ORGANIC
LETTERS
2006
Vol. 8, No. 24
5621-5624
Synthesis of 2-Azaindolizines by Using
an Iodine-Mediated Oxidative
Desulfurization Promoted Cyclization of
N-2-Pyridylmethyl Thioamides and an
Investigation of Their Photophysical
Properties
Fumitoshi Shibahara,* Asumi Kitagawa, Eiji Yamaguchi, and Toshiaki Murai*
Department of Chemistry, Faculty of Engineering, Gifu UniVersity, Yanagido, Gifu
501-1193, Japan
fshiba@gifu-u.ac.jp; mtoshi@gifu-u.ac.jp
Received September 26, 2006
ABSTRACT
Iodine-mediated, oxidative desulfurization promoted cyclization of N-2-pyridylmethyl thioamides serves as an efficient and versatile method
for the preparation of 2-azaindolizines (imidazo[1,5-a]pyridines) and rare 2-azaindolizine sulfur-bridged dimers. The 2-azaindolizines prepared
in this manner are readily converted to a variety of fluorescent compounds by using transition-metal-catalyzed cross-coupling reactions.
Bicyclic heteroaromatics, in which the nitrogen atom is lo-
cated at ring-fusion positions, comprise an important family
of compounds owing to their unique photophysical and biolog-
ical properties.1 Recently, increasing attention has been given
to members of this family that contain the imidazo[1,5-a]-
pyridine (2-azaindolizine) skeleton.2-5 Potential applications
of these substances have been actively probed in the context
of organic light-emitting diodes (OLED)2 and organic thin-
layer field effect transistors (FET).3 In addition, 2-azain-
dolizines have been investigated as pharmaceuticals (eg.,
HIV-protease inhibitors)4 and as precursors of N-heterocyclic
carbenes5 whose synthesis and applications are now under
active exploration. Despite this high interest, existing syn-
thetic routes which target 2-azaindolizines, relying mainly
on traditional Vilsmeier-type cyclizations of N-2-pyridylm-
ethyl amides, are only modestly efficient.6 Consequently, an
efficient synthetic approach to a wide variety of 2-azain-
dolizines is in strong demand.7,8 Methods that enable prep-
aration of 2-azaindolizines, which contain functional groups
that can be transformed to π-conjugated systems, would be
(1) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Black
Science: Oxford, U.K., 2000; Chapter 25.
(2) (a) Nakatsuka, M.; Shimamura, T. Jpn. Kokai Tokkyo Koho JP
2001035664; Chem. Abstr. 2001, 134, 170632. (b) Tominaga, G.; Kohama,
R.; Takano, A. Jpn. Kokai Tokkyo Koho JP 2001006877; Chem. Abstr.
2001, 134, 93136. (c) Kitazawa, D.; Tominaga, G.; Takano, A. Jpn. Kokai
Tokkyo Koho JP 2001057292; Chem. Abstr. 2001, 134, 200276.
(3) Nakamura, H.; Yamamoto, H. PCT Int. Appl. WO 2005043630;
Chem. Abstr. 2005, 142, 440277.
(4) (a) Degoey, D. A.; Flentge, C. A.; Flosi, W. J.; Grampovnik, D. J.;
Kempf, D. J.; Klein, L. L.; Yeung, M. C.; Randolph, J. T.; Wang, X. C.;
Yu, S. U.S. Pat. Appl. Publ. U.S. 2005148623; Chem. Abstr. 2005, 143,
133693. (b) Kim, D. et al. Bioorg. Med. Chem. Lett. 2005, 15, 2129. See
Supporting Information for full list of authors.
(6) Bower, J. D.; Ramage, G. R. J. Chem. Soc. 1955, 2834.
(7) For recent advances in the synthesis of 2-azaindolizines via an acetic
acid mediated condensation pathway, see: (a) Wang, J.; Mason, R.;
VanDerveer, K.; Feng, D.; Bu, X. R. J. Org. Chem. 2003, 68, 5415. (b)
Dyers, J. W. L., Jr.; Mason, R., Jr.; Amoyaw, P.; Bu, X. R. J. Org. Chem.
2005, 70, 2353 and references cited therein.
(8) For recent advances in the synthesis of 2-azaindolizines via an
oxidative pathway, see: (a) Bluhm, M. E.; Ciesielski, M.; Go¨rls, H.; Do¨ring,
M. Angew. Chem., Int. Ed. 2002, 41, 2962. (b) Bluhm, M. E.; Folli, C.;
Pufky, D.; Kro¨ger, M.; Walter, O.; Do¨ring, M. Organometallics 2005, 24,
4139 and references cited therein.
(5) (a) Alcarazo, M.; Roseblade, S. J.; Cowley, A. R.; Ferna´ndez, R.;
Brown, J. M.; Lassaletta, J. M. J. Am. Chem. Soc. 2005, 127, 3290. (b)
Burstein, C.; Lehmann, C. W.; Glorius, F. Tetrahedron 2005, 61, 6207. (c)
Hahn, F. E. Angew. Chem., Int. Ed. 2006, 45, 1348.
10.1021/ol0623623 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/25/2006