A novel synthesis of 1,3,5-trisubstituted pyrazoles through a spiro-pyrazoline intermediate via a tandem 1,3-dipolar cycloaddition/elimination

Article abstract of DOI:10.1016/j.tetlet.2008.10.145

The syntheses of an important class of hitherto unreported 1,3,5-pyrazoles, inspired by an unanticipated eliminatory ring opening are described. The reported pyrazole compounds were constructed through the Huisgen cyclization of 2-methylene-1,3,3-trimethy

Full text of DOI:10.1016/j.tetlet.2008.10.145

Tetrahedron Letters 50 (2009) 291–294
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Tetrahedron Letters
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A novel synthesis of 1,3,5-trisubstituted pyrazoles through
a spiro-pyrazoline intermediate via a tandem 1,3-dipolar
cycloaddition/elimination
Sureshbabu Dadiboyena a, Edward J. Valente b, Ashton T. Hamme II a,
*
a Department of Chemistry, College of Science, Engineering and Technology, Jackson State University, Jackson, MS 39217, USA
b Department of Chemistry and Biochemistry, Mississippi College, Clinton, MS 39058, 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 1,3,5-pyrazoles, inspired by an unanticipated
eliminatory ring opening are described. The reported pyrazole compounds were constructed through the
Huisgen cyclization of 2-methylene-1,3,3-trimethylindoline and an in situ generated nitrile imine. The
newly formed spiro-pyrazoline intermediate presumably then undergoes a ring opening/elimination pro-
cess to afford a pyrazole, as evidenced by single X-ray crystal data. The current report constitutes the first
formal observation of this kind of ring opening involving a spiro-pyrazoline intermediate.
Published by Elsevier Ltd.
Received 12 September 2008
Revised 29 October 2008
Accepted 30 October 2008
Available online 5 November 2008
Keywords:
Cycloaddition
Ring fragmentation
Heterocycles
Spirocycles
Tandem reactions
Regioselectivity
1. Introduction
methylindoline (1) was reacted with the in situ generated nitrile
imine from hydrazonyl chloride11 (2), pyrazole (4) was the only
Heterocycles are popularly known for displaying a wide range
of biological properties.1 The recent success of pyrazole based
COX-II inhibitors and their application in medicinal chemistry have
amplified the importance of pyrazoles to even a greater extent.2
Several pharmaceutical drugs including celecoxib2 and rimona-
bant3 utilize the pyrazole as their core molecular entity,4,5 and a
regioselective synthetic method for the synthesis of trisubstituted
pyrazoles is still in demand.3,5–7 Pyrazoles and pyrazolines are of-
ten synthesized by the 1,3-dipolar cycloaddition reaction of nitril-
imines with alkynes,8 alkyne surrogates,6,9 or alkenes,5,7,8 and
other methods.4 Special attention is warranted toward the syn-
thetic design and development of pyrazoles because of their high
demand in academic and pharmaceutical sectors. Herein we report
the synthesis of 1,3,5-trisubstituted pyrazoles through a 1,3-dipo-
lar cycloaddition/ring opening process.
product that was isolated rather than the expected spiro-pyrazo-
line (3) (Scheme 1). The formation of a trisubstituted pyrazole is
in quite contrast to the expected spiro-pyrazoline product. On
the basis of this result, we decided to investigate the generality
of this 1,3-dipolar cycloaddition /ring opening reaction toward
the synthesis of 1,3,5-trisubstituted pyrazoles.
Two additional hydrazonyl chlorides containing an electron
withdrawing group in the para position of the aromatic ring were
exposed to triethylamine to afford the analogous nitrile imines
in situ. These nitrile imines then followed the aforementioned
1,3-dipolar cycloadditon/ring opening reaction pathway to afford
the corresponding pyrazoles. (Table 1) Interestingly, when 2,6-
dichlorophenyl hydrazonyl chloride (7) was used, only the spiro-
pyrazoline (8) was isolated (Scheme 2). Two additional hydrazonyl
chlorides possessing electron withdrawing groups in either the
ortho- or meta-positions as well as electron donating groups at
the ortho- and para-positions reacted with 1 to give the expected
spiro-pyrazoline as the only product (Table 2). It appears that
either a hydrogen or an electron withdrawing group in the para-
position of the aromatic ring of the spiro-pyrazoline intermediate
is required for the rupturing of the spirocyclic ring to give rise to
the pyrazole product.
In continuance of our interest in the 1,3-dipolar cycloaddition
chemistry, we describe our endeavor toward the synthesis of
1,3,5-trisubstituted pyrazoles on the basis of the 1,3-dipolar cyclo-
addition protocol,8,10 which was then followed by an unforeseen
ring opening. During our investigation on the synthesis of spiro-
pyrazolines, we discovered that when 2-methylene-1,3,3-tri-
The existence of pyrazole (4) as a crystalline solid enabled us to
perform the X-ray studies to reveal its stereo-structural features.
* Corresponding author. Tel.: +1 601 979 3713; fax: +1 601 979 3674.
E-mail address: ashton.t.hamme@jsums.edu (A. T. Hamme II).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.10.145

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S. Dadiboyena et al. / Tetrahedron Letters 50 (2009) 291–294
H
N
N
Cl
N
N
2
N
N
Elimination
N
N
Et3N, CH2Cl2
NH
CH3
4
1
3
Scheme 1. Pyrazole synthesis from the spiro-pyrazoline intermediate 3.
Table 1
1,3,5-Trisubstituted pyrazoles isolated from the 1,3-dipolar cycloaddition reaction
Entry Alkene -Chloro hydrazone
a
Product
Yield (%)
N
1
88
N
N
HN
N
NH
Cl
CH3
4
N
N
N
HN
Cl
2
84
N
NH
CH3
Br
5
Br
N
N
N
HN
Cl
3
75
N
NH
CH3
Cl
6
Cl
H
N
N
N
N
Et3N, CH2Cl2
Cl
N
N
+
Cl
Cl
8
Cl
1
7
Cl
Scheme 2. Synthesis of spiro-pyrazoline (8) without ring cleavage.
Compound 4 was unambiguously confirmed by the X-ray struc-
tural analysis as a trisubstituted pyrazole rather than the expected
spiro-pyrazoline (Fig. 1). The structures of the remaining pyrazoles
were elucidated based upon their NMR spectroscopic data and
their comparison to pyrazole (4).
compound 12 reverting to 11, the enamine tautomer undergoes
an eliminatory ring cleavage of the indoline ring at the spirocyclic
carbon affording pyrazole (13). The X-ray crystal data from 4 show
that the benzene ring B is nearly coplanar to the pyrazole. The
presence of a coplanar relationship between phenyl ring B in the
A proposed mechanism for formation of the pyrazole via spiro-
pyrazoline ring opening is shown in Scheme 3. After the formation
of the cycloadduct (11), an imine to enamine tautomerization oc-
curs to form the enamine tautomer (12) (Scheme 3). Instead of
spiro-pyrazoline intermediates 11 and 12 would assist in
contact between the phenyl ring B and the spiro-pyrazoline imine
and enamine systems. On the other hand, an 84° twisting of the
phenyl ring A occurs relative to the pyrazole (4) in order to avoid
p-orbital
p

S. Dadiboyena et al. / Tetrahedron Letters 50 (2009) 291–294
293
Table 2
Spiro-pyrazolines isolated from the 1,3-dipolar cycloaddition reaction
Entry
Alkene
a-Chloro hydrazone
Product
Yield (%)
H
N
N
N
N
N
Cl
N
4
89
N
N
Cl
Cl
Cl
Cl
8
H
N
N
N
N
N
5
78
Cl
9
NO2
O2N
H
N
N
N
N
N
6
76
Cl
HO
OCH3
HO
10
OCH3
hind the ring opening could be a combination of the relief of strain
at the spirocyclic carbon along with concomitant formation of the
aromatic pyrazole ring.
2. Conclusions
In summary, we report a unique route for the synthesis of novel
1,3,5-trisubstituted pyrazoles13 through a novel 1,3-dipolar cyclo-
addition/ring opening of a spiro-pyrazoline intermediate.14 The
construction of the aromatic pyrazole ring could be the driving
force behind the eliminative ring opening process. Along with
NMR data, X-ray crystallographic analysis also confirms the struc-
ture of the distinctive pyrazole compounds. Future investigations
of the ring opening mechanism and the proposed imine/enamine
tautomerization of spiro-pyrazolines are in progress.
Figure 1. Thermal ellipsoid plot of the structure of pyrazole (4).12
Acknowledgments
any potential steric interaction with the substitutents on the adja-
cent quaternary carbon. If the aforementioned interactions are
present in the spiro-pyrazoline intermediate, the driving force be-
We thank the National Institutes of Health MBRS-SCORE and
RCMI programs (3S06 GM 008047-34S1 and G12RR13459 (NMR
H+
A
A
A
N
N
imine/enamine
tautomerism
N
N
N
H
Elimination
N
N
N
Aromatization
NH
B
B
CH3
B
11
12
13
R
R
R
R = H, Br, Cl
Scheme 3. Proposed mechanism for the spiro-pyrazoline ring fragmentation to form the corresponding pyrazole.

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S. Dadiboyena et al. / Tetrahedron Letters 50 (2009) 291–294
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, the solvent was evaporated under reduced pressure.
For pyrazoles 4, 5, and 6, the crude products were purified by triturating with
hexanes. For Spiro-pyrazolines 8, 9, and 10, the crude products were purified
by flash column chromatography over silica gel by using 4:1, 9:1, and 7:3
hexanes–ethyl acetate eluant systems, respectively.
and analytical CORE facilities)) and the National Science Founda-
tion NSF-RISE program (HRD-0734645). EJV gratefully acknowl-
edges the support of the National Science Foundation grant MRI
0618148 and the W. M. Keck Foundation for crystallographic
resources.
11. Sibi, P. M.; Stanley, M. L.; Jasperse, P. C. J. Am. Chem. Soc. 2005, 127, 8276.
12. Structural information for pyrazole (4) has been deposited with the CCDC as
701051, available free of charge from www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the CambridgeCrystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.145.
13. Representative analytical data for a pyrazole: 2-(2-(1,3-Diphenyl-1H-pyrazol-5-
yl)propan-2-yl)-N-methylaniline (4): After concentrating the reaction mixture,
the residual product was purified by triturating with hexanes, this compound
was obtained as light yellow crystalline solid (0.97 g, 88%), mp 180–181 °C; IR
References and notes
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.
(s, 3H), 2.68 (s, 3H), 3.42 (d, J = 19.5 Hz, 1H), 3.78 (d, J = 19.5 Hz, 1H), 6.19 (d,
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10. General cycloaddition procedure:
A solution of the 2-methylene-1,3,3-
trimethylindoline (3 mmol) and the hydrazonyl chloride (3 mmol) in 10 mL