A novel method for the synthesis of 4(3H)-quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2004.03.003

Condensation of anthranilamide with aryl, alkyl or heteroaryl aldehydes in refluxing ethanol and the presence of CuCl₂ afforded the corresponding 2-substituted quinazolinones in excellent yields.

Full text of DOI:10.1016/j.tetlet.2004.03.003

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3475–3476
A novel method for the synthesis of 4(3H)-quinazolinones
Raid J. Abdel-Jalil,a,* Wolfgang Voelterb and Muhammad Saeedc
aChemistry Department, Faculty of Sciences and Arts, Hashemite University, Zarka 13133, Jordan
bAbteilung f€ur Physikalische Biochemie des Physiologisch-chemischen Instituts der Universit€at T€ubingen, Hoppe-Seyler Strasse 4,
D-72076 T€ubingen, Germany
cEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
Received 30 September 2003; revised 26 February 2004; accepted 1 March 2004
Abstract—Condensation of anthranilamide with aryl, alkyl or heteroaryl aldehydes in refluxing ethanol and the presence of CuCl2
afforded the corresponding 2-substituted quinazolinones in excellent yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Quinazolinone derivatives have drawn much attention
due to their broad range of pharmacological activities,1
for example, anticancer,2 antiinflammatory,3 anticon-
vulsant4 and antidituric5 activities. Therefore, consider-
able efforts have been made to explore new simple and
direct approaches towards the construction of 4(3H)-
quinazolinone skeletons, for example, via cyclization of
o-acylaminobenzamides,6 amidation of 2-aminobenzo-
nitrile followed by oxidative ring closure7 and Pd-cata-
lyzed heterocyclization of nitroarenes.8 However, most
of the reported methods suffer from tedious procedures
and often from low yields. Therefore, simpler and high
yield approaches towards this valuable nucleus is much
desirable.
sponding 4(3H)-quinazolinones 3a–g in 79–88 overall
yield (Table 1). Typically, anthranilamide (1 mmol) was
stirred with furfural (1.2mmol) and copper chloride
(3 mmol) in ethanol (100 mL) at 70–75 °C for 3 h to yield
after conventional work up the 2-furan-2-yl-3H-quin-
azolin-4-one 3g in 86% yield (Scheme 1).
Although, 2-substituted-4-quinazolinone nucleus has
been similarly synthesized via condensation of anthra-
nilamides with aldehydes followed by oxidation reaction
using NaHSO3 or DDQ10 in good yields. Our present
9
method has the advantage of the low temperature nee-
ded to achieve complete conversion of the anthranil-
imide to the quinazolinone derivatives.11 The use of high
temperature may produce complex decomposition mix-
tures.10a
Herein, we want to present a high yield condensation of
aryl, alkyl and heteroaryl aldehydes with anthranilamide
to 4(3H)-quinazolinones. In the present study, the
intermediate Schiff bases 2a–g were synthesized within
3 h via condensation of anthranilamide 1 with the cor-
responding aldehyde in ethanol in 82–91% yields. The
latter were converted within 2h to the corresponding
4(3H)-quinazolinones 3a–g in the presence of 3 equiv of
copper chloride in refluxing ethanol.
In conclusion, an easy and simple method for 2-substi-
tuted-4(3H)-quinazolinones is reported. Efforts are cur-
rently under way to elucidate the mechanism of the
conversion, especially the involvement of the copper
Table 1. Reaction conditions and yields of the quinazolinone 3a–e
Entry
Solvent
Time (h)
Yield (%)
Alternatively, these quinazolinone derivatives can also
be prepared via one-pot procedure. Thus, anthranil-
amide, aldehyde and copper chloride were allowed to
react in refluxing ethanol for 2–3 h to yield the corre-
a
a
a
b
c
d
e
f
Ethanol
Methanol
2-Propanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
3
82
71
77
3
3
288
2.5
3
84
79
285
3
Keywords: Quinazolinone; Synthesis; Schiff base; Anthranilimide.
* Corresponding author. Tel.: +962-5-3826600; fax: +962-5-3826613;
e-mail: jalil@hu.edu.jo
81
86
g
3
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.003

3476
R. J. Abdel-Jalil et al. / Tetrahedron Letters 45 (2004) 3475–3476
O
O
O
N
NH2
NH2
NH
ii
i
NH2
N
R
1
3a-g
2a-g
R
e
g
No.
R.
d
b
c
a
f
p-OCH3C6H4
p-ClC6H4
C6H5
Me
Bu
O
S
Scheme 1. Reagents and conditions: (i) RCHO, EtOH, 70 °C, 3 h; (ii) CuCl2, EtOH, 70 °C, 3 h.
5. Lyle, F. R. U.S. Patent 5,973,257, 1985; Chem. Abstr.
1985, 65, 2870.
6. Armarego, W. L. F. Adv. Heterocycl. Chem. 1979, 24,
1–62.
salt, and extend this principle of reaction for the
straightforward access to other heterocyclic systems.
7. Segarra, V.; Crespo, M. I.; Pujol, F.; Belata, J.; Domen-
ech, T.; Miralpeix, M.; Palacios, J. M.; Castro, A.;
Martinez, A. Bioorg. Med. Chem. Lett. 1998, 505–510.
8. Akazome, M.; Yamamoto, J.; Kondo, T.; Watanabe, Y.
J. Organomet. Chem. 1995, 494, 229–233.
9. Lopez, S. E.; Rosales, M. E.; Urdaneta, N.; Gody, M. V.;
Charris, J. E. J. Chem. Res. (S) 2000, 6, 258–259.
10. (a) Deepthi, K. S.; Reddy, D. S.; Reddy, P. P.; Reddy, P.
S. N. Indian J. Chem., Sect. B 2000, 39, 220–222; (b)
Naleway, J. J.; Fox, C. M. J.; Robinhold, D.; Terpets-
ching, E.; Olsen, N. A.; Haugland, R. P. Tetrahedron Lett.
1994, 46, 8569–8572.
Acknowledgements
We would like to thank Dr. Monther Khnafar and Mr.
Ehab El-Moumany for the assistance with the NMR
experiments. Financial support, provided by the Hash-
emite University, is greatly acknowledged. We express
€
€
our gratitude to Internationales Buro of BMBF, Julich,
for a fellowship granted to Dr. R. J. A.-J.
11. General procedure for quinazolinone: A mixture of anthra-
nilimide (3 mmol), CuCl2 (3 mmol) and the appropriate
aldehyde (3.3 mmol) in ethanol (10 mL) was refluxed for
2–3 h. The reaction mixture was then allowed to cool to rt,
the solvent was removed in vacuo, and the crude product
was purified by column chromatography over silica gel to
provide pure quinazolinone in high yields (Table 1).
Selected data; compound 2g (intermediate 2g was purified
by column chromatography for spectroscopic analysis): off
white prisms, mp 162–164 °C (from ethanol), EI-MS; m=z
References and notes
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1
212, H NMR (250 MHz, DMSO-d6) d: 5.82(s, 1H, NH),
6.3 (br d, 1H, furyl), 6.43 (s, 1H, NH), 6.75 (m, 2H, furyl),
7.29, 7.67 (m, m, 2H, 2H, phenyl), 8.50 (s, 1H, N@CH);
13C NMR (250 MHz, DMSO-d6) d: 105.7, 108.9, 113.5,
115.8, 125.9, 131.9, 141.3, 145.7, 153.1, 161.9. Compound
1
3g: off white prisms, mp 218–220 °C, EI-MS; m=z 212, H
NMR (250 MHz, DMSO-d6) d: 6.98 (dd, 1.0, 2.3 Hz, 1H,
furyl), 7.70–8.38 (m, 6H, phenyl+furyl), 12.76 (s, 1H, NH);
13C NMR (250 MHz, DMSO-d6) d: 112.0, 114.0,
120.6, 125.4, 125.9, 126.7, 134.1, 143.5, 145.5, 146.1,
148.1, 161.0.