ZnO nanoparticles catalyzed efficient one-pot three-component synthesis of 2,3-disubstituted quinalolin-4(1H)-ones under solvent-free conditions

Article abstract of DOI:10.1007/BF03246559

ZnO nanoparticles were prepared and applied as a favorable catalyst in three-component one-pot cyclocondensation reaction of isatoic anhydride with amines and aldehydes to afford the corresponding 2,3-disubstituted quinalolin-4(1H)-ones in good yields. Reactions occurred under solvent-free conditions in high atom economy.

Full text of DOI:10.1007/BF03246559

J. Iran. Chem. Soc., Vol. 8, No. 4, December 2011, pp. 1030-1035.
JOURIrNaAnLiaOnF THE
Chemical Society
ZnO Nanoparticles Catalyzed Efficient One-Pot Three-Component Synthesis of 2,3-
Disubstituted Quinalolin-4(1H)-ones under Solvent-Free Conditions
I. Yavari* and S. Beheshti
Department of Chemistry, Tarbiat Modares University, P. O. Box: 14115-175, Tehran, Iran
(Received 17 January 2011, Accepted 22 April 2011)
ZnO nanoparticles were prepared and applied as a favorable catalyst in three-component one-pot cyclocondensation reaction
of isatoic anhydride with amines and aldehydes to afford the corresponding 2,3-disubstituted quinalolin-4(1H)-ones in good
yields. Reactions occurred under solvent-free conditions in high atom economy.
Keywords: ZnO nanoparticles, Isatoic anhydride, Quinazolinone, Solvent-free
INTRODUCTION
and aldehydes (Scheme 1).
The development of efficient and environmentally benign
chemical processes using recyclable catalysts and
environmentally benign solvents is one of the major tasks in
organic synthesis [1]. Quinazolin-4(1H)-ones have been
reported to have various biological activities, such as
anticancer [2], antidiuretic [3], anticonvulsant [4]. Several
methods have been reported for synthesis of quinazolinones.
EXPERIMENTAL
All chemicals were purchased from Fluka and used
without further purification. Melting points were measured on
an Electrothermal 9100 apparatus. Elemental analyses for C, H
and N were performed using a Vario EL III CHNOS elemental
analyzer and the results agreed favorably with the calculated
values. Mass spectra were recorded on a Finnigan MAT 8430
mass spectrometer operating at an ionization potential of 70
eV. IR spectra were measured on a Shimadzu IR-460
Common
synthetic
methods
for
aryl-substituted
quinazolinones included cyclization of o-acylamino-
benzamides [5], amidation of 2-aminobenzonitrile followed by
oxidative ring closure [6], solid-phase synthesis of 2-
arylamino-substituted quinazolinones [7], preparation from
isatoic anhydride [8-14] and Pd-catalyzed heterocyclization of
nitroarenes [15]. These procedures have certain limitations
such as long reaction time, harsh reaction conditions, and low
yields. Herein, we describe the use of ZnO nanoparticles
(ZnONPs), as Lewis acid catalyst, for the synthesis of
quinazolinone derivatives via a one-pot, three- component
cyclocondensation reaction of isatoic anhydride with amines
1
spectrometer. H and 13C NMR spectra were measured on a
Bruker DRX-500 Avance instrument at 500.1 and 125.7 MHz,
respectively. Scanning electron microscopy (SEM) images
were obtained using a Stereo Scan XL-30 Philips.
General Procedure
A mixture of isatoic anhydride (0.163 g, 1 mmol), amines
(1 mmol), benzaldehydes (1 mmol) and ZnO NPs (20 mol-%)
was heated at 70 ºC for 3 h. After completion of the reaction
as indicated by TLC [petroleum ether/EtOAc (4/1)], the
reaction mixture was cooled to room temperature. The solid
*Corresponding author. E-mail: yavarisa@modares.ac.ir

Yavari & Beheshti
O
O
R
ZnO NPs (20 mol%)
solvent-free, 70 oC, 3 h
N
O
R'-CHO
+
+
R-NH2
N
H
R'
N
H
O
4
1
2
3
Amine 2
Aldehyde 3
Product 4
Yield (%)a TONb
TOF (h-1)c
R
R’
Me
Et
Et
Ph
Ph
Bn
Ph
4a
92
94
97
88
93
92
90
89
95
96
4.6
4.7
4.8
4.4
4.6
4.6
4.5
4.5
4.8
4.8
1.5
1.6
1.6
1.5
1.5
1.5
1.5
1.5
1.6
1.6
p-MeOC6H4
m-O2NC6H4
Ph
m-O2NC6H4
p-ClC6H4
p-MeOC6H4
p-Tolyl
4b
4c
4d
4e
4f
4g
4h
4i
p-MeOC6H4CH2
p-MeOC6H4CH2
p-MeOC6H4CH2
p-MeOC6H4CH2
m-O2NC6H4
p-O2NC6H4
4j
aThe yields refer to pure isolated products characterized by spectral data. Turnover number
b
(average number of product molecules produced per mole of the catalyst). cTurnover frequency
(turnover number per time).
Scheme 1
residue was dissolved in hot ethanol and centrifuged to
70.4 (CH), 114.5 (CH), 115.8 (C), 119.5 (CH), 126.6 (C),
127.6 (CH), 128.0 (2CH), 128.6 (2CH), 128.9 (CH), 129.1
(2CH), 133.8 (2CH), 135.2 (CH), 136.6 (C), 137.9 (C), 144.9
(C), 163.1 (C=O) ppm.
separate the catalyst. The isolated catalyst can be reused
without appreciable loss of its catalytic activity. By
recrystallization from ethanol, pure products were obtained.
Compounds 4a-4e are known and were characterized by
comparison of their spectroscopic and physical data with those
reported in the literature [20,21]. The unknown compounds 4f-
4j are properly characterized by their spectroscopic data.
3-Benzyl-2-(4-chlorophenyl)-2,3-dihydroquinazolin-4
(1H)-one (4f). White powder; yield 0.32 g (92%); m.p.: 122-
3-(4-Methoxybenzyl)-2,3-dihydro-2-(4-methoxyphenyl)
quinazolin-4(1H)-one (4g). White powder; yield 0.34 g
(90%); m.p.: 159-161 °C; IR (KBr):
= 3310, 1626 cm-1;
EI-MS: m/z = 374 (M+, 14), 253 (52), 267 (89), 136 (28), 121
1
(100); H NMR (CDCl3): δ = 3.61 (1 H, d, 2J = 15.0 Hz, CH),
3.81 (3H, s, MeO), 3.82 (3H, s, MeO), 4.36 (1H, br s, NH),
5.52 (1H, d, 2J = 15.0 Hz, CH), 5.59 (1H, s, CH), 6.51 (1H, d,
3J = 8.0 Hz, CH), 6.83-6.89 (5H, m, CH), 7.14 (2H, d, 3J = 8.4
124 °C; IR (KBr):
= 3305, 1630 cm-1; EI-MS: m/z = 350
(M+ +2, 6), 348 (M+, 16), 257 (56), 237 (93), 214 (11), 180
(14), 120 (13), 106 (31), 91 (100), 65 (16); 1H NMR (CDCl3):
δ = 3.68 (1H, d, 2J = 15.4 Hz , CH), 4.56 (1H, br s, NH), 5.58
(1H, d, 2J = 15.4 Hz, CH), 5.6 (1H, br s, CH), 6.53 (1H, d, 3J =
3
3
Hz, CH), 7.22 (2H, d, J = 8.5 Hz, CH), 7.27 (1H, d, J = 7.7
Hz, CH), 8.04 (1H, d, 3J = 7.8 Hz, CH) ppm; 13C NMR
(CDCl3): δ = 46.1 (CH2), 55.3 (MeO), 55.4 (MeO), 70.6 (CH),
113.9 (2CH), 114.2 (2CH), 115.9 (C), 119.1 (CH), 128.1
(2CH), 128.8 (CH), 128.9 (C), 129.5 (2CH), 131.5 (C), 133.5
(CH), 145.2 (C), 159.02 (C), 160.4 (C), 163.2 (C=O) ppm.
3
3
8.0 Hz, CH), 6.88 (2H, t, J = 7.4 Hz, CH), 7.22 (3H, d, J =
3
8.3 Hz, CH), 7.23-7.34 (6H, m, CH), 8.03 (1H, dd, J = 7.7
Hz, 4J = 1.2 Hz, CH) ppm; 13C NMR (CDCl3): δ = 47.0 (CH2),
1031

ZnO Nanoparticles Catalyzed Efficient One-Pot Three-Component Synthesis
3-(4-Methoxyphenyl)-2,3-dihydro-2-p-tolylquinazolin-
133.9 (CH), 134.0 (C), 137.7 (C), 139.7 (C), 159.0 (C), 162.8
4(1H)-one (4h). White powder; yield 0.32 g (89%); m.p.: 151-
(C=O) ppm.
153 °C; IR (KBr):
= 3315, 1625 cm-1; EI-MS: m/z = 358
1
(M+, 18), 267 (95), 237 (58), 136 (35), 121 (100); H NMR
(CDCl3): δ = 2.34 (3H, s, Me), 3.58 (1H, d, 2J = 15.0 Hz, CH),
3.80 (3H, s, MeO), 4.54 (1H, br s, NH), 5.56 (1H, d, 2J = 15.0
RESULTS AND DISCUSSION
The choice of an appropriate reaction medium is important
for successful synthesis. Initially, the three-component
reaction of isatoic anhydride, benzaldehyde, and aniline as a
simple model was investigated to optimize the reaction
conditions (Table 1). Different amounts of the catalyst were
used in the model reaction. As shown in Table 1, best result
was obtained with a 20 mol-% of ZnO NPs, and the desired
product 4d was obtained in 88%. Using lower amount of
catalyst resulted in lower yields, while higher amount of
catalyst did not affect reaction times and yields (Table 1).
After optimizing the reaction conditions, a variety of
aromatic aldehydes and amines were employed under similar
reaction conditions to evaluate the scope of this reaction. The
results are shown in Scheme 1. These reactions proceeded
smoothly and no undesirable side reactions were observed.
The aromatic aldehydes carrying both electron-withdrawing
and electron-releasing substituents were converted to the
corresponding quinazolinones 4a-4j in good yields.
3
Hz, CH), 5.57 (1H, br s, CH), 6.49 (1H, d, J = 8.0 Hz, CH),
6.83-6.86 (3H, m, CH), 7.12-7.27 (7H, m, CH), 8.01 (1H, d,
3J = 7.7 Hz, CH) ppm; 13C NMR (CDCl3): δ = 21.2 (Me), 46.2
(CH2), 55.3 (MeO), 70.7 (CH), 114.0 (2CH), 114.3 (CH),
115.8 (C), 119.0 (CH), 126.5 (2CH), 128.7 (CH), 128.9 (C),
129.5 (2CH), 129.6 (2CH), 133.5 (CH), 136.6 (C), 139.2 (C),
145.2 (C), 159.0 (C), 163.2 (C=O) ppm.
3-(4-Methoxybenzyl)-2,3-dihydro-2-(3-nitrophenyl)
quinazolin-4(1H)-one (4i). Yellow powder; yield 0.37 g
(95%); m.p.: 189-191 °C; IR (KBr):
= 3270, 1618 cm-1;
EI-MS: m/z = 389 (M+, 21), 268 (60), 267 (88), 135 (29), 121
1
2
(100); H NMR (CDCl3): δ = 3.78 (1H, d, J = 15.1 Hz, CH),
3.80 (3H, s, MeO), 4.59 (1H, br s, NH), 5.51 (1H, d, 2J = 15.1
Hz, CH), 5.73 (1H, s, CH), 6.57 (1H, d, 3J = 8.0 Hz, CH), 6.84
3
3
(2H, d, J = 8.4 Hz, CH), 6.93 (1H, t, J = 7.5 Hz, CH), 7.14
3
3
(2H, d, J = 8.4 Hz, CH), 7.30 (1H, t, J = 7.7 Hz, CH), 7.49
(1H, t, 3J = 8.0 Hz, CH), 7.65 (1H, d, J = 7.7 Hz, CH), 8.04
3
3
3
(1H, d, J = 7.8 Hz, CH), 8.12 (1H, s, CH), 8.18 (1H, d, J =
7.9 Hz, CH) ppm; 13C NMR (CDCl3): δ = 46.9 (CH2), 55.3
(MeO), 69.8 (CH), 114.2 (2CH), 114.8 (CH), 116.2 (C), 120.1
(CH), 121.8 (CH), 124.0 (CH), 128.2 (C), 128.9 (CH), 129.5
(2CH), 130.0 (CH), 132.2 (CH), 133.9 (CH), 141.9 (C), 144.2
(C), 148.5 (C), 159.3 (C), 162.8 (C=O) ppm.
A plausible mechanism for this reaction is shown in
Scheme 2. It is conceivable that the ZnO NPs are coordinated
to the oxygen atom of the carbonyl groups in different stages
of the reaction activating them for the nucleophilic attack of
the amine and amide nitrogen atoms. The high surface area-to-
volume ratio of ZnO NPs is mainly responsible for their
3-(4-Methoxybenzyl)-2,3-dihydro-2-(4-nitrophenyl)
quinazolin-4(1H)-one (4j). Yellow powder; yield 0.37 g
= 3275, 1619 cm-1;
Table 1. Reaction between Isatoic Anhydride,
Benzaldehyde, and Aniline, under Different
Conditions
(96%); m.p.: 190-192 °C; IR (KBr):
EI-MS: m/z = 389 (M+, 23), 268 (58), 267 (90), 135 (25), 121
1
2
(100); H NMR (CDCl3): δ = 3.67 (1H, d, J = 15.1 Hz, CH),
3.81 (3H, s, MeO), 4.51 (1H, br s, NH), 5.59 (1H, d, 2J = 15.1
Hz, CH), 5.70 (1H, d, J = 3.1 Hz, CH), 6.55 (1H, d, J = 8.0
3
3
Catalyst (mol%)
(%)
Time (h)
Yeild
3
3
Hz, CH), 6.85 (2H, d, J = 8.6 Hz, CH), 6.93 (1H, t, J = 7.6
Hz, CH), 7.16 (2H, 3J = 8.6 Hz, CH), 7.30 (1H, dt, 3J = 7.6 Hz,
4J = 1.6 Hz, CH), 7.45 (2H, d, 3J = 8.7 Hz, CH), 8.05 (1H, dd,
None
14
8
8
3
3
50
70
72
80
88
88
Bulk ZnO (20)
Bulk ZnO (30)
ZnO NPs (10)
ZnO NPs (20)
ZnO NPs (30)
3J = 7.8 Hz, J = 1.3 Hz, CH), 8.17 (2H, d, J = 8.7 Hz, CH)
ppm; 13C NMR (CDCl3): δ = 46.8 (CH2), 55.3 (MeO), 69.6
(CH), 114.2 (2 CH), 114.7 (C), 114.8 (CH), 120.1 (CH), 124.2
(2CH), 127.4 (2CH), 128.1 (C), 128.9 (CH), 129.5 (2CH),
4
3
3
1032

Yavari & Beheshti
O
N
O
- CO2
NHR
R'
NHR
NH2
R'-CHO
ZnO NPs
1
2
+
6
5
ZnO
O
O
N
H+ Shift
NHR
NHR
R'
4
N
OZn
R'
Scheme 2
Fig. 1. XRD pattern of synthesized ZnO nanoparticles.
catalytic properties [16-18].
CONCLUSIONS
The ZnO NPs were prepared through a solid-state reaction
[19]. Figure 1 shows XRD pattern of the ZnO NPs. All of the
diffraction peaks are in agreement with the JCPDS file of ZnO
(JCPDS No. 36-1451). The morphology and grain size of the
ZnO NPs were investigated by SEM (Fig. 2). They have a
narrow distribution of sizes, from 32 nm to 48 nm.
In Table 2, the catalytic activity of the synthesized ZnO
NPs to catalyze the formation of compounds 4 is compared
with other catalyst [8-14]. In most cases, the ZnO NPs are
comparable or better than other catalysts.
In conclusion, we have developed an efficient ZnO NPs as
Lewis acid catalyst for the synthesis of quinazolinones by a
one-pot, three-component condensation of isatoic anhydride
with amines and aldehydes in high atom economy under
solvent-free conditions. The ZnO NPs would act as a catalyst
to activate the substrate molecules. Moreover, the catalyst can
be recovered conveniently and reused for at least three
reaction cycles without appreciable loss of activity.
1033

ZnO Nanoparticles Catalyzed Efficient One-Pot Three-Component Synthesis
Fig. 2. SEM image of the synthesized ZnO NPs.
Table 2. A comparision of Catalytic Activity of Various Catalysts in Condensation
Reaction of Isatoic Anhydride, Benzaldehyde and Aniline
Conditions
Yield (%)
Ref.
Alum, H2O, reflux, 1 h
65
78
81
79
82
85
80
80
80
88
[8]
[8]
Alum, EtOH, reflux, 4 h
Amberlyst 15, solvent-free, MW, 3 min
Ga(OTf)3, EtOH, 70 °C, 1 h
Zn(PFO)2, H2O/EtOH (1:3), reflux, 6 h
SSA, H2O, 80 °C, 4.5 h
[9]
[10]
[11]
[12]
SSA, solvent-free, 80 °C, 5 h
[12]
-
[bmim]BF4 , 70 °C, 1.5 h
[13]
Fe3O4 NPs, H2O, reflux, 2 h
[14]
ZnO NPs, solvent-free, 70 °C, 3 h
This work
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