Zirconyl(IV) chloride catalyzed three component one-pot synthesis of quinazolin-4(3H)-ones

Article abstract of DOI:10.1007/s00706-007-0746-7

An efficient one-pot method for synthesis of an array of quinazolin-4(3H)-ones from anthranilic acid, triethyl orthoformate, and amines using ZrOCl₂ is described. This method offers improvements for the synthesis of quinazolin-4(3H)-ones with r

Full text of DOI:10.1007/s00706-007-0746-7

Monatshefte f u¨ r Chemie 138, 1289–1291 (2007)
DOI 10.1007/s00706-007-0746-7
Printed in The Netherlands
Zirconyl(IV) Chloride Catalyzed Three Component One-pot
Synthesis of Quinazolin-4(3H)-ones
1
1;2
1;Ã
Jaiprakash N. Sangshetti , Nagnnath D. Kokare , and Devanand B. Shinde
1
Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, India
2
New Drug Discovery, Wockhardt Research Centre, Aurangabad, India
Received June 4, 2007; accepted (revised) June 19, 2007; published online October 19, 2007
Springer-Verlag 2007
#
Summary. An efficient one-pot method for synthesis of an
array of quinazolin-4(3H)-ones from anthranilic acid, triethyl
orthoformate, and amines using ZrOCl is described. This
method offers improvements for the synthesis of quinazolin-
4(3H)-ones with regard to short reaction time, yield of pro-
ducts, and simplicity in operation.
However, in spite of their potential utility some of
the reported methods suffer from drawbacks, like
longer reaction time, unsatisfactory yields, cumber-
some product isolation, and multi-step synthesis.
Thus, there is still need of a simple and general
procedure for one-pot synthesis of quinazolin-4(3H)-
ones under mild conditions.
2
Keywords. Quinazolin-4(3H)-ones; ZrOCl catalyst; Anthra-
2
nilic acid; Amines; Triethyl orthoformate.
In continuation of our ongoing research for the
development of simple and efficient methods for
the synthesis of various heterocyclic compounds
Introduction
[
13], herein we wish to report a simple, economic,
Quinazolines from natural and synthetic origin rep-
resent an important heterocyclic class with diverse
biological activities [1–6]. At present, some synthetic
quinazoline-based drugs, such as metolazone, quine-
thazone, and prazosin have achieved medicinal
approval for their unique pharmacological indices,
and many others are under clinical evaluation
and efficient one-pot method for the synthesis of
quinazolin-4(3H)-ones using anthranilic acid, substi-
tuted anilines, and triethyl orthoformate as substrates
in presence of the zirconyl(IV) chloride catalyst.
Zirconyl(IV) chloride is a moisture stable, readily
available, and inexpensive oxy-salt of zirconium,
which is not much explored in synthetic organic
chemistry as a mild and versatile Lewis acid catalyst.
Compared to conventional Lewis acids, zirconyl(IV)
chloride has the advantages of low catalyst loading,
moisture stability, and catalyst recycling. In the pres-
ent work, we have demonstrated the ability of
[7, 8]. Of the different quinazoline derivatives quin-
azolin-4(3H)-ones are the most important interme-
diates in the synthesis of different recent anticancer
quinazolines [9]. As a consequence of these impor-
tant properties, many approaches have been devel-
oped to synthesize quinazolin-4(3H)-ones. Usually,
ZrOCl as a catalyst for the synthesis of an array
2
4
[
H-3,1-benzoxazin 4-ones [10] and anthranilic acid
11, 12] have been used as a starting materials.
of substituted quinazolin-4(3H)-ones.
Results and Discussion
Ã
Initially, we studied the catalytic property of ZrOCl2
for the synthesis of quinazolin-4(3H)-ones 4 using
Corresponding author. E-mail: dbshinde.2007@rediffmail.
com

1
290
J. N. Sangshetti et al.
Table 1. Optimization of reaction conditions and the quantity
of ZrOCl Á 8 H O for the synthesis of 3-phenyl-quinazolin-
for the synthesis of 4a (98% in 30 min). The meth-
odology was extended for the synthesis of an array
of quinazolin-4(3H)-ones using different anilines
(Table 2). Good yields were obtained for synthe-
sis of all the quinazolin-4(3H)-one derivatives. All
synthesized derivatives were characterized using
2
2
4
(3H)-one (4a)
Solvent
Mol%
Reaction
Yield=
%
ZrOCl Á 8H O time=min
2
2
THF
Acetonitrile
Ethanol
Ethanol:water (3:1)
Ethanol:water (3:1)
Ethanol:water (3:1)
Ethanol:water (3:1)
20
20
20
20
15
10
05
60
50
30
30
30
30
60
85
91
98
98
98
98
91
1
mass and H NMR spectroscopy. The present meth-
od was found to be effective for both electron-donat-
ing and electron-withdrawing substituted anilines.
In conclusion, quinazolin-4(3H)-ones were effi-
ciently synthesized with high yields using 10 mol%
ZrOCl as the catalyst. For all the presented reac-
2
tions, the ethanol–water solvent was used, which is
relatively environmentally benign and supporting
Green Chemistry. The advantages of the reported
method are the use of a cheap catalyst, shorter reac-
tion times, easy work-up, and better yields. Hence
anthranilic acid, aniline, and triethyl orthoformate
to yield 4a as an example in various solvents like
THF, acetonitrile, and ethanol. Among the results
obtained, use of 10 mol% ZrOCl in ethanol–water
2
gave the best yield (98%) for the synthesis of 4a
(Table 1). The use of environmentally benign sol-
vent, such as water, has got very much importance
in ‘Green Chemistry’. To study this aspect, the reac-
tion was carried out for the synthesis of 4a using
the utility of ZrOCl catalyst for synthesis of quina-
2
zolin-4(3H)-ones would be a precious addition to
available methods.
1
0 mol% ZrOCl and the corresponding substrates
2
Experimental
in water. The reaction was found to be sluggish,
and this may be due to the low solubility of the
substrates. To avoid this problem, the ethanol:water
solvent (3:1; v=v) was used and found to be effective
1
Melting points were determined in capillary tubes. The H
NMR spectra were recorded on a 400 MHz Varian-Gemini
spectrometer. Mass spectra were taken with Micromass –
QUATTRO-II of WATERS mass spectrometer.
Table 2. ZrOCl -catalyzed synthesis of quinazolin-4(3H)-ones derivatives
2
ꢀ
mp= C
Compound
Ar of ArNH2
Time=min
Yield=%
Found
Ref. [12]
4
a
Ph–
30
40
50
40
50
30
50
40
40
30
98
90
90
97
90
96
98
90
92
98
139–140
136–137
137–138
145–146
180–181
179–180
136–138
154–155
154–155
166–167
139–140
137–138
136–137
146–147
180–181
182–183
134–135
156–158
154–156
165–166
4
b
2-Me–Ph–
3-Me–Ph–
4-Me–Ph–
2-Cl–Ph–
4-Cl–Ph–
3,4-diMe–Ph–
4
c
4
d
4
4
4
e
f
g
4
h
2-NO –Ph–
2
4
4
i
j
3-NO –Ph–
2
4-NO –Ph–
2
Scheme 1

One-pot Synthesis of Quinazolin-4(3H)-ones
1291
Typical Experimental Procedure for the Synthesis
of 3-Phenylquinazolin-4(3H)-ones (4a)
A mixture of 1.37 g anthranilic acid (10 mmol), 1.13 g aniline
[4] Abdel-Rahman MM, Mangoura SA, El-Bitar HI (1990)
Bull Pharm Sci Assiut Univ 13: 137
[
[
[
5] Hori M, Iemura R, Hara H, Ozaki A, Sukamoto T,
Ohtaka H (1990) Chem Pharm Bull 38: 681
6] Hess HJ, Cronin TH, Sciabine A (1968) J Med Chem 11:
130
7] Jackman AL, Kimbell R, Aherne GW, Brunton L, Jansen
G, Stephens TC, Smith MN, Wardleworth JM, Boyle FT
3
3
(
1.1cm , 12 mmol), 1.9 g triethyl orthoformate (2.1 cm ,
3
3mmol), and 0.32 g ZrOCl (1mmol) in 20 cm ethanol:
1
water (3:1; v=v) was heated at 60 C until completion of reac-
2
ꢀ
tion (monitored by TLC). The reaction mixture was diluted
3
with water and extracted with 3Â10 cm ethyl acetate. The
(1997) Clin Cancer Res 3: 911
combined organic layer was dried over Na SO and concen-
2
4
[
[
8] Rafi I, Taylor GA, Calvete JA, Boddy AV, Balmanno K,
Bailey N, Lind M, Calvert AH, Webber S, Jackson RC,
Johnston A, Clendeninn N, Newell DR (1995) Clin
Cancer Res 1: 1275
9] Colotta V, Catarzi D, Varano F, Lenzi O, Filacchioni G,
Costagli C, Galeotti N, Gratteri P, Sgrignani J, Deflorian
F, Moro S (2006) J Med Chem 49: 6015
trated in vacuo to afford the crude compound. The crude
compounds were purified by recrystallization with ethyl acet-
ate:n-hexane (2:8) to afford 2.19 g 4a (98%) in pure form.
Acknowledgements
[
10] a)ErradeLA,MebredyJJ,OienHT(1977)JOrgChem42:
56; b) Kornet MJ, Varia T, Beaven WJ (1983) J Hetero-
The authors are thankful to the Head Dr. D.B. Shinde,
Department of Chemical Technology, Dr. Babasaheb
Ambedkar Marathwada University, Aurangabad – 431004
6
cycl chem 20: 1553; c) Parkanyi C, Yuan HL, Stromberg
BHE, Evenzahav AJ (2002) J Heterocycl Chem 57: 323
11] a) Sauter F, Fr }o hlich J, Blasl K, Gewald K (1995)
Heterocycles 40: 851; b) Prashad M, Chen L, Repic
O, Blacklock TJ (1998) Synth Commun 28: 2125; c)
Connollty DJ, Guirry PJ (2001) Synlett: 1707
(MS), India for providing the laboratory facility.
[
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