One pot spiropyrazoline synthesis via intramolecular cyclization/ methylation

Article abstract of DOI:10.1016/j.tetlet.2011.03.004

Regioisomeric spiropyrazolines were synthesized through a tandem intramolecular cyclization/methylation reaction of a functionalized 5,5-disubstituted pyrazoline in one reaction vessel. The 5,5-pyrazolines were constructed through a 1,3-dipolar cycloaddit

Full text of DOI:10.1016/j.tetlet.2011.03.004

Tetrahedron Letters 52 (2011) 2536–2539
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One pot spiropyrazoline synthesis via intramolecular cyclization/methylation
⇑
Sureshbabu Dadiboyena , Ashton T. Hamme II
Department of Chemistry and Biochemistry, College of Science, Engineering and Technology, Jackson State University, Jackson, MS 39217, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioisomeric spiropyrazolines were synthesized through a tandem intramolecular cyclization/methyla-
tion reaction of a functionalized 5,5-disubstituted pyrazoline in one reaction vessel. The 5,5-pyrazolines
were constructed through a 1,3-dipolar cycloaddition reaction of aromatic ring containing nitrile imines
and a disubstituted geminal alkene. An evaluation of the relative location of the nucleophilic and electro-
philic functional groups on the pyrazoline was performed in order to ascertain the best pyrazoline system
for the intramolecular cyclization/methylation reaction. Higher spiropyrazoline isolated yields were real-
ized from pyrazolines with the electrophilic ester located further away from the pyrazoline when com-
pared to pyrazolines with a directly bonded ester.
Received 23 November 2010
Revised 14 February 2011
Accepted 1 March 2011
Available online 6 March 2011
Keywords:
Spiropyrazolines
Intramolecular cyclization
Cycloaddition
Ó 2011 Elsevier Ltd. All rights reserved.
Regioselectivity
Heterocycles
Spirocycles
1. Introduction
surrogates,6h,q or alkenes,10 closely related [2+3] cycloaddi-
tions,6d,r,11 and other methods.12 Special attention is warranted
The spirocyclic molecular framework is a prevalent feature for a
number of biologically active heterocyclic natural products,1,2 and
among the FDA approved pharmaceutically relevant heterocycles,
the pyrazole and isoxazole moieties are found in the COX II inhib-
itors, celebrex and bextra.3,4 Furthermore, as the syntheses of isox-
azoles and pyrazoles flourished,5,6 the corresponding synthetic
methodologies targeting spiroisoxazolines and spiropyrazolines
were also developing.7,8 While the major structural feature of a
number of biologically active bromotyrosine derived heterocyclic
marine natural products is the spiroisoxazoline,1,2,7 spiropyrazo-
lines have an extra nitrogen, in place of isoxazoline oxygen, and
offer the feasibility to construct structurally relevant analogues
for the exploration of potential biological activity (Fig. 1). In
general spiropyrazolines8 contain the common basic molecular
architecture derived from the corresponding pyrazoline and are
characterized by a unique spiro fusion at the C-5 position of a
pyrazoline ring. These spiropyrazoline heterocycles are interesting
targets for synthesis based upon the interesting spirocyclic skele-
ton that is often associated with potential bioactive properties.
A variety of methods exist for the synthesis of functionalized
spiropyrazolines. General and classical syntheses of pyrazoles
and pyrazoline derivatives rely on the 1,3-dipolar cycloaddition9
of diazoalkanes or nitrile imines with alkynes,5d,6c–g,j,l–n alkyne
toward the synthetic design and development of pyrazoles, pyraz-
olines, and their derivatives because of their high demand in
academic and pharmaceutical sectors. Our recent report on spirois-
oxazoline synthesis utilized intramolecular alkylation/methylation
of a 5,5-disubstituted isoxazoline as the central spiroisoxazoline
synthetic pathway.13 In this Letter, we extend the application of
this practical synthetic methodology toward the synthesis of func-
tionalized unsaturated carbocyclic spiropyrazolines while also
determining the best pyrazoline system for the intramolecular
cyclization/methylation reaction.
2. Results and discussion
Synthesis of the spiropyrazoline precursor 3a was initiated by
the regioselective 1,3-dipolar cycloaddition of the readily available
alkene dipolarophile 1.14 The reaction of
a-chlorohydrazone 2 with
triethylamine results in the in situ generation of the corresponding
nitrile imine6h,i,8a which combines with 1 in a 1,3-dipolar fashion
to afford the highly functionalized 5,5-disubstituted pyrazoline in
moderate to good yields as a single regioisomer15 (Scheme 1).
The 1,3-dipolar cycloaddition of 1 with a variety of substituted aro-
matic nitrile imines was then pursued in order to investigate the
scope and limitations of 5,5-disubstituted pyrazolines as precur-
sors to spiropyrazolines via the intramolecular cyclization/methyl-
ation synthetic methodology. The 1,3-dipolar cycloaddition results
are shown in Scheme 1. All of these cycloadditions occurred with
complete regiochemical integrity and in reasonable to good iso-
lated yields.
⇑
Corresponding author. Fax: +1 601 979 3674.
E-mail address: ashton.t.hamme@jsums.edu (A.T. Hamme II).
Present address: Torrey Pines Institute for Molecular Studies, Port St. Lucie,
FL 34987, USA.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.004

S. Dadiboyena, A. T. Hamme II / Tetrahedron Letters 52 (2011) 2536–2539
2537
OMe
OMe
OMe
OMe
Br
Br
Br
Br
Br
Br
Br
Br
HO
HO
OH
HO
O
N
O
N
O
N
H
O
N
H
Br
O
N
H
N
N
N
H
n
NH
O
Me
O
O
N
O
N
n = 2, aerothionin
n = 3, homoaerothionin
Br
Me
aerophobin 1
purealidin Q
O
OMe
Br
O
Br
Br
O
H
N
O
N
O
Structural
Br
O
O
OH
N
H
N
H
OH
Resemblance
O
N
N
H
N
O
N
H
N
O
N
Isoxazoline
Pyrazoline
O
OH
O
HO
Br
O
epi-fistularin-3
calafianin
Br
Br
Br
O
OMe
Figure 1. Naturally occurring spiroisoxazolines and spiropyrazoline structural resemblance.
CH3CH2O
O
O
R1
(C2H5)3N
CH2Cl2
N
N
N
R1
+
H
N
CH3
OCH2CH3
O
R2
Cl
CH3
O
R1
2
R1
R2
1
3
Entry Pyrazoline
R1
H
R2 % Yield
1
2
3
4
3a
3b
3c
3d
H
H
67
73
Cl
H
Br
Cl
85
77
H
Scheme 1. Synthesis of highly functionalized pyrazoline 3.
Suitable bases for the intramolecular cyclization process were
evaluated in conjunction with solvent compatibility and temper-
ature. Optimal reaction conditions were realized for the intramo-
lecular cyclization/methylation reaction by employing potassium
t-butoxide as the base in anhydrous toluene.16 The intramolecu-
lar cyclization/methylation was achieved in one reaction vessel,
and each step was monitored via TLC through the consumption
of the starting materials. Spiropyrazoline 6a was isolated in
37% yield, and its regioisomer, 7a, was isolated in 24% yield
(Scheme 2). The isolation of the two spiropyrazoline regioisom-
ers results from the O-methylation of both spiropyrazoline eno-
lates (Scheme 2).
Based upon the positive results obtained from the intramolecu-
lar cyclization/methylation of 3a, the application of this synthetic
methodology was applied toward a variety of pyrazoline deriva-
tives for spiropyrazoline construction. The isolated yields of
various spiropyrazolines arising from pyrazoline intramolecular
cyclization/methylation are shown in Scheme 2. The overall yields
for the isolation of the spiropyrazoline regioisomers range from
55% to 73% for the two-step one pot process. Each spirocyclic
regioisomer was identified based upon the unique nature of the
13C chemical shift of the quaternary carbon of the pyrazoline.
Generally, when the pyrazoline quaternary carbon is located alpha
to the carbonyl, as found in compound 6, the 13C chemical shift is
greater than 70 ppm. However, due to the non availability of car-
bonyl’s deshielding effect, the pyrazoline quaternary carbon of
the alternate regioisomer, such as compound 7, gives rise to a
13C chemical shift that is less than 70 ppm. These spectroscopic
observations are in correlation with previous results reported from
our research laboratories.13 Even though the isolated yields for the
aforementioned spiropyrazolines were good, we decided to inves-
tigate the potential of improving the intramolecular cyclization/
methylation yields by repositioning the electrophilic ester to a
more remote location relative to the pyrazoline ring thereby
potentially decreasing the steric environment of the ester.
The cycloaddition of the nitrile imine arising from 2a with 817
affords functionalized 5,5-disubstituted pyrazoline 9a in high yield
as a single regioisomer. Scheme 3 illustrates the products and the
isolated yields of the pyrazolines derived from 1,3-dipolar cycload-
dition reactions of 8 with the corresponding
a-chloro hydrazone
precursor. Intramolecular cyclization/methylation of 9a was
achieved to afford spiropyrazolines 6a and 7a in 36% and 39%
respective isolated yields which represents an overall 15% increase
for the isolation of 6a and 7a arising from pyrazoline 3a.16 Im-
proved overall isolated yields were realized for the syntheses of
both regioisomers for other spiropyrazolines as shown in Scheme
4. Higher isolated yields for these spiropyrazolines likely result
from decreasing the steric environment of the pyrazoline ester.13b

2538
S. Dadiboyena, A. T. Hamme II / Tetrahedron Letters 52 (2011) 2536–2539
R2
R2
R1
R1
O
R1
R1
R1
O
O
KOt-Bu, Toluene;
K
N
N
+
CH3
OCH2CH3
N
N
N
N
R2
R1
O
O
O
K
3
4
5
(CH3)2SO4, Δ
(CH3)2SO4, Δ
Entry Pyrazoline Spiropyrazoline
R1
H
R2 % Yield
Ratio 6/7
37/24
1
2
3
4
3a
3b
3c
3d
6a/7a
6b/7b
6c/7c
6d/7d
H
H
61
73
66
55
R2
R2
Cl
H
31/42
Br
Cl
31/35
H
31/24
R1
R1
R1
R1
O
OCH3
+
N
N
N
N
OCH3
O
6
7
Scheme 2. Synthesis of spiropyrazoline regioisomers 6 and 7.
CH3
O
O
R1
(C2H5)3N
N
N
N
H
N
R1
+
OCH2CH3
CH2Cl2
O
R2
Cl
CH3
OCH2CH3
O
R1
R1
R2
8
9
2
Entry Pyrazoline
R1
H
R2 % Yield
1
2
3
9a
9b
9c
H
71
76
78
Cl
H
H
Br
Scheme 3. 5,5-Disubstituted pyrazolines isolated from the 1,3-dipolar cycloaddition reaction.
R2 R2
R1
R1
O
R1
R1
R1
KOt-Bu, Toluene;
O
OCH3
N
N
+
OCH2CH3
(CH3)2SO4, Δ
N
N
N
N
R2
CH3
O
R1
OCH3
O
9
7
6
Entry Pyrazoline Spiropyrazoline
R1
H
R2 % Yield
Ratio 6/7
36/39
1
2
3
9a
9b
9c
6a/7a
6b/7b
6c/7c
H
H
75
78
80
Cl
H
36/42
Br
37/43
Scheme 4. Spiropyrazoline regioisomers 6 and 7 arising from the intramolecular cyclization/methylation reactions of 9.

S. Dadiboyena, A. T. Hamme II / Tetrahedron Letters 52 (2011) 2536–2539
2539
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3. Conclusions
In conclusion, we have developed a synthetic methodology to
construct unsaturated spiropyrazolines through an intramolecular
cyclization/methylation process. 1,3-Dipolar cycloaddition of the
functionalized alkene with nitrile imines led to the formation of
the 5,5-disubstituted pyrazolines. The latter was used as the
precursor to prepare the corresponding spiropyrazolines as two
regioisomers through sequential intramolecular cyclization/meth-
ylation reactions. Future studies directed toward the synthesis of
spiropyrazoline derivatives and other natural product analogues
through intramolecular cyclization/methylation are currently in
progress.
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Acknowledgments
The project described was supported by Award Numbers
SC3GM094081, G12RR13459 (NMR and Analytical CORE facilities)
from the National Institute of General Medical Sciences, and HRD-
0734645 (HBCU-RISE) from the National Science Foundation. The
content is solely the responsibility of the authors and does not nec-
essarily represent the official views of the National Institute of
General Medical Sciences, the National Institutes of Health, or the
National Science Foundation.
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