ORGANIC
LETTERS
2009
Vol. 11, No. 10
2097-2100
One-Pot Synthesis of N-Arylpyrazoles
from Arylhalides
Brian S. Gerstenberger,* Mark R. Rauckhorst, and Jeremy T. Starr
Pfizer Global Research and DeVelopment, 445 Eastern Point Road,
Groton, Connecticut 06340
brian.gerstenberger@pfizer.com
Received March 16, 2009
ABSTRACT
A simple one-pot method for the synthesis of diversely functionalized pyrazoles from aryl nucleophiles, di-tert-butylazodicarboxlate, and
1,3-dicarbonyl or equivalent compounds is presented.
N-Arylpyrazoles, although virtually unknown in natural
products, are an important structural class in pharmaceuticals
and agrochemicals including Celebrex (1), Pyracolfos, and
Fipronil (2) (Figure 1).1 Currently, two methods predominate
in the synthesis of this key structure. The first is direct
N-arylation of a 1 H-pyrazole via either a direct SNAr
substitution or a transition-metal-catalyzed C-N cross-
coupling reaction, and the second is the cyclocondensation
of an arylhydrazine with a 1,3-difunctionalized three-carbon
donor such as a diketone or ꢀ-aminoacrolein.2 Even though
transition-metal-catalyzed N-arylation using a variety of
nitrogen nucleophiles has made tremendous progress in the
past decade, including the use of palladium,3 copper,4-9 or
iron,10 these reactions still have limitations including non-
generalization, lack of application to systems with sensitive
functional groups, and limited examples of the use of 1H-
pyrazoles as the nucleophilic component.11 Conversely, the
cyclocondensation method requires access to an appropriately
substituted arylhydrazine, an often multistep synthesis when
not commercially available, and further limited by compat-
ibility of the free hydrazine with other functionality in the
intermediate. Preparation of arylhydrazines from anilines via
diazotization-reduction does not lend well to complex
molecules with susceptible moieties. Additionally, these
preparations of hydrazines usually are not appropriate at scale
due to thermal instability and explosive characteristics of
the intermediates. An ideal protocol would install the desired
pyrazole onto an aryl halide, or even Ar-H, precursor in a
functional group-tolerant, time-efficient, one-pot procedure.
In our research, we required access to N-arylpyrazole 4
(Scheme 1), with initial attempts focused on metal-catalyzed
arylation using 4-chloro-1H-pyrazole under a variety of
conditions. Unfortunately, all gave only low yields and
required long reaction times (up to 5 days). Attempts to
increase the rate or yield of the reaction by changing the
(7) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.sEur.
J. 2004, 10, 5607–5622.
(1) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of Hetero-
cycles, 2nd ed.; Wiley & Sons: New York, 2004; pp 179-184.
(2) Withbroe, G. J.; Singer, R. A.; Sieser, J. E. Org. Process ReV. DeV.
2008, 12, 480–489.
(8) Klapars, A.; Antilla, J, C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727–7729.
(9) Zhu, L.; Guo, P.; Li, G.; Lan, J.; Xie, R.; You, J. J. Org. Chem.
2007, 72, 8535–8538.
(3) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R. A.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2006, 45, 6523–6527.
(10) Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862–8865.
(11) For an example of the state of the art, CuI-catalyzed N-arylation
of pyrazole or 3-methyl-1H-pyrazole proceeded in 71% and 50% yield,
respectively, after 40 h reaction time. Regioselectivity of arylation of
3-methyl-1H-pyrazole was 5:1 favoring the opposite regioisomer to the
analogous example in our own work (Table 1, entry 4). See: Zhu, L.; Li,
G.; Luo, L.; Guo, P.; Lan, J.; You, J. J. Org. Chem. 2009, 74, 2200–2202.
(4) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org.
Chem. 2004, 69, 5578–5587
(5) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684–11688
(6) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Eur. J.
Org. Chem. 2004, 695–709
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10.1021/ol900515a CCC: $40.75
Published on Web 04/22/2009
2009 American Chemical Society