Efficient iodine-catalyzed synthesis of 3-Aryl 4(3H)-quinazolinones

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Efficient Iodine-catalyzed Synthesis of 3-
Aryl 4(3H)-quinazolinones
Min Wang a , Zhi-Guo Song b & Ting-Ting Zhang a
a College of Chemistry and Chemical Engineering , Bohai University ,
Jinzhou, P. R. China
b Center for Science & Technology Experiment , Bohai University ,
Jinzhou, P. R. China
Published online: 07 Apr 2010.
To cite this article: Min Wang , Zhi-Guo Song & Ting-Ting Zhang (2010) Efficient Iodine-catalyzed
Synthesis of 3-Aryl 4(3H)-quinazolinones, Organic Preparations and Procedures International: The New
Journal for Organic Synthesis, 42:2, 169-173, DOI: 10.1080/00304941003697669
To link to this article: http://dx.doi.org/10.1080/00304941003697669
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Organic Preparations and Procedures International, 42:169–173, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304941003697669
Efficient Iodine-catalyzed Synthesis of 3-Aryl
4(3H)-quinazolinones
Min Wang,1 Zhi-Guo Song,2 and Ting-Ting Zhang1
1College of Chemistry and Chemical Engineering, Bohai University, Jinzhou,
P. R. China
2Center for Science & Technology Experiment, Bohai University, Jinzhou,
P. R. China
Compounds with a 4-quinazolinone motif have displayed a variety of interesting phar-
macological properties such as antimalarial, antitumor, anticonvulsant, antiinflammatory,
fungicidal, antimicrobial and calcilytic activities.1–7 An examination of the literature in-
dicates that 4-quinazolinones substituted at the 3-position are attracting the attention of
chemists because they appear to have important sedative, hypnotic and anticonvulsive
effects.8 There are several methods for the preparation of this class of compounds. The
most direct procedure includes the condensation of anthranilic acid, ortho esters and amines
in the presence of various catalysts such as NaHSO4 or Amberlyst-15,9 Yb(III)-resin,10
Yb(OTf)3,11 Bi(TFA)3-[nbp]FeCl4 ionic liquid,12 La(NO3)3·6H2O or p-toluenesulfonic
acid,13 Keggin-type heteropolyacid,14 SnCl4·4H2O,15 and SiO2-FeCl3.16 While this type
of multi-component reaction (MCR) can produce the desired products in a single step,
some of these methods have certain drawbacks such as expensive catalysts, high temper-
atures (60–80◦C), long reaction times (20 h), and the use of harmful organic solvents.
Most so-called “solvent-free” techniques still require an organic solvent such as CH2Cl2
during work up to remove the support, reagents or side-products. Therefore, it is desirable
to develop simple, efficient, and green methods for the synthesis of 4(3H)-quinazolinones.
In this regard, in recent years, molecular iodine has received considerable atten-
tion as an inexpensive and easily available catalyst for various organic transforma-
tions such as esterification,17 oxidation,18 acetylation,19 Hantzsch,20 Biginelli reaction,21
aziridination,22 allylation,23 Michael addition,24 Johnson–Claisen rearrangement,25 and
Diels–Alder reactions.26 We report the synthesis of 3-aryl 4(3H)-quinazolinones by the
condensation of anthranilic acid 1, ortho esters 2 and aromatic amines 3 in the presence of
a catalytic amount of I2 at room temperature without solvent (Scheme 1).
A model reaction of anthranilic acid with triethyl orthoformate and aniline carried out
at room temperature in the absence of catalyst gave only a 5% yield after 1 h. However, a
Submitted November 6, 2009.
Address correspondence to Min Wang, College of Chemistry and Chemical Engineering, Bohai
University, Jinzhou 121000, P. R. China. E-mail: minwangszg@yahoo.com.cn
169

170
Wang, Song, and Zhang
O
N
R1
COOH
NH2
I
N
2 (3 mol%)
r.t.
HC(OR)3
R1NH2
)
4 (a-o
1
2
3
Scheme 1
quantitative yield (99%) of the product was obtained after only 40 min when 3 mol% of
iodine was added. It was observed that 3 mol% of iodine catalyzed the reaction efficiently
but increasing the amount of catalyst did not lead to better yields.
Table 1 illustrates the scope and generality of the reaction of anthranilic acid 1, triethyl
or trimethyl orthoformate 2, and different aryl amines. Aryl amines carrying either electron-
donating or electron-withdrawing groups reacted smoothly at room temperature and, except
in the case of 2-nitroaniline, steric effects did not influence the yields significantly. Although
benzylamine gave a moderate yield of the desired product (Entry 4n), no product was
Table 1
I2-Catalyzed Synthesis of 3-Substituted 4(3H)-Quinazolinones 4(a-o)a
mp (◦C)
Timeb (time)c
(min)
Yieldb (yield)c
(%)
Product
R1
Found
lit.11
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
Ph
40 (30)
90 (120)
180 (360)
18 (42)
40 (90)
18 (30)
5 (10)
9 (120)
6 (12)
330 (150)
5 (2)
99 (92)
99 (99)
99 (60)
97 (87)
99 (99)
99 (92)
86 (78)
81 (90)
98 (82)
41 (45)
82 (93)
99 (99)
87 (86)
30 (61)
0 (0)
140–141
158–159
137–139
143–146
151–153
132–134
117–120
122–124
149–151
153–155
150–153
166–168
240–242
154–155
—
139–140
—
136–137
146–147
—
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
4-MeOC6H4
2-ClC6H4
—
—
—
—
4-ClC6H4
4-BrC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-HO2CC6H4
PhCH2
156–158
154–156
165–166
—
5 (2)
1 (1)
2 (30)
1200 (1200)
—
—
n-C4H9
1
a) The structures of the products were determined from spectral (IR and H NMR) data and
elemental analysis.
b) Time and yield with triethyl orthoformate.
c) Time and yield with trimethyl orthoformate.

Synthesis of 3-Aryl 4(3H)-quinazolinones
171
obtained from n-butylamine (Entry 4o). All crude products after simple washing were pure
enough (testified by elemental analysis) without further purification.
In summary, we disclose here an efficient method for multi-component synthesis of
4(3H)-quinazolinones under mild conditions, with simple work-up, and using ethanol as
the only solvent.
Experimental Section
Melting points were determined using an RY-1 micromelting point apparatus and were
uncorrected. Infrared spectra were recorded on a Scimitar 2000 series Fourier Transform
instrument of VARIAN. 1H NMR spectra were recorded on a Bruker ARX-500 spectrometer
in DMSO-d6 using TMS as an internal standard. Elemental analyses were carried out on
an EA 2400II elemental analyzer (Perkin-Elmer).
Representative Procedure for the Synthesis of 4(a–o)
A mixture of anthranilic acid (1.371 g, 10 mmol), the orthoester (12 mmol), the amine
(12 mmol), and I2 (0.076 g, 0.3 mmol) was stirred at room temperature for an appropriate
time (Table 1). The reaction was monitored by TLC (silica gel 60 F 254 TLC plates,
cyclohexane: ethyl acetate, 1: 1 v/v). After completion of the reactions, all products were
collected and washed thoroughly with EtOH during filtration and dried. All crude products
thus obtained were sufficiently pure (single spot on TLC) without further purification. The
1
obtained products were identified by IR, H NMR, and elemental analysis. Spectral data
and elemental analysis for new compounds are as follows:
3-(2-Methylphenyl)quinazolin-4(3H)-one (4b), white solid. IR (KBr): 1688, 1595,
1
1489 cm−1; H NMR (500 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.31 (d, J = 7.2 Hz, 1H),
7.76–7.52 (m, 2H), 7.24–7.07 (m, 5H), 2.31 (s, 3H).
Anal. Calcd. for C15H12N2O: C, 76.26; H, 5.12. Found: C, 76.38; H, 5.09.
3-(2-Methoxyphenyl)quinazolin-4(3H)-one (4e), white solid. IR (KBr): 1682, 1595,
1456 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 8.36 (s, 1H), 8.19 (d, J = 7.7 Hz, 1H), 7.45
(d, J = 6.8 Hz, 1H), 7.25 (t, J = 7.0 Hz, 1H), 7.08–7.03 (m, 2H), 6.94 (t, J = 7.1 Hz, 1H),
6.78 (d, J = 8.2 Hz, 1H), 6.54 (t, J = 7.3 Hz, 1H), 3.85 (s, 3H).
Anal. Calcd. for C15H12N2O2: C, 71.42; H, 4.80. Found: C, 71.31; H, 4.83.
3-(4-Methoxyphenyl)quinazolin-4(3H)-one (4f), white solid. IR (KBr): 1717, 1591,
1
1454 cm−1; H NMR (500 MHz, DMSO-d6): δ 8.54 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H),
7.54–7.51 (m, 2H), 7.16 (t, J = 7.5 Hz, 1H), 6.98 (dd, J = 8.5, 9.5 Hz, 4H), 3.74 (s, 3H).
Anal. Calcd. for C15H12N2O2: C, 71.42; H, 4.80. Found: C, 71.30; H, 4.84.
3-(2-Chlorophenyl)quinazolin-4(3H)-one (4g), yellow solid. IR (KBr): 1667, 1601,
1
1415 cm−1; H NMR (500 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.01 (d, J = 7.7 Hz, 1H),
7.73–7.71 (m, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.25–7.16 (m, 2H), 6.76 (d, J = 8.1 Hz, 1H),
6.54 (t, J = 7.2 Hz, 1H).
Anal. Calcd. for C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91. Found: C, 65.63; H, 3.50;
N, 10.88.
3-(4-Chlorophenyl)quinazolin-4(3H)-one (4h), pale yellow solid. IR (KBr): 1671,
1
1616, 1484 cm−1; H NMR (500 MHz, DMSO-d6): δ 8.53 (s, 1H), 7.71–7.69 (m, 2H),
7.24–7.19 (m, 2H), 6.75 (d, J = 7.5 Hz, 2H), 6.52 (d, J = 7.2 Hz, 2H).

172
Wang, Song, and Zhang
Anal. Calcd. for C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91. Found: C, 65.62; H, 3.51;
N, 10.86.
3-(4-Bromophenyl)quinazolin-4(3H)-one (4i), white solid. IR (KBr): 1712, 1587,
1443 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.60
(t, J = 7.5 Hz, 1H), 7.46–7.43 (m, 4H), 7.19 (d, J = 7.5 Hz, 2H).
Anal. Calcd. for C14H9BrN2O: C, 55.84; H, 3.01; N, 9.30. Found: C, 55.73; H, 3.00;
N, 9.36.
3-(4-Carboxylphenyl)quinazolin-4(3H)-one (4m), white solid. IR (KBr): 1701,
1592, 1483 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.34 (s, 1H), 7.92–7.88
(m, 3H), 7.71 (t, J = 8.5 Hz, 2H), 7.63 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 6.56
(d, J = 5.5 Hz, 1H).
Anal. Calcd. for C15H10N2O3: C, 67.67; H, 3.79. Found: C, 67.77; H, 3.76.
3-Benzylquinazolin-4(3H)-one (4n), white solid. IR (KBr): 1678, 1621, 1459 cm−1
;
1H NMR (500 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.54–7.47 (m,
2H), 7.41–7.37 (m, 4H), 7.31 (t, J = 6.8 Hz, 1H), 7.14 (t, J = 7.0 Hz, 1H), 4.61 (s, 2H).
Anal. Calcd. for C15H12N2O: C, 76.26; H, 5.12. Found: C, 76.39; H, 5.08.
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