Eco-friendly and efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones

Article abstract of DOI:10.1002/cjoc.201180290

A simple and facile method for the synthesis of 2,3-dihydroquinazolin-4(1H) -ones through the direct cyclocondensation of one-pot three-component cyclocondensation of isatoic anhydride, ammonium acetate (or primary amines) and aldehydes; and anthranilamide and aldehydes using silica supported ferric chloride (SiO₂-FeCl₃) as catalyst under solvent-free conditions is described.

Full text of DOI:10.1002/cjoc.201180290

FULL PAPER
Eco-friendly and Efficient Synthesis of
2,3-Dihydroquinazolin-4(1H)-ones
Majid, Ghashang
Kobra, Azizi
Hamed, Moulavi-Pordanjani
Hamid Reza, Shaterian*
Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, PO Box 98135-674,
Zahedan, Iran
A simple and facile method for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones through the direct cyclocon-
densation of one-pot three-component cyclocondensation of isatoic anhydride, ammonium acetate (or primary
amines) and aldehydes; and anthranilamide and aldehydes using silica supported ferric chloride (SiO2-FeCl3) as
catalyst under solvent-free conditions is described.
Keywords solvent-free, synthetic methods, aldehydes, 2,3-dihydroquinazolin-4(1H)-one, anthranilamide, isatoic
anhydride
Introduction
times, high temperatures, harsh reaction conditions, ex-
pensive reagents, and low yields. Thus, the development
of novel methods for the synthesis of dihydroquina-
zolin-4(1H)-ones is of great importance because of their
potential biological and pharmaceutical activities.
As part of our ongoing research in the development
of novel synthetic routes to the synthesis of biologically
active heterocyclic compounds using heterogeneous and
recyclable catalysts,26 herein we report a simple and
convenient method for the synthesis of 2,3-dihydro-
quinazolin-4(1H)-one derivatives via a) one-pot three-
component cyclocondensation of isatoic anhydride,
ammonium acetate or primary amines, and aldehydes
(Scheme 1); and b) two-component reaction of an-
thranilamide and aldehydes by using silica supported
ferric chloride (SiO2-FeCl3)27 as catalyst under thermal
solvent-free conditions (Scheme 2).
Dihydroquinazolin-4(1H)-one skeletons constitute a
governing class of synthetic compounds that have been
long and widely employed for pharmacological proper-
ties and clinical applications.1 In particular dihydro-
quinazolin-4(1H)-one scaffolds were found as a core
unit in a number of biologically active compounds that
include anticancer, antidituric, and anticonvulsant ac-
tivities.1
Literature survey showed that several methods in
synthesis of quinazolinone derivatives were reported
such as cyclization of o-acylaminobenzamides,2 amida-
tion of 2-aminobenzonitrile followed by oxidative ring
closure,3 solid-phase synthesis of 2-arylaminosubsti-
tuted quinazolinones,4 reduction of the azide functional-
ity,5 reaction of isatoic anhydrides and Schiff bases,6
conversion of 2-nitro-N-arylbenzamides to 2,3-dihydro-
quinazo-lin-4(1H)-ones using SnCl2, and Pd-catalyzed
heterocyclization of nitroenes.7 Also, quinazolinones
were prepared from a) three-component reactions of
isatoic anhydride, primary amine or ammonium acetate
and aldehydes in the presence of p-toluenesulfonic ac-
ids,8 silica sulfuric acid,9 KAl(SO4)2•12H2O (alum),10
montmorillonite K-10,11 zinc(II) perfluorooctanoate,12
gallium(III) triflate,13 Amberlyst-15,14 and 1-butyl-3-
methyl-imidazolium bromide[bmim]Br or [bmim]PF6 as
ionic liquids,15 Fe3O4 nanoparticles,16 copolymer-p-
TSA,17 [Al(H2PO4)3];18 and b) the condensation of an-
thranilamide and aldehydes by using p-TSA/NaHSO3,19
TiCl4/Zn,20 CuCl2,21 and ionic liquid-water,22 TFA,23
ammonium chloride,24 and chiral phosphoric acids25 as
catalysts. However, some of these procedures have cer-
tain limitations such as tedious process, long reaction
Scheme 1
Scheme 2
*
E-mail: hrshaterian@chem.usb.ac.ir; Tel.: 0098-541-2446565; Fax: 0098-541-2431067
Received November 12, 2010; revised February 24, 2011; accepted April 29, 2011.
Chin. J. Chem. 2011, 29, 1617— 1623
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Majid et al.
FULL PAPER
Experimental
V∶V). After completion of the reaction, it was cooled
to room temperature and the crude solid product was
dissolved in hot ethanol, and filtered for separation of
the catalyst. The filtrate ethanol solution was concen-
trated. The solid product was purified by recrystalliza-
tion procedure in aqueous EtOH (70%). All the products
were characterized by comparison of their spectroscopic
and physical data with the authentic samples.
All reagents were purchased from Merck and
Sigma-Aldrich and used without further purification.
SiO2-FeCl3 was prepared according to the reported pro-
cedure.27 All yields refer to isolated products after puri-
fication. The NMR spectra were recorded on a Bruker
Avance DPX 500 MHz instrument. IR spectra were re-
corded on a JASCO FT-IR 460 plus spectrophotometer.
Mass spectra were recorded on an Agilent technologies
5973 network mass selective detector (MSD) operating
at an ionization potential of 70 eV. Melting points were
determined in open capillaries with a BUCHI 510 melt-
ing point apparatus. TLC was performed on Silica-gel
polygram SILG/UV 254 plates.
Results and discussion
Firstly, when a mixture of isatoic anhydride (1
mmol), ammonium acetate (1.2 mmol) and benzalde-
hyde (1 mmol) was stirred under thermal solvent-free
conditions in the absence of SiO2-FeCl3 as catalyst, the
reaction was not progressed within 24 h. Thus, the reac-
tion requires catalyst for preparation of 2,3-dihydro-
quinazolin-4(1H)-ones. At the second stage, to optimize
the reaction conditions, we carried out the reaction of
isatoic anhydride (1 mmol), ammonium acetate (1.2
mmol), and benzaldehyde (1 mmol) in the presence of
different amounts of the catalyst at different temperature
under solvent-free conditions (Table 1). As it was shown
from Table 1, the best results were obtained using 0.005
g of SiO2-FeCl3 as catalyst at 80 ℃.
General procedure for the synthesis of 2,3-dihydro-
quinazolin-4(1H)-ones in three-component reaction
of isatoic anhydride, primary amine or ammonium
acetate, and aldehydes using SiO2-FeCl3 as catalyst
(Method a)
A stirred mixture of isatoic anhydride (1 mmol),
primary amine (1.1 mmol) or ammonium acetate (1.2
mmol), aldehydes (1 mmol) and SiO2-FeCl3 (0.005 g)
was reacted in an oil bath at 80 ℃ for the appropriated
times. Completion of the reaction was indicated by TLC
(eluent: n-hexane/ethyl acetate＝4/1). After completion
of the reaction, it was cooled to room temperature and
the crude solid product was dissolved in hot ethanol,
and filtered for separation of the catalyst. The filtrate
ethanol solution was concentrated. The solid product
was purified by recrystallization procedure in aqueous
EtOH (70%). All the products were characterized by
comparison of their spectroscopic and physical data
with the authentic samples. The spectral data for one
selected product are given below:
Table 1 Optimization amount of SiO2-FeCl3 as catalyst and
reaction temperature in the reaction of isatoic anhydride (1 mmol),
ammonium acetate (1.2 mmol), and benzaldehyde (1 mmol) for
preparation of 2,3-dihydroquinazolin-4(1H)-ones
Entry
Catalyst/g
0.1
T/℃
125
125
125
125
125
100
80
Time/min
Yielda/%
1
2
3
4
5
6
7
8
9
9
8
60
0.05
66
0.025
0.01
7
67
6
68
2-(2,4-cyanophenyl)-2,3-dihydroquinazolin-4(1H)-
one (Table 2, Entry 10) 1H NMR (DMSO-d6, 500 Hz)
δ: 5.85 (s, 1H, CH), 6.67 (t, J＝7.45, 1H, Ar), 6.76 (d,
J＝8.05, 1H, Ar), 7.23—7.27 (m, 2H, Ar & NH), 7.60
(d, J＝7.20, 1H, Ar), 7.66 (d, J＝8.25, 2H, Ar), 7.86 (d,
J ＝ 8.30, 2H, Ar), 8.46 (s, 1H, NH); 13C NMR
(DMSO-d6, 500 Hz) δ: 65.50, 111, 114.5, 114.9, 117.4,
118.6, 127.4, 127.6, 132.3, 133.5, 147.27, 147.29, 163.3;
IR (KBr) ν: 3336 & 3353 (2NH), 2227 (CN), 1666 (C＝
0.005
0.005
0.005
0.005
0.005
6
75
8
85
18
75
120
89
50
55
25 (r.t.)
—
a Isolated yield.
Using these optimized reaction conditions, the
cyclocondensation reaction between isatoic anhydride,
aryl aldehydes and ammonium acetate as source of
ammonia or primary amines proceeded well and af-
forded the desired products (Table 2) in good to excel-
lent yields.
As shown in Table 2, aryl aldehydes bearing either
electron-donating or electron-withdrawing groups on
the aromatic ring were investigated. The substitution
group on the phenyl ring did not make any difference in
this reaction.
－1
O),＋1611, 1508, 1485 cm ; MS (EI, 70 eV) m/z: 249
(M , 26), 248 (26), 247 (36), 147 (100), 120 (48), 119
(53), 92 (34), 65 (15).
General procedure for the synthesis of 2,3-dihydro-
quinazolin-4(1H)-ones in direct reaction of an-
thranilamide and aldehydes using SiO2-FeCl3 as
catalyst (Method b)
A mixture of aromatic aldehydes (1 mmol), an-
thranilamide (1 mmol), and SiO2-FeCl3 (0.005 g) under
solvent-free conditions was stirred at 80 ℃ for a speci-
fied time (Table 3). Completion of the reaction was in-
dicated by TLC (eluent: n-hexane∶ethyl acetate＝4∶1,
In continuation of our work, using these optimized
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Chin. J. Chem. 2011, 29, 1617— 1623

Eco-friendly and Efficient Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones
Table 2 Synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives using isatoic anhydride (1 mmol), primary amine (1.1 mmol) or am-
monium acetate (1.2 mmol), aldehydes (1 mmol) and SiO2-FeCl3 (0.005 g) under solvent-free conditions (Method a)
Entry
Aldehyde
Amine
Product
Time/min
Yielda/%
1
NH4OAc
18
89
2
3
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
10
17
80
60
22
27
11
9
87
71
45
88
87
90
91
89
87
4
5
6
7
8
9
10
15
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Majid et al.
FULL PAPER
Continued
Entry
11
Aldehyde
Amine
Product
Time/min
20
Yielda/%
NH4OAc
80
75
89
75
88
89
12
13
14
15
16
NH4OAc
Aniline
50
27
60
6
4-Chloroaniline
Ethylamine
Ethylamine
120
a Isolated yields. All known products have been reported previously in the literature and were characterized by comparison of IR and
NMR spectra with authentic samples.2-18
reaction conditions, the scope and efficiency of the re-
action were explored for the synthesis of 2,3-dihydro-
quinazolin-4(1H)-one derivatives through direct con-
densation of aromatic aldehydes (1 mmol), anthranila-
mide (1 mmol) and SiO2-FeCl3 (0.005 g) as catalyst
under solvent-free conditions (Table 3).
yields.
The suggested mechanism of the SiO2-FeCl3 cata-
lyzed preparation of quinazolinone is shown in Scheme
3. According to observation of evolution in the reaction
conditions and also other reported mechanism in the
literature,18 interaction of SiO2-FeCl3 as catalyst and
isatoic anhydride to produce a reactive intermediate (I).
The N-nucleophilic primary amine attacks on the car-
bonyl unit of I to produce a reactive intermediate II,
which in turn affords III through decarboxylation reac-
tion. The proton transfer of III affords 2-amino-N-
substituted-amide IV. Subsequently, the reaction of ac-
tivated aldehyde with IV proceeds to produce the imine
intermediate V. The part of amide functional group in
intermediate IV could be formed using tautomerism
phenomenon in the presence of the catalyst. Thus, in-
termediate VI could be prepared by intermolecular nu-
cleophilic attack of the amide nitrogen on activated
imine carbon, followed by a 1,5-proton transfer to yield
the final 2,3-dihydroquin-azoline-4-(1H)-ones as
We can compare results of preparation of
2,3-dihydroquinazolin-4(1H)-one derivatives through
the direct cyclocondensation of a) one-pot three-
component cyclocondensation of isatoic anhydride,
ammonium acetate (or primary amines) and aldehydes
(Table 2); and b) anthranilamide and aldehydes (Table 3)
using silica supported ferric chloride (SiO2-FeCl3) as
catalyst under solvent-free conditions. Method a pro-
duces 2,3-dihydroquinazolin-4(1H)-ones in shorter re-
action times and higher yields than method b, because
isatoic anhydride is more reactive than anthranilamide.
Loss of CO2 from isatoic anhydride is an excellent driv-
ing force for the reaction and preparation of a more re-
active intermediate for synthesis of 2,3-dihydroquin-
azolin-4(1H)-ones in shorter reaction times and higher
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Chin. J. Chem. 2011, 29, 1617— 1623

Eco-friendly and Efficient Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones
Table 3 Synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives using aldehydes (1 mmol), anthranilamide (1 mmol) and SiO2-FeCl3
(0.005 g) under solvent-free conditions (Method b)
Entry
Aldehyde
Product
Time/h
6
Yielda/%
1
87
2
3
4
5
6
7
8
9
4
93
91
96
81
77
84
90
87
16
72
11
3
17
42
7
a Isolated yields. All known products have been reported previously in the literature and were characterized by comparison of IR and
NMR spectra with authentic samples.19-25
products.
It is noteworthy, the reaction of 2-pyridine carbal-
dehyde in method a and b in the presence of the catalyst
did not react and failed to give any desired product be-
cause pyridine ring with its lone pair of electrons acts as
base and inactive catalyst for activation of substrates
and intermediates in the path of the reaction (Scheme 4).
In addition, the reaction of anthranilic acid instead of
isatoic anhydride did not afford any product after 24 h
in 100 ℃ (Scheme 5).
Chin. J. Chem. 2011, 29, 1617— 1623
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Majid et al.
FULL PAPER
Scheme 3
Scheme 4
Scheme 5
conditions is described. Simple reaction and work-up
procedure, solvent-free conditions using heterogeneous
silica supported ferric chloride as catalyst are advan-
tages of the present work.
Acknowledgement
Conclusion
We are thankful to the Sistan and Baluchestan Uni-
versity Research Council for the partial support of this
research.
An efficient procedure for the synthesis of
2,3-dihydroquinazolin-4(1H)-ones through the direct
cyclocondensation of a) one-pot three-component
cyclocondensation of isatoic anhydride, ammonium
acetate (or primary amines) and aldehydes; and b) an-
thranilamide and aldehydes using silica supported ferric
chloride (SiO2-FeCl3) as catalyst under solvent-free
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Chin. J. Chem. 2011, 29, 1617— 1623

Eco-friendly and Efficient Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones
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