LETTER
Rapid Synthesis of Oxazoles under Microwave Conditions
1643
tween the cycles. When TLC and LC-MS analysis
indicated the absence of starting material, the crude reac-
tion mixtures were passed through a short column of silica
gel to remove the polar degradation products of Burgess
reagent. Examples of 2-, 2,5- and 2,4,5-substituted ox-
azoles were synthesized. This procedure is very conve-
nient to carry out, avoids tedious work up and
purification, and rapidly provides high yields of ox-
azoles.16,17 Polyethylene glycol-supported Burgess
reagent13,15 was also used successfully in several cases,
however, a moderate reduction in yield was observed. De-
tails of the microwave conditions and yields are reported
in Table 1.
References and Notes
(1) Robinson, R. J. Chem. Soc. 1909, 95, 2167.
(2) Review: Turchi, I. J. In The Chemistry of Heterocyclic
Compounds, 45; Wiley: New York, 1986; p1.
(3) (a) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. J.
Chem. Soc. Perkin Trans. 1 1998, 591. (b) Wipf, P.;
Yokokawa, F. Tetrahedron Lett. 1998, 39, 2223. (c) Wipf, P.;
Lim, S. J. Am. Chem. Soc. 1995, 117, 558 (d) Wipf, P.; Miller,
C. P. J. Org. Chem. 1993, 58, 3604. (e) Gordon, T. D.; Singh,
J.; Hansen, P. E.; Morgan, B. A. Tetrahedron Lett. 1993, 34,
1901.
(4) Only two examples of the cyclodehydration of 2-acylamino
aldehydes were found in the literature: Sen, P. K.; Veal, C. J.;
Young, D. W. J. Chem. Soc. Perkin Trans. 1 1981, 3053.
(8.5% yield using SOCl2). Wipf3d reported the preparation of
a 2-monosubstituted oxazole by Dess-Martin periodinane
oxidation of a 2-acylamino alcohol followed by PPh3/I2/Et3N
induced cyclodehydration (17% overall).
The high yielding synthesis of the 2-monosubstituted ox-
azoles 1g,h from the parent 2-acylamino alcohols 3g,h by
catalytic TEMPO oxidation followed by cyclodehydra-
tion with Burgess reagent is particularly noteworthy. This
represents a synthetically useful extension of the scope of
the Robinson-Gabriel process to include the hitherto prob-
lematic 2-acylamino aldehydes.4
(5) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90,
4744.
(6) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 1575.
(7) The usual reagent for the oxidative aromatization of
oxazolines, NiO2, provides oxazoles in moderate and variable
yields, requires long reaction times and is sensitive to steric
hindrence at C(5): (a) Evans, D. A.; Gage, J. R.; Leighton, J.
L.; Kim, A. S. J. Org. Chem. 1992, 57, 1961. (b) Evans, D. A.;
Minster, D. K.; Jordis, U.; Hecht, S. M.; Mazzu, A. L. Jr.;
Meyers, A. I. J. Org. Chem. 1979, 44, 497.
(8) (a) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207.
(b) Barrish, J. C.; Singh, J.; Spergel, S. H.; Han, W-C.;
Kissick, T. P.; Kronenthal, D. R.; Mueller, R. H. J. Org.
Chem. 1993, 58, 4494.
(9) Shipton, M. R. Synlett 1992, 491.
(10) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
Chem. Commun. 1987, 1625.
(11) Anelli, P. L.; Biffi, C.; Montanari, F; Quici, S. J. Org. Chem.
1987, 52, 2559.
In summary, we have devised an efficient and experimen-
tally convenient variation of the classical Robinson-Gab-
riel reaction. Cyclodehydration of 2-acylamino carbonyl
compounds with Burgess reagent proceeds rapidly and
cleanly under monomode microwave conditions. This
new method compares favourably with activated triphe-
nylphosphine-based cyclodehydration procedures3 and
avoids the sometimes troublesome removal of the triphe-
nylphosphine oxide byproduct. Our method would be par-
ticularly suitable for high- throughput synthetic
procedures. The broader scope of this procedure is cur-
rently under investigation.
(12) 1g,h were obtained using ethyl acetate/water as the biphasic
system. Use of dichloromethane/water tended to result in
emulsion formation and concomitant degradation of the
aldehydes.
(13) The quality of commercial Burgess reagent has been reported
to be batch-dependent: Wipf, P.; Venkatraman, S.
Tetrahedron Lett. 1996, 37, 4659.
Acknowledgement
We thank Drs Andrew Culshaw and Esteban Pombo-Villar, Novar-
tis Pharma, Nervous System Research, for their helpful comments
and interest.
Synlett 1999, No. 10, 1642–1644 ISSN 0936-5214 © Thieme Stuttgart · New York