ORGANIC
LETTERS
2012
Vol. 14, No. 2
640–643
Petasis Three-Component Coupling
Reactions of Hydrazides for the Synthesis
of Oxadiazolones and Oxazolidinones
Sebastian T. Le Quement,† Thomas Flagstad,† Remi J. T. Mikkelsen,†
Mette R. Hansen,† Michael C. Givskov,‡ and Thomas E. Nielsen*,†
Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby,
Denmark, and Department of International Health, Immunology and Microbiology,
University of Copenhagen, DK-2200 Copenhagen, Denmark
Received December 8, 2011
ABSTRACT
An application of readily available hydrazides in the Petasis 3-component coupling reaction is presented. An investigation of the substrate scope
was performed to establish a general, synthetically useful protocol for the formation of hydrazido alcohols, which were selectively converted to
oxazolidinone and oxadiazolone ring systems through triphosgene-mediated cyclization reactions.
Considering the huge potential of the three-component
reaction of amines (primary or secondary), R-hydroxy
aldehydes, and substituted vinyl or aryl boronic acids, also
known as the Petasis three-component coupling reaction
(Petasis 3-CCR),1 for the stereoselective synthesis of
amino alcohols,2 there have been surprisingly few reports
onitsapplication insyntheticorganicchemistry.3 Evidence
for the unique reliability of the reaction is illustrated
by applications in the synthesis of natural products,4
carbohydrate derivatives,5 and unnatural amino acids.6
Advantages of the reaction comprise simple and mild
reaction conditions, broad substrate scope, easy access to
building blocks, and amenability to combinatorial synthe-
sis strategies, including those that aim for structurally
diverse molecular libraries.7
As part of ongoing efforts aimed at identifying novel
antibacterial compounds, we became interested in synthetic
methods that allowed the rapid generation of compounds
incorporating heterocyclic motifs analogous to those of
renowned bioactives.
In this context, we have been particularly interested in
the oxazolidinone core which is a key structural element of
several known antibiotics, such as Linezolid8 and N-thio-
lated 2-oxazolidinones.9 This heterocycle could also serve
† Technical University of Denmark.
‡ University of Copenhagen.
(1) For early accounts on the Petasis three-component coupling
reaction, see: (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett.
1993, 34, 586–583. (b) Harwood, L. M.; Currie, G. S.; Drew, M. G. B.;
Luke, R. W. A. Chem. Commun. 1996, 1953–1954. (c) Dyker, G. Angew.
Chem., Int. Ed. 1997, 36, 1700–1702.
(2) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798–
11799.
(3) For reviews on the Petasis three-component coupling reaction,
ꢀ
see: (a) Petasis, N. A. In Multicomponent Reactions; Zhu, J., Bienayme,
H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; pp 199ꢀ223. (b) Batey,
R. A. In Boronic Acids; Hall., D. G., Ed.; Wiley-VCH: Weinheim, Germany,
2005; pp 279ꢀ304. (c) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.;
Gois, P. M. P. Chem. Rev. 2010, 110, 6169–6193.
(4) For selected examples, see: (a) Batey, R. A.; MacKay, D. B.
Tetrahedron Lett. 2000, 41, 9935–9938. (b) Jiang, B.; Xu, M. Angew.
Chem., Int. Ed. 2004, 43, 2543–2546. (c) Sugiyama, S.; Arai, S.; Ishii, K.
Tetrahedron: Asymmetry 2004, 15, 3149–3153. (d) Furstner, A.; Ackerstaff,
J. Chem. Commun. 2008, 2870–2872.
(5) (a) Davis, A. S.; Pyne, S. G.; Skelton, B. W.; White, A. H.
J. Org. Chem. 2004, 69, 3139–3143. (b) Hong, Z.; Liu, L.; Hsu,
C.-C.; Wong, C.-H. Angew. Chem., Int. Ed. 2006, 45, 7417–7421.
(6) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119,
445–446. (b) Currie, G. S.; Drew, M. G. B.; Harwood, L. M.; Hughes,
D. J.; Luke, R. W. A.; Vickers, R. J. J. Chem. Soc., Perkin Trans. 1 2000,
2982–2990.
(7) (a) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 3635–3638. (b) Muncipinto, G.; Kaya, T.; Wilson,
J. A.; Kumagai, N.; Clemons, P. A.; Schreiber, S. L. Org. Lett. 2010, 12,
5230–5233. (d) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed.
2008, 47, 48–56.
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10.1021/ol203280b
Published on Web 01/10/2012
2012 American Chemical Society