Synthesis of Tetrasubstituted Pyrazoles from Substituted Hydrazines and β-Keto Esters

Article abstract of DOI:10.1002/ejoc.201601093

Herein we report the synthesis of tetrasubstituted pyrazoles from simple hydrazines and β-keto esters under mild, basic conditions. This reaction enables the selective synthesis of pyrazolones, alkoxypyrazoles, and tetrasubstituted pyrazoles for a large v

Full text of DOI:10.1002/ejoc.201601093

A Journal of
Accepted Article
Title: Synthesis of Novel Tetrasubstituted Pyrazoles from Substituted Hydrazines
and β-Ketoesters
Authors: Ian J Bakanas; Gustavo Moura-Letts
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601093
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European Journal of Organic Chemistry
10.1002/ejoc.201601093
COMMUNICATION
Synthesis of Novel Tetrasubstituted Pyrazoles from Substituted
Hydrazines and -Ketoesters
Ian J. Bakanas and Gustavo Moura-Letts*
Similarly, most of these methods provide scaffolds with little
Abstract: Herein we report the novel synthesis of tetrasubstituted
room for diversification due to the difficulty of introducing
pyrazoles from simple hydrazines and -ketoesters under mild basic
relevant functional groups. Thus, the development of general
methods that allow for the synthesis of highly substituted
pyrazoles from simple, easily accessible starting materials
remains a goal in the field of organic chemistry.
conditions. This reaction allows for the selective synthesis of
pyrazolones, alkoxypyrazoles and tetrasubstituted pyrazoles for a
large variety of aromatic hydrazines and substituted -ketoesters
with high yields and selectivities. This method permits access to a
novel scaffold with four orthogonal diversification groups to access
highly complex pyrazole molecular frameworks.
Pyrazoles are important nitrogen-containing heterocyclic
compounds used extensively in agrochemical, catalysis and as
pharmacophores for natural product and commercial drug
synthesis.1 These key scaffolds display a broad spectrum of
biological activities, including antibacterial,2 anticancer,3 anti-
inflammatory,4 antiviral,5 analgesic,6 estrogen receptor agonistic7
and cannabinoid receptor antagonistic.8 They can also act as
ligands in coordination complexes9 and serve as optical
brighteners,10 UV stabilizers,11 and building blocks in
supramolecular assemblies.12 Apart from their medicinal values,
polysubstituted pyrazoles have been utilized for many other
purposes, such as ligands for cross coupling reactions and
dyes.13
Scheme 1. Reaction Discovery
The search for such methods has led us to focus on the
development of novel and efficient synthetic methods for the
production of nitrogen-containing heterocycles.15 This study
began with the discovery that ethyl acetoacetate and
o
phenylhydrazine with NaOEt in ethanol at 50 C failed to provide
the expected pyrazolone 2 or ethoxypyrazole 3 and instead
produced tetrasubstituted pyrazole 1 in 64% yield (Scheme 1).
This new scaffold allows for the introduction of four orthogonal
diversification groups (alkyl, aryl, ester, and ketone) and to the
best of our knowledge is the first report for such a transformation
among other pyrazole forming reactions.
Due to their many applications and high recurrence among
pharmacologically relevant natural products and drugs, many
methods have been developed for their synthesis.14 The main
synthetic strategies have historically relied on either the
cyclocondensation of hydrazines and 1,3-dicarbonyls or the
cycloaddition of suitable dipoles (diazo compounds, azomethine
imines) and dipolarophiles. Despite their relative success they
often suffer from poor selectivities, low yields, cumbersome
purifications and limited scope due to complexity of substrates.
Efforts assessing the reactivity of hydrazines and -ketoesters
have provided an array of different substituted heterocycles,16
but the formation of tetrasubstituted pyrazoles is completely
unprecedented. Thus, we initially were interested in assessing
the productivity of this specific transformation; the results of the
optimization efforts are summarized in Table 1. The results
showed that pyrazole 1 was obtained in much lower yields in
non-protic solvents (Entries 2-4). The reaction in MeOH/NaOMe
displayed a slightly lower yield (Entry 5). Surprisingly, at 70 oC in
EtOH/NaOEt we were able to isolate the observed pyrazole 1 in
97% yield (Entry 6), the control experiment in the absence of
NaOEt provided no tetrasubstituted pyrazole.
Dr Gustavo Moura-Letts
Department of Chemistry and Biochemistry
Rowan University
201 Mullica Hill Rd., Glassboro, New Jersey, USA
E-mail: moura-letts@rowan.edu
www.gmlreseachgroup.com
Supporting information for this article is given via a link at the end of
the document.
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The effect of green inorganic bases on this this reaction was of
significant interest; however, we discovered that Na, K, and Cs
carbonates provided pyrazole 1 in moderate yields but not
comparable to EtOH/NaOEt (Entries 8-10). Similarly, organic
bases (pyridine, Et3N) proved to produce the desired pyrazole in
moderate to good yields (Entries 11 and 12). Lastly, we
hypothesized that metal oxides would be suitable promoters for
this reaction. Unfortunately, CaO and TiO2/NaOEt did not show
comparable yields (Entries 13 and 14). The focus then turned
towards assessing the stoichiometry of the reaction. The results
Table 2. Reaction Scope for Hydrazines
quickly indicated that formation of pyrazole
1 is heavily
dependent on the excess of -ketoesters. The yield for 1 drops
considerably when using 2 or 3 equivalents of ester. At this point
we were satisfied with the set of optimal conditions for the
selective formation of tetrasubstituted pyrazole. Thus, the next
step would focus on assessing the scope of the reaction among
different hydrazine and -ketoesters substrates (Table 2).
Table 1. Reaction Optimization
Based on the already established reactivity pattern among
hydrazines, it was expected that the electronic and steric
properties of substituted hydrazines would drastically affect the
outcome of this reaction.17 Thus, it was observed p-chlorophenyl,
phenyl and p-fluorophenyl provided the tetrasubstituted pyrazole
in great yields as the only isomer (Entries 1-3). Moreover, 3,4-
and 3,5-dichlorophenyl hydrazines were also successful at
providing the desired pyrazole (Entries 4 and 5).
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Surprisingly, deactivated m-nitro and p-cyano phenyl hydrazines
also proved to be great substrates for the synthesis of
tetrasubstituted pyrazoles (Entries 6 and 8). The reaction began
to display erosion on the chemoselectivity when m-fluorophenyl
hydrazine provided a separable mixture of tetrasubstituted
pyrazole 1 and ethoxypyrazole 3 (64/12%, Entry 7).
Table 3. Reaction Scope for -Ketoesters
Further assessment of the scope successfully revealed that p-
trifluoromethylphenyl and, tosyl hydrazine provided the expected
tetrasubstituted pyrazole in great yields (Entries 9-10).
Substituents on the ortho position are known for affecting the
nucleophilicity of the internal nitrogen on hydrazone scaffolds.18
Thus, the results showed that o-trifluoromethylphenyl hydrazine
provided a 2:1 mixture of pyrazole 1 and 3 (Entry 11). Moreover,
o-bromo and o-chloro, and o-methyl provided almost 1:1
mixtures of 1 and 3 (Entries 12-14). Similarly, activated
hydrazines
would predictably favor
faster
pyrazole-
condensations; indeed p-isopropyl, 2,4-dimethyl, and p-methoxy
provided mixtures where ethoxypyrazole 3 was the predominant
product (Entries 15-17). The scope study demonstrated that
acetoacetates and hydrazines efficiently provided the proposed
tetrasubstituted pyrazoles. A final example entry aimed to
compare the reactivity of bulkier esters and the results showed
that t-butyl ketoesters and phenyl hydrazine provided pyrazole 1
in 89% yield (Entry 18). The high productivity observed among
aromatic hydrazines emphasized the robustness and practicality
of this novel transformation. Furthermore, due to the highly
orthogonal nature of the functional groups on the targeted
pyrazole, we were satisfied that halogenated aromatic
hydrazines provided pyrazole 1 with almost complete selectivity.
Moreover, the reaction was successfully scaled-up (10 g. of
hydrazine) to provide large amounts (19.2 g, 96%) of
tetrasubstituted pyrazole 1.
Due to the wide array of possible pyrazole products, assessing
the potential mechanisms taking place during this reaction
became our next objective (Scheme 2). On one end, initial heat
promoted condensation provides a hydrazone intermediate that
can undergo Claisen condensation followed by intramolecular
pyrazole formation to provide the unprecedented pyrazole 1. On
the other hand, slow Claisen condensation due to a more
sterically demanding substrate allowed for either faster
cyclization with loss of ethanol to form pyrazolone 2 or
condensation to form ethoxypyrazole 3. Preference for products
2 and 3 from o-substituted phenylhydrazines due to limited
The success on the hydrazine scope study produced great
interest in observing the reactivity of more complex -ketoesters
(Table 3). Unfortunately, ethyl propionylacetate and p-
chlorophenylhydrazine reacted with opposite chemoselectivity to
produce a 64:31% ratio of pyrazole 3 to pyrazolone 2 (Entry 2).
Similar results were obtained with methyl-3-oxoheptanoate and
p-chlorophenyl hydrazine (Entry 3). The selectivity for
ethoxypyrazole 3 increased with bulkier substrates (Entries 4
and 5), but neither provided isolatable amounts of pyrazole 1.
On the other hand, aromatic acetoacetates were completely
selective for the formation of pyrazolone 2 (Entries 6 and 7).
This quick study of the -ketoester scope has revealed a clear
preference for either ethoxypyrazole 3 for alkyl substrates and
pyrazolone 2 for aromatic substrates. Despite their synthetic
utility, neither substrate produces the unprecedented
tetrasubstituted pyrazole 1.
nucleophilicity of the internal
N
can be attributed to
intramolecular H-bonding.18 The rate of the Claisen
condensation step is directly affected by increasing the steric
demand around the substituent next to the hydrazone carbonyl
carbon. Efforts towards optimizing this step always led to low
conversions or complex mixtures of pyrazole isomers.
Furthermore, highly activated aromatic hydrazines would favor
faster condensation with high selectivity for ethoxypyrazole 3.
Interestingly, sterically demanding ortho-substituted hydrazines,
rather than slowing the rate of hydrazone condensation had, an
unpredictable preference for providing ethoxypyrazole 3. Efforts
to slow down the rate of condensation over Claisen by adding
bulky ester substituents (t-butyl, isopropyl) failed to provide
useful conversions with relative preference for pyrazole 1.
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European Journal of Organic Chemistry
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COMMUNICATION
S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S.
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Scheme 2. Proposed Reaction Mechanism
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In summary, a novel method for the synthesis of tetrasubstituted
pyrazoles from simple -ketoesters and aromatic hydrazines
was discovered. The scope for this reaction extends to
halogenated and deactivated hydrazines. Moreover, activated
and ortho-substituted hydrazines provided ethoxypyrazoles with
almost complete reversal of the selectivity. The scope on the -
ketoesters is reduced to unsubtituted and highly deactivated -
ketoesters. This study also demonstrated that more sterically
demanding -ketoesters provide pyrazolone 2 with almost
complete reversal of the selectivity. A mechanism for the
formation of each pyrazole scaffold and a rationalization for the
unexpected substrate selectivity have been proposed. Further
efforts are directed towards developing reaction conditions that
would allow overcoming the apparent substrate control observed
for these substrates.
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W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.;
Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
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ACKNOWLEDGMENT
The donors of the American Chemical Society Petroleum
Research Fund financially supported these research efforts. We
are also thankful to Dr. John F. Eng at Princeton University for
his help with HRMS analysis.
Keywords: Tetrasubstituted pyrazoles • pyrazolones •
Hydrazines • Claisen condensation • -ketoesters
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COMMUNICATION
10.1002/ejoc.201601093
Ian J. Bakanas and Gustavo Moura-
Letts*
Page No. – Page No.
Synthesis of Novel
Tetrasubstituted
Pyrazoles from
Substituted
This effort shows the novel synthesis of tetrasubstituted pyrazoles from simple
hydrazines and -ketoesters under mild basic conditions. This novel approach
provides access to orthogonally functionalized tetrasubstituted pyrazoles with high
efficiencies for a variety of substituted hydrazines. This method permits access to a
novel access to highly complex pyrazole molecular frameworks.
Hydrazines and -
Ketoesters
* Novel synthesis of tetrasubstituted pyrazoles
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