (0.5 mol%), in MeCN (3.0 mL).
bYield of isolated products.
14

Table 3. In vitro cytotoxicity evaluation of compounds 3a-3y
Compounds IC50 values (in μM)a
(µg mL-1)
A549 (Lung
cancer)
MCF7 (Breast
cancer)
HeLa (Cervical
cancer)
DU145 (Prostate
cancer)
b
b
21.5 ± 0.22
25.2 ± 0.32
-
22.4 ± 0.32
22.4 ± 0.26
-
3a
3b
3c
3d
3e
3f
b
b
-
-
b
b
b
b
-
-
-
-
b
b
-
82.4 ± 0.52
-
80.4 ± 0.48
b
b
b
b
-
-
-
-
b
b
19.7 ± 0.18
-
18.7 ± 0.19
-
b
b
b
b
-
-
-
-
3g
3h
3i
20.6 ± 0.21
50.1 ± 0.48
18.3 ± 0.32
60.2 ± 0.12
b
b
b
b
-
-
-
-
b
b
38.6 ± 0.42
28.9 ± 0.32
38.5 ± 0.24
12.5 ± 0.18
13.9 ± 0.12
10.5 ± 0.08
-
34.8 ± 0.43
25.8 ± 0.25
34.8 ± 0.34
10.7 ± 0.26
11.2 ± 0.18
8.8 ± 0.15
-
3j
15.0 ± 0.24
24.3 ± 0.18
44.2 ± 0.42
12.7 ± 0.26
6.0 ± 0.16
12.0 ± 0.14
9.9 ± 0.26
14.5 ± 0.32
17.4 ± 0.33
12.1 ± 0.21
21.3 ± 0.13
61.8 ± 0.52
11.4 ± 0.24
4.1 ± 0.11
9.6 ± 0.22
7.2 ± 0.08
11.7 ± 0.16
14.3 ± 0.40
3k
3l
3m
3n
3o
3p
3q
3r
3s
b
b
-
-
22.5 ± 0.22
32.9 ± 0.18
46.9 ± 0.26
20.1 ± 0.17
31.2 ± 0.27
44.6 ± 0.21
15

20.9 ± 0.24
8.9 ± 0.18
12.9 ± 0.15
11.9 ± 0.21
9.6 ± 0.09
8.8 ± 0.12
8.2 ± 0.22
10.4 ± 0.36
19.1 ± 0.25
7.8 ± 0.14
10.4 ± 0.21
9.8 ± 0.16
8.1 ± 0.27
7.9 ± 0.20
5.1 ± 0.19
9.1 ± 0.13
3t
3u
b
b
-
-
3v
41.3 ± 0.32
7.9 ± 0.15
14.1 ± 0.21
39.2 ± 0.29
6.3 ± 0.09
3w
3x
14.05 ± 0.42
3y
Doxorubici
n (Standard)
0.1 ± 0.04
0.1 ± 0.08
0.09 ± 0.02
0.06 ± 0.04
b
aResults are expressed as the means ± SD of three independent experiments. No activity
16

Figure 1. Some marketed drugs and natural products with dihydroquinazolinone and
quinazolinone core skeleton.
17

Figure 2. A plausible mechanism.
18