Application of the ultrasound in the mild synthesis of substituted 2,3-dihydroquinazolin-4(1H)-ones catalyzed by heterogeneous metal-MWCNTs nanocomposites

Article abstract of DOI:10.1016/j.molstruc.2014.05.002

A practical method were applied successfully to synthesize mono- and disubstituted dihydroquinazolinones through three-component condensation of isatoic anhydride, primary amines or ammonium acetate with aromatic aldehydes in the presence of some transiti

Full text of DOI:10.1016/j.molstruc.2014.05.002

Accepted Manuscript
Application of the Ultrasonic in the Mild Synthesis of Substituted 2,3-Dihydro-
quinazolin-4(1H)-ones Catalyzed by Heterogeneous Metal-MWCNTs Nano-
composites
Javad Safari, Soheila Gandomi-Ravandi
PII:
S0022-2860(14)00460-8
DOI:
http://dx.doi.org/10.1016/j.molstruc.2014.05.002
MOLSTR 20600
Reference:
Journal of Molecular Structure
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 March 2014
1 May 2014
1 May 2014
Please cite this article as: J. Safari, S. Gandomi-Ravandi, Application of the Ultrasonic in the Mild Synthesis of
Substituted 2,3-Dihydroquinazolin-4(1H)-ones Catalyzed by Heterogeneous Metal-MWCNTs Nanocomposites,
Journal of Molecular Structure (2014), doi: http://dx.doi.org/10.1016/j.molstruc.2014.05.002
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Application of the Ultrasonic in the Mild Synthesis of Substituted 2,3-
Dihydroquinazolin-4(1H)-ones Catalyzed by Heterogeneous Metal-MWCNTs
Nanocomposites
Javad Safari*, Soheila Gandomi-Ravandi
Laboratory of Organic Compound Research, Department of Organic Chemistry, College of Chemistry,
University of Kashan, P.O. Box: 87317-51167, Kashan, I.R. IRAN
Tel.: +98-(0)361-591-2320; Fax: +98-(0)361-591-2397, e-mail: Safari@kashanu.ac.ir
Abstract
A practical method has been applied successfully to synthesize mono- and disubstituted dihydroquinazolinones
through three-component condensation of isatoic anhydride, primary amines or ammonium salts with aromatic
aldehydes in presence of some transition metals-carbon nanotubes under sonication. Also, CNT-supported
metals have shown excellent catalytic performance for above-mentioned condensation. This methodology
provides general, easy and versatile approach to afford the corresponding aryl substituted quinazolinone
derivatives using mentioned nanocomposites as catalyst under sonication in excellent yields. The advantages of
present protocol are convenient reaction and simple work-up, greenness, energy efficiency, green and reusable
catalyst as well as mild reaction conditions. The employed Metal-CNTs catalyst is heterogeneous and
recyclable, that makes the process more environmentally friendly.
Keywords: Ultrasound irradiation, Quinazolinone, Transition metals, Supported catalyst
1. Introduction
Multicomponent reactions (MCRs) are emerging increasingly as an attractive synthetic strategy to be
developed fast in biologically active compounds and natural products with several degrees of structural diversity
[1-5]. MCRs as an important subclass of tandem reactions are in agreement with Principles of Green Chemistry
in chemical biology and drug discovery [6-9]. Moreover, MCRs have the significant virtues including of
convergent nature, simplicity, superior atom economy, facile execution, and synthetic efficiency as well as
environmentally friendlier aspects in a conventional linear-type synthesis [10]. Quinazolinone scaffold is a
1

privileged structure in a variety of biologically active compounds with unique position in the field of medicinal
chemistry [11]. 2,3-Dihydroquinazolinones are an important class of bioactive heterocyclic compounds with a
broad spectrum of pharmacological, biological and medicinal activities [12]. Additionally, the 2,3-disubstituted
quinazolinones have been reported to possess antihypertensive and antiviral activities [13]. 2,3-Disubstuted-2,3-
dihydroquinazoline-4(1H)-one alkaloids also have a key role in various cellular processes and exhibit a variety
of pharmaceutical activity [14] including of anticancer, antibacterial, antidepressant, antimicrobial, and anti-
inflammatory [15]. The first reported synthesis of quinazolinone occurred in 1869 which was prepared from
anthranilic acid and cyanogen in ethanol in the synthesis of 2-ehoxy-4(3H)-quinazolinone [16]. The pyrimidine
ring adopts a skew-boat conformation. Boat conformation of the pyrimidinone ring shows the pseudoaxial
orientation of the C4 aryl group and out-of plane positions of the C4 and N1 atoms [17]. Therefore, compounds
contain a flat aromatic area of quinazoline, hydrogen bond acceptor at position 4, hydrophobic part at position 3,
aromatic region at positions 1 or 2 of the quinazoline-4-one nucleus [18]. Type and position of the substituent on
the C4 and C5 atoms, dihedral angle of the aryl group (on the C4 atom) relative to the heterocycle ring,
orientation of the carbonyl group (on the C5 atom) relative to the C5=C6 bond of the heterocycle ring and
deviation of the C4 and N1 atoms from the boat plane affect their structural factors [17]. In view of their
significance, novel chemical processes or methodologies should be benefited for synthesis of substituted 2,3-
dihydroquinazolin-4(1H)-ones in terms of Green Chemistry in both of synthetic and medicinal chemistry.
Recently, some reported synthetic routes are included isatoic anhydride, and aldehydes with ammonium acetate
or primary amine in the presence of various reagents or catalysts [19–21].
Among the different types of supports used in heterogeneous catalysis, considerable interesting research was
done on carbon nanotubes (CNTs) owing to the porosity and surface chemistry, inertness and lower catalyst-
support interactions, and good mechanical strength [22–25]. The decoration of metal nanoparticles onto the
external surfaces of carbon nanotubes (MWNTs) is effective for attractive potential applications such as
catalysts in fuel cells [26–28], reversible interconnections in sensors [29], drug carrier [30], and cold electron
sources in field emission displays [31–33]. The researchers suggested that the metal-nanoparticle/CNT
nanocomposites increase the reactive surface area of the metal and reduce the metal size, and also intimate
interphase contact between the metal nanoparticles and MWCNTs resulted other synergistic effects [34]. The
synergistic or cooperative effects of CNTs and metal NPs makes CNTs/metal heterostructures possessing the
unique properties of the two types of components (CNTs and metal NPs) [35]. However, the surface of pristine
CNTs, which are generally produced from decomposition of hydrocarbons, is inert and hydrophobic [36–40].
2

Therefore, favorable interaction and uniform dispersion of metallic nanoparticles on CNTs surface is a challenge
owing to their almost perfect structure. Consequently, many protocols have been established to functionalize
CNTs surface such as modification of CNTs with polymers [41,42], functionalization with amine, carboxyl,
and/or sulfone groups [43,44], enlargement of their surface area with KOH [45,46], and chemical treatment with
agents such as oxygen, ozone, HCl, oxidizing acids (nitric acid, sulfuric acid, perchloric acid), potassium
permanganate, and hydrogen peroxide (H2O2) [47–58]. Such surface modification introduces an opportunity for
metal NPs precursors to be correlated with MWCNTs and prompts the deposition of metals on the external
walls.
The use of ultrasound is well known as useful tool in the design and development of green methods and
promotion of organic reactions. Sonication accelerates the reaction by providing driving energy by cavitation
and the formation and collapse of bubbles (production of high pressure and high temperature) and confirms a
better contact, increasing the reaction rate and selectivity. Benefits further include the simplicity of the
experimental procedure, higher yields and rate, shorter reaction times and the clean nature [59]. Our efforts for
development of green and new synthetic methods for various heterocyclic compounds prompted us to
investigate the utility of metals supported on CNTs as heterogeneous catalyst under sonication to be afforded
substituted quinazolinones. Therefore, we would like to disclose a versatile procedure for the fabrication of
mono and di-substituted 2,3-dihydroquinazolin-4(1H)-ones selectively in the presence of metal-CNTs catalytic
systems employing three-component reactions of isatoic anhydride with aldehydes and primary amines (or
ammonium salts) (Scheme 1).
O
O
Ar/H
N
O
Co-CNTs
U.S.
+
Ar'CHO
+
ArNH2 / NH4OAc
N
H
Ar'
N
H
O
Scheme 1. Co-CNTs-catalyzed synthesis of mono- and disubstituted 2,3-dihydroquinazolin-4(1H)-ones in
ethanol under sonication
2. Experimental
All the commercial available reagents were obtained from Merck and Aldrich and were used as was received.
MWCNTs were purchased from Nanotech Port Co. (Taiwan). These MWCNTs were produced via the chemical
3

vapor deposition (CVD, or sometimes was called catalytic pyrolysis) method. The outer diameter of CNT was
between 10 and 20 nm. Purity of the compounds and completion of reactions was monitored by TLC,
visualizing with ultraviolet light. All melting points (m.p.) were measured in an Electrothermal MK3 apparatus
and were uncorrected. The Fourier transform infrared spectroscopy (FTIR) was used to detect the functional
groups on the surface of CNTs. Infrared spectra were recorded on KBr pellets on a Perkin Elmer FT–IR 550
1
spectrophotometer at 400-4000 cm-1 with 16 scan's numbers in room temperature. The H NMR and 13C NMR
spectra were recorded on a Bruker DRX–400 spectrometer at 400 and 100 MHz in DMSO-d6, respectively. The
chemical shifts (δ) are given in ppm using TMS as internal reference. The scanning electron micrograph (SEM)
was obtained using a TESCAN model VEGA II scanning electron microscope (SEM) operated at a 15 kV
accelerating voltage. The obtained nanocomposites were characterized by XRD on a on Holland Philips Xpert
X-ray diffraction (XRD) diffractometer (CuK, radiation, λ= 0.154056 nm), at a scanning speed of 2°/min from
10° to 100° (2θ).
2.1. Ultrasound-promoted general synthesis of mono- and disubstituted quinazolinones
A stirred mixture of isatoic anhydride (1 mmol), ammonium acetate (1.1 mmol) or primary amine (1.2 mmol),
benzaldehyde (1 mmol) and Co-CNTs (0.04 g) was sonicated at 35 kHz to stipulate time at 40 ºC. After
completion of the reaction, as indicated by TLC (ethyl acetate: petroleum ether, 1:3), the solid catalyst was
separated by filtration. After that, the filtrate was poured into crushed ice with thorough stirring for several min.
The precipitated solids were filtered off and finally purified by recrystallization from ethanol.
3. Results and discussion
We introduced very convenient and environmentally benign synthesis of mono- and disubstituted 2,3-dihydro-
4(1H)-quinazolinones under ultrasonic irradiation. Monosubstituted 2,3-dihydro-4(1H)-quinazolinones were
synthesized efficiently by the condensation of isatoic anhydride and aryl aldehydes in the presence of
ammonium acetate in ethanol under heterogeneous supported catalyst (Scheme 1). Moreover, treatment of
isatoic anhydride and aromatic aldehydes with primary aromatic amines in the presence of heterogeneous
supported catalyst in ethanol were afforded disubstituted derivatives of 2,3-dihydro-4(1H)-quinazolinone in
excellent yields (Scheme 2). Our attempt has been focused to apply novel green metals-CNTs for ultrasound-
assisted synthesis of substituted quinazolinones. These Lewis acidic nanocomposites can be prepared simply
according to literature procedures [60–63]. Current study investigates the catalytic activity of nanocomposites of
4

the formula metal-CNTs as a heterogeneous catalyst in the ultrasound sponsored modified synthesis of
quinazolinone derivatives. A diversity of supported catalysts in the synthesis of this heterocyclic scaffold was
investigated to compare their efficiency. Initially, the reaction was performed in the presence of several metals
supported on CNTs including of Cu-CNTs, Ag-CNTs, Co-CNTs and Pt-CNTs. Catalysts screening results are
listed in Table 1. It is clear that these supported heterogeneous nanocomposites promoted successfully this
multi-component reaction with high yields. Among the evaluated nanocatalysts, Co-CNT nanocomposites were
superior to others and produced the best yield and time in the synthesis of the target substituted 2,3-dihydro-
4(1H)-quinazolinones. The more number of empty d-orbitals of metal, and more stability are the advantages of
Co-CNTs with consumption of the low amount of catalyst in compared with existing ones. Additionally, the
activities of these promoters were found to decrease in the following order: Co-CNTs > Pt-CNTs > Cu-CNTs >
Ag-CNTs. Currently, Co-CNTs are a novel and heterogeneous promoter to facile and generally to prepare
substituted-2,3-dihydro-4(1H)-quinazolinones under mild reaction conditions.
Table 1. Comparison between the efficiency of various catalysts in the synthesis of disubstituted 2,3-dihydro-
4(1H)-quinazolinone derivatives
Entry
Catalyst
Time (min)
Yield (%)
1
2
3
4
Cu-CNTs
Ag-CNTs
Co-CNTs
Pt-CNTs
25
20
6
78
70
97
89
10
The catalytic efficiency of Co-CNTs also was studied for this condensation reaction. As indicated in Table 2,
increase in the amount of catalyst, initially, led to improved yield at short reaction time and optimum amount of
catalyst to ensure high reaction efficiency was 0.04 g. Increment in the amount of catalyst higher than 0.04 g did
not show any effect on the product yield and reaction time. Only a trace amount of the corresponding product
was formed in the absence of catalyst at a long time. We performed the model reaction using different quantities
of reagents to determine the appropriate molar ratio of reactants. The best yield and the shortest reaction time
5

were obtained with a 1:1:1:1.2 ratios of isatoic anhydride, benzaldehyde, and aniline or ammonium acetate,
respectively.
Table 2. Investigation of the amounts of catalyst in the reaction of isatoic anhydride, benzaldehyde, and
ammonium acetate
Entry
Catalyst (g)
0
Time (min)
Yield (%)
1
2
3
4
5
6
45
30
20
15
6
15
65
76
84
97
97
0.01
0.02
0.03
0.04
0.05
6
The ultrasound mediated reactions have widely used in various organic transformations. A variety of reactions
were successfully carried out under ultrasound irradiation within short reaction time and under mild conditions
in a high yielding process. We also performed all the experiments without sonication to evaluate the role of
understand irradiation and results show that the reaction without ultrasound irradiation took place in very long
time and the relatively low yields. Thus, it seemed that ultrasound irradiation had a main role in enhancement of
the reaction rate and the combination of ultrasound and Co-CNTs was establish to be ideal for the faster
synthesis in high yield. In order to investigate the effect of irradiation power, the experiments were performed in
different powers of ultrasound irradiation. As shown in Table 3, 70 W was found to be the most suitable power
for the model reaction. With increase in irradiation power, considerable change was not observed in the reaction
time and yield.
Table 3. Optimization of the irradiation power for the synthesis 4a catalyzed by Co-CNTs
Entry
power (W)
Temperature (°C) Time (min) Yield (%)
6

1
2
3
4
5
6
20
40
50
60
70
90
40
40
40
40
40
40
56
40
25
15
6
55
60
79
88
97
97
6
Also, this work has been extended to observe the effect of solvent on reaction in different solvents including
ethanol, CH3CN, dioxane, DCM and THF as the medium in the presence of 0.04 g of the catalyst. The results
are given in Table 4. Based on reaction yield, time, and environmental acceptance, the best result was observed
when the reaction was performed in ethanol. This indicates that the solvent polarity and solubility of reactants
and catalyst could play an important role in this process under ultrasound irradiation.
Table 4. Effect of different solvents in the model reaction in the presence of Co-CNTs
Solvent
EtOH
6
CH3CN
10
Dioxane
25
DCM
46
THF
35
Time (min)
Yield (%)
97
91
61
42
53
The reusability of catalyst is one of the most important its properties from an environmental point of view and
economic consideration. Upon completion, the catalyst is easily separated from the reaction medium by
filtration and washing with alkaline aqua solution (PH 9). It can be seen from Fig. 1 that the recycled catalyst
was active even after five successive runs without obvious loss of activity and figures within parentheses show
the corresponding yield for each run.
7

Fig. 1. Catalytic recyclability of Co-CNT nanocomposites
From the point of view of the success of the reaction and investigation in the scope and efficiency of the
process, the wide range of substituted and structurally divers aldehydes and also aniline derivatives was treated
to synthesize the corresponding products in excellent yields. From Table 5, it was clear that no simple
relationship was observed between the electronic nature of substituent of the aryl groups and the desired
quinazolinone products. The results illustrate the high ability of this methodology for synthesis of substituted
2,3-dihydroquinazoline-4(1H)-ones with varied structures. The structures of the products were established by
1
IR, H NMR and 13C NMR spectroscopy and the purity of the compounds was determined by TLC and
elemental analysis.
Table 5. Ultrasonic synthesis of mono- and disubstituted 2,3-dihydroquinazolin-4(1H)-ones in the presence of
Co-CNTs in ethanol
M.p (°C)
Product Amine
Ar'
Time (min) Yield (%)
Ref.
Found
Reported
4a
4b
4c
4d
PhNH2
C6H5
6
97
85
87
89
214–215 214–216
223–225 222–224
241–243 244–245
248–250 249–252
[64]
[65]
[66]
[67]
PhNH2
4-Me C6H5
4-OMe C6H5
4-Me C6H5
20
15
20
4-Me PhNH2
4-OH PhNH2
8

4e
4f
PhNH2
4-Br C6H5
4-Cl C6H5
4-F C6H5
15
20
10
15
90
87
93
89
220–222 219–223
269–272 270–274
235–237 235–238
204–206 205–207
[68]
[69]
[68]
[70]
4-Me PhNH2
PhNH2
4g
4h
PhNH2
4-OMe C6H5
4i
4-Me PhNH2
PhNH2
4-F C6H5
10
15
20
35
25
95
91
84
76
82
240–242 241–243
223–225 222–224
[71]
[72]
[68]
[66]
[68]
4j
4-Cl C6H5
4-Me C6H5
4-OMe C6H5
4-Cl C6H5
4k
4l
4-Me PhNH2
4-Cl PhNH2
244–246
245–247
235–236
243–247
244–247
235–237
4m
5-Cl,2-OH
PhNH2
4n
4o
4p
4q
4r
4s
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
2,3-Cl2 C6H5
2-F C6H5
15
10
10
7
85
93
93
95
90
81
223–225 225–227
265–267 266–267
198–200 199–201
196–198 195–196
204–205 203–205
[73]
[74]
[72]
[72]
[75]
[76]
4-NO2 C6H5
3-NO2 C6H5
2-Cl C6H5
15
20
4-OH,3-OMe C6H5
226–228
226–227
SEM was used to observe the surface morphology of composites. Fig. 2 displays SEM images of the metal
supported on carbon nanotubes. TEM analysis was carried out in Fig. 2 to determine the dispersion of cobalt
nanoparticles, which is quite uniform without any detectable local aggregation.
9

Fig. 2. The scanning electron microscope (SEM) micrographs of a) Co-CNTs, b) Pt-CNTs, c) Ag-CNTs and d)
Cu-CNTs, Images of the TEM of Co nanoparticles supported on carbon nanotubes
According to evolution of the reaction conditions, a possible mechanism is presented to synthesize these
products in Scheme 2. It is proposed that, at first, the intermediate I is formed through nucleophilic attack of the
amino group in 2-aminobenzamide at the activated carbonyl group in aldehyde by metal as a supported catalyst.
Also the part of amide in imine intermediate II is converted into its tautomer in the presence of catalyst. Then
the Schiff base intermediate III is produced by intermediate II dehydration. Then the intramolecular
nucleophilic addition reaction between the amide group nitrogen and activated Schiff base carbon gives
intermediate IV, which was followed by a 1,5-proton transfer takes place to give the products.
10

HO
H
N
O
NH2
HO
I
H
NH2
N
OH
O
+
NH2
N
H
H
Ar
N
O
II
N
H
Ar
Ar
H
HO
O
H
N
H
N
N
Ar
N
H
Ar
III
IV
Scheme 2. Possible mechanism for the synthesis of quinazolinonones
4. Conclusions
The present study highlights the identification of several novel highly reactive nanocomposites as heterogeneous
catalyst to prepare mono- and disubstituted quinazolinones in a one-pot MCR protocol. Thus, the present
synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives created by the reaction of a range of amines and
aldehydes with isatoic anhydride under sonication, will be served as an exclusive method of preparative
importance for this class of heterocyclic compounds. The Co-CNTs exhibits promising and superior catalytic
activity for this transformation over other investigated transition metals supported on CNTs, which would make
this process suitable and attractive for parallel synthesis in drug discovery. Noteworthy features of this process
are the cleaner reaction profile, conditional generality, the easy use of accessible starting materials, atomic
economy, the feasible reusability of the catalyst and environmentally benign nature, and action under mild
reaction conditions, which is important from the view point of green chemistry. These features will enable this
protocol to find extensive applications in the field of medicinal chemistry.
Acknowledgment
We wish to express our gratitude to the University of Kashan.
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15

Scheme 1. Co-CNTs-catalyzed synthesis of mono- and disubstituted 2,3-dihydroquinazolin-4(1H)-ones in ethanol under
sonication
Table 1. Comparison between the efficiency of various catalysts in the synthesis of 4a
Table 2. Investigation of the amounts of catalyst in the reaction of isatoic anhydride, benzaldehyde, and ammonium acetate
Table 3. Optimization of the irradiation power for the synthesis 4a catalyzed by Co-CNTs
Table 4. Effect of different solvents in the model reaction in the presence of Co-CNTs
Fig. 1. Catalytic recyclability of Co-CNT nanocomposites
Table 5. Ultrasonic synthesis of mono- and disubstituted 2,3-dihydroquinazolin-4(1H)-ones in the presence of Co-CNTs in
ethanol
Fig. 2. The scanning electron microscope (SEM) micrographs of a) Co-CNTs, b) Pt-CNTs, c) Ag-CNTs and d) Cu-CNTs,
Images of the TEM of Co nanoparticles supported on carbon nanotubes
Scheme 2. Possible mechanism for the synthesis of quinazolinonones
16

Graphical Abstract
Application of the Ultrasonic in the Mild Synthesis of Substituted 2,3-Dihydroquinazolin-4(1H)-
ones Catalyzed by Heterogeneous Metal-MWCNTs Nanocomposites
O
O
Ar/H
Ar'
Metal-CNTs
U.S.
N
O
+
+
Ar'CHO
ArNH2 / NH4OAc
N
H
N
H
O
Highlight
•
•
•
This methodology provides general, easy and versatile approach.
The employed catalyst (Metal-CNTs) is heterogeneous and recyclable.
The Co-CNTs exhibits promising and superior catalytic activity for this reaction.
17