ORGANIC
LETTERS
2008
Vol. 10, No. 5
1021-1023
A Practical, Metal-Free Synthesis of
1H-Indazoles
Carla M. Counceller, Chad C. Eichman, Brenda C. Wray, and James P. Stambuli*
EVans Chemical Laboratories, Department of Chemistry, The Ohio State UniVersity,
100 West 18th AVenue, Columbus, Ohio 43210
Received January 9, 2008
ABSTRACT
The synthesis of 1H-indazoles is achieved from o-aminobenzoximes by the selective activation of the oxime in the presence of the amino
group. The reaction occurs with a variety of substituted o-aminobenzoximes using a slight excess of methanesulfonyl chloride and triethylamine
at 0
−23 °C and is amenable to scale-up. The synthesis of 1H-indazoles under these conditions is extremely mild compared with previous
synthetic approaches and affords the desired compounds in good to excellent yields.
The diverse pharmacological properties exhibited by 1H-
indazoles have sparked the emergence of novel methods
toward their synthesis. The use of 1H-indazoles as anti-
cancer, -inflammatory, and -microbial agents has been
documented in recent patents and publications.1 Although
many new methodologies have been reported to synthesize
1H-indazoles, a mild, general method still remains an
ongoing challenge.
Condensation reactions of o-fluorobenzaldehydes and
excess hydrazine provide a metal-free synthesis of 1H-
indazoles; however, the method is limited in scope and
requires the use of the o-fluoroarenes.3 The palladium-
catalyzed synthesis of 1H-indazoles from aryltosylhydrazones
requires high catalyst loadings and only provides tosyl-
protected indazoles.4 Other recent metal-catalyzed routes to
1H-indazoles employ low catalyst loadings of CuO but give
N-methylindazoles in moderate yields,5 and an iron-catalyzed
route to 1H-indazoles from o-nitrooximes requires 150 °C
and a high pressure of CO.6 Most recently, Yamamoto
reported the synthesis of 1H-indazoles via the 1,3-dipolar
cycloaddition of arynes and diazoalkanes.7 We report a
simple, metal-free synthesis of substituted 1H-indazoles that
occurs from readily available aminobenzoximes under mild
conditions.
Classical routes to 1H-indazoles typically require harsh
or inconvenient conditions such as diazotizations and nitro-
sation reactions.2 The large number of recently published
methods that aim to improve the traditional routes to 1H-
indazole signifies the importance of these compounds.
(1) (a) Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Aran, V. J.; Ocariz, C.
O. Mini-ReV. Med. Chem. 2005, 5, 869. (b) Feng, Y.; Cameron, M. D.;
Frackowiak, B.; Griffin, E.; Lin, L.; Ruiz, C.; Schroeter, T.; LoGrasso, P.
Bioorg. Med. Chem. Lett. 2007, 17, 8, 2355. (c) Goodman, K. B.; Cui, H.;
Dowdell, S. E.; Gaitanopoulos, D. E.; Ivy, R. L.; Sehon, C. A.; Stavenger,
R. A.; Wang, G. Z.; Viet, A. Q.; Xu, W.; Ye, G.; Semus, S. F.; Evans, C.;
Fries, H. E.; Jolivette, L. J.; Kirkpatrick, R. B.; Dul, E.; Khandekar, S. S.;
Yi, T.; Jung, D. K.; Wright, L. L.; Smith, G. K. J. Med. Chem. 2007, 50,
1, 6. (d) Zhu, G.-D.; Gandhi, V. B.; Gong, J.; Thomas, S.; Woods, K. W.;
Song, X.; Li, T.; Diebold, R. B.; Luo, Y.; Liu, X.; Guan, R.; Klinghofer,
V.; Johnson, E. F.; Bouska, J.; Olson, A.; Marsh, K. C.; Stoll, V. S.; Mamo,
M.; Polakowski, J.; Campbell, T. J. J. Med. Chem. 2007, 50, 13, 2990. (e)
Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.; Nugiel, D. A. J. Org.
Chem. 1997, 62, 5627.
Recently, practical syntheses of tertiary amines have been
developed using electrophilic amination strategies involving
(3) Lukin, K.; Hsu, M. C.; Fernando, D.; Leanna, M. R. J. Org. Chem.
2006, 71, 8166.
(4) Inamoto, K.; Katsuno, M.; Yoshino, T.; Arai, Y.; Hiroya, K.;
Sakamoto, T. Tetrahedron 2007, 63, 2695.
(5) Vina, D.; Olmo, E. d.; Lopez-Perez, J. L.; Feliciano, A. S. Org. Lett.
2007, 9, 525.
(2) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Wiley-
VCH: Weinheim, 2003.
(6) O’Dell, D. K.; Nicholas, K. M. Heterocycles 2004, 63, 373.
(7) Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 3323-3325.
10.1021/ol800053f CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/30/2008