Green and catalyst-free one-pot synthesis of 2,3-dihydroquinazolin-4(1H)-ones in water

Article abstract of DOI:10.1007/s10593-015-1793-3

A facile and highly efficient protocol was successfully applied to synthesize mono- and disubstituted dihydroquinazolinones through a three-component coupling reaction of isatoic anhydride, aniline or ammonium acetate, and aromatic aldehydes in refluxing

Full text of DOI:10.1007/s10593-015-1793-3

DOI 10.1007/s10593-015-1793-3
Chemistry of Heterocyclic Compounds 2015, 51(10), 899–902
Green and catalyst-free one-pot synthesis
of 2,3-dihydroquinazolin-4(1H)-ones in water
Abolfazl Olyaei1*, Fatemeh Rahbarian1, Mahdieh Sadeghpour2
1 Department of Chemistry, Payame Noor University,
PO BOX 19395-3697, Tehran, Iran; e-mail: olyaei_a@pnu.ac.ir
2 Department of Chemistry, College of Science, Takestan Branch, Islamic Azad University,
Takestan, Iran; e-mail: m.sadeghpour@tiau.ac.ir
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(10), 899–902
Submitted September 14, 2015
Accepted after revision October 23, 2015
O
NH4OAc
NH
Ar
O
N
ArCHO
H
O
O
H2O, , 2 h
NH2
N
H
O
N
N
H
Ar
A facile and highly efficient protocol was successfully applied to synthesize mono- and disubstituted dihydroquinazolinones through
a three-component coupling reaction of isatoic anhydride, aniline or ammonium acetate, and aromatic aldehydes in refluxing water with
excellent yield without using any catalysts. The protocol avoids the use of hazardous solvents and chromatographic separation. The
generality and functional tolerance of this convergent and environmentally benign method is demonstrated.
Keywords: aromatic aldehyde, dihydroquinazolinone, isatoic anhydride.
Quinazolin-4-ones are important bicyclic heterocycles
which have been found to possess valuable biological and
pharmacological activities involving antifungal,1,2 analge-
sic,3 antidiabetic,4 antitumor,5 antibacterial,6 anticonvul-
sant,7 and antihypertensive.8 In addition, these compounds
can easily be oxidized to their 4-alkynyl-4-(trifluoro-
methyl)-3,4-dihydroquinazolin-2(1H)-one analogs9 which
also are important pharmacologically active com-
pounds.10,11
Due to the significant interest in 2,3-dihydroquinazolin-
4(1H)-ones, several synthetic strategies12–14 have been
developed for the preparation of substituted dihydro-
quinazolin-4(1H)-ones. The formation of these compounds
generally can be accomplished by condensation of isatoic
anhydride, aldehydes, and amines in the presence of
montmorillonite K-10,15 silica sulfuric acid,16 zinc(II)
perfluorooctanoate,17 MCM-41-SO3H,18 Amberlyst-15,19
Ga(OTf)3,20 p-toluenesulfonic acid,21 Al(H2PO4)3,22
SiO2–FeCl3,23 SnCl2,24 ceric ammonium nitrate,25 silica-
bonded S-sulfonic acid,26 and Al/Al2O3,27 Fe3O4 nano-
particles,28 metal complexes with multi-walled carbon
nanotubes,29 silica-supported ceric ammonium nitrate,30
SiO2-ZnCl2,31 KAl(SO4)2·12H2O,32 TiO2 nanoparticles,33
and ionic liquids.34 However, some reported methods have
certain disadvantages, such as tedious process, long
reaction times, harsh reaction conditions, high reaction
temperature, and low yields with the use of various
catalysts. Therefore, the development of a clean, high
yielding, and eco-friendly approach is highly desirable.
Due to growing environmental concerns, carrying out
multicomponent reactions (MCRs) in water has become
highly desirable, and several reports of organic synthesis in
water have appeared during the past decade.35–38 As the
most abundant, cheapest, and environmentally friendly
solvent, water offers several practical advantages over
conventional organic solvents such as easy availability, low
costs, and safe handling.39 Furthermore, besides having a
unique reactivity and selectivity, water also offers an easy
separation. The above advantages have been attributed to
many factors, including the hydrophobic effect, enhanced
hydrogen bonding in the transition state, and the high
cohesive energy density of water.39
Due to our interest in developing multicomponent
reactions,40–42 we report here an efficient procedure for the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones through a
one-pot three-component condensation of isatoic anhydride,
0009-3122/15/5110-0899©2015 Springer Science+Business Media New York
899

Chemistry of Heterocyclic Compounds 2015, 51(10), 899–902
Table 1. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones 3a–j
With these optimized conditions in hand, the reaction of
isatoic anhydride (1) with a wide range of aromatic
aldehydes 2 and either aniline or ammonium acetate was
examined to explore the scope and generality of the present
protocol for the synthesis of various 2,3-dihydroquinazolin-
4(1H)-ones 3a–j and 4a–c, respectively (Table 1). Thus,
we were in position to investigate the scope and efficiency
of this reaction and to study the effect of substituents on the
product formation. It was found that this method had good
tolerance for various substitutions. It should be noted that
the electronic nature and position of substituent on the
phenyl rings did not show strong influence on the reaction,
and the products in all cases were obtained in high to
excellent yields (84–90%). After completion of the reac-
tion, water was decanted, and the pure product was con-
veniently obtained by recrystallization from ethanol. The
products 3a–g,i,j and 4a–c have been described before,
while compound 3h is reported for the first time.
According to evolution of the reaction conditions, a
possible mechanism for the formation of products 3a–j is
presented in Scheme 1. It is proposed that, at first, water
acts as a hydrogen bond donor to activate carbonyl group
of isatoic anhydride 1. Then, as a result of ring opening and
decarboxylation caused by nucleophilic attack of amine to
the carbonyl group intermediate anthranilamide 5 is
formed. Subsequently, the reaction of activated aldehyde
with anthranilamide 5 proceeds to afford the imine
intermediate 6. The tautomerization of amide group and
activation of the imine moiety in the intermediate 6 can be
catalyzed in water by formation of hydrogen bonding to
give the intermediate 7. This intermediate can convert to
the title product 3 by cyclization via intramolecular
nucleophilic attack of carboximidate nitrogen on imine
carbon. The pathway to compounds 4a–c would be
analogous.
and 4a–c
Mp, °C
Yield,
%
Entry
Ar
Product
Found
Reported
1
2
3
4
5
6
7
Ph
88
89
87
88
90
85
87
213–214
212–213
213–215
186–188
191–193
216–218
231–233
214–21520
3a
3b
3c
3d
3e
3f
4-MeC6H4
4-MeOC6H4
3-O2NC6H4
4-O2NC6H4
4-BrC6H4
4-FC6H4
213–21445
218–22044
186–18815
195–19732
221–22330
235–23823
224–22648
–
3g
8
2-HO-3-MeOC6H3
2,6-Cl2C6H3
2-Naphthyl
Ph
85
87
85
88
89
90
204–206
218–220
229–230
227–228
230–232
187–189
3h
3i
9
234–23643
24344
10
11
12
13
3j
225–22647
233–23420
192–19346
4a
4b
4c
4-MeC6H4
4-MeOC6H4
aromatic aldehyde, and amine in aqueous medium. To the
best of our knowledge, there are no literature examples of
the synthesis of 2,3-dihydroquinazolin-4(1H)-ones in water
under catalyst-free conditions.
In conclusion, we described a simple, highly efficient,
and straightforward protocol for the synthesis of 2,3-di-
hydroquinazolin-4(1H)-ones in water under reflux con-
ditions. Furthermore, the protocol offers several advantages
including facile experimental procedure without using
catalysts and toxic solvents, simple work-up and purifi-
cation, and high isolated yields of the pure products. The
simplicity of the procedure and predictable low costs
makes it a useful and attractive strategy for the synthesis of
dihydroquinazolinones.
In the efforts to develop an efficient and environ-
mentally benign methodology for the synthesis of 2,3-di-
hydroquinazolin-4(1H)-ones, we initiated our studies by
the reaction of isatoic anhydride, benzaldehyde, and aniline
in water at room temperature. When the reaction was
carried at room temperature in the absence of catalyst, it
was not complete even after a longer time (10 h), and the
resulting yield was poor. To study the temperature effect,
the reaction was carried out at different temperatures. It
was found that under reflux conditions an excellent yield of
the corresponding product was achieved, and the reaction
required 2 h for completion.
Experimental
IR spectra were recorded on a Shimadzu 4300 spectro-
1
photometer in KBr. The H and 13C NMR spectra were
recorded on a Bruker DRX-300 Avance spectrometer
Scheme 1
900

Chemistry of Heterocyclic Compounds 2015, 51(10), 899–902
The authors thank the Research Council of Payame
Noor University for financial support.
(300 and 75 MHz, respectively) in DMSO-d6. The internal
1
standard for the
and 13C NMR spectra was TMS. Mass
spectra (electron impact ionization, 70 eV) were obtained
with an Agilent technologies HP 5973 mass spectrometer.
Elemental analyses were carried out on a Heraeus CHN-
Rapid elemental analyzer. Melting points were determined
with an Electrothermal model 9100 apparatus and are
uncorrected. All commercially available chemicals and
reagents were used without further purification.
Synthesis of 2,3-dihydroquinazolin-4(1H)-one deriva-
tives 3a–j and 4a–c (General method). A 25-ml round-
bottomed flask was charged with isatoic anhydride (1)
(0.163 g, 1.0 mmol), aniline (0.093 g, 1.0 mmol) or
ammonium acetate (0.077 g, 1.0 mmol), aromatic aldehyde
2 (1.0 mmol), and water (10 ml). The mixture was stirred
under reflux for 2 h. Afterwards, the reaction mixture was
cooled to room temperature, and water was decanted to
afford the crude product which was recrystallized from
ethanol to get the pure final product.
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1
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