Synthesis of novel pyrazoles via [2+3]-dipolar cycloaddition using alkyne surrogates

Article abstract of DOI:10.1016/j.tetlet.2010.01.017

The syntheses of an important class of hitherto unreported novel pyrazoles are described. The regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles was achieved by the Huisgen cyclization of nitrile imines with a trisubstituted bromoalkene. The substituted bromoalkene functions as an alkyne synthon which was used to construct 5,5-disubstituted bromopyrazoline intermediates that undergo aromatization to the analogous pyrazoles through the loss of HBr. The cycloaddition regioselectivity was confirmed through single X-ray crystal data of one of the pyrazoles.

Full text of DOI:10.1016/j.tetlet.2010.01.017

Tetrahedron Letters 51 (2010) 1341–1343
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel pyrazoles via [2+3]-dipolar cycloaddition using
alkyne surrogates
Sureshbabu Dadiboyena a, Edward J. Valente b, Ashton T. Hamme II a,
*
a Department of Chemistry and Biochemistry, College of Science, Engineering and Technology, Jackson State University, Jackson, MS 39217, USA
b Department of Chemistry, University of Portland, 5000 N. Willamette Blvd., Portland, OR 97203, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The syntheses of an important class of hitherto unreported novel pyrazoles are described. The regioselec-
tive synthesis of 1,3,4,5-tetrasubstituted pyrazoles was achieved by the Huisgen cyclization of nitrile imi-
nes with a trisubstituted bromoalkene. The substituted bromoalkene functions as an alkyne synthon
which was used to construct 5,5-disubstituted bromopyrazoline intermediates that undergo aromatiza-
tion to the analogous pyrazoles through the loss of HBr. The cycloaddition regioselectivity was confirmed
through single X-ray crystal data of one of the pyrazoles.
Received 22 December 2009
Revised 6 January 2010
Accepted 7 January 2010
Available online 13 January 2010
Keywords:
Cycloaddition
Ó 2010 Elsevier Ltd. All rights reserved.
Regioselectivity
Heterocycles
Alkyne surrogate
Dehydrohalogenation
1. Introduction
usual dipolarophiles for this purpose are alkynes8 and alkyne
equivalents.6,9 The use of alkyne synthons9,10 can serve to alleviate
Heterocycles are popularly known for displaying a wide range
of biological properties,1 and the recent success of pyrazole-based
COX-II inhibitors and their application in medicinal chemistry have
amplified the importance of pyrazoles.2 Several pharmaceutical
drugs including celecoxib2 and rimonabant3 utilize the pyrazole
as their core molecular entity,4,5 and a regioselective synthetic
method for the synthesis of these and other substituted pyrazoles
is still in demand.3,5–7 (Fig. 1) One of the most frequently used pro-
tocols for pyrazole synthesis is 1,3-dipolar cycloaddition, and the
many of the alkyne preparatory and cycloaddition regioselectivity
issues. These alkyne proxies are usually alkenes that have a func-
tional group that can be eliminated in situ during cycloaddition.9,10
Recently, we reported the application of geminally disubstituted
alkenes, with a bromine atom as one of the substituents, as effec-
tive alkyne replacements toward the regioselective synthesis of
disubstituted isoxazoles.11 In order to build upon this premise,
we investigated the application of this protocol toward the regiose-
lective construction of tetrasubstituted pyrazoles. Herein we
O O
S
O O
S
CH3
Cl
Cl
Cl
N
H2N
N
N
O
N
CF3
N
N
CF3
HN
N
CH3
H3C
Celecoxib
SC-125
Rimonabant
F
Figure 1. Examples of pharmaceutically relevant pyrazoles.
* Corresponding author. Tel.: +1 601 979 3713; fax: +1 601 979 3674.
E-mail address: ashton.t.hamme@jsums.edu (A.T. Hamme).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.017

1342
S. Dadiboyena et al. / Tetrahedron Letters 51 (2010) 1341–1343
O
O
O
Br
(C2H5)3N
H
N
-HBr
76%
N
N
+
H
N
H
N
H
N
CH2Cl2
Br
Cl
1
2
4
3
Scheme 1. Pyrazole synthesis from a-bromocinnamaldehyde through the 5-bromo pyrazoline intermediate 3.
report the synthesis of 1,3,4,5-tetrasubstituted pyrazoles through
the regioselective 1,3-dipolar cycloaddition of a nitrile imine with
a trisubstituted bromoalkene which serves as an alkyne surrogate.
While investigating the synthesis of pyrazoles and pyrazolines,
(Scheme 1) The most probable driving force for the formation of 4
is the creation of a stable aromatic system through the loss of
HBr. Since the reaction conditions are basic, it is quite possible for
the bromo alkene, 1, to decompose to the corresponding alkyne be-
fore reacting with the nitrile imine. In order to rule out this reaction
pathway, compound 1 was exposed to triethylamine for 24 h at
we discovered that when
a-bromocinnamaldehyde (1) was used
as the alkene, pyrazole (4)12,13 was the only product isolated.
Table 1
1,3,4,5-Tetrasubstituted pyrazoles isolated from the 1,3-dipolar cycloaddition reaction
Entry
Alkene
a-Chloro hydrazone
Product
Yield (%)
O
H
N
N
Br
H
O
H
Cl
N
1
76
N
O
H
N
N
Br
H
O
H
Cl
N
N
2
70
OCH3
OCH3
O
H
N
Br
N
Cl
H
O
H
Cl
N
3
86
N
Cl
Cl
Cl
O
H
N
Br
N
H
O
H
Cl
N
N
4
73
NO2
O2N
O
H
N
Br
N
H
O
H
Cl
N
N
5
84
Cl
Cl

S. Dadiboyena et al. / Tetrahedron Letters 51 (2010) 1341–1343
1343
Acknowledgments
We thank the National Institutes of Health MBRS-SCORE and
RCMI programs (3S06 GM 008047-34S1 and G12RR13459 (NMR
and Analytical CORE facilities)) and the National Science Founda-
tion NSF-RISE program (HRD-0734645). E.J.V. gratefully acknowl-
edges the support of the National Science Foundation grant MRI
0618148 and the W. M. Keck Foundation for crystallographic
resources.
References and notes
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Chem., Int. Ed. Engl. 1963, 2, 633; (c) Browne, D. L.; Vivat, J. F.; Plant, A.; Gomez-
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Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. J. Org. Chem. 2003, 68, 5381; (e)
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Jimenez, R.; Perez, L.; Tamariz, J.; Salgado, H. Heterocycles 1993, 35, 591.
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Figure 2. Thermal ellipsoid plot of 4 drawn at the 50% probability level.13
room temperature, and no decomposition to the corresponding al-
kyne was observed. The study of the 1,3-dipolar cycloaddition reac-
tion of compound 1 with other nitrile imines was undertaken in
order to determine the general efficacy of a-bromocinnamaldehyde
as an alkyne equivalent. All these cycloadditions occurred with
complete regiochemical integrity in reasonable to good isolated
yields. The results of the cycloaddition of 1 with five different nitrile
imines with various functionalities are shown in Table 1.
The existence of pyrazole (4) as a crystalline solid enabled us to
perform X-ray studies to reveal compound’s regio-structural fea-
tures. Compound 4 was unambiguously confirmed by X-ray struc-
tural analysis as a 1,3,4,5-tetrasubstituted pyrazole where the
benzene rings are located at the 3 and 4 positions of the pyrazole.
(Fig. 2) This X-ray analysis provided evidence that the Huisgen
cyclization occurred through intermediate 3 as shown in Scheme
1. The structures of the remaining pyrazoles were elucidated based
upon their NMR spectroscopic data.
12. Dawood, K. M.; Fuchigami, T. J. Org. Chem. 2005, 70, 7537.
13. Structural information for pyrazole (4) has been deposited with the CCDC as
744851, available free of charge from www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033).
2. Conclusion
In summary, we report a facile and regioselective synthesis of
1,3,4,5-tetrasubstituted pyrazoles through the 1,3-dipolar cycload-
dition of nitrile imines with a-bromocinnamaldehyde (1) as an al-
14. General experimental procedure for the 1,3-dipolar cycloaddition: A solution of a-
bromocinnamaldehyde (1) (3 mmol) and the hydrazonyl chloride (3 mmol) in
10 mL of either dry chloroform or dichloromethane was treated with
triethylamine (0.46 mL, 3.3 mmol). The reaction mixture was stirred at rt
until the disappearance of the starting materials, as evidenced by TLC. After the
reaction was complete (7–10 h), the solvent was evaporated under reduced
pressure. The crude products were purified by flash column chromatography
over silica gel by using a hexanes–ethyl acetate ratio as an eluant system. This
procedure provided pure pyrazole products for entries 1–5 in 70–86% yield.
kyne surrogate.14 The construction of the stable aromatic pyrazole
system could be the driving force behind the dehydrobromination
process. Along with the NMR data, X-ray crystallographic analysis
also confirmed the regiochemistry of the distinctive pyrazole com-
pounds. Future investigations of 1,3-dipolar cycloaddition reac-
tions with various alkyne surrogates toward the synthesis of
pyrazoles and other heterocyclic compounds are in progress.