Green chemical multi-component one-pot synthesis of fluorinated 2,3-disubstituted quinazolin-4(3H)-ones under solvent-free conditions and their anti-fungal activity

Article abstract of DOI:10.1016/j.jfluchem.2004.06.009

A rapid one-pot solvent-free procedure has been developed for the synthesis of fluorinated 2,3-disubstituted quinazolin-4(3H)-ones by neat three-component cyclocondensation of anthranilic acid, phenyl acetyl chloride and substituted anilines under microwa

Full text of DOI:10.1016/j.jfluchem.2004.06.009

Journal of Fluorine Chemistry 125 (2004) 1835–1840
www.elsevier.com/locate/fluor
Green chemical multi-component one-pot synthesis of fluorinated
2,3-disubstituted quinazolin-4(3H)-ones under solvent-free
conditions and their anti-fungal activity
*
Anshu Dandia , Ruby Singh, Pritima Sarawgi
Department of Chemistry, University of Rajasthan, Jaipur 302004, India
Received 31 March 2004; received in revised form 10 June 2004; accepted 15 June 2004
Available online 30 July 2004
Abstract
A rapid one-pot solvent-free procedure has been developed for the synthesis of fluorinated 2,3-disubstituted quinazolin-4(3H)-ones by neat
three-component cyclocondensation of anthranilic acid, phenyl acetyl chloride and substituted anilines under microwave irradiation. The
experimental methodology and microwave conditions described here are well established, allowing significant rate enhancement and good
yields compared to conventional reaction conditions. The reaction is generalized for O, M & P substituted anilines to give quinazolin-4(3H)-
ones. Synthesized compounds have been screened for their antifungal activity.
# 2004 Published by Elsevier B.V.
Keywords: Quinazolines; Three-component system; Microwave irradiation
1. Introduction
important antifungal [6], herbicidal [7], pesticidal [8], CNS
depressant [9] and AMPA inhibitors [10] etc. Thus, their
synthesis has been of great interest in the elaboration of
biologically active heterocyclic compounds.
Quinazoline compounds are reported to be physiologi-
cally and pharmacologically active and find applications in
the treatment of several diseases like leprosy and mental
disorder and also exhibit a wide range of activities [1]. A
well known methaquolone [2] having quinazoline nucleus, is
a sedative and hypnotic drug and reported to possess antic-
onvulsant activity.
Microwave induced rate enhancement of various reac-
tions becoming popular with organic chemists [11]. How-
ever, recently, more interest has been focussed on ‘‘dry
media’’ synthesis and particularly on solvent-free proce-
dure using various mineral oxides [12] and solvent-less
reactions with neat reactants in the absence of a catalyst or
solid support [13]. Recently, the diversity generating
potential of multi-component reactions (MCR’s) has been
recognized and their utility in preparing libraries to screen
for functional molecules is well appreciated. Conse-
quently, the design of novel MCR’s is an important field
of research [14].
Recently, several scientists elucidated that quinazoline
system possess variable sites at positions 2 and 3 which
can be suitably modified by the introduction of different
heterocyclic moieties to yield the potential anticonvulsant
agents [3].
Incorporation of fluorine atoms or CF3 group to hetero-
cycles is known to influencing the biological activity [4].
Fluorinated quinazoline has been focused the attraction of
pharmacologist and chemists during last several years due to
wide variety of activity possess by them [5]. Number of
patents mention the utility of fluorinated quinazolines as
Conventional synthesis of disubstituted quinazolin-
4(3H)-ones involves two steps [15] i.e. (i) cyclodehydration
of 2-benzamidobenzoic acid I with excess of acetic anhy-
dride under anhydrous conditions and removal of excess of
acetic anhydride under reduced pressure to give benzoxazin-
4-one II (ii) refluxing the II with amines in glacial acetic
* Corresponding author. Tel.: +91-141-520301; fax: +91-141-523637.
0022-1139/$ – see front matter # 2004 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2004.06.009

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A. Dandia et al. / Journal of Fluorine Chemistry 125 (2004) 1835–1840
Table 1
Comparative studies for the synthesis of IVa
Method
Medium
MW Power (W)
Time (min)
Yield (%)
Tempa (8C)
A
(a) Acidic alumina
640
640
640
640
640
4 + 10
82
88
92
91
90
132
141
165
162
164
(b) Montmorillonite KSF
Neat (without solvent & support)
Neat (Path-I)
3 + 7
B
5
4
5
C
Neat (Path-II)
a
Time 4 + 10 indicates first irradiation for 4 min gives compound II (detected by TLC) and then further irradiation after adding 3-trifluoromethyl aniline for
10 min yield IVa.
Scheme 1.
acid/pyridine [16]. The products were obtained in moderate
yield and require 10–12 h refluxing.
2. Results and discussion
The synthesis of quinazolin-4(3H)-one core nucleus
under microwaves is reported involving the reaction of
anthranilic acid with formamide [17]. But to the best of
our knowledge, no report is available in the literature for
fluorinated disubstituted quinazolines involving multi-com-
ponent reaction for the synthesis of series of compound to
make them available for bioactivity evaluation.
In method A the intermediate benzoxazin-4-one II was
synthesized ‘‘in situ" by the cyclodehydration of I with
acetic anhydride using inorganic solid supports. The method
is environmentally friendly, as acetic anhydride remains
adsorbed over the solid support and there is no evaporation
into the atmosphere.
The condensation reaction of II with para/meta/ortho
substituted fluorinated anilines have been studied. Meta/
para substituted anilines gave cyclized product quinazoline
IV. While the ortho substituted anilines gave, an intermedi-
ate O-acylaminobenzanilide III, which in contrast to earlier
report of Mishra et al. [15] where they reported the forma-
tion of cyclized quinazolones in case of ortho substituted
anilines also.
For the aforementioned reasons and in view of our
general interest in the development of environmentally
friendlier synthetic alternatives using microwaves [18],
we studied extensively the synthesis of fluorine containing
quinazolin-4(3H)-ones under microwave irradiation by
various methods (Table 1) i.e., (A) using inorganic solid
support montmorillonite KSF/acidic alumina (Scheme 1);
(B) neat one-pot synthesis without using any dehydrating
agent, solvent or support (Schemes 2 and 3). The best
results obtained from neat synthesis (method B) have been
reported.
Although, the solvent-free procedure using inorganic
support under microwaves is an attractive ecofriendly meth-
odology, but it requires appreciable amount of solvent for
adsorption of reactants and elution of products.
Further, in view of our aim to synthesize a series of
fluorinated 2,3-disubstituted quinazolones with pharmaco-
phoric groups and to establish structure activity relationship
in quinazolones, we have developed a ‘green chemistry
procedure’ using neat multi-component reaction conditions,
which aims at complete elimination of the solvent as well as
solid support from the reaction. These no solvent reactions,
Scheme 2.

A. Dandia et al. / Journal of Fluorine Chemistry 125 (2004) 1835–1840
1837
Scheme 3.
when coupled with microwave irradiation prove to be
advantageous for environmental reasons as well, due to
their uniforating effect and shorter reaction time.
were used. While conventional method was failed to give IV
in case of O-substituted anilines.
The formation of O-acyl aminobenzanilide III and qui-
nazoline 4(3H)-ones IV have been confirmed on the basis of
spectral studies. The IR spectra of IIIa–b (Table 2) showed
characteristic absorption bands at 3360–3400 (NH), 1700–
Experimentally, anthranilic acid, phenyl acetyl chloride
and corresponding substituted anilines (X = 2-CF3; 2-F; 3-
CF3,4-Cl; 3-F; 3-CF3) are admixed and irradiated inside the
microwave oven. The formation of final product quinazo-
lone IV can proceed via two pathways I & II (Scheme 3).
Path I involves first N-phenylacetylation of anthranilic
acid and condensation of resultant 2-benzamidobenzoic acid
I with the amines and then intramolecular amidation of the
intermediate amidine V afforded the desired final product
IV. While an another path II involves N-phenylacetylation
of amines instead of anthranilic acid. The possibility of all
routes are confirmed by isolation of intermediates in some
cases or the reaction of 2-benzamidobenzoic acid I with 3-
trifluoromethylaniline and the condensation of VI with
anthranilic acid were conducted under microwave irradia-
tion, the desired product IVa was obtained in few minutes.
Thus, N-phenylacetylation step occurs very quickly.
Attempts to use PhCH2COOH instead of PhCH2COCl were
not successful.
1
1680 (both C=O). The H NMR spectra of IIIa–b showed
broad peaks at d 8.92 & 9.25 due to two NHCO protons
(exchangeable with D2O) and a singlet at d 4.22–4.26 ppm
due to COCH2Ph protons. 13C NMR spectrum of IIIa also
showed the presence of two carbonyl signals at d169.9 and
169.2 ppm. The remaining signals were obtained at d 140.8,
133.9, 133.6, 133.4, 130.7, 128.8, 128.3, 127.9, 126.4,
126.3, 125.5, 125.3, 121.8, 120.1, 119.2, (aromatic and
CF3 carbon) (CO–CH2) 45.0 ppm.
IR spectra of quinazolones IVa–f showed the only one
carbonyl absorption band at 1695–1700 and 1605–1610
(C=N) cmÀ1 confirms the ring closure in all compounds.
It was further confirmed on the basis of 13C NMR spectrum
of IVd which showed only one signal at d 169.7 (C=O) ppm
along with other peaks at 155.4 (C=N), 139.5, 138.6, 137.5,
135.8, 131.3, 130.9, 129.3, 128.6, 127.3, 126.4, 125.6,
123.3, 122.0, 120.7, 119.5 (aromatic and CF3 carbon) and
(CH2Ph) 24.1 ppm. Further, the disappearance of NH peaks
in IVa–f peaks at (d 8.92 and 9.25 ppm) showed the for-
mation of quinazolones IV. The presence of fluorine
attached to phenyl ring has been confirmed by 19F NMR.
The detailed spectral data of compound IIIa–b and IVa–f
In conclusion, we have introduced a simple one-pot
multi-component cyclocondensation reaction for the synth-
esis of disubstituted quinazolin-4(3H)-ones without using
any dehydrating agent, solvent or support. Reaction
occurred in shorter time with easier work-up process and
this method was applicable even when o-substituted anilines
Table 2
Physical and analytical data of O-acylaminobenzanilide IIIa–b
Compound
R
Time (min)
Yield (%)
Tempa (8C)
mp (8C)
Molecular formula
IIIa
IIIb
a
2-CF3C6H4
2-FC6H4
3 + 7
3 + 6
89
85
140
139
160
168
C22H17F3N2O2
C21H17FN2O2
Measured immediately after the reaction using a glass thermometer.

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A. Dandia et al. / Journal of Fluorine Chemistry 125 (2004) 1835–1840
Table 3
Spectral data of compouds IIIa–b & IVa–f
Compound
IR (cmÀ1
)
1H NMR (d, ppm)
19F NMR (d, ppm)
À64.21 (s, CF3)
IIIa
3365–3395 (2 Â NH), 3060, 2940, 2850
(aromatic and aliphatic C–H), 1700,
1680 (2 Â C=O), 1490 (NO2)
d 4.22 (s, 2H, CH2Ph), 6.90–8.35
(m, 13H, Ar–H), 8.92 & 9.25(2 Â bs,
2 Â 1H, 2x NH exchangeable with D2O)
d 4.26 (s, 2H, CH2Ph), 6.98–8.26
IIIb
IVa
IVb
IVc
IVd
IVe
IVf
3360–3400 (2 Â NH), 3060, 2955,
2860 (aromatic and aliphatic C–H),1700,
1685 (2 Â C=O), 680, 720.
À119.90 (s,2-F)
À63.38 (s, CF3)
À119.61 (s, 3-F)
À63.21 (s, CF3)
–64.45 (s, CF3)
À119.61 (s,2-F)
À118.88 (s,4-F)
(m, 13H, Ar–H), 8.95 & 9.22 (2 Â bs,
2 Â 1H, 2x NH exchangeable with D2O)
d 3.96 (s, 2H, CH2Ph), 6.88–7.19
3050, 2940, 2840 (aromatic and aliphatic
C–H), 1700 (C=O), 1605 (C=N)
(m, 5H, Phenyl ring protons of CH2Ph),
7.22–8.18 (m, 7H, Ar–H), 8.40 (dd, 1H, 5-H).
d 3.95 (s, 2H, CH2Ph), 6.84–7.10
3050, 2980, 2860 (aromatic and aliphatic
C–H), 1695 (C=O), 1605 (C=N)
(m, 5H, Phenyl ring protons of CH2Ph),
7.19–8.14 (m, 7H, Ar–H), 8.39 (dd, 1H, 5-H).
d 3.98 (s, 2H, CH2Ph), 6.86–7.12
3040, 2970, 2860 (aromatic and aliphatic
C–H), 1705 (C=O), 1608 (C=N)
(m, 5H, Phenyl ring protons of CH2Ph),
7.25–8.15 (m, 6H, Ar–H), 8.38 (dd, 1H, 5-H).
d 3.95 (s, 2H, CH2Ph), 6.82–7.15
3040, 2970, 2860 (aromatic and aliphatic
C–H), 1700 (C=O), 1608 (C=N)
(m, 5H, Phenyl ring protons of CH2Ph),
7.31–8.25 (m, 7H, Ar–H), 8.45 (dd, 1H, 5-H).
d 3.96 (s, 2H, CH2Ph), 6.85–7.18
3050, 2980, 2850 (aromatic and aliphatic
C–H), 1700 (C=O), 1610 (C=N)
(m, 5H, Phenyl ring protons of CH2Ph),
7.21–8.10 (m, 7H, Ar–H), 8.40 (dd, 1H, 5-H).
3.97 (s, 2H, CH2Ph), 6.88–7.19
3060, 2980, 2860 (aromatic and aliphatic
C–H), 1700 (C=O), 1615 (C=N)
(m, 5H, Phenyl ring protons of CH2Ph),
7.10–8.10 (m, 7H, Ar–H), 8.39 (dd, 1H, 5-H).
are given in Table 3. In the mass spectrum of representative
compounds the molecular ion peak at m/z 398 and 380
(100%) was corresponding to the molecular weight of
compounds IIIa and IVd, respectively.
flasks and sterilized. To this medium, a requisite quantity of
solution was added and then the medium was poured into
petri plates in three replication. A culture of test fungus was
grown on PDA for 6–7 days. Small disc (4 mm) of fungus
culture was cut with a sterile corkborer and transferred
asceptically, upside-down in the center of petridishes con-
taining the medium and fungicides. Plates were incubated at
25 Æ 1 8C for 6 days. Colony diameter were measured and
data was statistically analysed (Table 4).
2.1. Evaluation of anti-fungal activity
The synthesized compounds were screened for antifungal
activity against three pathogenic fungi, namely Rhizoctonia
solani, causing root rot of okra, Fusarium oxysporum,
causing wilt of mustard and Colletotrichum capsici causing
leaf spot and fruit rot of chilli. It was done by two methods.
2.3. Pot trial method [20]
White seeded sorghum grains were soaked in water for
about 12 h, 160 g of the soaked kernels were placed in
500 ml flasks and 20 ml of water was added to each. The
material was autoclaved twice on successive days before
inoculation. After sterilization, fungus bits were inoculated
in each flask and flasks were kept for 10 days at 25–27 8C.
2.2. Poison plate technique [19]
The compounds synthesized were dissolved in acetone
and compounds were prepared in 1000 and 500 ppm con-
centrations. Potato-dextrose-agar medium was prepared in
Table 4
Effect of concentrations of different chemicals on the mean radial growth (cms) of different fungus in vitro
Compound no.
Rhizoctonia solani
Fusarium oxysporum
Colletotrichum capsici
1000 ppm
500 ppm
1000 ppm
500 ppm
1000 ppm
500 ppm
IVa
IVb
IVc
IVd
IVe
1.08a
2.58
1.83
2.08
6.67
1.92
9.00
1.22
1.75
1.50a
2.58
7.67
8.25
3.83
9.00
1.02
1.58
1.60
2.25
2.92
1.08a
1.25
8.17
0.77
1.83
3.92
4.25
5.00
1.67
1.58a
8.17
1.14
1.33
2.58
1.75
1.50
0.75a
2.50
7.33
1.03
2.17
3.67
3.25
3.50
1.25a
4.08
7.33
1.08
IVf
Check
CD 1%
a
Minimum value.

A. Dandia et al. / Journal of Fluorine Chemistry 125 (2004) 1835–1840
1839
Table 5
were Aldrich product and used as received. 2-benzamido-
benzoic acid has been synthesized by literature method
[21].
Evaluation of quinazolin-4(3H)-ones derivatives as seed dressers against
Rhizoctonia solani causing root rot of okra (in pot trial)
Compound no.
Percent germination
7 DAS
Plant stand
25 DAS
2-Phenylmethyl-3-(3-trifluoromethylphenyl)-quinazo-
lin-4(3H)-one IVa was prepared by three different proce-
dures under microwave irradiation.
IVa
IVb
IVc
IVd
Ve
Vf
42.00
63.00
70.00
58.00
28.00
59.00
98.00
79.00
12.00
95.00
48.00
45.00
42.00
41.00
21.00
40.00
64.00
68.00
4.00
3.1. Method A; Using inorganic solid supports
(Scheme 1)
Baynate (0.2%)
Thiram (0.3%)
Check with inoculum
Check without inoculum
A mixture of 2-benzamidobenzoic acid I (2 mmol) and
acetic anhydride (2.5 mmol) was adsorbed on acidic alumina/
montmorillonite KSF (2 g), mixed thoroughly and irradiated
inside the microwave oven at 640 W until the completion of
reaction (TLC). After completion of reaction the 3-trifluoro-
methylaniline (2 mmol) was added to the reaction mixture
and irradiated for appropriate time (Table 1). The product
was extracted into ethanol and the excess solvent was
evaporated on a roto-evaporator to give compound, which
was purified by methanol and identified as IVa.
From the comparative results, it has been observed that
the montmorillonite KSF is the best solid support as com-
pared to acidic alumina (Table 1). The remaining com-
pounds IVb–c and IVf (in case of meta/para substituted
anilines) and IIIa–b (in case of ortho substituted anilines)
were similarly prepared by using montmorillonite KSF.
90.00
DAS: Days after sowing.
100 seeds of okra were taken for one treatment of each
compound. Inoculum was added @ 2 g/kg of soil, 3 days
prior to sowing. Sowing was done after 3 days and germina-
tion data were recorded after 7, 15, 25 days of sowing.
Suitable checks were maintained and the data was statisti-
cally analysed (Table 5). ‘Baynate’ and ‘Thiram’, standard
fungicides as seed dressers to control this disease. ‘Baynate’
was found best in reducing the plant mortality.
3. Experimental
3.2. Method-B; Neat-three-component cyclocondensation
(Scheme 2)
Melting points were determined in open glass capillary
and were uncorrected. IR spectra were recorded on a Perkin-
1
Elmer (model-577) in KBr pellets. H NMR and 13C NMR
An equimolar mixture of anthranilic acid (2 mmol),
phenyl acetyl chloride (2 mmol) and 3-trifluoromethylani-
line (2 mmol) contained in a Erlenmeyer flask fitted with
condensor was placed in the microwave oven and irradiated
for 5 min (TLC) at 640 W. The reaction mixture was cooled
at room temperature to give solid mass which was crystal-
lized from ethanol.
were recorded on Jeol model FX 90Q and Bruker-DRX-300
using CDC13 as solvent and TMS as internal reference at
89.55 and 75.47 MHZ, respectively. 19F NMR was recorded
on Jeol model FX 90Q at 84.25 MHz, using CDCl3 as
solvent and or hexafluorobezene as external reference. Mass
spectrum of representative compound was recorded on
Kratos 50 mass spectrometer at 70 eV. Purity of all com-
pounds were checked by TLC using silica gel ‘G’ coated
glass plates and benzene-ethylacetate (8:2) as eluent. The
microwave-induced reactions were carried out in BMO-
700T modified domestic oven fitted with a condenser and
a magnetic stirrer. Montmorillonite KSF and acidic alumina
3.3. Method-C; Alternative procedure for preparation of
IVa (Scheme 3)
A mixture of I (2 mmol) and 3-triflouromethyl aniline
(2 mmol) was irradiated for 4 min (TLC) at 640 W. After
Table 6
Physical and analytical data of 2-phenylmethyl-3-(substituted-phenyl)-quinazolin-4(3H)-ones IVa–f
Method-A
Compound
Method-B
R
Time
(min)
Yield
(%)
Tempa
Time
(min)
Yield
(%)
Tempa
mp
Molecular
formula
(8C)
(8C)
(8C)
IVa
IVb
IVc
IVd
IVe
IVf
a
3-CF3ÁC6H4
3-FÁC6H4
3 + 7
3 + 6
3 +7
–
88
82
81
–
141
142
137
–
5
5
5
4
6
5
92
87
88
92
91
90
165
165
164
159
150
155
101
185
166
129
182
142
C22H15F3N2O
C21H15FN2O
C22H14C1N2O
C22H15F3N2O
C21H15FN2O
C21H15FN2O
3-CF3,4-ClÁC6H3
2-CF3ÁC6H4
2-FÁC6H4
–
–
–
4-FÁC6H4
–
–
–
Measured immediately after the reaction using a glass thermometer. Method A: using inorganic solid support; method B: neat one-pot synthesis. All
compounds gave satisfactory elemental analysis (C, H and N) within Æ .25% of theoretical value.

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A. Dandia et al. / Journal of Fluorine Chemistry 125 (2004) 1835–1840
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nol yielding 91% of IVa (path I).
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Offen DE 19,918 574 (1999);
In order to verify the viability of path II under the above
conditions, a mixture of phenyl acetyl anilide VI (2 m mol)
and anthranilic acid (2 m mole) was irradiated (5 min, TLC).
The resultant residue was crystallized from ethanol to give
IVa yield = 90%.
The identity of compounds synthesized by various
method was established by their mixed mp, IR and 1H
NMR spectral studies.
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All compounds IVb–f listed in Table 6 were similarly
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in high yield and reduced time.
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authors (R.S.) is also grateful for providing SRF. We are also
thankful to Department of Pathology, Durgapura, Jaipur for
antifungal screening and RSIC, CDRI, Lucknow, for the
elemental and spectral analyses.
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