A novel, one-pot, solvent-, and catalyst-free synthesis of 2-aryl/alkyl-4(3H)-quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2009.06.034

A novel and one-pot synthesis of 2-aryl/alkyl-4(3H)-quinazolinones is described. The in situ prepared amidoximes from the reaction between nitriles and hydroxylamine are condensed with anthranilic acids under solvent- and catalyst-free conditions to produ

Full text of DOI:10.1016/j.tetlet.2009.06.034

Tetrahedron Letters 51 (2010) 30–32
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel, one-pot, solvent-, and catalyst-free synthesis of
2-aryl/alkyl-4(3H)-quinazolinones
a
a
b
Mehdi Adib a, , Samira Ansari , Ali Mohammadi , Hamid Reza Bijanzadeh
*
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
b Department of Chemistry, Tarbiat Modarres University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and one-pot synthesis of 2-aryl/alkyl-4(3H)-quinazolinones is described. The in situ prepared
amidoximes from the reaction between nitriles and hydroxylamine are condensed with anthranilic acids
under solvent- and catalyst-free conditions to produce the title compounds in excellent yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 October 2008
Revised 26 May 2009
Accepted 5 June 2009
Available online 11 June 2009
Keywords:
Anthranilic acids
Nitriles
Amidoximes
2-Aryl/alkyl-4(3H)-quinazolinones
Solvent-free
Catalyst-free
4(3H)-Quinazolinones, an important class of fused heterocyclic
compounds,1,2 have attracted much synthetic attention because of
their wide range of pharmacological and therapeutic activities such
as anticancer,3 antiinflammatory,4 anticonvulsant,5 antiulcer,6 and
hypolipidemic.7 Some quinazolinones have been reported as po-
tent chemotherapeutic agents in the treatment of tuberculosis.8
The bioactive natural products, febrifugine and isofebrifugine, con-
tain a quinazolinone moiety and possess antimalarial activity.9,10
The most common approach for the preparation of 2-aryl/alkyl-
4(3H)-quinazolinones involves amidation of anthranilonitrile,
anthranilic acid, or anthranilamide followed by cyclization of the
resulting intermediate.11–13 Other methods involve condensation
of imidates with anthranilic acid,14,15 hetero-Diels–Alder
reaction of 1-aryl-4-dimethylamino-2-phenyl-1,3-diaza-1,3-but-
adienes and phenyl isocyanate,16 reaction of nitriles with lithiated
anthranilamides,17 thermolysis of 3-arylideneamino-1,2,3-benzo-
triazin-4-ones,18 and direct condensation of aldehydes and anthra-
nilamide or its derivatives in the presence of CuCl2.19 However,
most of these multi-step procedures have significant drawbacks
such as long reaction times, low yields of the products, harsh reac-
tion conditions, difficult work-up, and the use of expensive and
environmentally toxic catalysts, reagents, or media. Furthermore,
some of the starting materials have to be synthesized and purified
first, hence these methods are time-consuming. The development
of simple and efficient methods for the synthesis of 4(3H)-quinaz-
olinones is therefore desirable.
Taking into account the pharmacological importance of
4(3H)-quinazolinones, and as part of our continuing efforts on
the development of new routes for the preparation of biologically
active heterocyclic compounds,20 we have recently focused on
improving the synthesis of this nucleus.
Herein we report a novel synthesis of 4(3H)-quinazolinones via
a one-pot reaction. Thus, a mixture of a nitrile 1 and hydroxyl-
amine was converted in situ into amidoxime 2. Next, the amidox-
ime was condensed with anthranilic acids 3 under solvent- and
catalyst-free conditions to produce 2-aryl/alkyl-4(3H)-quinazoli-
nones 4a–s in 85–93% yields (Scheme 1).
The reactions were carried out by first heating the mixture of
the nitrile and hydroxylamine under solvent-free conditions. After
nearly complete conversion into an intermediate presumed to be
amidoxime 2 (as indicated by TLC), the anthranilic acid 3 was
added to the reaction mixture which was heated for a further 2 h
at 150 °C. 1H NMR analysis of the reaction mixtures clearly indi-
cated formation of 4(3H)-quinazolinones 4 in excellent yields.21
When the reaction was performed by heating a mixture of a ni-
trile, hydroxylamine, and an anthranilic acid via a one-step proce-
dure, the corresponding 4(3H)-quinazolinone was obtained in
much lower yields on the basis of NMR analysis of the reaction
mixture. On the other hand, when hydroxylamine was omitted
from the reaction mixture, the corresponding 4(3H)-quinazolinone
was formed in much lower yields under the same conditions.
* Corresponding author. Tel./fax: +98 21 66495291.
E-mail address: madib@khayam.ut.ac.ir (M. Adib).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.034

M. Adib et al. / Tetrahedron Letters 51 (2010) 30–32
31
CO2H
NH2
X
O
N
3
X
NH2
NH
solvent-free
120 OC, 1.5 h
R
NH2OH
+
RCN + NH2OH
solvent-free
150 OC, 2 h
R
NOH
4
1
2
4 R
X
% Yielda
a C6H5
b 4-H3CC6H4
H
90
91
92
87
91
85
89
90
H
H
H
H
H
H
H
c
4-FC6H4
d 3-ClC6H4
e
f
4-ClC6H4
4-BrC6H4
g 4-CH3OC6H4
h 4-O2NC6H4
i
j
C6H5
4-H3CC6H4
Cl 88
Cl 90
Cl 92
Cl 86
Cl 90
k 4-FC6H4
3-ClC6H4
m 4-ClC6H4
l
n 4-CH3OC6H4 Cl 88
o CH2C6H5
p CH2C6H5
H
93
Cl 90
q CH2CH2C6H5
H
92
89
r
s
CH2CH2C6H5 Cl 88
CH2CH2CH3
H
a Isolated yield
Scheme 1.
2. Armarego, W. L. F. Fused Pyrimidines, Part 1: Quinazolines; Interscience: New
York, 1967.
3. Cao, S.-L.; Feng, Y.-P.; Jiang, Y.-Y.; Liu, S.-Y.; Ding, G.-Y.; Li, R.-T. Bioorg. Med.
Chem. Lett. 2005, 15, 1915–1917.
4. Kenichi, O.; Yoshihisa, Y.; Toyonari, O.; Toru, I.; Yoshio, I. J. Med. Chem. 1985, 28,
568–576.
5. Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.; Greenwood, T. D. J. Med.
Chem. 1990, 33, 161–166.
When the reactions were carried out using an amine such as
aniline or benzylamine, instead of hydroxylamine, a complex mix-
ture was obtained and most of the anthranilic acid, the nitrile, and
the amine were recovered unchanged. The nucleophilicity of these
amines is less than that of hydroxylamine and amidoxime forma-
tion is not possible as a result.
6. Tereshima, K.; Shimamura, H.; Kawase, A.; Tanaka, Y.; Tanimura, T.; Kamisaki,
T.; Ishizuka, Y.; Sato, M. Chem. Pharm. Bull. 1995, 43, 2021–2023.
7. Kurogi, Y.; Inoue, Y.; Tsutsumi, K.; Nakamura, S.; Nagao, K.; Yohsitsugu, H.;
Tsuda, Y. J. Med. Chem. 1996, 39, 1433–1437.
The structures of the isolated products were confirmed by ele-
mental analyses and from spectral data (mass, 1H, and 13C NMR
spectra) and by comparison of their mp values with those of
authentic samples.21
ˇ
8. Kuneš, J.; Bazant, J.; Pour, M.; Waisser, K.; Šlosárek, M.; Janota, J. Il Farmaco.
2000, 55, 725–729.
In conclusion, we have developed a novel and one-pot reaction
of nitriles, hydroxylamine, and anthranilic acids for the preparation
of 4(3H)-quinazolinones of potential synthetic and pharmacologi-
cal interest. The simplicity of the starting materials, excellent
yields of the products, fairly fast reaction time, neutral reaction
conditions as well as solvent- and catalyst-free conditions are the
advantages of this method. Furthermore, product isolation does
not require purification by column chromatography. We believe
that this experimentally simple approach could be a useful addi-
tion to reported methods.11–19,22
9. (a) Jang, C. S.; Fu, F. Y.; Wang, C. Y.; Huang, K. C.; Lu, G.; Thou, T. C. Science 1946,
103, 59; (b) Koepfli, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem. Soc. 1947,
69, 1837.
10. Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H. Tetrahedron Lett. 1999, 40,
2175–2178.
11. Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491–2515.
12. Witt, A.; Bergman, J. Tetrahedron 2000, 56, 7245–7253.
13. Hattori, K.; Kido, Y.; Yamamoto, H.; Ishida, J.; Kamijo, K.; Murano, K.; Ohkubo,
M.; Kinoshita, T.; Iwashita, A.; Mihara, K.; Yamazaki, S.; Matsuoka, N.;
Teramura, Y.; Miyake, H. J. Med. Chem. 2004, 47, 4151–4154.
14. Ried, W.; Stephan, W. Chem. Ber. 1962, 95, 3042–3047.
15. Connolly, D. J.; Guiry, P. J. Synlett 2001, 1707–1710.
16. Croce, P. D.; Ferracioli, R.; La Rosa, C. Heterocycles 1997, 45, 1309–1318.
17. Couture, A.; Cornet, H.; Grandclaudon, P. Synthesis 1991, 1009–1010.
18. Paterson, T. McC.; Smalley, R. K.; Suschitzky, H. Synthesis 1975, 187–188.
19. Abdel-Jalil, R. J.; Voelter, W.; Saeed, M. Tetrahedron Lett. 2004, 45, 3475–3476.
20. Adib, M.; Sheibani, E.; Bijanzadeh, H. R.; Zhu, L. G. Tetrahedron 2008, 64, 10681–
10686; Adib, M.; Mohammadi, B.; Bijanzadeh, H. R. Synlett 2008, 177–180;
Adib, M.; Sayahi, M. H.; Ziyadi, H.; Bijanzadeh, H. R.; Zhu, L. G. Tetrahedron
2007, 63, 11135–11140; Adib, M.; Mahdavi, M.; Alizadeh Noghani, M.;
Bijanzadeh, H. R. Tetrahedron Lett. 2007, 48, 8056–8059; Adib, M.; Mahdavi,
M.; Abbasi, A.; Haghighat Jahromi, A.; Bijanzadeh, H. R. Tetrahedron Lett. 2007,
48, 3217–3220; Adib, M.; Mahdavi, M.; Alizadeh Noghani, M.; Mirzaei, P.
Tetrahedron Lett. 2007, 48, 7263–7265; Adib, M.; Sheibani, E.; Mostofi, M.;
Ghanbary, K.; Bijanzadeh, H. R. Tetrahedron 2006, 62, 3435–3438; Adib, M.;
Acknowledgment
This research was supported by the Research Council of the Uni-
versity of Tehran as research project (6102036/1/03).
References and notes
1. Undheim, K.; Benneche, T.. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. V. F., Eds.; Pergamon Press: London,
1996; Vol. 6, pp 93–231. Chapter 2.

32
M. Adib et al. / Tetrahedron Letters 51 (2010) 30–32
Mahdavi, M.; Mahmoodi, N.; Pirelahi, H.; Bijanzadeh, H. R. Synlett 2006, 1765–
J = 7.4 Hz, 2CH), 7.38 (2H, d, J = 7.5 Hz, 2CH), 7.44 (1H, t, J = 7.5 Hz, CH), 7.59
(1H, d, J = 8.1 Hz, CH), 7.74 (1H, t, J = 7.5 Hz, CH), 8.07 (1H, d, J = 7.8 Hz, CH),
12.39 (1H, br s, NH). 13C NMR (125.8 MHz, CDCl3): d 40.73 (CH2), 120.71 (C),
125.63, 126.08, 126.70, 126.86, 128.40, 128.80, and 134.26 (9CH), 136.50,
148.87, and 155.88 (3C), 161.80 (C@O). 2-Phenethyl-4(3H)-quinazolinone (4q)
colorless crystals, mp 208 °C, yield: 0.46 g, 92%. Anal. Calcd for C16H14N2O
(250.30): C, 76.78; H, 5.64; N, 11.19. Found: C, 76.6; H, 5.8; N, 11.0. 1H NMR
(500.1 MHz, CDCl3): d 2.89 (2H, t, J = 7.5 Hz, CH2), 3.04 (2H, t, J = 7.5 Hz, CH2),
7.16–7.20 (1H, m, CH), 7.25–7.29 (4H, m, 4CH), 7.45 (1H, t, J = 7.8 Hz, CH), 7.61
(1H, d, J = 8.1 Hz, CH), 7.77 (1H, dt, J = 1.5, 8.1 Hz, CH), 8.07 (1H, d, J = 7.9 Hz,
CH), 12.23 (1H, br s, NH). 13C NMR (125.8 MHz, CDCl3): d 32.39 and 36.23
(2CH2), 120.79 (C), 125.63, 125.93, 126.00, 126.75, 128.26, 128.28, and 134.21
(9CH), 140.69, 148.83, and 156.53 (3C), 161.72 (C@O).
1767; Adib, M.; Ghanbary, K.; Mostofi, M.; Bijanzadeh, H. R. Tetrahedron 2005,
61, 2645–2648.
21. The procedure for the preparation of 2-(4-methylphenyl)-4(3H)-quinazolinone
4b is described as an example: A mixture of 4-methylbenzonitrile (0.23 g,
2 mmol) and hydroxylamine (50%, 0.20 g, 3 mmol) was stirred at 120 °C for
1.5 h. After nearly complete conversion into an intermediate presumed to be
the corresponding amidoxime (as indicated by TLC), anthranilic acid (0.27 g,
2 mmol) was added to the reaction mixture, which was stirred at 150 °C for a
further 2 h. Next, the reaction mixture was cooled to room temperature and
the product was purified by crystallization from ethanol as colorless crystals,
mp 242 °C (lit 240–242 °C),23 yield: 0.43 g, 91%. EI-MS, m/z (%): 236 (M+, 97),
219 (6), 192 (8), 165 (6), 119 (9), 103 (6), 91 (24), 76 (6), 65 (12). Anal. Calcd for
C15H12N2O (236.27): C, 76.25; H, 5.12; N, 11.86. Found: C, 76.1; H, 5.3; N, 11.7.
1H NMR (500.1 MHz, CDCl3): d 2.47 (3H, s, CH3), 7.38 (2H, d, J = 8.2 Hz, 2CH),
7.50 (1H, dt, J = 1.5, 8.1 Hz, CH), 7.80 (1H, dt, J = 1.5, 8.1 Hz, CH), 7.83 (1H, d,
J = 6.9 Hz, CH), 8.15 (2H, d, J = 8.2 Hz, 2CH), 8.34 (1H, d, J = 7.8 Hz, CH), 11.51
(1H, s, NH). 13C NMR (125.8 MHz, CDCl3): d 21.51 (CH3), 120.83 (C), 126.38,
126.56, 127.25, 127.93, and 129.77 (7CH), 130.00 (C), 134.81 (CH), 142.20,
149.65, and 151.70 (3C), 163.73 (C@O). 2-Benzyl-4(3H)-quinazolinone (4o):
colorless crystals, mp 247–249 °C, yield: 0.44 g, 93%. Anal. Calcd for C15H12N2O
(236.27): C, 76.25; H, 5.12; N, 11.86. Found: C, 76.2; H, 5.2; N, 11.7. 1H NMR
(500.1 MHz, CDCl3): d 3.94 (2H, s, CH2), 7.22 (1H, t, J = 7.2 Hz, CH), 7.30 (2H, t,
22. Narasimhulu, M.; Mahesh, K. C.; Reddy, T. S.; Rajesh, K.; Venkateswarlu, Y.
Tetrahedron Lett. 2006, 47, 4381–4383; Khosropour, A. R.; Mohammadpoor-
Baltork, I.; Ghorbankhani, H. Tetrahedron Lett. 2006, 47, 3561–3564; Salehi, P.;
Dabiri, M.; Zolfigol, M. A.; Baghbanzadeh, M. Tetrahedron Lett. 2005, 46, 7051–
7053; Xue, S.; McKenna, J.; Shieh, W. C.; Repi, O. J. Org. Chem. 2004, 69, 6474–
6477; Kamal, A.; Reddy, K. S.; Prasad, B. R.; Babu, A. H.; Ramana, A. V.
Tetrahedron Lett. 2004, 45, 6517–6521.
23. Arfan, M.; Khan, R.; Anjum, S.; Ahmad, S.; Iqbal Choudhary, M. Chin. Chem. Lett.
2008, 19, 161–165.