Eco-friendly, solvent-free novel one-pot, three-component synthesis of quinazolinones at ambient temperature catalyzed by silica gel-supported phosphomolybdic acid

Article abstract of DOI:10.1002/jhet.361

(Chemical Presented) Silica gel supported Phosphomolybdic acid (PMA.SiO₂) catalyzes efficiently the one-pot three-component coupling reaction of anthranilic acid, orthoesters, and amines at room temperature to afford 4(3H)-Quinazolinones in hig

Full text of DOI:10.1002/jhet.361

May 2010
Eco-Friendly, Solvent-Free Novel One-Pot, Three-Component
Synthesis of Quinazolinones at Ambient Temperature Catalyzed
by Silica Gel-Supported Phosphomolybdic Acid
589
Gowravaram Sabitha,* N. Mallikarjuna Reddy, M. Nagendra Prasad,
G. S. K. Raja, and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, Andra Pradesh,
India
*E-mail: gowravaramsr@yahoo.com
Received July 24, 2009
DOI 10.1002/jhet.361
Published online 29 April 2010 in Wiley InterScience (www.interscience.wiley.com).
Silica gel supported Phosphomolybdic acid (PMA.SiO2) catalyzes efficiently the one-pot three-com-
ponent coupling reaction of anthranilic acid, orthoesters, and amines at room temperature to afford
4(3H)-Quinazolinones in high to excellent yields under solvent-free conditions. The supported catalyst
can be recovered and reused.
J. Heterocyclic Chem., 47, 589 (2010).
INTRODUCTION
acids. The supported HPAs are more active than typical
solid acids and attracted much attention in organic syn-
thesis owing to easy workup procedures, easy filtration,
and minimization of cost and waste generation due to
reuse and recycling of the catalysts [19]. Supported
reagents enhance their application in ‘green synthesis’.
Silica gel [17] is most commonly used as support, even
though alumina, active carbon, and acidic ion-exchange
resins are considered as suitable supports.
The demand for increasingly clean and efficient
chemical syntheses is continuously becoming more
urgent from both an economic and an environmental
standpoint. Organic reactions under solvent-free condi-
tions are advantageous because of enhanced selectivity
and efficiency, ease of manipulation, and more impor-
tantly, toxic and often volatile solvents are avoided.
These would be especially important during industrial
production. Hence, the organic transformations under
solvent-free conditions are attracting increasing
attention.
Natural products containing quinazolinone moiety
possess a broad spectrum of biological properties, such
as anticancer, antimalarial, anticonvulsant, analgesic,
antihypertensive, antiviral, anti-tubercular, and anti-
inflammatory activities [20–34]. Febrifugine and isofe-
brifugine natural products [35,36] containing 4(3H)qui-
nazolinone scaffold have been used effectively against
malarial fever in china for centuries (Fig. 1). Similarly,
quinazolone containing compounds have been known as
tyrosine kinase inhibitors [37,38], dihydrofolate reduc-
tase inhibitors [39], and tubulin polymerization inhibi-
tors [40,41]. The interest in the quinazolone structural
motif, led to a number of different synthetic methods to
access this nucleus. The synthesis of 4(3H)-quinazoli-
none derivatives is achieved by cycloaddition reactions
of anthranilic acid with imidates and imino halides [42–
49]. The cyclization of cyano- and nitro- activated o-flu-
orobenzaldehydes with amidines and more recently, the
Heteropoly acids are economically and eco-friendly
green Lewis acids. Development of methods using heter-
opoly acids (HPAs) as catalysts for organic synthetic
processes related to fine chemicals, such as flavors,
pharmaceuticals, and food industries [1–4] have been
under attention in the last decade. Heteropolyacids are
more active catalysts than conventional inorganic and
organic acids for various reactions in solution [5–11].
They are used as industrial catalysts for several liquid-
phase reactions[12–15], such as alcohol dehydration
[16], alkylation [17], or esterification [18] reactions.
They are not corrosive and environmentally benign, pre-
senting fewer disposal problems. Phosphomolybdic acid
(PMA, H3PMo12O40) belongs to the class of heteropoly
C
V
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590
G. Sabitha, N. M. Reddy, M. N. Prasad, G. S. K. Raja, and J. S. Yadav
Vol 47
characterized by NMR, IR and mass spectroscopy and
also by comparison with authentic samples. As shown in
Table 1, both aniline derivatives and benzyl amine
reacted similarly under these reaction conditions without
any difference to give the corresponding 4(3H)-quinazo-
linones in high yields. The present procedure does not
require toxic or anhydrous organic solvents. The reac-
tion is general, clean, rapid, and efficient. It is important
to note that in the absence of catalyst the reaction did
not yield the products and only the starting materials
were isolated.
It is important to mention that in contrast to reported
procedures, m-nitroaniline reacted at room temperature
with anthranilic acid and trimethyl orthoformate to pro-
duce the product 4j in 88% yield within 15 min, while
many of the reports claim the reaction using aniline con-
taining a nitro group requires heating at 60ꢀC [54,56–
58]. The one-pot reaction proceeded smoothly with the
anilines containing electron-donating groups (such as
methoxy and methyl) as well as containing electron-
withdrawing groups (such as chloro, fluoro, and nitro).
In conclusion, we have demonstrated a three-compo-
nent, one-pot procedure for the synthesis of 4(3H)-qui-
nazolinones at ambient temperature using silica gel sup-
ported PMA. The noteworthy advantages of this method
are mild solvent-free heterogeneous reaction conditions,
improved yields, shorter reaction times, and operational
simplicity, which make it a useful and attractive process
for the synthesis of 4(3H)-quinazolinones. The supported
catalyst can be recovered and reused.
Figure 1. Quinazolinone moiety containing natural products.
condensation of fluoro substituted benzoyl chlorides
with 2-amino-N-heterocycles represent one-pot
approaches to quinazolines [50,51]. An intramolecular
aza-Wittig type transformation of o-azidobenzamide
derivatives has been employed as the key quinazoli-
none-forming step in the synthesis of the quinazoline
alkaloid vasicinone [52]. Usually, 4H-3,1-benzaxazin-4-
ones are valuable starting materials for the synthesis of
these compounds [53]. Recently, 4(3H)-quinazolinones
were prepared using Bi(TFA)3-[nbp]FeCl4 [54],
Yb(OTf)3 [55], La(NO3)3.6H2O [56], Silicagel/FeCl3
[57], Silicagel/NaHCO3 & Amberlist 15 [58]. Even-
though, many reports appeared in the literature, some of
these suffer from drawbacks, such as multi-step proce-
dures, long reaction time, expensive reagents, low
yields, harsh conditions, and cumber some product
isolation.
EXPERIMENTAL
All reactions were carried out under N2 atmosphere and
monitored by TLC on silica gel (60–120 mesh; Merck). IR
spectra were recorded on a Thermo Nicolet Nexus-670 spec-
trometer; in m/z. 1H NMR spectra were recorded on Bruker
(300/75 MHz) spectrometer in CDCl3; d in ppm, J in Hz. ESI
Mass spectra were recorded on Agilent LC-MSD-Trap-SL ap-
paratus; in m/z.
As part of our program aimed at developing new
green synthetic methodologies for the preparation of fine
chemicals, we wish to report herein a remarkable cata-
lytic activity of PMA for the one-pot synthesis of
4(3H)-quinazolinones.
General procedure for the preparation of Compound
4a. To a mixture of anthranilic acid 1 (1 mmol), trimethyl or
triethyl orthoformate 2 (1.2 mmol) and aniline 3a (1.2 mmol),
silicagel supported PMA [59] (0.01 mmol) was added. The
reaction mixture was stirred at room temperature for 5 min.
After completion of the reaction (monitored by TLC) 10 mL
of CH2Cl2 was added to the reaction mixture and the catalyst
RESULTS AND DISCUSSIONS
Thus carrying out the reaction of anthranilic acid 1
with trimethyl/ethyl orthoformate 2 and primary amine
3 in1:1.2:1.2 mole ratio in the presence of 1 mol % of
PMA.SiO2 [59] at room temperature gave the desired
4(3H)-quinazolinone 4 in 98% yield (Scheme 1). The
experimental procedure is simple and the reaction pro-
ceeds under solvent-free conditions. To expand the
scope of this method, various 4(3H)-quinazolinones
were synthesized under similar conditions in high to
excellent yields. All the reactions proceeded efficiently
at room temperature within 5–15 min in excellent yields
under solvent-free conditions and all the products were
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Table 1
PMA.SiO2 catalyzed one-pot synthesis of 4(3H)-quinazolinonesa at room temperature.
Entry
a
Anthranilic acid
Amine
Quinazolinone
Time (min)
5
Yield (%)b
98
b
c
d
e
f
5
5
98
96
95
95
94
94
92
92
88
95
90
91
95
92
92
94
5
8
8
g
h
i
8
10
10
15
8
j
k
l
8
m
n
o
p
q
5
8
10
10
6
a All products are characterized by NMR and Mass spectra.
b Yields refer to isolated pure products.

592
G. Sabitha, N. M. Reddy, M. N. Prasad, G. S. K. Raja, and J. S. Yadav
Vol 47
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