Mercury(II) p-toluenesulfonate mediated synthesis of oxazoles under microwave irradiation

Article abstract of DOI:10.1016/S0040-4039(00)00929-1

Direct transformation of aromatic ketones into oxazoles in the presence of mercury(II) p-toluenesulfonate under microwave irradiation is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00929-1

Tetrahedron Letters 41 (2000) 5891±5894
Mercury(II) p-toluenesulfonate mediated synthesis of
oxazoles under microwave irradiation
Jong Chan Lee* and In-Goul Song
Department of Chemistry, Chung-Ang University, Seoul 156-756, South Korea
Received 19 April 2000; revised 29 May 2000; accepted 2 June 2000
Abstract
Direct transformation of aromatic ketones into oxazoles in the presence of mercury(II) p-toluenesulfonate
under microwave irradiation is described. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: ketones; oxazoles; mercury(II) p-toluenesulfonate; microwave.
Oxazole ring system is a basic building block of several biologically interesting compounds.1,2
Although there are many indirect synthetic methods available for the formation of the oxazoles,
general methods for the direct preparation of oxazoles are relatively rare.3 6 Furthermore, there
is no general literature method for the direct preparations of 4-aryl-2-phenyloxazoles and 5-alkyl-
4-aryl-2-phenyloxazoles.7 9 In this paper, we wish to report a direct and rapid preparation
method for the 5-alkyl-4-aryl-2-phenyloxazoles and 4-aryl-2-phenyloxazoles, utilizing the reaction
of aromatic ketones with benzonitrile in the presence of mercury(II) p-toluenesulfonate under
microwave irradiation. To our knowledge, this is the ®rst report of direct conversion of ketones
to oxazoles under solventless reaction conditions.
Generally, a heterogeneous mixture of the aromatic ketone, Hg(OTs)2 (1.0 equiv.), and
benzonitrile (5.0 equiv.) was placed in a glass tube and the reaction mixture was exposed to
microwave irradiation in a domestic microwave oven for 2±4 min. The best results were obtained
by employing 5.0 equiv. of benzonitrile. The use of smaller amounts of benzonitrile gave reduced
yields. A range of 5-alkyl-4-aryl-2-phenyloxazoles and 4-aryl-2-phenyloxazoles were prepared in
* Corresponding author. E-mail: jclee@cau.ac.kr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00929-1

5892
the yields of 47±86% as summarized in the Table 1. Reactions of mercury(II) p-toluenesulfonate
with aromatic a-methylene ketones (entries 3±8) invariably provided better yields than in the case
of aromatic a-methyl ketones (entries 1 and 2). In fact, for the reaction of aromatic a-methyl
ketones, the addition of p-toluenesulfonic acid (1.0 equiv.) was necessary to improve the yields of
oxazole formations. This result clearly indicates that higher enol content of ketones is important
for successful reactions. To examine the feasibility of Cu(OTf)25 in the oxazole forming reaction,
the reactions were conducted with Cu(OTf)2 at the same reaction conditions, by replacing
Hg(OTs)2. However, no oxazole formation was noticed and only the starting materials were
recovered.
Table 1
Synthesis of 2,4- and 2,4,5-substituted oxazoles under microwave irradiation
Recently, oxazole-4-carboxylates received much attention due to their growing interest as
synthetic intermediates for the construction of naturally occurring oxazole systems.10 12 Thus, we
have examined the reaction of ethyl 2-oxoalkanoates under the same reaction conditions. The
results were successful to give ethyl 2-phenyloxazole-4-carboxylate and ethyl 5-methyl-2-phenyl-
oxazole-4-carboxylate in the yields of 47 and 65% respectively (entries 9 and 10). By analogy with
the formation of di(a-phenacyl)Hg(II)13,14 the ring formation process occurs probably through

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initial formation of di(a-arylalkanoyl)Hg(II) by the reaction of mercury(II) tosylate with the enol
tautomer of the ketones followed by attack of the nitrogen atom of benzonitrile to the carbonyl
carbon of ketones (Scheme 1).
Scheme 1.
In conclusion, the short reaction time, the high yield, and the simple work-up o€er signi®cant
advantages over existing methods for the multi-substituted oxazole ring formations.
Typical procedure: A mixture of propiophenone (1.0 mmol), Hg(OTs)2 (1.0 mmol), and
benzonitrile (5.0 mmol) was placed into a glass tube. The glass tube was placed in an alumina
bath inside a domestic microwave oven and irradiated for 30 s intervals. After this heating, a
period of 30 s was allowed for cooling to prevent excess heating. This process was repeated 4±8
times. After completion of the reaction, the product was extracted into dichloromethane (2Â20
ml), which was washed with water, and dried over MgSO4. The solvent was removed under
reduced pressure and the residue was chromatographed on silica gel using ethyl acetate/hexane
1
(1:9) as the eluent to give 5-methyl-2,4-diphenyloxazole in 85% yield. H NMR (300 MHz,
CDCl3): ꢀ 2.56 (s, 3H), 7.31±7.46 (m, 6H), 7.72±7.75 (m, 2H), 8.06±8.10 (m, 2H); MS (EI, m/z):
235 (M+).
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