Calcium acetate catalyzed synthesis of 4-arylidene-2-phenyl-5(4H)- oxazolones under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2003.10.125

Eight 4-arylidene-2-phenyl-5(4H)-oxazolones (azlactones) have been prepared via Erlenmeyer synthesis from aromatic aldehydes and hippuric acid using calcium acetate under solvent-free conditions with microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2003.10.125

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 425–427
Calcium acetate catalyzed synthesis of 4-arylidene-2-phenyl-
5(4H)-oxazolones under solvent-free conditions
a
a
b
Satya Paul,a, Puja Nanda, Rajive Gupta and Andre Loupy
*
ꢀ
aDepartment of Chemistry, University of Jammu, Jammu 180006, India
bLaboratoire des Reꢀactions Seꢀlectives sur Supports, CNRS UMR 8615, ICMMO, Universiteꢀ Paris-Sud, 91405 Orsay Cedex, France
Received 14 January 2003;revised 13 October 2003;accepted 22 October 2003
Abstract—Eight 4-arylidene-2-phenyl-5(4H)-oxazolones (azlactones) have been prepared via Erlenmeyer synthesis from aromatic
aldehydes and hippuric acid using calcium acetate under solvent-free conditions with microwave irradiation.
ꢀ 2003 Elsevier Ltd. All rights reserved.
4-Arylidene-2-phenyl-5(4H)-oxazolones are important
synthons for the synthesis of several biologically active
molecules.1 They are also precursors of amino acids
containing an aromatic side chain and can be converted
to the latter by treatment with red phosphorus and
hydrogen iodide. A number of methods are available for
the synthesis of azlactones2–8 including the recent use of
anhydrous zinc chloride9 or bismuth(III) acetate as
catalysts.10
Chemistry. Work in this direction has recently been re-
viewed.11
The synthesis of azlactones under MW irradiation has
been reported in open vessels using acetic anhydride,
which acts both as reagent and as the organic phase.12a;e
Acetic anhydride is a well-known toxic reagent and its
use for carrying out reactions under microwave irradi-
ation in open vessels would spoil the cavity of the oven
and also lead to the emission of toxic vapours into the
environment. Thus, the use of acetic anhydride as a
supported reagent was explored in continuation of our
ongoing work on the use of supported reagents with
microwave irradiation.13
The replacement of toxic organic solvents is one of the
most important goals in Green Chemistry, which inevi-
tably lead to solvent emission and/or waste. The use of
reagents supported on solid inorganic supports is also
an area currently under active investigation. These not
only avoid the use of solvents for carrying out reactions
but also induce significant simplifications to the reaction
procedures.
We selected calcium acetate as the support/catalyst,
which, besides being inexpensive and nontoxic, has not
been reported to have been used for this synthesis. In
view of the importance of azlactones as synthons for
biologically important compounds and the advantages
offered by coupling microwave activation with dry
media reactions, we report here a solvent-free procedure
for the synthesis of 4-arylidene-2-phenyl-5(4H)-oxazol-
ones 3a–h (Table 1) from arylaldehydes 1 and hippuric
acid 2 using calcium acetate under microwave irradia-
tion14 (Scheme 1).
The use of microwave irradiation for carrying out
organic reactions is a well-established procedure since
reactions are clean, fast and economical. Coupling of the
two techniques, that is, organic reactions using sup-
ported reagents with microwave irradiation has been a
field, which has shown excellent results leading to the
development of many reaction procedures, which are
environmental friendly falling in the domain of Green
The activity of calcium acetate for the synthesis of
azlactone 3a was first checked by mixing it with different
supports such as neutral and basic alumina, K2CO3,
KF–Al2O3 (Table 2). The best results were obtained
when calcium acetate was used alone as the support. The
amount of calcium acetate was found to be crucial for
Keywords: azlactones;calcium acetate;hippuric acid;solvent-free
conditions;microwave activation.
* Corresponding author. Fax: +91-191-2505086;e-mail: paul7@rediff-
mail.com
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.125

426
S. Paulet a.l / Tetrahedron Letters 45 (2004) 425–427
Table 1. Microwave-induced synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolones 3a–h using Ca(OAc)2 (power ¼ 300 W)
Product
Time (min)
Reaction temperaturea (ꢁC)
Yieldb (%)
Mp (ꢁC) found/reported
3a
3b
3c
3d
3e
3f
5
3
3
6
3
5
3
3
48–50
74–76
57–60
57–59
48–50
45–47
70–72
55–58
97
99
80
70
72
99
94
91
169–170/1709
164–165/1659
143–144/145–14617
203–204/19712e
164–165/16618
194–195/195–19619
150–152/151–1529
130–131/1309
3g
3h
a The final temperature was measured by immersing a glass thermometer in the reaction mixture at the end of exposure during the microwave
experiment and was an approximate temperature range.
b Yield of isolated products.
yield of 70%. This effect can be attributed to the car-
bonyl complexation by calcium cations leading to elec-
trophilic assistance during nucleophilic attack on this
group. When the reaction was carried out by irradiating
hippuric acid 2 alone, oxazolone 4 was formed in 10 min
and could be isolated in 70% yield (Ca(OAc)2 and Ac2O
were both required for the cyclization to azlactones 3).
O
O
Ar
Ac2O/Ca(OAc)2
MW, 300 W
ArCHO +
COOH
N
H
Ph
N
O
Ph
3
2
1
3a Ar = C6H5
3c Ar = 4-MeC6H4
3b Ar = 4-MeOC6H4
3d Ar = 4-ClC6H4
In order to check the possibility of the existence of a
specific (nonpurely thermal) microwave effect acceler-
ating the reaction with respect to conventional heating,
a pre-heated oil bath was used as a source of heat in
comparative experiments (Table 3). Lower yields were
obtained with conventional heating under the same
conditions of time and temperature. This observation is
consistent with the reaction mechanism of the reaction
as depicted in Scheme 2, which involves a polar transi-
tion state starting from a neutral ground state. This
enhancement in polarity during the reaction progress
can thus induce an improved stabilization of the tran-
sition state by microwaves (dipole–dipole interaction),
leading to a lowering in the activation energy.16
3e Ar = 2-NO2C6H4
3g Ar = 3,4-(OMe)2C6H3
3f Ar = 3-NO2C6H4
3h Ar = -CH=CHC6H4
Scheme 1.
Table 2. Effect of solid support in dry media for the synthesis of 3a
under microwave irradiation (power ¼ 300 W)
Support
Timea
(min)
Reaction
temperatureb
(ꢁC)
Yieldc (%)
Ca(OAc)2/B Al2O3
Ca(OAc)2/N Al2O3
Ca(OAc)2/K2CO3
Ca(OAc)2/KF–Al2O3
Ca(OAc)2/B Al2O3/
K2CO3
4
5
5
5
100–105
55–57
45–47
42
0
53
28
98–100
General procedure for the synthesis of 4-arylidene-2-
phenyl-5(4H)-oxazolones 3a–h. The appropriate aro-
matic aldehyde 1 (1 mmol), hippuric acid 2 (1 mmol) and
acetic anhydride (3 mmol) were introduced into a beaker
(50 mL). Calcium acetate (0.5 g) was added and the
contents mixed thoroughly with a glass rod. The paste
so obtained was irradiated in a microwave oven at a
power output of 300 W for the appropriate time (Table
1). After irradiation, cold methanol (20 mL) was added
for extraction. The solid obtained after solvent evapo-
ration was washed with hot water (3 · 20 mL), dried and
5
5
5
5
5
40–42
60–62
48–50
80–91
70–72
0
70
97
10
10
CaCO3
Ca(OAc)2
NH4OAc
NaOAc
B Al2O3: basic alumina;N Al 2O3: neutral alumina.
a Time at which maximum yield was obtained.
b The final temperature was measured by immersing a glass thermo-
meter in the reaction mixture at the end of the exposure during the
microwave experiment and was an approximate temperature range.
c Yield of isolated products.
Table 3. Comparison of microwave activation (MW) and thermal
heating (D) in the case of 3a under microwave irradiation (power ¼
300 W)
obtaining optimum results. It has been found that for
1 mmol of aldehyde, 1 mmol of hippuric acid and
3 mmol of acetic anhydride, 0.5 g of calcium acetate was
required. A power setting of 300 W appeared to be the
best compromise between efficiency and safety.15
Product
Method
Reaction tem- Time (min) Yield (%)
peraturea (ꢁC)
3a
MW
D
D
48–50
48–50
48–50
5
5
35b
97
50
81
Calcium acetate appeared to be an efficient catalyst.
Blank experiments have shown the fundamental role of
calcium cations, whereas Ca(OAc)2 led to a quasi-
quantitative yield (97%), NaOAc and NH4OAc gave
only 10% yields. On the other hand, acetate anions seem
to be less influential as CaCO3 led to a more satisfactory
a The final temperature was measured by immersing a glass thermo-
meter in the reaction mixture at the end of exposure during the
microwave experiment and was an approximate temperature range.
b Time at which maximum yield was obtained.

S. Paulet a.l / Tetrahedron Letters 45 (2004) 425–427
427
Ph
O
O
Ph
N
O
Ph
H
O
Ph
H
O
δ
H
OH
OAc
OH
H
O
3
N
δ
δ
C
N
N
O
Ar
H
O
C
O
O
H
Ar
Ca2+
4
Scheme 2.
5. Buck, J. S.;Ide, W. S. J. Am. Chem. Soc. 1932, 54,
3302.
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9. Shantham Rao, P.;Venkatratnam, R. V. Indian J. Chem.
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crystallized from ethyl acetate: pet. ether as yellow co-
loured crystals in 70–99% yields.
The structures of the products were confirmed by IR, 1H
NMR, mass spectroscopy and by comparison with
authentic samples prepared according to literature
methods.
In conclusion, a reliable, rapid and environmentally
benign method for synthesizing 4-arylidene-2-phenyl-
5(4H)-oxazolones has been developed, which involves
the use of inexpensive and relatively nontoxic reagents
and calcium acetate under microwave irradiation. In
addition, high yields of the products, short reaction
times, ease of work-up and low cost make the above
method advantageous in comparison to other existing
methods.
10. Monk, K. A.;Sarapa, D.;Mohan, R. S. Synth. Commun.
2000, 30, 3167.
11. (a) Caddick, S. Tetrahedron 1995, 51, 10403;(b) Loupy,
A.;Petit, A.;Hamelin, J.;Texier-Boullet, F.;Jacquault, P.;
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Ortis, A.;Moreno, A.;Langa, F. Eur. J. Org. Chem. 2000,
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Acknowledgements
451;(d) Zhou, J.;Xu, J.;Zhong, H.
Huaxue Yanjiu Yu
We thank Dr. G. N. Qazi, Director, Regional Research
Laboratory, Jammu for extending library and instru-
mental facilities.
Yingyong 2001, 13, 78, CAN 135:303798;(e) Bautista, F.
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Tetrahedron
References and Notes
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microwave oven BPL BMO 800T having a maximum
output of 800 W operating at 2450 MHz.
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