Ultrasound promoted and ionic liquid catalyzed cyclocondensation reaction for the synthesis of 4(3H)-quinazolinones

Article abstract of DOI:10.1002/cjoc.201090037

4(3H)-Quinazolinones were synthesized in high yields by one-pot three-component condensation of anthranilic acid, carboxylic acid and aniline in the presence of ionic liquid such as 1-n-butyl-3-methylimidazolium tetrafluoroborate (BMImBF₄) as c

Full text of DOI:10.1002/cjoc.201090037

FULL PAPER
Ultrasound Promoted and Ionic Liquid Catalyzed Cyclocon-
densation Reaction for the Synthesis of 4(3H)-Quinazolinones
,a
Chavan, Fulchand R.b
Sakate, Sachin S.c
*
Pawar, Omprakash B.
,a
*
Shinde, Narayan D.
a Department of Chemistry, Shri Chhatrapati Shivaji College, Omerga-413606, India
b Department of Chemistry, Vasantrao Naik College, Aurangabad-431003, India
c Department of Chemistry, Modern College, Shivajinagar, Pune-411005, India
4(3H)-Quinazolinones were synthesized in high yields by one-pot three-component condensation of anthranilic
acid, carboxylic acid and aniline in the presence of ionic liquid such as 1-n-butyl-3-methylimidazolium tetra-
fluoroborate (BMImBF4) as catalyst under solvent free and neutral conditions.
Keywords 4(3H)-quinazolinone, ionic liquid, ultrasound
Introduction
of ionic liquids need no additional solvent. Ionic liquids
have attracted much attention due to their unique physi-
cal and chemical properties such as thermal stability,
negligible vapour pressure, ability to dissolve a large
range of organic and inorganic compounds, easy recy-
clability, milder reaction conditions, better yields and
shorter reaction time.15 Various reactions have been
reported recently using ionic liquids as a catalyst,16 re-
action medium9b,17 and rate enhancer.9b
Combinatorial chemistry is playing an increasingly
important role as one of the tools of modern medicinal
chemistry as the rapid discovery of new leads.1 The
preparation of libraries of small organic molecules is a
rapidly evolving area of research.2 Recently much atten-
tion has been devoted towards 4(3H)-quinazolinones
derivatives due to their significant therapeutic and
medicinal properties such as anti-inflammatory,3
anti-convulsant,4 anti-hypertensive,5 antimalarial,6 anti-
parkinsons activities7 and they also show blood platelet
anti-aggregating activity.8 Therefore, several methods
for synthesis of substituted 4(3H)-quinazolinones have
been reported in the literature.9 However, some of these
methods are associated with one or more disadvantages
such as long reaction time, harsh reaction conditions,
unsatisfactory yields, tedious work-up, use of environ-
mentally toxic reagents or solvents and use of large
amount of solid supports, which result in the generation
of a large amount of toxic waste. Consequently, there is
scope for further development of mild reaction condi-
tions, better yields, free of organic solvent and easy
synthetic procedure.
Experimental
General procedure
Melting points were determined in open glass capil-
1
laries and are uncorrected. H NMR and 13C NMR
spectra were recorded at room temperature on a 300
MHz Varian Inova spectrometer in CDCl3 using TMS as
an internal standard. Sonication was performed in a
Shanghai Branson-CQX ultrasonic cleaner with a fre-
quency of 25 kHz and a nominal power 500 W. The
reaction flask was located in the water bath of the ultra-
sonic cleaner, and the temperature of the water bath was
controlled by a current of water at room temperature.
Reactions were monitored by TLC on aluminum sheets
precoated with silica gel 60F254. Column chromatogra-
phy was performed using silica gel (60— 120 mesh size).
All the products are known compounds and character-
Ultrasound irradiation has been increasingly used in
organic synthesis in last three decades, than traditional
methods, which is more conveniently and easily
controlled. A large number of organic reactions have
been carried out in higher yields, shorter time and
milder conditions under ultrasound irradiation.10-12 Re-
cently, significant progress has been made in the appli-
cation of ionic liquids to catalytic processes.13,14
1
ized by comparing their IR, H NMR, 13C NMR and
melting points with those reported in literature.
Typical procedure for the synthesis of 3-(4-
chloro phenyl)-4(3H)-quinazolinone (4b) A mixture
of anthranilic acid (0.01 mol), formic acid (0.01 mol),
4-chloroaniline (0.01 mol) and BMImBF4 (0.01 mol)
was irradiated at room temperature under ultrasound
Ionic liquids are the salts of organic heterocyclic
cations and inorganic anions. They exist in liquid state
at ambient temperature; hence, reactions in the presence
*
E-mail: drnds09@rediffmail.com
Received July 19, 2009; revised September 7, 2009; accepted September 30, 2009.
Chin. J. Chem. 2010, 28, 69— 71
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
69

Pawar et al.
FULL PAPER
irradiation for 10 min. The reaction was monitored by
TLC. After completion of the reaction, the mixture was
extracted with Et2O (3×15 mL). The organic layer was
washed with water and dried over anhydrous MgSO4.
Organic solvent was evaporated and residue was chro-
matographed on silica gel (ethyl acetate/hexane) to af-
ford the pure product in 93% yield.
yields obtained in the presence of ionic liquid
(BMImBF4), a further study of 4(3H)-quinazolinone
synthesis was carried out using different aliphatic and
aromatic carboxylic acids (Scheme 1). The optimized
results are summarized in Table 1.
Table 1 Synthesis of 4(3H)-quinazolinone derivatives using
Typical procedure for the synthesis of 2-(2-hydro-
ionic liquid (BMImBF4)
xyphenyl)-3-phenyl-4(3H)-quinazolinone (4h)
A
Compounda
R1
R2
Time/min Yieldb/%
mixture of anthranilic acid (0.01 mol), 2-hydroxyben-
zoic acid (0.01 mol), aniline (0.01 mol) and BMImBF4
(0.01 mol) was irradiated at room temperature under
ultrasound irradiation for 15 min. The reaction was
monitored by TLC. After completion of the reaction, the
mixture was extracted with Et2O (15 mL×3). The or-
ganic layer was washed with water and dried over an-
hydrous MgSO4. Organic solvent was evaporated and
residue was chromatographed on silica gel (ethyl ace-
tate/hexane) to afford the pure product in 90% yield.
4a
4b
4c
4d
4e
4f
C6H5
H
7
10
12
12
12
20
10
15
15
12
12
96
93
89
90
92
77c
93
90
88
88
92
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
C6H5
H
H
H
H
H
4g
4h
4i
C6H5
C6H5
2-HOC6H4
4-MeC6H4
Methyl
3-(4-Chlorophenyl)-4(3H)-quinazolinone
(4b)
C6H5
1
m.p. 182 ℃; H NMR (CDCl3 300 MHz) δ: 8.33 (d,
J＝7.5 Hz, 1H), 8.13 (s, 1H), 7.68—7.71 (m, 2H), 7.48
(t, J＝7.3 Hz, 1H), 7.38 (d, J＝7.6 Hz, 2H), 7.25 (d, J＝
8.6 Hz, 2H); 13C NMR δ: 160.2, 148.8, 146.6, 136.1,
135.2, 134.6, 132.7, 130.5, 128.3, 127.2, 127.8, 125.1;
IR νmax: 1696, 1601, 1462 cm － 1. Anal. calcd for
C14H9ClN2O: C 65.51, H 3.53, N 10.91; found C 65.50,
H 3.41, N 11.0.
4j
C6H5
4k
C6H5
Octanyl
a All products were characterized by H NMR, 13C NMR and IR
spectroscopic data and their m.p. compared with literature val-
ues.9,18 b Isolated yields. In parallel non-sonicated experiments,
the anthranilic acids were stirred magnetically with primary aro-
matic amines and carboxylic acids in the presence of BMImBF4
for 30 min at room temperature; no product was detected in the
absence of ultrasound. c Irradiation at 50 ℃.
1
Results and discussion
Conclusion
Herein, we report the synthesis of 4(3H)-quinazoli-
nones promoted by the ionic liquid catalyst, 1-n-butyl-3-
methylimidazolium tetrafluoroborate (BMImBF4)16 at
room temperature under ultrasound irradiation in high
yields with shorter reaction time.
In the present work, we achieved a one-pot three-
component condensation of anthranilic acid (1), primary
aromatic amine (2) and carboxylic acid (3) in the pres-
ence of ionic liquid (BMImBF4) under the influence of
ultrasound irradiation as a new efficient method to pro-
duce 4(3H)-quinazolinones 4 (Scheme 1). The reaction
proceeded at room temperature within a few minutes in
excellent yields. Only the reaction with 4-nitroaniline
required 50 ℃ temperature and the time required was
20 min. This is due to the presence of an electron with-
drawing group.
In summary, we have found a practical and green
synthesis procedure for preparing 4(3H)-quinazolinones
by condensation of anthranilic acid, primary aromatic
amine and carboxylic acid in the presence of ionic liq-
uid (BMImBF4) under ultrasound irradiation. The main
advantages of this methodology are simple catalyst sys-
tem, higher yields, free of organic solvent, and easy
synthetic procedure.
Acknowledgements
The authors are thankful to Dr. M. S. Shingare (De-
partment of Chemistry), Dr. Babasaheb Ambedkar
(Marathwada University, India) for encouragement dur-
ing the process of carrying out this work and Prof. S. R.
Pokharkar (Head, Department of Chemistry, Modern
College, Shivajinagar, MS., Pune-05, India) for provid-
ing the laboratory facility.
Scheme 1
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