Efficient synthesis of multi-substituted oxazoles under solvent-free microwave irradiation

Article abstract of DOI:10.1016/S0040-4039(02)02493-0

A new and efficient method for the synthesis of multi-substituted oxazoles from various carbonyl compounds has been developed using sequential treatment of carbonyl compounds with HDNIB and amides such as acetamide or benzamide under solvent-free microwave irradiation conditions.

Full text of DOI:10.1016/S0040-4039(02)02493-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 123–125
Efficient synthesis of multi-substituted oxazoles under
solvent-free microwave irradiation
Jong Chan Lee,* Hyun Jung Choi and Yong Chan Lee
Department of Chemistry, Chung-Ang University, Seoul 156-756, South Korea
Received 19 September 2002; revised 31 October 2002; accepted 1 November 2002
Abstract—A new and efficient method for the synthesis of multi-substituted oxazoles from various carbonyl compounds has been
developed using sequential treatment of carbonyl compounds with HDNIB and amides such as acetamide or benzamide under
solvent-free microwave irradiation conditions. © 2002 Elsevier Science Ltd. All rights reserved.
Oxazoles have attracted great interest due to their
appearance as subunit of various biologically active
natural products as well as their utilities as valuable
precursors in many useful synthetic transformations.1
Oxazoles are commonly prepared from methods utiliz-
ing synthetic intermediates such as a-halo ketones,2
a-diazo ketones,3 a-acyloxy ketones,4 and a-acylamino
ketones.5 However, preparations of these reactive inter-
mediates are not always straightforward to carry out
because of various drawbacks involved in these reac-
tions, such as long reaction times, low yields, and
forced reaction conditions. Although there are many
useful synthetic methods reported for the substituted
oxazoles, practical and convenient methods for the
synthesis of 2,4,5-trisubstituted oxazoles, which are
widely found in the skeleton of oxazole containing
natural products, have been quite limited.6 In addition,
only a few synthetic methods for the direct and conve-
nient conversion of ketones to substituted oxazoles,
without isolation of the reactive intermediates, have
been known. These include the reaction of ketones with
nitriles as solvents in the presence of copper(II) triflate,7
thallium(III) triflate,8 and iodobenzene diacetate.9 Fur-
thermore, although there have been a couple of meth-
ods reported on the conversion of 2-halo-1,3-dicarbonyl
compounds to oxazoles in modest yields utilizing the
reaction with amide in refluxing carboxylic acid
media,10 there have been no examples to date for a
convenient approach for the preparation of substituted
oxazoles directly from 1,3-dicarbonyl compounds.
Therefore, development of a more convenient and
efficient method is required for the conversion of car-
bonyl compounds to multi-substituted oxazoles.
Recently organic transformations accelerated under sol-
vent-free microwave irradiation conditions gained wide
popularity due to many practical advantages associated
with enhanced reaction rates, high yields, improved
selectivity,
and
environment-friendly
reaction
conditions.11
In conjunction with our program to utilize hypervalent
iodine(III) sulfonates in microwave promoted chem-
istry, we wish to report herein a novel and efficient
one-pot method for the synthesis of multi-substituted
oxazoles by the reaction of amides with intermediary
a-[(2,4-dinitrobenzene)sulfonyl]oxy
carbonyl
com-
pounds, formed in situ from the reaction of [hydroxy-
(2,4-dinitrobenzenesulfonyloxy)iodo]benzene (HDNIB)
with carbonyl compounds, under solvent-free micro-
wave irradiation (MWI) conditions. The required
HDNIB was prepared in satisfactory yields from the
reaction of 2,4-dinitrobenzenesulfonic acid with
iodobenzene diacetate.12 Initial reaction of aromatic
ketones with 1.2 equiv. of HDNIB under microwave
irradiation for 20–40 s provided a-[(2,4-dinitroben-
zene)sulfonyl]oxy ketone intermediates which were then
converted to oxazoles by subsequent treatment with
acetamide or benzamide (2.0 equiv.) under microwave
irradiation for 1–2 min (Scheme 1). In all cases investi-
gated, the oxazole formation reactions proceeded
efficiently with high to excellent yields in short reaction
times. We have also examined the scope of this proto-
col for the oxazole formation reactions of 1,3-dicar-
bonyl compounds under the same reaction conditions.
Keywords: amides; carbonyl compounds; hypervalent elements;
microwave heating; oxazoles.
* Corresponding author. Tel.: +82-2-820-5202; fax: +82-2-825-4736;
e-mail: jclee@cau.ac.kr
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02493-0

124
J. C. Lee et al. / Tetrahedron Letters 44 (2003) 123–125
Table 1. Preparation of oxazoles from ketones under
in a 50 mL of glass tube. The reaction mixture was
inserted in an alumina bath inside a household
microwave oven and irradiated (850 W) twice for a
period of 20 s with a 10 s interval. After the reaction
mixture was cooled to room temperature, an amide (2.0
mmol) was added and irradiated an additional three
times for a period of 20 s with 10 s intervals. The
reaction mixture was extracted with dichloromethane
(2×25 mL) and washed with water (40 mL). The
dichloromethane layer was separated and dried over
MgSO4. After evaporation of the solvent, the residue
was purified by flash column chromatography (SiO2,
ethyl acetate:hexane=1:2) to afford pure oxazole.
microwave irradiation
Entry
R1
R2
R2
Yield (%)a
1
2
3
4
5
6
7
8
Ph
Ph
H
Me
Me
Me
COMe
COOEt
COOEt
CONEt2
Ph
Ph
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
92 (78)b
94 (72)b
p-MeC6H4
p-ClC6H4
Me
Me
Ph
Me
Ph
Ph
Ph
94
83
82
58
91
82
70
68
9
10
11
12
13
14
15
16
17
18
77 (63)b
85 (62)b
80
87
87
74
90
In conclusion, we have described a rapid and highly
efficient method for the synthesis of multi-substituted
oxazoles starting from carbonyl compounds under sol-
vent-free microwave irradiation reaction conditions.
With such successful results of the otherwise difficult
oxazole formation reaction of 1,3-dicarbonyl com-
pounds, this convenient and efficient oxazole ring form-
ing protocol should provide a superior alternative of
the existing methods because of its fast and clean
reactions and high yields.
Ph
p-MeC6H4
p-ClC6H4
Me
Me
Ph
Me
COMe
COOEt
COOEt
CONEt2
Me
63
a Isolated yields of pure products.
b Yields obtained from replacing HDNIB by HTIB under the same
reaction conditions.
Acknowledgements
To our satisfaction, the reactions proceeded well not
only for 1,3-diketone (entries 5 and 15) but also for
b-keto ester (entries 6, 7 and 16, 17) and b-keto amide
(entries 8 and 18) to give the corresponding oxazoles in
high yields. Results of the reactions of several sub-
strates are listed in Table 1. Under present reaction
conditions, the oxazole formation reactions were highly
regioselective to give only a single oxazole product
without any regioisomeric oxazoles, as determined by
GC–MS analysis.13 When the oxazole forming reaction
of aromatic ketones attempted in the presence of
We appreciate the financial support for this research by
a grant from the Korea Research Foundation (KRF-
2002-015-CP0217).
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