Solvent Free Synthesis of Quinazolin-4(3H)-ones

1. 1019
Solvent-free syntheses of some quinazolin-4(3H)-
ones derivatives
S. Mohana Roopan, T. Maiyalagan, and F. Nawaz Khan
Abstract: Solvent-free syntheses of quinazolin-4(3H)-ones were performed by reaction of anthranillic acid with differ-
ent amides, such as nicotinamide, benzamide, formamide, etc., on montmorillonite K-10. Products were confirmed by
FTIR, 1HNMR, and 13CNMR spectroscopic techniques. All synthesized compounds exhibited antioxidant properties and
have been compared with standard antioxidant BHT.
Key words: quinazolinone, montmorillonite K-10, solvent-free conditions, antioxidant properties.
Résumé : On a réalisé des synthèses sans solvant de quinazolin-4(3H)-ones par réaction de l’acide anthranillique avec
divers amides, tel le nicotinamide, le benzamide et le formamide sur de la montmorillonite K-10. Les produits ont été
caractérisés par la spectroscopie infrarouge avec transformée de Fourier (IR-TF), et par les méthodes spectroscopiques
de RMN du 1H et du 13C. Tous les produits synthétisés présentent une propriété antioxydante et ils ont été comparés
avec l’antioxydant standard, BHT.
Mots-clés : quinazolinone, montmorrillonite K-10, conditions sans solvant, propriétés antioxydante
[Traduit par la Rédaction] Roopan et al. 1025
Introduction tally and industrially important organic syntheses that are
more effective and eco-friendly than conventional reactions
The quinazoline ring skeleton is widely found in alkaloids (19, 20).
and many biologically active compounds. In general, quina- In continuation of our interest in C–C bond-forming reac-
zolones were considered important compounds in the fields tions (21–25), we have explored a one-pot synthesis of
of pharmacology and biology (1) because of their wide range quinazolin-4(3H)-ones (Schemes 1 and 2, Tables 1 and 2)
of strong biological activities (2–6). Some of these com- from anthranillic acid and amides, such as formamide,
pounds are identified as drugs (7) and as diuretics. Among acetamide, benzamide, nicotinamide, etc., in the presence of
this class of molecules, quinazolin-4-ones and their deriva- montmorillonite K-10 catalyst and other inorganic catalysts
tives are well-known to possess an array of physiological such as acidic alumina, bentonite, etc., (Table 3), under
activities, e.g., antitubercular (8), antifungal (9), antibacterial solvent-free conditions. The above reactions, carried out
(10), anti-inflammatory, anticancer (11), and anti-proliferative over montmorillonite K-10 clay, give good yields because of
(5) activities. the ditopic nature (26, 27) of montmorillonite K-10 clay.
Quinazolin-4(3H)-one was prepared by many methods (5, However, the reaction takes less time to complete. The opti-
8, 10–13). However, quinazoline derivatives were synthe- mization of catalyst amount was also done (Table 4). Thus,
sized mainly by a common approach involving amidation, we have developed a simple, economical, and environmen-
starting from anthranilic acid, 2-aminobenzonitrile, and 2- tally benign synthesis of classical procedures, by avoiding
aminobenzamide. Other methods included the condensation volatile and toxic organic solvents. The reusability of the
of anthranilic acid, ammonium acetate, and the orthoesters catalyst in synthesis has also been explored (Table 5). Scope
(14), reaction of imidates and anthranilic acid (15), reaction of the reaction (Tables 1 and 2) and antioxidant properties of
of polymer-bound isothioureas with isatoic anhydride deriv- the reaction products have also been discussed.
atives (16), and were associated with drawbacks such as
multistep procedures (17), costly reagents, harse reaction
conditions, complex experimental procedures, and low Experimental
yields (18). Previous methods have been excluded from Anthranillic acid and amides used for the reaction were
practical applications because of environmental and eco- from Sigma-Aldrich Co., and montmorillonite K-10 was ob-
nomic considerations. Finding an efficient method for the tained from Fluka. The substances were used as provided
synthesis of quinazolin-4(3H)-one is still a challenge. Nowa- with no other purification. Melting points were taken in
days, solvent-free organic reactions have led to experimen- open capillary tubes and are corrected with reference to ben-
Received 17 March 2008. Accepted 29 August 2008. Published on the NRC Research Press Web site at canjchem.nrc.ca on
8 October 2008.
S.M. Roopan, T. Maiyalagan,1 and F.N. Khan.1 School of Science and Humanities, Organic Chemistry Division, VIT University,
Vellore 632 014, Tamil Nadu, India.
1
Corresponding authors (e-mail: maiyalagan@gmail.com, nawaz_f@yahoo.co.in).
Can. J. Chem. 86: 1019–1025 (2008) doi:10.1139/V08-149 © 2008 NRC Canada

2. 1020 Can. J. Chem. Vol. 86, 2008
Table 1. Synthesis of 2-substituted quinazolinone by solvent-free montmorillonite K-10 catalysis.
Scheme 1. Montmorillonite K-10 catalysed reaction of Scheme 2. Montmorillonite K-10 catalysed reaction of
anthranillic acid and different amides. anthranillic acid with urea and thiourea.
zoic acid. IR spectra in KBr pellets were recorded on Nucon General procedure for the synthesis of 2-substituted-
infrared spectrophotometer. Nuclear Magnetic Resonance 3H-quinazolin-4-ones and 1H,3H-quinazolin-2,4-diones
(1H and 13C) spectra were recorded on a Bruker Spectrospin A mixture of anthranillic acid, 1 amide, 2 or 4a or 4b, and
Avance DPX400 Ultrashield (400 MHz) spectrometer. montmorillonite K-10 clay when heated under reflux
Chemical shifts are reported in parts per million (δ) conditions gave 2-substituted-3H-quinazolin-4-one 3 or
downfield from an internal tetramethylsilane reference. 1H,3H-quinazolin-2,4-dione 5 (Scheme 1). After completion
© 2008 NRC Canada

3. Roopan et al. 1021
Table 1 (concluded).
Note: 1 = 10 mmol, 2 = 10 mmol, catalyst = 0.1 g.
a
3 in isolated yields after column chromatography.
b
All products were characterized by 1H NMR and IR spectroscopic data and their melting points were compared with
literature values (31–32).
of the reaction, ethyl acetate was added to the reaction mix- Synthesis of 2-pyridin-3-yl-3H-quinazolin-4-one (3a)
ture, and the catalyst was recovered by filtration. Filtrate Anthranillic acid 1 (10 mmol), nicotinamide 2a
was washed with a 10% NaHCO3 solution to remove any (10 mmol), and montmorillonite K-10 (0.1 g) were placed in
unreacted acid and further washed with water to remove any a mortar and mixed well, transferred to a 50 mL round-
inorganic materials. The organic layer was dried, solvent bottomed flask, and refluxed at 150 °C for 30 min. The reac-
evaporated to obtain the products. FT-IR and NMR spectral tion was monitored by TLC, and after completion of the re-
techniques were used for product analysis. action, work-up was performed as above to give crude
© 2008 NRC Canada

4. 1022 Can. J. Chem. Vol. 86, 2008
Table 2. Synthesis of quinazolidione by solvent-free montmorillonite K-10 catalysis.
Note: 1 = 10 mmol, 4 = 10 mmol, catalyst = 0.1g.
a
5 in isolated yields.
Table 3. Selection of catalyst.
Refluxing at 150 °C solvent-free conditions
Sl. No. Catalyst used Catalyst amount (mg) Time (h) Product 3a
1 Silica gel 10 4 Nil
2 Bentonite 10 4 Nil
3 Montmorillonite KSF 10 4 Nil
4 Acidic alumina 10 4 Low yield
5 Montmorillonite K10 10 0.5 High yield
Note: Anthranilic acid 1 (1 mmol) and nicotinamide 2a (1 mmol).
Table 4. Optimization of catalyst concentration.
Refluxing at 150 °C solvent-free conditions
Amide, R Montmorillonite Time Product 3a Yielda
Sl. No. RCONH2 K-10 (g) (h) (R) (%)
1 -C5H4N None 2 -C5H4N 40
2 -C5H4N 0.02 1 -C5H4N 59
3 -C5H4N 0.04 1 -C5H4N 67
4 -C5H4N 0.06 1 -C5H4N 65
5 -C5H4N 0.08 0.5 -C5H4N 71
6 -C5H4N 0.1 0.5 -C5H4N 85
7 -C5H4N 0.12 0.5 -C5H4N 86
8 -C5H4N 0.14 0.5 -C5H4N 86
Note: 1 = 10 mmol, 2a = 10mmol, refluxed at 150 °C.
a
3a in isolated yields.
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5. Roopan et al. 1023
Table 5. Life cycle of catalyst. Fig. 1. Time vs. absorbance graph for antioxidant property of
quinazolinone derivatives.
Catalyst Yield
Entry Cycle No. amount (g) (%)
1 Cycle I 0.1 85
2 Cycle II 0.096 82
3 Cycle III 0.091 81
product. Pure 2-pyridin-3-yl-3H-quinazolin-4-one 3a was
obtained by performing column chromatography using silica
gel and petroleum ether/ethyl acetate as eluent. Yield was
determined (Table 1, compound 3a). The quinazolinone 3a
was recrystallized from petroleum ether and ethyl acetate.
The melting point was found to be 114 °C.
A similar procedure was followed to obtain other
quinazolinone derivatives 3 from different amides 2
(Scheme 1 and Table 1). Products were characterized by
FTIR, 1HNMR, 13CNMR, and GCMS spectral techniques,
and known compounds were compared with literature re-
ports. The recrystallization of products was effected using
petroleum ether and ethyl acetate.
tems. In this study, the free-radical scavenging activity of
Synthesis of 1H,3H-quinazolin-2,4-dione (5a)
quinazolin-4(3H)-ones derivative was measured by a 1,1-
A mixture of anthranillic acid 1 (10 mmol), urea 4a
diphenyl-2-picryl-hydrazyl (DPPH) method. This activity
(10 mmol), and 0.1 g of montmorillonite K-10 was heated
was measured by the following Blos methodology as as-
under reflux conditions (150 °C) for 2 h. After completion
sessed by Ansari et al. (28). The absorbance of DPPH is
of the reaction, the catalyst was removed by filtration; the
monitored at a characteristic wavelength in the presence of a
mixture was poured into ice-cooled water and extracted with
synthesized sample. In its radical form, DPPH absorbs at
ethyl acetate. The product 5a, obtained after solvent re-
517 nm, but upon reduction by an antioxidant or a radical
moval, was purified by performing column chromatography
species its absorption decreases. Briefly, a 1.5 × 10–4
using silica gel and petroleum ether/ethyl acetate as eluent
(Scheme 2, Table 2). The quinazolindione 5a was mmol/L solution of DPPH in ethanol was prepared and 1
recrystallized from petroleum ether and ethyl acetate. The mL of this solution was added to 3 mL of 1.5 × 10–4 mmol/L
melting point was found to be >300 °C. of quinazolinone in ethanol. At each 5 min interval,
absorbance was measured at 517 nm until 30 min. The stan-
dard used was butylated hydroxyl toluene (BHT), (1.5 × 10–
Synthesis of 2-thioxo-2,3-dihydro-1H-quinazolin-4-one 4
mmol/L) in ethanol solution. Lower absorbance of reaction
(5b)
A mixture of anthranillic acid 1 (10 mmol), thiourea 4b mixture indicates higher free-radical scavenging activity.
(10 mmol), and 0.1 g of montmorillonite K-10 was heated Absorbance of the DPPH (control) is 1.544. The capability
under reflux conditions (150 °C) for 2 h. After completion to scavenge DPPH radical (28, 29) was calculated using the
of the reaction, the catalyst was removed; the mixture was following equation,
poured into ice-cooled water and extracted with ethyl ace- DPPH Scavenging effect (%)
tate. The product 5b, obtained after solvent removal, was pu-
rified by column chromatography (Scheme 2, Table 2). The = [(Acontrol – Asample / Acontrol) * 100]
dihydroquinazolinone 5b was recrystallized from ethyl ace- where Acontrol is the absorbance of the DPPH solution and
tate. The melting point was found to be >300 °C. Asample is the absorbance in the presence of quinazolinone.
Two different graphs (Figs. 1 and 2) are plotted with time
Life cycle of the catalyst vs. absorbance and time vs. % inhibition.
The reusability of catalyst was explored by checking the
successive runs of the reactions on recycled catalyst; i.e., af- Results and discussion
ter first run of the reaction, the catalyst was recovered by a
simple filtration from reaction mixture, washed with ethyl Solvent-free syntheses of quinazolinone 3a from
acetate, and dried. Then it was utilized in the second run of anthranillic acid 1 and nicotinamide 2a have been explored
the reaction. It was noticed that use of recycled catalyst in by using inorganic catalysts such as montmorillonite K-10,
subsequent experiments gave similar yields (Table 5). Thus, silica gel, acidic alumina, etc. (Table 3). Preliminary results
the catalyst is not leached. indicated the formation of quinazolinone in high yield only
in the case of montmorillonite K-10. The optimization of
Free-radical scavenging activity of quinazolinone catalyst amount was done to improve the yield (Table 4).
derivatives Montmorillonite K-10 has had a great impact in organic syn-
Radical scavenging activities are very important due to the thesis and has offered major breakthroughs for the manufac-
deleterious role of free radicals in foods and biological sys- ture of fine chemicals. This reagent has advantages over the
© 2008 NRC Canada

6. 1024 Can. J. Chem. Vol. 86, 2008
Fig. 2. Time vs. % inhibition graph for antioxidant property of compared with commercial antioxidant butylated hydroxyl
quinazolinone derivatives. toluene (BHT). 2-Thioxo-2,3-dihydro-1H-quinazolin-4-one
had relatively high DPPH radical-scavenging activity. As
shown in Figs. 1 and 2, all quinazolinone derivatives were
found to have the ability to scavenge hydroxyl radical at a
concentration of 1.5 × 10–4 mmol/L.
Analytical data
Data of the new compound 3a and that of a few known
compounds, 3b–3d, 5a–5b, which have not been reported
earlier are given below. The data of a few compounds that
have been found to be identical to those reported (30–32) are
given as Supplementary Data available with this paper.2
2-Pyridin-3-yl-3H-quinazolin-4-one (3a)
Colourless solid, mp 114 °C. IR (KBr pellets, cm–1) ν:
3351.67, 1655.03, 1601.16, 1585.32, 1535.27, 1491.45. 1H
NMR (300MHz, CDCl3) δ: 9.1 (s, 1H), 8.76–8.75 (d, J =
4.56Hz, 1H), 8.23–8.20 (d, J = 7.77Hz, 1H), 8.13 (s, 1H),
7.66–7.64 (d, 1H), 7.46–7.41 (m, 1H), 7.39–7.36 (d, J =
7.56, 2H), 7.21–7.16 (m, 1H). 13C NMR (100 MHz, CDCl3)
δ: 163.92 (C=O), 152.37, 147.82, 137.49, 135.49, 130.86,
conventional homogeneous solution techniques: easy set-up
129.17, 125.08, 123.73, 120.51. EI-Mass: 223. GC-MS m/z
and work-up, mild experimental conditions, and high yield.
223 (M+) C13H9N3O (mol. wt. 223.23) calcd.: C 69.95, H
As part of our research, quinazolin-4(3H)-ones were synthe-
4.06, N 18.82, O 7.17; found: C 69.83, H 4.14, N 18.75, O
sized using K-10 as catalyst (Schemes 1 and 2). The results
7.01.
of the quinazolinones synthesis are summarized (Tables 1–
5). The essence of the catalyst can be understood from the 2-Phenyl-3H-quinazolin-4-one (3b)
following facts: when anthranillic acid 1 was treated with Mp 242–246 °C (lit. value (32), 242–246 °C). IR (KBr
montmorillonite K-10 under conventional heating in the pellets, cm–1) ν: 3342.55, 1654.76, 1437.47. 13C NMR
presence of nicotinamide 2a, the product 3a was obtained in (100MHz, CDCl3) δ: 165.70 (C=O), 137.85, 134.93, 131.78,
quantitative yield (Table 3, entry 5). When the same reaction 129.03, 128.72, 126.95, 124.51, 120.14. C14H10N2O (mol.
was performed without montmorillonite catalyst, 3a was wt. 222.24) calcd.: C 75.66, H 4.54, N 12.60, O 7.20; found:
obtained in much lower yield in 2 h (Table 4, entry 1). The C 75.54, H 4.46, N 12.52, O 7.11.
reaction optimization with different amounts of montmoril-
lonite K-10 was carried out, and at 0.1 g, the yield was good 2-Methyl-3H-quinazolin-4-one (3c)
(Table 4). Mp 240–248 °C (lit. value (32), 238–240 °C). IR (KBr
In the IR spectra of all 4-quinazolinones 3, absorption pellets, cm–1) ν: 3295.81, 1666.07, 1434.67. C9H8N2O (mol.
bands are observed in the region of 1690–1730 (Ar C=O), wt. 160.17) calcd.: C 67.49, H 5.03, N 17.49, O 9.99; found:
1600–1635, 1510–1570, 1460–1500 cm –1 (the quinazolone C 67.31, H 5.13, N 17.51.
ring). Assignments of 1H NMR signals of quinazolinones 3
were derived from splitting patterns and characteristic chem- 3H-Quinazolin-4-one (3d)
ical shift values. The data consistently show that the White solid, mp 216 °C (lit. value (32), 215–216 °C). IR
homocyclic proton signal with the lowest field shift in series (KBr pellets, cm–1) ν: 3428.88, 1704.98, 1665.87. 13C NMR
of compounds is a doublet with additional fine structure due (75MHz, CDCl3) δ: 143.34, 134.89, 127.76, 127.42, 126.35.
to further meta and para couplings. This signal is assigned C8H6N2O (mol. wt. 146.15) calcd.: C 65.75, H 4.14, N
to H-5 on the basis of the proximity to the carbonyl group. 19.17, O 10.95; found: C 65.80, H 4.03, N 19.04, O 10.86.
The assignment of H-5 led to the assignment of H-8 by de-
fault. In the same spectral region, the signal for H-2 is found (4-Oxo-quinazolin-2yl)-acetonitrile (3e)
as a singlet. The signals for protons H-6 and H-7 show two Colourless solid, mp 240 °C (lit. value (32), 242 °C.
ortho couplings. We have assigned the H-7 signal to the C10H7N3O (mol. wt. 185.18) calcd.: C 64.86, H 3.81, N
lower field. 22.69, O 8.64; found: C 64.74, H 3.91, N 22.57, O, 8.58.
In the present study, quinazolinone derivatives were evalu-
ated for their free-radical scavenging activity using the 2-(4-Methylphenyl)quinazolin-4(3H)-one (3g)
DPPH radical assay. Reduction of DPPH radicals can be ob- Colourless solid, mp 240 °C (lit. value (31), 239 °C). 13C
served by a decrease in absorbance at 517 nm. Different de- NMR (75MHz, CDCl3) δ: 159.9, 147.34, 146.20, 134.31,
rivatives of quinazolinones reduced DPPH radicals 133.20, 131.58, 128.15, 127.12, 126.35, 125.14, 124.81,
significantly. The activity of quinazolinone derivatives was 124.13, 122.11, 19.30. GC-MS m/z 236 (M+).
2
Supplementary data for this article are available on the journal Web site (canjchem.nrc.ca) or may be purchased from the Depository of
Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 3833. For more
information on obtaining material refer to cisti-icist.nrc-cnrc.gc.ca/cms/unpub_e.shtml.
© 2008 NRC Canada

7. Roopan et al. 1025
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easy product isolation, coupled with high purity and yields. 23. V.R. Hathwar, P. Manivel, F. Nawaz Khan, and T.N. Guru
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24. V.R. Hathwar, P. Manivel, F. Nawaz Khan, and T.N. Guru
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© 2008 NRC Canada