Cation-exchange resin as an efficient hetero- Geneous catalyst for one-pot three-component synthesis of 2,3-dihydro-4(1H)-quinazolinones

Article abstract of DOI:10.1007/s10593-012-1073-4

Various mono- and disubstituted 2,3-dihydro-4(1H)-quinazolinones were synthesized efficiently by a one-pot three-component condensation of isatoic anhydride, aromatic aldehydes, and ammonium salts or primary amines using a strong acidic cation-exchange resin as the catalyst in EtOH-H₂O solution. The catalyst is cheap, efficient, stable, and reusable under the reaction conditions. The novel method offers several advantages, such as excellent yields, environmentally friendly reaction media, and simple procedure.

Full text of DOI:10.1007/s10593-012-1073-4

Chemistry of Heterocyclic Compounds, Vol. 48, No. 6, September, 2012 (Russian Original Vol. 48, No. 6, June, 2012)
CATION-EXCHANGE RESIN AS AN EFFICIENT HETERO-
GENEOUS CATALYST FOR ONE-POT THREE-COMPONENT
SYNTHESIS OF 2,3-DIHYDRO-4(1H)-QUINAZOLINONES
M. Wang1*, T. T. Zhang1, J. J. Gao1, and Y. Liang1
Various mono- and disubstituted 2,3-dihydro-4(1H)-quinazolinones were synthesized efficiently by a
one-pot three-component condensation of isatoic anhydride, aromatic aldehydes, and ammonium salts
or primary amines using a strong acidic cation-exchange resin as the catalyst in EtOH–H2O solution.
The catalyst is cheap, efficient, stable, and reusable under the reaction conditions. The novel method
offers several advantages, such as excellent yields, environmentally friendly reaction media, and simple
procedure.
Keywords: 2,3-dihydro-4(1H)-quinazolinones, isatoic anhydride, cation-exchange resin, multicompo-
nent reactions.
2,3-Dihydroquinazolinones are an important class of heterocycles that exhibit biological activities, such
as anti-inflammatory and analgesic [1], antitumor [2], anticancer [3], antibacterial [4], and diuretic activities [5].
In addition, these compounds can easily be oxidized to their corresponding quinazolin-4(3H)-ones [6], which
are important biologically active heterocyclic compounds too [7, 8].
Different strategies for the synthesis of 2,3-dihydro-4(1H)-quinazolinones have been described in the
literature: a) condensation of anthranilamide with an aldehyde or ketone using p-toluenesulfonic acid as a
catalyst [3]; b) desulfurization of 2-thioxo-4(3H)-quinazolinones [9]; c) reaction of isatoic anhydride with Schiff
bases [10]; d) one-step conversion of 2-nitrobenzamides to 2,3-dihydro-4(1H)-quinazolinones [11];
e) condensation of anthranilamide with benzil [12]; f) two-step synthesis starting from isatoic anhydride and
amines, then annelated with ketones [13].
Multicomponent reactions (MCR) are highly flexible, chemoselective, convergent, and atom efficient
processes. In 2005, Salehi and Dabiri first reported MCR preparation methods for the synthesis of 2,3-dihydro-
4(1H)-quinazolinones from isatoic anhydride, aldehydes, and amines [14, 15]. Later some acid catalysts like
p-toluenesulfonic acid [16], Zn(PFO)2 [17], Ga(OTf)3 [18], ionic liquid [19, 20], Al(H2PO4)3 [21], and I2 [22]
were also reported for this conversion. Recently solid acid catalysts, such as Al/Al2O3 nanoparticles [23],
copolymer-PTSA [24], MCM-41-SO3H [25], silica sulfuric acid [26], silica-bonded N-propylsulfamic acid [27],
montmorillonite K-10 [28], and Amberlyst-15 microwave-assisted [29] have also been reported. However, the
majority of them suffers from one or more disadvantages: low conversion rate, high cost and toxicity of the
_______
*To whom correspondence should be addressed, e-mail: minwangszg@yahoo.com.cn.
1College of Chemistry, Chemical Engineering and Food Safety, Bohai University, Jinzhou 121000, China.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 965-971, June, 2012. Original
article submitted July 16, 2011.
0009-3122/12/4806-0897©2012 Springer Science+Business Media New York
897

solvent, and the need to use additional microwave irradiation. As a part of our study towards the synthesis of
highly substituted heterocycles and the application of solid acid catalysts, we wish to report an efficient
procedure for the synthesis of mono- and disubstituted 2,3-dihydro-4(1H)-quinazolinones via a one-pot
condensation of isatoic anhydride, aldehydes, and ammonium salts or primary amines in the presence of a
strong acid cation-exchange resin (732-resin) under classical heating conditions.
At the outset, to optimize the reaction conditions, we carried out the reaction of isatoic anhydride (1)
(5.5 mmol) with benzaldehyde (5.0 mmol) and ammonium acetate (5.5 mmol) as a model reaction in the
presence of different amounts of solvent and catalyst under reflux (Table 1). The reactions were carried out in
pure water, EtOH, or EtOH–H2O. After several runs, the results showed that the EtOH–H2O, 1:3, system was
the best choice.
O
O
O
NH
Ph
732-Resin
+ PhCHO + NH4OAc
EtOH–H2O, 
N
H
O
N
H
1
2a
The recyclability of the catalyst was investigated also by using the above model reaction. After
completion of the reaction, the resin catalyst was filtered, washed and dried. Then, the recycled catalyst was
used for further runs and its catalytic activity did not show any decrease even after four runs (entries 9–12).
Next, we applied the optimal reaction conditions to synthesize monosubstituted 2,3-dihydro-4(1H)-quin-
azolinones 2a–i. In order to compare the efficiency of ammonium salts, the reactions were carried out using
ammonium acetate, carbonate, and chloride under the same conditions (Table 2). In all cases, ammonium acetate
and ammonium carbonate afforded the products in good yields. However, the reaction did not proceed with
TABLE 1. Optimization of the Solvent and the Catalyst for the Synthesis
of 2-Phenyl-2,3-dihydro-4(1H)-quinazolinone 2a
Entry
Solvent (ml)
Mass of 732-resin, g
Time, h
Yield, %
1
EtOH (5)
0.00
0.03
0.06
0.12
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
0.06
2.0
2.0
2.0
2.0
2.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
39
2
EtOH (5)
62
3
EtOH (5)
70
4
EtOH (5)
64
5
H2O (5)
52
6
EtOH–H2O = 1:1 (5)
EtOH–H2O = 3:1 (5)
EtOH–H2O = 1:3 (5)
EtOH–H2O = 1:3 (3)
EtOH–H2O = 1:3 (3)
EtOH–H2O = 1:3 (3)
EtOH–H2O = 1:3 (3)
—
68
7
65
8
84
9
87
10
85*
87*2
86*3
76*4
11
12
13
_______
* Catalyst of entry 9 was reused for the first time.
*2 Catalyst of entry 9 was reused for the second time.
*3 Catalyst of entry 9 was reused for the third time.
*4 Reaction temperature was kept at 90°C.
898

O
NH
732-Resin
EtOH–H2O (1:3)

1
+ RCHO + (NH4)nX
N
H
R
2a–i
TABLE 2. Cation-exchange Resin-catalyzed Synthesis of 2-Substituted
2,3-Dihydro-4(1H)-quinazolinones 2a–i
Com-
pound
R
(NH4)nX
Time, h
Yield, %
Mp, °C
Ph
NH4OAc
(NH4)2CO3
NH4Cl
1.0
0.7
8.0
4.0
2.5
2.0
5.0
3.0
2.0
2.0
2.0
1.0
0.7
0.5
0.7
1.0
3.0
0.5
1.0
87
95
0
218-220 (218-220 [28])
2a
—
—
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
2-ClC6H4
NH4OAc
(NH4)2CO3
NH4OAc
(NH4)2CO3
NH4OAc
(NH4)2CO3
NH4OAc
(NH4)2CO3
NH4OAc
(NH4)2CO3
NH4OAc
(NH4)2CO3
NH4OAc
(NH4)2CO3
NH4OAc
(NH4)2CO3
93
92
94
92
93
95
80
86
92
89
90
87
94
85
86
85
192-194 (190-192 [30])
2b
2c
2d
2e
2f
197-199 (190-192 [30])
198-200 (198-200 [30])
202-204 (203-205 [30])
204-206 (205-206 [18])
222-224 (225-227 [31])
177-179 (178-180 [28])
207-209 (206-208 [30])
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-Me2NC6H4
2g
2h
2i
ammonium chloride. Aromatic aldehydes were found to be effective substrates. All the products 2a–i were
known compounds and were identified by comparing their physical and spectral data with those of authentic
samples [18, 28, 30, 31].
Disubstituted 2,3-dihydro-4(1H)-quinazolinones 3a–m were also synthesized by treatment of isatoic
anhydride with aromatic aldehydes and primary amines in the presence of 732-resin in refluxing EtOH–H2O under
optimal conditions (Table 3). In general, aromatic aldehydes bearing either electron-donating or electron-
withdrawing groups all afforded the corresponding disubstituted 2,3-dihydro-4(1H)-quinazolinones in good
yields. Further, this three-component reaction also proceeded very smoothly when aliphatic amines were used.
According to the reported mechanism in the literature [18], we propose a plausible mechanism for the
strong acidic cation-exchange resin-catalyzed preparation of quinazolinones. Taking the synthesis of 2,3-di-
substituted 2,3-dihydro-4(1H)-quinazolinones 3 as an example, first, isatoic anhydride 1 is activated by H+
followed by the N-nucleophilic attacks of amine on the carbonyl. After loss of carbon dioxide, N-substituted
2-aminobenzamide 4 is generated. Meanwhile, H+ increases the electrophilic character of the aldehydes.
899

O
R1
R
N
732-Resin
EtOH–H2O (1:3)

1
+
RCHO
+
R1NH2
N
H
3a–m
TABLE 3. Cation-exchange Resin-catalyzed Synthesis of 2,3-Disubstituted
2,3-Dihydro-4(1H)-quinazolinones 3a–m
Com-
pound
R
R1
Time, h
Yield, %
Mp, °C
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Ph
1.5
2.0
1.0
2.0
1.5
1.0
0.2
6.0
3.0
6.0
6.0
6.0
6.0
91
98
95
93
93
92
80
82
88
78
94
74
90
210-212 (214-215 [18])
224-226 (219-220 [18])
205-207 (204-205 [17])
206-208 (210-212 [17])
195-197 (196-199 [17])
205-208
4-ClC6H4
4-MeOC6H4
Ph
4-ClC6H4
4-MeC6H4
4-MeC6H4
Me
Ph
4-O2NC6H4
4-O2NC6H4
Ph
3g
3h
3i
207-209
Et
133-136 (134-137 [28])
178-180 (176-178 [28])
132-134 (132-135 [28])
128-130
3-O2NC6H4
4-ClC6H4
Ph
Et
3j
Et
3k
3l
n-Pr
Ph
n-Bu
120-122 (120-122 [17])
157-159
3m
Ph
PhCH2
Subsequently, the activated aldehyde reacts with compound 4 to afford intermediate 5. The imine fragment in
intermediate 5 is activated by H+. Thus, intermediate 5 could convert to intermediate 6 by an intramolecular
cyclization. Finally, disubstituted 2,3-dihydro-4(1H)-quinazolinones 3 could be formed by a 1,5-proton transfer
of compound 6.
H+
O
O
O
R1
R
H
N
O
R1NH2
+
H
H+
–H2O
–CO2
NH2
N
H
O
4
1
H+
+
O
OH
OH
R1
R
R1
R
1,5-H+ transfer
N
N
N
R1
–2H+
N
H
N
N
R
–
6
3
H+
5
Thus, we have developed an efficient one-pot procedure for the synthesis of structurally diverse mono-
and disubstituted 2,3-dihydro-4(1H)-quinazolinones by a three-component condensation of isatoic anhydride,
aromatic aldehydes, and ammonium salts or primary amines in the presence of cation-exchange 732-resin in
EtOH–H2O. The catalyst could be easily recovered and reused for at least four cycles without any loss of
activity. We believe that the present methodology could be an important addition to the existing methodologies.
900

EXPERIMENTAL
IR spectra were recorded on a Varian Scimitar 2000 series Fourier Transform instrument using KBr
pellets. 1H and 13C NMR spectra were recorded on a Bruker ARX-500 spectrometer in DMSO-d6 using TMS as
internal standard. Mass spectra were obtained with an Agilent 1100 series LC/MSD VL ESI instrument,
electrospray ionization (ESI). Elemental analyses were carried out on an EA 2400II elemental analyzer
(PerkinElmer). Melting points were determined using an RD-II micromelting point apparatus (Tianjin
Tianguang Optical Instrument Limited Company). The progress of the reactions was monitored by TLC using
silica gel polygram SIL G/UV 254 plates and n-hexane–EtOAc, 2:1, as eluent.
The catalyst used in this study was a commercial strong acid cation-exchange 732-resin and was obtained
from Tianjin Guangfu Fine Chemical Research Institute (China). It is based on a styrene–divinylbenzene copolymer
and contains sulfonic acid groups. It had the following properties: exchange capacity (mmol/g [H+])≥4.2, bead size
0.3–1.2 mm (≥95%), moisture content 46–52%, true density 1.24–1.28 g/ml, apparent density 0.77–0.87 g/ml.
One-pot Synthesis of 2,3-Dihydro-4(1H)-quinazolinones 2a–i and 3a–m (General Method). A
stirred mixture of isatoic anhydride (1) (0.90 g, 5.5 mmol), aldehyde (5.0 mmol), ammonium salt or primary
amine (5.5 mmol) and 732-resin (0.06 g) in EtOH–H2O (1:3 (v/v), 3 ml) was refluxed for an appropriate time as
indicated in Tables 2 and 3. After completion of the reaction (as indicated by TLC), the reaction mixture was
cooled to room temperature, and hot EtOH (25 ml) was added. The catalyst was filtered, washed with hot EtOH,
and dried. The pure product was recrystallized from EtOH.
3-(4-Methylphenyl)-2-(4-nitrophenyl)-2,3-dihydro-4(1H)-quinazolinone (3f). Pale-blue crystals. IR
spectrum, , cm-1: 3650, 3030, 2361, 1660, 1594, 1515, 1457, 762. 1H NMR spectrum, , ppm (J, Hz): 10.41 (1H, s,
NH); 8.82 (1H, s, H-2); 8.37 (2H, d, J = 8.7, H Ar); 8.20 (2H, d, J = 8.7, H Ar); 7.84 (1H, dd, J = 1.0, J = 6.5, H Ar);
7.62-7.56 (3H, m, H Ar); 7.45 (1H, t, J = 7.4, H Ar); 7.36 (1H, d, J = 7.8, H Ar); 7.12 (2H, d, J = 8.3, H Ar); 2.25
(3H, s, CH3). 13C NMR spectrum, , ppm: 160.5; 149.1; 148.2; 141.0; 136.3; 132.5; 131.6; 130.2; 129.8; 129.2;
129.1; 126.7; 124.0; 119.5; 119.0; 70.2; 20.3. Mass spectrum, m/z (Irel, %): 360 [M+H]+ (100), 361 (25), 358 (7), 227
(8). Found, %: C 70.30; H 4.89; N 11.53. C21H17N3O3. Calculated, %: C 70.18; H 4.77; N 11.69.
3-Methyl-2-(4-nitrophenyl)-2,3-dihydro-4(1H)-quinazolinone (3g). Yellow crystals. IR spectrum, ,
cm-1: 3309, 2360, 1644, 1599, 1521, 1457, 1407, 763. 1H NMR spectrum, , ppm (J, Hz): 8.74 (1H, s, NH); 8.37 (3H,
d, J = 8.5, H-2, H Ar); 8.20 (2H, d, J = 8.6, H Ar); 7.76 (1H, d, J = 6.9, H Ar); 7.53 (1H, t, J = 6.9, H Ar); 7.35 (1H, t,
J = 7.4, H Ar); 7.27 (1H, d, J = 7.8, H Ar); 2.80 (3H, d, J = 4.6, CH3). 13C NMR spectrum, , ppm: 160.2; 149.0;
148.2; 141.1; 131.2; 129.9; 129.7; 129.2; 126.5; 124.0; 119.0; 70.1; 26.1. Mass spectrum, m/z (Irel, %): 284 [M+H]+
(100), 282 (22). Found, %: C 63.44; H 4.55; N 14.97. C15H13N3O3. Calculated, %: C 63.60; H 4.63; N 14.83.
2-Phenyl-3-(n-propyl)-2,3-dihydro-4(1H)-quinazolinone (3k). White crystals. IR spectrum, , cm-1:
1
3303, 3065, 2361, 1630, 1588, 1507, 1458, 748. H NMR spectrum, , ppm (J, Hz): 7.65 (1H, dd, J = 1.2,
J = 6.5, NH); 7.34-7.27 (6H, m, H Ar); 7.18 (1H, dt, J = 1.5, J = 6.8, H Ar); 6.66-6.62 (2H, m, H Ar); 5.83 (1H,
d, J = 2.5, H-2); 3.86-3.81 (1H, m) and 2.75-2.69 (1H, m, CH2CH2CH3); 1.63-1.41 (2H, m, CH2CH3); 0.82 (3H,
t, J = 7.4, CH3). 13C NMR spectrum, , ppm: 162.1; 146.2; 141.2; 133.0; 128.4; 128.2; 127.3; 126.0; 117.0;
115.0; 114.2; 70.1; 46.0; 20.6; 11.1. Mass spectrum, m/z (Irel, %): 267 [M+H]+ (100), 268 (19). Found, %: C 76.81;
H 6.73; N 10.39. C17H18N2O. Calculated, %: C 76.66; H 6.81; N 10.52.
3-Benzyl-2-phenyl-2,3-dihydro-4(1H)-quinazolinone (3m). White crystals. IR spectrum, , cm-1: 3401,
3023, 2361, 1633, 1580, 1502, 1447, 749. 1H NMR spectrum, , ppm (J, Hz): 7.70 (1H, dd, J = 1.4, J = 6.4, NH);
7.36-7.20 (12H, m, H Ar); 6.69-6.63 (2H, m, H Ar); 5.74 (1H, d, J = 2.6, H-2); 5.34 (1H, d, J = 15.4) and 3.83 (1H,
13
d, J = 15.4, CH2Ph). C NMR spectrum, , ppm: 162.3; 146.2; 140.5; 137.4; 133.3; 128.5; 128.4; 127.6; 127.4;
127.1; 126.1; 117.2; 114.6; 114.3; 69.8; 47.1. Mass spectrum, m/z (Irel, %): 315 [M+H]+ (100), 316 (24). Found, %:
C 80.34; H 5.86; N 8.77. C21H18N2O. Calculated, %: C 80.23; H 5.77; N 8.91.
This work was carried out with financial support from the Education Committee of Liaoning Province
of China (No. L2011198).
901

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