ORGANIC
LETTERS
2005
Vol. 7, No. 20
4487-4489
One-Pot Construction of Pyrazoles and
Isoxazoles with Palladium-Catalyzed
Four-Component Coupling
Mohamed S. Mohamed Ahmed, Kei Kobayashi, and Atsunori Mori*
Chemical Resources Laboratory, Tokyo Institute of Technology, R1-4 4259 Nagatsuta,
Yokohama 226-8503, Japan
Received August 1, 2005
ABSTRACT
Four-component coupling of a terminal alkyne, hydrazine (hydroxylamine), carbon monoxide, and an aryl iodide furnishes pyrazole or isoxazole
derivatives in the presence of a palladium catalyst. The reaction proceeds at room temperature and an ambient pressure of carbon monoxide
in an aqueous solvent system.
Heteroaromatic compounds have attracted considerable at-
tention in the design of biologically active molecules and
advanced organic materials.1 Hence, a practical method for
the preparation of such compounds is of great interest in
synthetic organic chemistry. We have been studying to
introduce a substituent into heteroaromatic compounds with
a transition metal catalyst and have shown that several
arylation reactions take place at the C-H bond of thiazoles
and thiophenes.2 In addition to the modification of heteroaro-
matic compounds, efficient construction of the ring structure
is also an important issue in organic synthesis. Thereby, one-
pot construction of heterocycles with simple organic mol-
ecules as the components, if successful, would be a facile
and practical method.3 We herein describe four-component
one-pot construction of five-membered heteroaromatics, such
as pyrazoles and isoxazoles, via a palladium-catalyzed
coupling of terminal alkynes, hydrazine (hydroxylamine),
carbon monoxide, and aryl iodides.
Treatment of phenylethyne (1a), aqueous hydrazine,
carbon monoxide, and iodobenzene (2a) in the presence of
PdCl2(PPh3)2 in THF at room temperature and an ambient
pressure of CO afforded 3,5-diphenylpyrazole (3aa) in 59%
yield after stirring for 36 h. Table 1 summarizes the results
of the four-component coupling reaction. The use of 3 equiv
of 0.5 M aqueous hydrazine solution resulted in giving
pyrazole in the highest yield, while the reaction with aqueous
hydrazine of higher concentration resulted in inferior yields.
The yield of pyrazole was found to be the best when 3 mol
amount of hydrazine toward 2a was employed. Although the
reaction with a more excess amount afforded pyrazole 3aa
in a comparable yield, the use of a smaller amount of
hydrazine was found to be less effective. The reaction with
DMF as a solvent was also found to give 3aa in 47% yield.
The reaction would be sequential reactions of carbonylative
Sonogashira coupling4 and following ring formation of R,â-
(1) (a) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991. (b)
Haino, T.; Tanaka, M.; Ikeda, K.; Kubo, K.; Mori, A.; Fukazawa, Y.
Tetrahedron Lett. 2004, 45, 2277.
(2) (a) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.;
Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700.
(b) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074.
(c) Masui, K.; Mori, A.; Okano, K.; Takamura, K.; Kinoshita, M.; Ikeda,
T. Org. Lett. 2004, 6, 2011.
(3) An example of recent multicomponent construction of ring structures
with a transition metal catalyst: (a) Yamamoto, Y.; Ishii, J.; Nishiyama,
H.; Itoh, K. J. Am. Chem. Soc. 2004, 126, 3712. (b) Krazinski, A.; Radic,
Z.; Manetsch, R.; Raushel, J.; Taylor, P.; Sharpless, K. B.; Kolb, H. C. J.
Am. Chem. Soc. 2005, 127, 6686.
(4) (a) Mohamed Ahmed, M. S.; Mori, A. Org. Lett. 2003, 5, 3057. (b)
Mohamed Ahmed, M. S.; Sekiguchi, A.; Masui, K.; Mori, A. Bull. Chem.
Soc. Jpn. 2005, 78, 160.
10.1021/ol051841j CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/01/2005