KAl(SO4)2·12H2O (Alum) catalyzed one-pot three-component synthesis of 2-alkyl and 2-aryl-4(3H)-quinazolinone under microwave irradiation and solvent free conditions

Article abstract of DOI:10.1002/cjoc.201180344

Twenty 2,3-disubstituted-4(3H)-quinazolinones were synthesed by one-pot three-component method with isatoic anhydride, orthoesters and amines as raw materials in the presence of KAl(SO₄)₂·12H ₂O (Alum) under microwave irradiation and solvent-free conditions. 6-Bromo-2-propyl-3-p-tolylquinazolin-4(3H)-one (4m), 6-bromo-2-methyl-3- phenethylquinazolin-4(3H)-one (4n) and 6-bromo-2-ethyl-3-phenethylquinazolin- 4(3H)-one (4o) were characterized by IR, ¹H NMR, ¹³C NMR and elemental analysis. Twenty 2,3-disubstituted-4(3H)-quinazolinones were synthesed by one-pot three-component method with isatoic anhydride, orthoesters and amines as raw materi-als in the presence of KAl(SO₄) ₂·12H₂O (Alum) under microwave irradiation and solvent-free conditions. 6-Bromo-2-propyl-3-p-tolylquinazolin-4(3H)-one (4m), 6-bromo-2-methyl-3-phenethylquinazolin-4(3H)-one (4n) and 6-bromo-2-ethyl-3- phenethylquina-zolin-4(3H)-one (4o) were characterized by IR, ¹H NMR, ¹³C NMR and elemental analysis. Copyright

Full text of DOI:10.1002/cjoc.201180344

NOTE
KAl(SO4)2•12H2O (Alum) Catalyzed One-Pot Three-Component
Synthesis of 2-Alkyl and 2-Aryl-4(3H)-quinazolinone under
Microwave Irradiation and Solvent Free Conditions
Mohammadi, Ali A.*,a
Sadat Hossini, S. S.b
a Department of Chemistry, Sabzevar Branch, Islamic Azad University, Sabzevar, Iran
b University of Applied Science and Technology, Tehran P. O. Box 14155-1644, Tehran, Iran
Twenty 2,3-disubstituted-4(3H)-quinazolinones were synthesed by one-pot three-component method with isa-
toic anhydride, orthoesters and amines as raw materials in the presence of KAl(SO4)2•12H2O (Alum) under micro-
wave irradiation and solvent-free conditions. 6-Bromo-2-propyl-3-p-tolylquinazolin-4(3H)-one (4m), 6-bromo-2-
methyl-3-phenethylquinazolin-4(3H)-one (4n) and 6-bromo-2-ethyl-3-phenethylquinazolin-4(3H)-one (4o) were
characterized by IR, 1H NMR, 13C NMR and elemental analysis.
Keywords isatoic anhydride, orthoesters, ammonium acetate, 4(3H)-quinazolinone, multi component, micro-
wave-assisted reactions
Introduction
with a stemless funnel and irradiated with power and
time as indicated in Table 1. After completion of the
reaction (monitored by TLC, ethyl acetate/n-hexane,
1/1), water (15 mL) was added to the reaction mixture,
and the resulting solid was separated by filtration. The
crude product was recrystallized from ethanol to give
the pure product in good yield.
4(3H)-Quinazolinones is a frequently encountered
heterocycle in pharmacological literatures. Among the
most important effects are hypnotic, anticonvulsant,1
muscle relaxant,2 analgesic,3 antiinflammatory,4 anti-
bacterial5 activites and as a potent non-nucleoside re-
verse transcriptase inhibitors, of human immunodefi-
ciency virus (HIV-1).6 These useful compounds are pre-
pared by various methods.7-9
Multi-component reactions (MCRs) constitute an
especially attractive synthetic strategy for rapid and ef-
ficient library generation due to the fact that the diver-
sity can be achieved simply by varying the reacting
components.
6-Bromo-2-propyl-3-p-tolylquinazolin-4(3H)-one
1
(4m) 95%, m.p. 160—62 ℃; H NMR (CDCl3, 300
MHz) δ: 0.86 (t, J＝7.3 Hz, 3H, CH3), 1.66—1.78 (m,
2H, CH2), 2.37 (t, J＝7.8 Hz, 2H, CH2), 2.47 (s, 3H,
CH3), 7.13 (d, J＝8.1 Hz, 2H, Ar), 7.32 (d, J＝8.1 Hz,
2H, Ar), 7.56 (d, J＝8.7 Hz, 1H, Ar), 7.82 (dd, J＝2.0,
8.7 Hz, 1H, Ar), 8.39 (d, J＝2.0 Hz, 1H, Ar); 13C NMR
(CDCl3, 75 MHz) δ: 0.03, 13.79, 20. 41, 21.33, 37.69,
119.83, 122.19, 127.87, 128.92, 129.45, 130.61, 134.38,
137.52, 139.46, 146.43, 157.－68, 161.46; IR (KBr) ν:
Experimental
1
3063, 2＋972, 1679 (C＝O) cm ; MS (70 eV) m/z (%):
Melting points were measured on the Electrothermal
9100 apparatus and are uncorrected. IR spectra were
measured on a Shimadzu IR-470 Spectrophotometer. 1H
NMR and 13C NMR spectra were determined on Bruker
300 DRX Avance instrument at 300 and 75 MHz, re-
spectively. MS spectra were recorded on a Shimadzu QP
1100EX mass spectrometer operating at an ionization
potential of 70 eV. Elemental analyses were performed
using a Heracus CHN-O-Rapid analyzer.
357 (M , 25), 340 (35), 329 (100), 240 (30), 197 (60),
91 (50), 65 (35), 41 (25). Anal. calcd for C18H17BrN2O:
C 60.52, H 4.80, N 7.84; found C 60.40, H 4.71, N 7.76.
6-Bromo-2-methyl-3-phenethylquinazolin-4(3H)-
1
one (4n) 94%, m.p. 140—42 ℃; H NMR (CDCl3,
300 MHz) δ: 2.44 (s, 3H, CH3), 3.04 (t, J＝7.5 Hz, 2H,
CH2), 4.28 (t, J＝7.5 Hz, 2H, CH2), 7.22—7.38 (m, 5H,
Ar), 7.46 (d, J＝8.7 Hz, 1H, Ar), 7.89 (dd, J＝2.3, 8.7
Hz, 1H, Ar), 8.43 (d, J＝2.3 Hz, 1H, Ar); 13C NMR
(CDCl3, 75 MHz) δ: 23.19, 34.47, 46.61, 119.79, 121.86,
127.06, 128.61, 128.83, 128.88, 129.24, 137.45, 137.74,
146.11, 154.62, 160.85; IR (KBr) ν: 3047, 2963, 1674
General procedure
A mixture of isatoic anhydride (0.34 g, 2.5 mmol),
orthoesters (4 mmol), amine (2.5 mmol), and
KAl(SO4)2•12H2O (Alum) (0.1 g) in a tall beaker was
placed in the microwave oven and beaker was covered
＋
－1
(C＝O) cm ; MS (70 eV) m/z (%): 344 (M , 55), 138
(70), 222 (35), 104 (100), 91 (40), 75 (30), 65 (25). Anal.
*
E-mail: Aliamohammadi@iaus.ac.ir
Received March 24, 2011; revised April 13, 2011; accepted May 10, 2011.
1982
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1982— 1984

One-Pot Three Component Synthesis of 2-Alkyl and 2-Aryl-4(3H)-quinazolinone
calcd for C17H15BrN2O: C 59.49, H 4.41, N 8.16; found
C 59.38, H 4.35, N 8.07.
ter, recyclable, and easy available reagent.
In the present work, we achieved a one-pot, three-
component condensation of isatoic anhydride 1, triethyl
ortoacetate 2a, and aniline 3a on the surface of Alum
under microwave irradiation as a new efficient method
to produce 2-methyl-3-phenyl quinazolin-4(3H)-ones
(4a) (Figure 1). Encouraged by this success, we ex-
tended this reaction to a range of other orthoesters 2b—
2u and amine 3b—3u under similar conditions, fur-
nishing the respective 2,3-disubstituted 4(3H)-quinazo-
linones (4b—4u) in good yields. The optimized results
are summarized in Table 1. The structures of the prod-
6-Bromo-2-ethyl-3-phenethylquinazolin-4(3H)-
one (4o) 93%, m.p. 116—118 ℃; 1H NMR (CDCl3,
300 MHz) δ: 1.32 (t, J＝7.3 Hz, 2H, CH3), 2.65 (q, J＝
7.3 Hz, 2H, CH2), 2.98 (t, J＝7.6 Hz, 2H, CH2), 4.25 (t,
J＝7.6 Hz, 2H, CH2), 7.23—7.40 (m, 5H, Ar), 7.49 (d,
J＝8.6 Hz, 1H, Ar), 7.87 (dd, J＝2.2, 8.6 Hz, 1H, Ar),
8.43 (d, J＝2.2 Hz, 1H, Ar); 13C NMR (CDCl3, 75 MHz)
δ: 0.06, 11.34, 28.22, 34.71, 45.54, 119.69, 121.84,
126.98, 128.82, 128.86, 128.93, 129.16, 137.24, 137.78,
146.14, 157.97, 161.03; IR (KBr) ν: 2971, 2925, 1677
＋
－1
1
(C＝O) cm ; MS (70 eV) m/z (%): 358 (M , 35), 252
(85), 210 (35), 104 (100), 91 (25), 75 (25), 65 (35). Anal.
calcd for C18H17BrN2O: C 60.52, H 4.80, N 7.84; found
C 60.42, H 4.73, N 7.73.
ucts are supported by IR, H NMR and 13C NMR spec-
tral data.
According to the results, the reaction can be mecha-
nistically considered to proceed via the initial formation
of the intermediates 5 from isatoic anhydride and
amines, and then the former reaction followed by reac-
Results and discussion
We reported the preparation of quinazolinediones,10
imidazoles,11 6-oxopyrano[2,3-c]isochromenes,12 and 2-
amino-4H-chromenes13 via multi-component reactions.
In addition, we have reported the ability of KAl(SO4)2•
12H2O (Alum) as an effective catalyst in the synthesis
of cis-isoquinolonic acid,14 and di-hydropyrimidi-
nones.15 In view of this and also in continuation to our
interest on multi-component reactions (MCR), we report
herein, a simple, facile, rapid and efficient MCRs for the
preparation of some new 2,3-disubstituted 4(3H)-
quinazolinone derivatives with KAl(SO4)2•12H2O
(Alum) as a nontoxic, inexpensive, very soluble in wa-
Figure 1 The synthetic route of the 2,3-disubstituted-4(3H)-
quinazolinone (4).
Table 1 Synthesis of 2,3-disubstituted-4(3H)-quinazolinone 4
Product 4
4a
R1
H
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
H
H
H
H
H
H
R2
R3 (R4)
Me (Et)
Me (Et)
Ph (Me)
n-Pr (Me)
Et (Et)
Time/min
Yielda/%
96, 95, 93, 92b
m.p./℃
Lit. m.p./℃
Ph
5
6
6
6
5
7
5
5
6
6
7
7
6
6
6
7
7
7
8
6
144—146
158—159
179—180
120—121
170—171
64—66
145—14616
4b
4c
p-ClC6H4
96
97
97
96
85
82
92
89
90
86
95
94
93
92
95
96
94
94
95
157—15817
180—18118
121—12219
170—17220
64—6521
131—13222
194—19618
127—12823
144—14524
115—11625
—
p-MeC6H4
Ph
4d
4e
p-BrC6H4
4f
Et
Me (Et)
Ph (Et)
4g
Me
129—131
195—197
126—128
143—144
114—116
160—162
140—142
116—118
214—215
235—236
235—236
197—198
158—159
237—238
4h
4i
Me
Me (Et)
H (Et)
p-EtC6H4
4j
p-MeC6H4
PhCH2
H (Et)
4k
4m
4n
4o
H (Et)
p-MeC6H4
PhCH2CH2-
PhCH2CH2-
H from (NH4AcO)
H from (NH4AcO)
H from (NH4AcO)
H from (NH4AcO)
H from (NH4AcO)
H from (NH4AcO)
n-Pr (Et)
Me (Me)
Et (Me)
H (Et)
—
—
4p
4q
4r
216—21826
236—23727
23528
Me (Et)
Et (Et)
4s
n-Pr (Me)
n-Bu (Me)
Ph (Et)
206—20728, 19029
4t
15730
4u
235—23631
a Isolated yields. b The same KAl(SO4)2•12H2O (Alum) was used for each of the four runs.
Chin. J. Chem. 2011, 29, 1982— 1984
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1983

Mohammadi & Sadat Hossini
NOTE
Figure 2 Plausible mechanism for the synthesis of 2,3-disubstituted-4(3H)-quinazolinone catalyzed by KAl(SO4)2•12H2O (Alum).
8
9
Abou-Seri, S. M.; Abouzid, K.; Abou El Ella, D. A. Eur. J.
Med. Chem. 2011, 46, 647.
Makino, S.; Suzuki, N.; Nakaishi, E.; Tsuji, T. Synlett 2000,
11, 1670.
tion with orthoesters in the presence of alum gives the
intermediate 6. Once intermediate 6 is formed, a nu-
cleophilic attack takes place by the nitrogen group, and
then elimination of ROH and Alum occures to produce
the final product (Figure 2).
10 Azizian, J.; Mohammadi, A. A.; Karimi, A. R. Synth. Com-
mun. 2003, 33, 415.
11 Mohammadi, A. A.; Mivechi, M.; Kefayati, H. Monatsh.
Chem. 2008, 139, 935.
Conclusions
In summary, we have described a successful strategy
including an efficient and convenient green synthesis,
for the preparation of some new 2,3-disubstituted-4-
(3H)-quinazolinone in three-component cyclocondensa-
tion reaction of isatoic anhydride, orthoesters and
amines. The method offers several advantages including
high yield of products, using the inexpensive, nontoxic,
and easily available KAl(SO4)2•12H2O catalyst, and an
easy experimental workup procedure that makes it a
useful process for the synthesis of 2,3-disubstituted-
4(3H)-quinazolinones.
12 Mohammadi, A. A.; Akbarzadeh, R.; Rohi, R. Comb. Chem.
High Throughput Screen. 2009, 12, 536.
13 Makarem, S.; Mohammadi, A. A.; Fakhari, A. R. Tetrahe-
dron Lett. 2008, 49, 7194.
14 Azizian, J.; Mohammadi, A. A.; Karimi, A. R.; Moham-
madizadeh, M. R. J. Org. Chem. 2005, 70, 350.
15 Azizian, J.; Mohammadi, A. A.; Karimi, A. R.; Moham-
madizadeh, M. R. Appl. Catal. A: Gen. 2006, 300, 85.
16 Kesarwani, A. P.; Srivastava, G. K.; Rastogi, S. K.; Kundu,
B. Tetrahedron Lett. 2002, 43, 5579.
17 Grimmel, W.; Guenther, A.; Morgan, J. F. J. Am. Chem. Soc.
1946, 68, 542.
Acknowledgement
18 Levy, P. R.; Stephen, H. J. Chem. Soc. 1956, 985.
19 Andrisano, R.; Chiesi, A. Ateneo Parmense 1961, 32, 671.
20 Jackman, G. B.; Petrow, V.; Stephenson, O. J. Pharm.
Pharmacol. 1960, 529.
21 Kato, T.; Takada, K. A.; Ueda, T. Chem. Pharm. Bull. 1976,
24, 431.
22 Al-Talib, M.; Jochims, J. C.; Hamed, A.; Wang, Q.;
El-Hamid Ismail, A. Synthesis 1992, 697.
23 Surendra, S.; Kishor, P. K.; Seth, P. K.; Arora, R. C. J. Med.
Chem. 1969, 12, 138.
We gratefully acknowledge the financial support
from the Research Council of Islamic Azad University,
branched Sabzevar.
References
1
2
Johne, S. Pharmazie 1981, 36, 583.
Tani, J.; Yamada, Y.; Ochiai, T.; Ishida, R.; Inoue, I.; One, T.
Chem. Pharm. Bull. 1979, 27, 2675.
24 Nagahara, K.; Takagi, K.; Ueda, T. Chem. Pharm. Bull.
1976, 24, 1310.
25 Arndt, R. R.; Eggers, S. H.; Jordaan, A. Tetrahedron 1967,
23, 3521.
3
4
Takesue, E. I.; Perrine, J. W.; Trapold, J. H. Arch. Int.
Pharmacodyn. Ther. 1976, 22, 122.
Nawrocka, W.; Stasko, J. J. Boll Chim. Farm. 1998, 137,
35.
26 Higashino, T. Yakugaku Zasshi 1960, 80, 1404.
27 Boltze, K. H.; Dell, H. D.; Lehwaid, H.; lorenz, D.; Rue-
berg-Schweer, M. S. Arzneimittel-forschung 1963, 13, 688.
28 Patel, V. S.; Patel, S. R. J. Indian Chem. Soc. 1965, 42, 531.
29 Cohen, V. I. J. Heterocycl. Chem. 1978, 15, 1415.
30 Noland, W. E.; Jones, D. A. Novel J. Org. Chem. 1962, 27,
341.
5
6
Sharma, S. D.; Kaur, V. Synthesis 1989, 677.
Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.;
Magnus, N. A.; Bachheler, L. T.; Diamond, S.; Jeffrey, S.;
Klabe, R. M.; Cordova, B. C.; Garber, S.; Logue, K.; Trai-
nor, G. L.; Anderson, P. S.; Erickson-Vitanen, S. K.; Erick-
son-Vitanen, K. J. Med. Chem. 2000, 43, 2019.
Shateria, H. R.; Oveisi, A. R. Chin. J. Chem. 2009, 27,
2418.
7
31 Pater, R. J. Heterocyclic. Chem. 1971, 8, 699.
(E1103246 Sun, H.)
1984
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1982— 1984