ORGANIC
LETTERS
2009
Vol. 11, No. 6
1457-1459
Nickel-Catalyzed Synthesis of Oxazoles
via C-S Activation
Kyoungsoo Lee, Carla M. Counceller, and James P. Stambuli*
EVans Chemical Laboratories, Department of Chemistry, The Ohio State UniVersity,
100 West 18th AVenue, Columbus, Ohio 43210
Received February 7, 2009
ABSTRACT
The synthesis of 2-substituted oxazoles is achieved via nickel-catalyzed cross-coupling reaction of 2-methylthio-oxazole and various organozinc
reagents. An extension of this method is demonstrated with a chemoselective, one-pot synthesis of unsymmetrical 2,5-disubstituted oxazoles.
This synthesis of 2- and 2,5-substituted oxazoles using this method provides great advantages over previous methods for these compounds
and is highly complementary to current cyclodehydration strategies.
Oxazoles are an important class of heterocycle that exhibit
diverse biological activities.1 Natural products containing the
oxazole substructure have been shown to exhibit potent
anticancer, -fungal, and -bacterial properties.2 Oxazoles that
are monosubstituted at C-2 have been used as synthetic
intermediates in the synthesis of natural products3 and
pharmaceuticals.4 However, a potential limitation to a greater
use of 2-substituted oxazoles in synthetic chemistry may be
caused by the lack of practical methods to produce 2-sub-
stituted oxazoles.
Current methods for the synthesis of oxazoles include
cyclodehydration reactions,5 oxidations of oxazolines,6 direct
metalations of the parent oxazole,7 and metal-catalyzed cross-
coupling reactions.8 The most common method to prepare
oxazoles involves cyclodehydrations, but this method pro-
vides low yields of 2-substituted oxazoles.9 A general
synthesis of 2-substituted oxazoles was reported via pal-
ladium-catalyzed Negishi cross-coupling using 2-oxazolylz-
inc chloride with aryl bromides.10 The reaction works well
for some aryl substrates but requires the use of 1.4 equiv of
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troscopy; John Wiley & Sons: Hoboken, 2003.
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Angew. Chem., Int. Ed. 2003, 42, 4961. (c) Kende, A. S.; Kawamura, K.;
DeVita, R. J. J. Am. Chem. Soc. 1990, 112, 4070. (d) Kobayashi, J.-I.;
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Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett.
2000, 2, 1165.
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Vedejs, E.; Monahan, S. D. J. Org. Chem. 1996, 61, 5192.
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10.1021/ol900260g CCC: $40.75
Published on Web 02/24/2009
2009 American Chemical Society