ORGANIC
LETTERS
2001
Vol. 3, No. 2
209-211
A General [3 + 2 + 1] Annulation
Strategy for the Preparation of Pyridine
N-Oxides
,†
Ian W. Davies,* Jean-Franc¸ois Marcoux,* and Paul J. Reider
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065
Received November 7, 2000
ABSTRACT
Stabilized ketone, aldehyde, and ester enolates react with vinamidinium hexafluorophosphate salts and hydroxylamine hydrochloride to give
access to the corresponding pyridine N-oxides. The annulation reactions proceed in good to excellent yields with vinamidinium salts with a
range of â-substituents (R3 ) halo, aryl, nitro, trifluoromethyl).
Pyridine N-oxides are used as antibacterial, antifungal, and
antiseborrheic agents.1 N-Oxides are very often metabolites
of pyridine-containing molecules and have been used to
determine structure-activity relationships. The most com-
monly used method for the preparation of these compounds
relies on oxidation of the parent pyridines.2 Cyclization of
nitroaromatics and oximes are also well-established methods
for preparation of fused pyridine N-oxides.3 Other less
general methods include reaction of pyrrilium salts or
dienones with hydroxylamine.4 N-Oxides are useful synthetic
intermediates since they exhibit different reactivity and
regioselectivity than the parent pyridine.
dinium salt 2, and ammonia in a [3 + 2 + 1] annulation
reaction (Scheme 1).5 The vinamidinium salts, which are
Scheme 1
The Cox-2 specific inhibitor Etoricoxib can be assembled
very efficiently in a single step from ketone 1, the vinami-
readily available from acetic acids, may contain a range of
functionality.6
(1) The Merck Index on CD-ROM, v. 12.3, Chapman & Hall, 2000.
(2) For example, see: Coperet, C.; Adolfsson, H.; Khuong, T.-A.; Yudin,
A. K.; Sharpless, K. B. J. Org. Chem. 1998, 63, 1740.
(3) For example, see: (a) Hirota, K.; Nakazawa, Y.; Kitade, Y.; Saijiki,
H. Heterocycles 1998, 47, 871. (b) Wrobel, Z.; Kwast, A.; Makosza, M.
Synthesis 1993, 1, 31. (c) Kusurkar, R. S.; Bhosdale, D. K. Tetrahedron
Lett. 1991, 32, 3199. (d) Nesi, R.; Giomi, D.; Papaleo, S.; Turchi, S.;
Dapporto, P.; Paoli, P. Heterocycles 1991, 32, 1913.
(4) Uncuta, C.; Caproiu, M. R.; Campeanu, V.; Petride, A.; Danila, M.
G.; Plaveti, M.; Balaban, A. T. Tetrahedron 1998, 54, 9747.
(5) Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, M.; Cai, D.-
W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.; DiMichele,
L.; Dormer, P.; Reider, P. J. Org. Chem. 2000, 65, 8415. Marcoux, J.-F.;
Corley, E. G.; Rossen, K.; Pye, P.; Wu, J.; Robbins, M. A.; Davies, I. W.;
Larsen, R. D.; Reider, P. J. Org. Lett. 2000, 2, 2339.
(6) Davies, I. W.; Marcoux, J.-F.; Wu, J.; Palucki, M.; Corley, E. G.;
Robbins, M.; Tsou, N.; Ball, R. G.; Dormer, P.; Larsen, R. D.; Reider, P.
J. Org. Chem. 2000, 65, 4571.
10.1021/ol006831r CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/22/2000