On water synthesis of N-unsubstituted pyrazoles: Semicarbazide hydrochloride as an alternative to hydrazine for preparation of pyrazole-3-carboxylate derivatives and 3,5-disubstituted pyrazoles

Article abstract of DOI:10.1039/c4gc02028f

A green, simple and highly efficient method for the synthesis of pyrazole-3-carboxylates and 3,5-disubstituted pyrazoles by cyclization of 4-aryl(hetaryl, alkyl)-2,4-diketoesters and 1,3-diketones with semicarbazide hydrochloride under on water conditions has been developed. This method also does not require toxic hydrazine and product purification, eliminating the use of toxic liquid chemicals.

Full text of DOI:10.1039/c4gc02028f

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COMMUNICATION
“
On Water” Synthesis of N-Unsubstituted Pyrazoles: Semicarbazide
Hydrochloride as an Alternative to Hydrazine for Preparation of
Pyrazole-3-carboxylate Derivatives and 3,5-disubstituted Pyrazoles
Violeta Marković and Milan D. Joksović*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A green, simple and highly efficient method for the synthesis
of pyrazole-3-carboxylates and 3,5-disubstituted pyrazoles by
Major synthetic strategy for preparation of 3(5)-substituted
pyrazole-5(3)-carboxylates include condensation of 4-aryl-2,4-
cyclization of 4-aryl(hetaryl, alkyl)-2,4-diketoesters and 1,3- 50 diketoesters with hydrazines (Knorr reaction), 1,3-dipolar
2
1
cycloaddition of 2-chloro-2-(2-arylhydrazono) acetates with 1-
1
0
diketones with semicarbazide hydrochloride in „on water“
conditions has been developed. This method also requires no
toxic hydrazine and no product purification, eliminating the
use of the toxic liquid chemicals.
2
2
aryl-1-enamines,
enaminoketoesters and regioselective cyclization of nitroallylic
reaction
of
hydrazines
with
β-
2
3
2
4
acetates with N-tosyl hydrazines (Scheme 1). Extremely toxic
hydrazine hydrate or substituted hydrazines appear as a main
nitrogen source for most of reactions and this reagent was often
applied in a large excess. Keeping in mind environmental
requirements and use of water as green solvent, we developed a
simple protocol for synthesis of 5-aryl(hetaryl)-1H-pyrazole-3-
carboxylates by condensation of 4-aryl-2,4-diketoesters and
semicarbazide hydrochloride in “on water” conditions.
5
5
During the last two decades, water has become a very attractive
solvent for a number of efficient organic reactions using insoluble
1
2
2
3
3
4
4
5
0
5
0
5
0
5
1
reactants at room or higher temperatures. This means that the
reactions occur as an emulsion or suspension formed by water
2
60
and organic compound, denoted earlier as “on water” conditions.
Water promotes or accelerates successfully these organic
transformations and serves also as an excellent supporting
medium with numerous advantages including ease of product
isolation, nontoxicity, nonflamability, high heat capacity and
redox stability. Several factors, such as hydrophobicity,
hydrogen-bonding, polarity and acidity contribute to the rate-
3
enhancing effect of water. Very recently, kinetic and
thermodynamic investigations have established a crucial role of
hydrogen-bonding ability of the surface water molecules
indicating the presence and the nature of the water substrate
interface as an essential criteria for “on water” mechanism during
4
a heterogenous reaction. Some examples of such organic
5
reactions include preparation of phenylselenoesters, synthesis of
6
heterocyclic ortho-quinones, bromination of ketons with H O -
2
2
7
8
HBr, coupling of indoles with 1,4-benzoquinones, preparation
of triaroylbenzenes by cyclotrimerization in hot water, direct Pd-
9
catalyzed
C-H
arylation
of
thiazolo[5,4-d]pyrimidine
1
0
2
derivatives, preparation of 1,2-diazetidines and 1,3-dipolar
cycloadditions.
Scheme 1 (a) Condensation of 4-aryl-2,4-diketoesters with hydrazines
(Knorr reaction); (b) 1,3-dipolar cycloaddition of 2-chloro-2-(2-
arylhydrazono) acetates with 1-aryl-1-enamines; (c) reaction of
hydrazines with β-enaminoketoesters; (d) regioselective cyclization of
nitroallylic acetates with N-tosyl hydrazines.
1
1
65
As an important class of heterocyclic pharmacophores,
pyrazole-3(5)-carboxylic acid derivatives constitute the core
structure of clinically interesting compounds. They act as potent
1
2
cannabinoid type 1 receptor antagonists, partial agonists for the
1
3
14
It is known that 3,5-dimethylpyrazole-1-thiocarboxamide
nicotinic acid receptors,
agonists for niacin receptors,
1
5
70 undergoes hydrolysis to 3,5-dimethylpyrazole with liberation of
selective inhibitors of cyclooxygenase-2,
arachidonic acid-induced platelet aggregation, inhibitors of
acrosin, regulators of apoptosis and autophagy in lung cancer
cells, cytotoxic agents and inhibitors of receptor for advanced
inhibitors of
2
5
1
6
HNCS after one week of standing in an aqueous solution.
1
7
Considering this reaction, we initially tried to use
thiosemicarbazide for the preparation of biologically versatile
pyrazole-3(5)-carboxylates from ethyl benzoylpyruvates.
1
8
19
2
0
glycation end products.
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However, no product was observed by vigorous stirring of a
“on water” reaction, it is possible to suppose that well soluble
suspension of water insoluble ester reactant for a long time at 20 SC∙HCl reacts with insoluble ethyl benzoylpiruvate on its oily
room temperature. In the next experiments, the acids like HCl,
acetic and p-toluenesulphonic were added, but the yields of
desired pyrazoles were still low (<20%). Significantly better
yields (up to 80%) were obtained at elevated temperatures but an
unpleasant odor and slightly colored product suggested the 25 according to well known reported procedures by oxalation of the
formation of sulfur side products. Then, we applied corresponding aryl methyl ketones in the presence of sodium
semicarbazide hydrochloride (SC∙HCl) instead of
thiosemicarbazide and yield of ethyl 5-phenyl-1H-pyrazole-3-
carboxylate (1) reached 95% after 2 h of gently reflux using water
as a solvent. At the beginning, the ester reactant was insoluble in 30 and all aryl methyl ketones were distilled or recrystallized before
surface in a heterogenous system.
With the optimized reaction conditions we next explored the
scope and generality of the cyclocondensation and various 4-aryl-
2,4-diketoester precursors were synthesized for this purpose
5
0
5
2
6
methoxide or ethoxide. Purity of the starting chemicals is
crucial for a clean reaction in “on water” heterogenous system.
For this reason, sodium ethoxide solution was freshly prepared
1
water forming an aqueous suspension. By heating, solid ester
initially existing in a suspension form began to transform into an
oily emulsion which is stable at reflux temperature. After about 1
h, the pyrazole product 1 started to separate affording a
use. The crude ester was used for the next step immediately after
synthesis without further purification because prolonged time of
exposure to air contributed to contaminated pyrazole products.
The reaction of all prepared diketoesters with SC∙HCl proceeded
1
suspension and this conversion was completely finished after 2 h 35 smoothly to give pyrazole products in excellent isolated yields
of heating at reflux. To explain the experimental behavior in the (85-98%), as presented in Scheme 2.
a
b
Isolated yields. Reaction product exists in the form of emulsion. It was extracted with ethyl acetate, the organic layer was dried and the solvent was
c
evaporated. After several days of standing, colorless oil solidifies. Solidification was accelerated by scratching the inside surface of the flask with a glass
rod.
4
0
Scheme 2 Preparation of ethyl 5-aryl-1H-pyrazole-3-carboxylate.
2
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The nature of the substituents or the presence of sterically
bulky groups at 2-position of the aromatic ring does not reduce
solubility in CDCl ) existed in the form of tautomeric mixture as
a consequence of the slow interconversion rate attributed to
3
the reactivity of the ester substrates. The starting esters with 55 solvent acceptor properties (Supporting Information). In addition,
1
3
electron-donating and electron-withdrawing substituents gave
excellent yields and high purity of pyrazole compounds 1-13. The
change of the aromatic unit with heterocyclic indolic one (12) or
introduction of the acetamido group on aromatic ring (13) does
not also influence on the ester reactivity. The acetamido group
was selected to test its reactivity and hydrolytic stability in this
“on water” system. Namely, hydrazine hydrate can induce
hydrazinolysis of amide bond converting these compounds into
C NMR signals of pyrazolic C , C and some neighboring
3 5
5
0
5
0
5
0
5
0
5
carbons in compounds 11 and 12 were not detected at 200 MHz
spectrometer and even at 500 MHz in 12, due to their long
relaxation time in the highly conjugated pyrazole ring.
In order to establish reaction pathways, we analyzed the water
part after filtration of pyrazole compound and detected only
ammonium chloride. The evaporated aqueous phase can be used
for many times in the same reaction. Based on experimental facts,
the proposed mechanism for the formation of the products is
3
0
60
1
1
2
2
3
3
4
4
2
7
hydrazides.
Under our experimental conditions, the
corresponding pyrazole derivative 13 was obtained in 96% yield 65 presented in Scheme 3.
and no hydrazide or hydrolityc impurities was detected in the
final product. High yields of pyrazole-3-carboxylates (14 and 15)
were also obtained when 4-alkyl-2,4-diketoester precursors were
used. Due to the better solubility of pyrazole products in water,
these two reactions were performed with more concentrated
mixtures of starting reactants.
In comparison with hydrazine hydrate, conversion efficiency
of the reaction (atom economy) is lower when semicarbazide
hydrochloride was used. However, from the toxicity point of
view, semicarbazide hydrochloride is much better choice than
genotoxic and carcinogenic hydrazine.
All pyrazoles 1-15 are known compounds and comparison of
our spectral data with reported values of the chemical shift allows
1
13
the assignment of H and C NMR signals but not exact position
of substituents of pyrazole ring. For example, pyrazole 4 exists as
2
8
3
-carboxylate tautomer while pyrazole 7 is in form of 5-
2
4
carboxylate on the basis of x-ray diffraction analysis.
Both compounds, prepared by different methods show very
similar values of the chemical shift in CDCl3 and correct
assignment of the tautoisomer using simple comparison with the
literature chemical shifts is not possible. To solve this indecision,
we obtained suitable single crystal of 9 by slow evaporation of
EtOAc-hexane solution and 3-carboxylate tautomeric structure
2
9
was confirmed by x-ray diffraction technique (Fig. 1).
Scheme 3 Proposed reaction pathway.
The first step, like hydrazine in Knorr reaction, includes
nucleophilic addition of semicarbazide to protonated ester A to
give imine intermediate B which undergoes an intramolecular
70
dehydration
affording
cyclocondensation
pyrazole-1-
thiocarboxamide derivate C. This compound exists in
a
protonated form D under acidic conditions and nucleophilic
attack of water leads to its transformation into intermediate E
Fig. 1 Crystal structure of 9
In CDCl and (CD ) CO solutions of 1-12, NMR experiments 75 which decomposes easily providing pyrazole F and protonated
3
3 2
at ambient temperature failed to detect one of two possible
tautomers (except for 14 and 15) because of rapid exchange
between tautomeric forms and only average signal for NH proton
carbamic acid G. Unsubstituted carbamic acid is unstable
compound and its proton-induced decomposition into ammonium
ion and CO proceedes via its cation form G as intermediate
2
5
0
was observed. However, in DMSO-d solution pyrazole 13 (low
formed through the protonation of the nitrogen atom. This step is
6
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consistent with disproportionation of aliphatic isocyanate under
acidic condition via protonated carbamic acid leading to the
formation of ammonium compounds with liberation of carbon
conditions such as ratio of starting diketone and water,
temperature and standing time of the mixture after reaction.
Repeating the reaction by slight varying these parameters, we
40 detected a presence of deprotonated pyrazole compound as a
result of incomplete proton transfer from HCl to pyrazole
3
1
dioxide.
5
With the optimized reaction conditions for 5-substituted-1H-
pyrazole-3-carboxylates, the scope of β-diketone substrates was
explored. For this purpose, three 1-aryl-1,3-diketones with
electron donating, electron withdrawing and no substituent on
3
3,34
molecule.
Interestingly, a complete loss of HCl was observed
after column chromatography on silica gel using chloroform/ethyl
acetate as eluent and free pyrazole base was solely product of
aromatic ring were selected (Scheme 4). The yields of 45 high purity (for comparison see NMR spectra in Supplementary
1
0
corresponding 3,5-disubstituted pyrazoles in the form of
hydrochlorides were lower due to their better solubility in water.
More concentrated mixtures were unfavorable because starting
insoluble diketone partly distilled with water and solidified at the
bottom of condenser during the reflux.
material).
1
H NMR spectrum of diluted CDCl solution of compound 16
displays integral intensity 2 for two pyrazole NH protons.
However, increasing the amount of 16 in the NMR tube, integral
50 intensity was decreased and singlet was shifted toward lower
field. This behavior is probably caused by formation of quasi-ion
3
+
-
35
pairs Pz∙∙∙H ∙∙∙Cl which is observed in nonaqueous systems.
Anyway, free pyrazole base can be completely generated from its
hydrochloride salt by simple treatment with KOH or NaOH.
Diketone precursors were less reactive than 2,4-diketo esters as
a consequence of the presence of methyl group at 3-position of
pyrazole ring. In distinction from electron withdrawing ester
group (1-15), the methyl group has the opposite effect lowering
the electrophilicity of carboxamide carbon and thus, making the
55
1
5
Scheme 4 Preparation of 3,5-disubstituted pyrazolium chlorides.
60 nucleophilic attack of water more difficult (Scheme 3, structure
D). This is particularly evident when another methyl group was
present in diketone molecule (17) requiring the longest reaction
time for full conversion of starting diketone.
The product identification was made by means of IR, NMR
and x-ray analysis. The suitable single crystal was obtained by
slow evaporation of dioxane solution during several days. X-ray
diffraction experiment gave more structural evidences for
compound 16 (Fig. 2). Both nitrogens of the pyrazole molecule
are protonated and outer-sphere chlorides form hydrogen bonds
with the hydrogens of NH groups of the two neighboring
pyrazole rings yielding dimeric associates. The same pyrazolium
salt obtained in reaction of 3(5)-methyl-5(3)-phenylpyrazole with
The greater affinity to protonation of 3,5-disubstituted
2
0
65
pyrazoles 16-18 and formation of hydrochloride salts can be
explained by enhanced nucleophilicity of pyrazole nitrogen as a
consequence of the presence of electron donating methyl group at
3
-position. In the other side, ester group at the same position
(compounds 1-15) removes electron density from pyrazole
2
5
70
nitrogen causing a reduced possibility for recombination with
proton.
3
2
HCl is also characterized by X-ray diffraction technique.
Conclusions
In summary, we have reported an elegant and efficient protocol
for facile synthesis of 5-substituted-1H-pyrazole-3-carboxylates
in excellent yields demonstrating very high tolerance to various
substituents. Under the similar conditions, 1,3-diketones afforded
pyrazolium chlorides in lower reaction yields. “On water”
conditions make the process clean with simple handling,
achieving the criteria of green chemistry. This environmental,
catalyst free protocol avoids use of toxic hydrazine and includes
relatively short reaction times, excellent yields, easy work-up
with no harmful by-products formation requiring no
chromatographic purification.
7
5
80
Fig. 2 Crystal structure of 16
The dimer is typical acid-base complex in which proton
transfers from hydrochloric acid to the base pyrazole according to
Scheme 5.
3
0
Experimental
85
Semicarbazide hydrochloride (1 mmol), dicarbonyl compound (1
mmol for 4-aryl(hetaryl)-2,4-diketoesters, 8 mmol for 4-alkyl-
2
(
,4-diketoesters and 2 mmol for 1-aryl-1,3-diketones) and water
10 ml) were refluxed for 2 h (3-10 h for 1-aryl-1,3-diketones).
The reaction mixture was cooled overnight in the refrigerator, the
Scheme 5 Proton transfer from HCl to pyrazole (Pz); HCl is generated by
4
hydrolysis of NH Cl (see Scheme 3)
3
5
The above mentioned species differ from one another in the 90 precipitated compounds were filtered and dried.
degree of proton transfer which is very dependent on reaction
4
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Y. T. Han, K. Kim, G.-I. Choi, H. An, D. Son, H. Kim, H.-J. Ha, J.-
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Acknowledgments
The authors are grateful to the Ministry of Science and
Technological Development of the Republic of Serbia for
financial support (Grant No 172016). We also wish to thank Prof.
Vukadin Leovac and Dr. Marko Rodić for their help and support
during the work on the single crystals and structure determination
based on x-ray diffraction technique.
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Faculty of Science, Department of Chemistry, University of Kragujevac,
R. Domanovica 12,
mjoksovic@kg.ac.rs.
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34000 Kragujevac, Serbia. E-mail:
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†
Electronic
Supplementary
Information
(ESI)
available:
1
[
Characterization data for all pyrazole compounds, and copies of H and
C NMR spectra.] See DOI: 10.1039/b000000x/
1
3
29 Crystallographic data for compound 9 (CCDC No. 1025549) have
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DOI: 10.1039/C4GC02028F
1
16x34mm (300 x 300 DPI)

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Green Chemistry
View Article Online
DOI: 10.1039/C4GC02028F
A method for the conversion of 4-substituted-2,4-diketoester and 1-aryl-1,3-diketones into pyrazole compounds in „on water“
conditions has been developed.