Ionic liquid promoted eco-friendly and efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones

Article abstract of DOI:10.1007/s00706-007-0635-0

2,3-Dihydroquinazolin-4(1H)-ones were efficiently synthesised by the reaction of isatoic anhydride, a primary amine or ammonium acetate, and different aromatic aldehydes in 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF₄) without using any acidic catalyst. Also a bis-derivative of the title compound as a polyheterocyclic system was synthesised successfully in high yield.

Full text of DOI:10.1007/s00706-007-0635-0

Monatshefte fu¨r Chemie 138, 1191–1194 (2007)
DOI 10.1007/s00706-007-0635-0
Printed in The Netherlands
Ionic Liquid Promoted Eco-friendly and Efficient Synthesis of
2,3-Dihydroquinazolin-4(1H)-ones
Minoo Dabiri1;ꢀ, Peyman Salehi2;ꢀ, and Mostafa Baghbanzadeh1
1
Department of Chemistry, Faculty of Science, Shahid Beheshti University, Evin, Tehran, Iran
2
Department of Phytochemistry, Medicinal Plants and Drugs Research Institute,
Shahid Beheshti University, Evin, Tehran, Iran
Received November 2, 2006; accepted (revised) November 28, 2006; published online June 11, 2007
# Springer-Verlag 2007
Summary. 2,3-Dihydroquinazolin-4(1H)-ones were effi-
amides [4]. Metolazone is a 3-phenyl-substituted
ciently synthesised by the reaction of isatoic anhydride, a
primary amine or ammonium acetate, and different aromatic
aldehydes in 1-butyl-3-methylimidazolium tetrafluoroborate
([bmim]BF4) without using any acidic catalyst. Also a bis-
derivative of the title compound as a polyheterocyclic system
was synthesised successfully in high yield.
quinazolinone diuretic agent that has been used ef-
fectively in treatment of hypertension [5]. One of the
main group of quinazolinones, are 2,3-dihydroquina-
zolin-4(1H)-ones, which have several biological ac-
tivities indeed [6], and are also key intermediates for
the synthesis of quinazolin-4(3H)-ones [7] as anoth-
er member of this biologically important family [8].
Furthermore, a literature search shows that the study
of polyheterocyclic systems based on a quinazoli-
none structural block has attracted interest owing
to their potential useful biological activities [9].
In view of an increasing interest in developing
environmentally benign reactions, atom-economic
catalytic processes or reactions without using any
catalyst and the use of green solvents are ideal pro-
cesses in organic chemistry. There is a widespread
interest in room temperature ionic liquids (ILs) as
new, non-volatile solvents in both academia and
industry research areas [10].
Keywords. 2,3-Dihydroquinazolinone; Heterocycles; Green
chemistry; Ionic liquid.
Introduction
Of the more than 20 million chemical compounds
currently registered, about one half contain hetero-
cyclic systems. Heterocycles are important, not only
because of their abundance, but above all because
of their chemical, biological, and technical signif-
icances. Heterocycles count among their number
many natural products, such as vitamins, hormones,
antibiotics, alkaloids, as well as pharmaceuticals, her-
bicides, and dyes. One of such systems are quinazo-
linones which have an important place in medicinal
and biological chemistry [1]. Several quinazolinone
derivatives have been synthesised as potential anti-
microbial [1], anticancer [2], and antimalarial agents
[3]. Cohen et al. were the first to report on the syn-
thesis and diuretic activity of quinazolinone sulfon-
As a continuation of our research devoted to the
development of the synthesis of quinazolinone deriv-
atives [11], herein we report an efficient and green
procedure for the synthesis of 2,3-dihydroquinazo-
lin-4(1H)-ones.
Results and Discussion
ꢀ
(M. Dabiri) and p-salehi@sbu.ac.ir (P. Salehi)
When a mixture of isatoic anhydride, a primary
amine, and an aromatic aldehyde in 1-butyl-3-meth-
Corresponding authors. E-mails: m-dabiri@sbu.ac.ir

1192
M. Dabiri et al.
Scheme 1
ylimidazolium tetrafluoroborate ([bmim]BF4) were
stirred at 70ꢁC without using any acidic catalyst,
the corresponding 2,3-dihydroquinazolin-4(1H)-ones
1 were obtained (Scheme 1). As shown in Table 1,
the desired products were obtained in excellent yields.
The reactions were completed smoothly within 1–2 h
and the products were isolated by a simple work-up
procedure. Despite other previously reported meth-
ods, heteroaromatic aldehydes and aromatic amines
worked well under the reaction conditions (Table 1).
According to the importance of the thiazole moi-
ety in biological and medicinal chemistry [12], 2-
amino thiazole was also used in the reaction, and
several new 3-(2-thiazolyl)-2-substituted-2,3-dihy-
droquinazolin-4(1H)-ones (Table 1, 1t–1y) were ob-
tained successfully. Along with the importance of
bis-heterocyclic systems and their potential biolog-
ical activities [13], we were interested to synthesize
a bis-3-(2-thiazolyl)-2-substituted-2,3-dihydroquina-
zolin-4(1H)-one (Table 1, 1z) through a pseudo-five-
component reaction using a dialdehyde substrate. It
is worth noting that in this compound two thiazole
and two quinazolinone moieties were gathered to-
gether and this could be interesting in the view of
medicinal chemistry. Conducting similar reactions in
conventional organic solvents such as ethanol, aceto-
nitrile, and chloroform under reflux conditions after
12 h gave only negligible amounts of the desired
product. It is also worth to mention that the synthe-
sis of 2,3-dihydroquinazolinones by this method in
organic solvents has been reported to need an acidic
catalyst [11].
In conclusion, a simple and green method for the
synthesis of a novel class of quinazolinone family
is introduced. The IL [bmim]BF4 is an efficient and
green medium for the synthesis of 2,3-dihydroqui-
nazolinones. The method offers several advantages,
such as omitting any toxic solvent or catalyst, simple
work-up procedure without using any chromatog-
raphic method, and improving the yields. Starting
materials are inexpensive and commercially avail-
able. We believe that many biologically active deriv-
atives could be synthesised by this multi-component
reaction with high atomic economy.
Table 1. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones
Producta
R1
R2
Yield=%b Time=h
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
Me
Me
Me
Et
Et
Et
Et
Et
Ph
Ph
Ph
90
92
89
91
87
93
85
83
80
85
90
94
89
91
89
92
85
90
92
82
80
85
83
80
85
78
1.5
2
2
1.5
2
2
4-ClC6H4
4-CH3OC6H4
Ph
4-ClC6H4
4-O2NC6H4
3-O2NC6H4
4-CH3OC6H4
Ph
4-O2NC6H4
3-O2NC6H4
Ph
4-NO2C6H4
4-HOC6H4
4-ClC6H4
Ph
2
1.5
1.5
2
1
2
1.5
1
1
1.5
1
1.5
2
2
2
2
2
2
2
2.5
Ph
4-ClC6H4
n-Pr
Et
n-Bu
H
H
H
H
4-ClC6H4
2-CH3OC6H4
4-CH3C6H4
1t
4-CH3C6H4 2-Thiazolyl
2-Thiazolyl
2-Thiazolyl
1u
1v
1w
1x
1y
1z
4-ClC6H4
4-HOC6H4
2,4-Cl2C6H3 2-Thiazolyl
3-O2NC6H4 2-Thiazolyl
4-O2NC6H4 2-Thiazolyl
Experimental
1,4-C6H4
2-Thiazolyl
Melting points were obtained in open capillary tubes and were
measured on an electrothermal 9200 apparatus. Mass spectra
were recorded on a Shimadzu QP 1100 BX mass spectro-
meter. Elemental analysis was performed for the novel com-
pounds 1o–1y using a Heracus CHNO-Rapid analyzer; their
a
The products 1a–1n were characterised by comparison of
their spectroscopic and physical data with authentic samples
synthesised by reported procedures [11c]
b
Isolated yield based on isatoic anhydride

Ionic Liquid Promoted Eco-friendly and Efficient Synthesis
1193
results agreed favorably with the calculated values. IR spectra
were recorded on KBr pellets on a Shimadzu IR-470 spectro-
2-(4-Chlorophenyl)-2,3-dihydro-3-(thiazol-2-yl)
quinazolin-4(1H)-one (1u, C17H12ClN3OS)
Mp 175–176ꢁC; IR (KBr): ꢀꢀ¼ 3360, 3333, 3078, 1624,
1
photometer. H and 13C NMR spectra were determined on a
Bruker 300 DRX Avance instrument at 300 and 75 MHz.
1613, 1508, 1433 cmꢂ1
;
1H NMR (DMSO-d6): ꢁ ¼ 6.76–
7.78 (m, 10Ar-Hþ CH), 8.18 (d, J ¼ 3.72Hz, NH) ppm; 13C
NMR (DMSO-d6): ꢁ ¼ 67.99, 114.18, 116.09, 116.31, 118.92,
128.06, 128.68, 129, 133.33, 135.65, 137.77, 139.41, 146.76,
157.96, 161.1 ppm; MS: m=z (%) ¼ 342 (Mþ þ 1, 60), 259
(34), 242 (100), 152 (25), 77 (20).
General Procedure for the Synthesis of 2,3-
Dihydroquinazolin-4(1H)-ones
A mixture of 0.163 g isatoic anhydride (1mmol), aromatic
aldehyde (1mmol), and amine or ammonium acetate (1mmol)
was added to 0.2 g [bmim]BF4 and stirred at 70ꢁC for an
appropriate period of time (Table 1). After completion of
the reaction, which was indicated by TLC (eluent: n-hexane=
ethyl acetate ¼ 2=1) H2O was added, and the mixture was
cooled to room temperature. The precipitated product was
filtered off and finally recrystallized from ethanol.
2,20-(1,4-Phenylen)bis-3-(2-thiazolyl)-2,3-dihydroquina-
zolin-4(1H)-one 1z was synthesized by a similar procedure
except that 2 mole equivalents of isatoic anhydride and 2-
aminothiazole were reacted with 1 equivalent of terephthaldi-
aldehyde.
2,3-Dihydro-2-(4-hydroxyphenyl)-3-(thiazol-2-yl)
quinazolin-4(1H)-one (1v, C17H13N3O2S)
Mp 263ꢁC (dec); IR (KBr): ꢀꢀ¼ 3346, 1638, 1614, 1511,
1
1453 cmꢂ1; H NMR (DMSO-d6): ꢁ ¼ 6.61–7.77 (m, 10Ar-
H), 7.27 (d, J ¼ 3.18 Hz, CH), 8.07 (d, J ¼ 3.2 Hz, NH), 9.47
(s, OH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 68.32, 114.18,
115.56, 115.94, 116.04, 118.52, 127.44, 128.61, 130.63,
135.45, 137.75, 147.12, 157.72, 158.1, 161.32 ppm; MS:
m=z (%) ¼ 324 (Mþ þ 1, 80), 239 (80), 224 (100), 120 (25),
77 (20).
Products (except 1o and 1s–1y) are known compounds and
1
their physical data, IR, and H NMR spectra were essentially
2-(2,4-Dichlorophenyl)-2,3-dihydro-3-(thiazol-2-
yl)quinazolin-4(1H)-one (1w, C17H11Cl2N3O2S)
Mp 226–228ꢁC; IR (KBr): ꢀꢀ¼ 3420, 3088, 2925, 1656,
identical with those of authentic samples. Other products,
1
which are new, were characterized by IR, H, and 13C NMR
spectroscopy, MS, and elemental analysis.
1614, 1586, 1503, 1457 cmꢂ1
;
1H NMR (DMSO-d6):
ꢁ ¼ 6.82–7.88 (m, 9Ar-H), 7.68 (s, CH), 7.98 (s, NH)
ppm; 13C NMR (DMSO-d6): ꢁ ¼ 66.43, 113.55, 116.34,
116.52, 119.15, 127.13, 127.97, 128.60, 130.29, 133.05,
134.38, 135.75, 136.33, 137.84, 145.51, 157.11, 161.28 ppm;
MS: m=z (%) ¼ 376 (Mþ, 25), 291 (100), 276 (80), 186 (20),
77 (25).
3-Butyl-2-(4-chlorophenyl)-2,3-dihydroquinazolin-
4(1H)-one (1o, C18H19ClN2O)
Mp 141–143ꢁC; IR (KBr): ꢀꢀ¼ 3302, 2935, 2866, 1629, 1488,
1413, 1370, 1322cmꢂ1
;
1H NMR (DMSO-d6): ꢁ ¼ 0.84 (t,
J ¼ 6.9 Hz, CH3), 1.257 (m, CH2), 1.47 (m, CH2), 2.73 (m,
CH), 3.88 (m, CH), 5.85 (s, CH), 6.6–7.64 (m, 9Ar-Hþ NH)
ppm; 13C NMR (DMSO-d6): ꢁ ¼ 14.12, 19.98, 30.03, 44.59,
69.68, 114.77, 115.48, 117.72, 127.89, 128.43, 128.94, 133.35,
133.64, 140.69, 146.44, 162.59ppm; MS: m=z (%) ¼ 315
(Mþ þ 1, 50), 314 (Mþ, 10), 242 (25), 203 (100), 147 (45),
41 (20).
2,3-Dihydro-2-(4-nitrophenyl)-3-(thiazol-2-yl)
quinazolin-4(1H)-one (1x, C17H12N4O3S)
Mp 185–187ꢁC; IR (KBr): ꢀꢀ¼ 3328, 3104, 1639, 1614, 1510,
1
1445, 1390cmꢂ1; H NMR (DMSO-d6): ꢁ ¼ 6.77–8.16 (m,
10Ar-Hþ CH), 8.26 (s, NH) ppm; 13C NMR (DMSO-d6):
ꢁ ¼ 68.04, 114.16, 116.16, 116.47, 119.21, 124.22, 127.54,
128.77, 135.74, 137.77, 146.46, 147.7, 147.75, 157.87,
160.98 ppm; MS: m=z (%) ¼ 353 (Mþ þ 1, 55), 352 (Mþ,
10), 268 (100), 254 (80), 207 (30), 77 (20).
2,3-Dihydro-2-p-tolylquinazolin-4(1H)-one (1s, C15H14N2O)
Mp 232–234ꢁC; IR (KBr): ꢀꢀ¼ 3312, 3194, 3061, 1662, 1610,
1509, 1485, 1438, 1386cmꢂ1; 1H NMR (DMSO-d6): ꢁ ¼ 2.28
(s, CH3), 5.7 (s, CH), 6.63–7.61 (m, 8Ar-H), 8.25 (s, NH) ppm;
13C NMR (DMSO-d6): ꢁ ¼ 21.18, 66.81, 114.85, 115.43,
117.52, 127.25, 127.78, 129.26, 133.72, 138.17, 139.09,
148.37, 164.11 ppm; MS: m=z (%) ¼ 239 (Mþ þ 1, 75), 238
(Mþ, 55), 237 (100), 147 (80), 120 (75), 65 (25).
2,3-Dihydro-2-(3-nitrophenyl)-3-(thiazol-2-yl)
quinazolin-4(1H)-one (1y, C17H12N4O3S)
Mp 165–167ꢁC; IR (KBr): ꢀꢀ¼ 3362, 3079, 2962, 1639, 1529,
1
1507, 1445, 1390 cmꢂ1; H NMR (DMSO-d6): ꢁ ¼ 6.77–8.19
(m, 10Ar-H), 7.51 (d, J ¼ 3.24 Hz, CH), 8.31 (d, J ¼ 3.24Hz,
NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 67.82, 114.12, 116.22,
116.55, 119.21, 121.16, 123.72, 128.75, 130.71, 132.41,
135.79, 137.81, 142.73, 146.48, 148.37, 157.88, 160.97 ppm;
MS: m=z (%) ¼ 353 (Mþ þ 1, 83), 268 (95), 253 (100), 207
(30), 77 (20).
2,3-Dihydro-3-(thiazol-2-yl)-2-p-tolylquinazolin-
4(1H)-one (1t, C18H15N3OS)
Mp 197–198ꢁC; IR (KBr): ꢀꢀ¼ 3408, 3048, 1635, 1505,
1
1451, 1392 cmꢂ1; H NMR (DMSO-d6): ꢁ ¼ 2.17 (s, CH3),
6.73–7.77 (m, 10Ar-H), 7.37 (d, J ¼ 3.27 Hz, CH), 8.14 (d,
J ¼ 3.27 Hz, NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 20.98,
68.37, 114.23, 115.98, 116.14, 118.65, 126.07, 128.60,
129.46, 135.48, 137.41, 137.76, 137.92, 147.04, 158.06,
161.3 ppm; MS: m=z (%) ¼ 322 (Mþ þ 1, 100), 238 (50),
222 (80), 165 (7), 91 (8).
Acknowledgement
Financial support by the Research Council of Shahid Beheshti
University is gratefully acknowledged.

1194
M. Dabiri et al.: Ionic Liquid Promoted Eco-friendly and Efficient Synthesis
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