ORGANIC
LETTERS
2012
Vol. 14, No. 21
5618–5620
Substitution of the Nitro Group with
Grignard Reagents: Facile Arylation and
Alkenylation of Pyridine N‑Oxides
Fang Zhang, Song Zhang, and Xin-Fang Duan*
College of Chemistry, Beijing Normal University, Beijing 100875, China
Received September 27, 2012
ABSTRACT
The unprecedented substitution of a nitro group with aryl or alkenyl groups of Grignard reagents affords 2-aryl or alkenylpyridine N-oxides in
modest to high yields with high chemoselectivity. This protocol allows a simple and clean synthesis of various 2-substituted pyridine N-oxides
and the corresponding pyridine derivatives. Furthermore, straightforward one-pot iterative functionality of pyridine N-oxides could also be
achieved simply by successive applications of two Grignard reagents.
Substituted pyridines occur ubiquitously in natural
products, biologically active compounds, and functional
materials.1 However, the functionalization of pyridine
rings, for example, by halogenation or nitration, is usually
difficultdue tothe overall low reactivityofpyridine toward
electrophilic aromatic substitution. Due to the limitations
of pyridine, pyridine N-oxides often serve as important
alternatives for the syntheses of substituted pyridines.2
Pyridine N-oxides are also important structural motifs in
natural products3 and biologically active compounds4 and
have found wide use as catalysts in asymmetric reactions.5
Consequently, efforts have been devoted to the develop-
ment of efficient methods for the arylation, alkenylation,
and alkylation of pyridine N-oxides. Among known
methods, transition-metal-catalyzed direct arylation via
CꢀH activation represents one of the major strategies.6,7
Herein we report an efficient transition-metal-free aryla-
tion and alkenylation of nitropyridine N-oxides based
on a novel substitution of the nitro group with Grignard
reagents.
(5) For review, see: (a) Malkov, A. V.; Kocovsky, P. Eur. J. Org.
Chem. 2007, 29. For recent representative examples, see: (b) Takenaka,
N.; Sarangthem, R. S.; Captain, B. Angew. Chem., Int. Ed. 2008, 47,
9708. (c) Chen, J.; Takenaka, N. Chem.;Eur. J. 2009, 15, 7268.
(6) For selected reviews, see: (a) Fagnou, K. Top. Curr. Chem. 2010,
292, 35. (b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792. (c) Daugulis, O.; Do, H. Q.; Shabashov, D. Acc.
Chem. Res. 2009, 42, 1074.
(7) For recent representative examples of direct arylation of pyridine
N-oxides, see: (a) Tan, Y.; Barrios-Landeros, F.; Hartwig, J. F. J. Am.
Chem. Soc. 2012, 134, 3683. (b) Gosselin, F.; Savage, S. J.; Blaquiere, N.;
Staben, S. T. Org. Lett. 2012, 14, 862. (c) Duric, S.; Tzschucke, C. C. Org.
Lett. 2011, 13, 2310. (d) Ackermann, L; Fenner, S. Chem. Commun.
2011, 47, 430. (e) Gong, X.; Song, G.; Zhang, H.; Li, X. Org. Lett. 2011,
13, 1766.
(1) (a) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem.
Rev. 2012, 112, 2642. (b) Joule, J. A.; Mills, K. Heterocyclic Chemistry;
John Wiley & Sons: New York, 2010. (c) Abass, M. Heterocycles 2005, 65,
901.
(2) Albini, A.; Pietra, S. Heterocyclic N-Oxides; CRC Press: Boca
Raton, FL, 1991.
(3) (a) Donnell, G. O.; Poeschl, R.; Zimhony, O.; Gunaratnam, M.;
Moreira, J. B. C.; Neidle, S.; Evangelopoulos, D.; Bhakta, S.; Malkinson,
J. P.; Boshoff, H. I.; Lenaerts, A.; Gibbons, S. J. Nat. Prod. 2009, 72, 360.
(b)Nicholas, G. M.; Blunt, J. W.; Munro, M. H. G. J. Nat. Prod. 2001, 64,
341.
(4) Oberwinkler, S. M.; Nowicki, B.; Pike, V. W.; Halldin, C.;
Sandell, J.; Chou, Y. H.; Gulyas, B.; Brennum, L. T.; Fardec, L.;
Wikstroma, H. V. Bioorg. Med. Chem. 2005, 13, 883.
r
10.1021/ol3026632
Published on Web 10/18/2012
2012 American Chemical Society