Hydrotrope: Green and rapid approach for the catalyst-free synthesis of pyrazole derivatives

Article abstract of DOI:10.1007/s00706-013-0944-4

An efficient synthesis of pyrazole derivatives by condensation of 1,3-diketone and hydrazines/hydrazides has been achieved in aqueous hydrotropic solution under catalyst-free conditions within a very short time. The present protocol is beneficial as it includes mild reaction conditions, shorter reaction times, use of universal solvent water, which avoids volatile organic solvents, high yields of products, and being environmentally friendly.

Full text of DOI:10.1007/s00706-013-0944-4

Monatsh Chem (2013) 144:1213–1218
DOI 10.1007/s00706-013-0944-4
ORIGINAL PAPER
Hydrotrope: green and rapid approach for the catalyst-free
synthesis of pyrazole derivatives
•
Madhuri Barge Santosh Kamble Arjun Kumbhar
•
•
•
Gajanan Rashinkar Rajashri Salunkhe
Received: 6 June 2012 / Accepted: 5 February 2013 / Published online: 3 April 2013
Ó Springer-Verlag Wien 2013
Abstract An efficient synthesis of pyrazole derivatives
by condensation of 1,3-diketone and hydrazines/hydrazides
has been achieved in aqueous hydrotropic solution under
catalyst-free conditions within a very short time. The
present protocol is beneficial as it includes mild reaction
conditions, shorter reaction times, use of universal solvent
water, which avoids volatile organic solvents, high yields
of products, and being environmentally friendly.
derivatives, such as 1,3-dipolar cycloadditions of diazo
compounds [12], reaction of chalcones [13, 14] and
hydrazines, four-component coupling of terminal
a
alkynes, hydrazine, carbon monoxide, and aryl iodides
[15], and the direct condensation of 1,3-diketones and
hydrazines in the presence of different acid catalysts such
as H2SO4 [16], PSSA [17], zirconium sulfophenyl phos-
phate [18], Sc(OTf)3 [19], Y-zeolite [20], K2CO3/
[Cp*IrCl2]2 [21], Al2O3/montmorillonite [22], H3PW12O40
[23], Zn[L-proline]2 [24], etc. However, the generality of
the existing reports is somewhat visited by the severe
reaction conditions, and the catalysts and solvents used are
not acceptable in the context of green synthesis. Thus,
developing versatile approaches to synthesize pyrazoles
still remains a highly desired goal in organic synthesis.
Avoiding the use of harmful organic solvents is a fun-
damental strategy to achieve environmentally benign and
economic syntheses in the area of research that is being
vigorously pursued. One of the most attractive alternatives
to organic solvents is water, which has witnessed increas-
ing popularity because of being inexpensive, readily
available, non-inflammable, non-toxic, and environmen-
tally benign. However, organic reactions in water are often
limited in scope because of the poor solubility of many
organic compounds. A possible new way to improve the
solubility of substrates is the use of amphiphiles such as
phase transfer catalyst, surfactants, and hydrotropes.
Keywords Green chemistry Á Surfactants Á Hydrotrope Á
Water Á Pyrazoles
Introduction
Pyrazole derivatives have aroused considerable interest
over the past few decades because of their wide variety of
pharmacological [1–6] properties including antiinflamma-
tory, antibacterial, antitumor, antipsychotic, antimicrobial,
and antiviral. They are also used as herbicides [7], fungi-
cides [8], pesticides [9], insecticides [10], and dyestuffs
[11].
The ever-increasing demands for novel medicinally
active compounds have led to the continuous search for
simple and efficient methods for generation of libraries for
biological screening. This has been the prime driving force
for the synthesis of various compounds incorporating the
pyrazole moiety. A literature survey revealed that several
methods have been reported for the synthesis of pyrazole
The solubility-enhancing surface active molecules are
termed hydrotropes. They increase the aqueous solubility
of organic substrates by 200 times. Hydrotrope aggregation
is responsible for the increase in aqueous solubility that
occurs beyond a certain hydrotrope concentration known as
the minimum hydrotrope concentration (MHC), analogous
to the critical micelle concentration (CMC) for a surfactant.
Hydrotropes are extensively used in drug solubilization,
M. Barge Á S. Kamble Á A. Kumbhar Á G. Rashinkar Á
R. Salunkhe (&)
Department of Chemistry, Shivaji University, Kolhapur 416004,
MS, India
e-mail: rss234@rediffmail.com
123

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M. Barge et al.
Table 1 Screening of various hydrotropes for the synthesis of pyrazoles
NHNH2
O
O
Hydrotrope
RT, 2-3 min
+
N
N
Entry
Hydrotrope (50 %w/v)
Time
Yielda/%
1
2
3
4
a
Sodium p-toluenesulfonate (NaPTS)
Sodium benzenesulfonate (NaBS)
Sodium p-xylenesulfonate (NaXS)
Water
2 min
2 min
2 min
5 h
90
85
78
Trace
Isolated yields after purification
detergent formulation, health care, and household appli-
cations as well as extraction agents for fragrances [25].
However, to the best of our knowledge, there are very few
reports about organic transformations using an aqueous
hydrotropic medium [26–28]. Hydrotropes offer a number
of benefits as they are air, water, and thermally stable and
less toxic. As hydrotropes increase the solubility of com-
pounds in many fold excess, this effect is attributed to a
direct interaction between the reactants that are practically
insoluble in water. It is interesting to note that the product
precipitated on dilution with water from hydrotropic solu-
tion, which leads to easy recovery of the product, and the
mother liquor could be used to concentrate the hydrotrope
for recycling.
Fig. 1 Effect of NaPTS concentration (%w/v) on pyrazole synthesis
It was interesting to note that all hydrotropes proved
applicable for this reaction furnishing the corresponding
pyrazoles in yields ranging from 78 to 90 % with NaPTS
being the best reaction medium. The higher activity of
NaPTS is attributed to its overall planar structure and
presence of more balanced hydrophobic and hydrophilic
regions that give rise to a self-association configuration
offering a microenvironment of lowered polarity stabiliz-
ing the reactants through a cooperative effect [32, 33]. As
excellent results were obtained in NaPTS, we employed
this particular hydrotrope for subsequent studies. From the
study of the concentration effect of selected hydrotropes on
the yield of the product, it was noted that the optimal
concentration effect obtained toward pyrazole derivatives
peaked at a concentration of 50 %. The use of lower as
well as higher concentrations than optimized concentration
(50 %) resulted in lower yields of the products. These
observations may be rationalized on the basis of the
decrease in the solubility of reactants in aqueous hydro-
tropic solutions at other concentrations than the optimized
one (Fig. 1).
Motivated by the aforementioned advantages and as part
of our ongoing research in the development of novel syn-
thetic routes for the synthesis of biologically active
heterocycles specially using hydrotrope as a reaction
medium [29–31], herein we would like to report a high-
speed and green method for the catalyst-free synthesis of a
diverse set of pyrazoles using 1,3-diketones and hydra-
zines/hydrazides as substrates under mild reaction
conditions in aqueous hydrotropic solution.
Results and discussion
Initially for optimizing the reaction conditions, phen-
ylhydrazine (1.2 mmol) and acetylacetone (1 mmol) were
used as model substrates in 50 % aqueous hydrotropic
solution at ambient temperature. The key focus of the use of
hydrotropes as a reaction medium depends on the nature of
the hydrotrope used and its MHC at which there is a maxi-
mum solubility of reactants. Thus, the investigation began
with the selection of an appropriate hydrotrope by examining
different hydrotropes such as sodium benzenesulfonate
(NaBS), sodium p-xylenesulfonate (NaXS), and sodium
p-toluenesulfonate(NaPTS)forthemodelreaction(Table 1).
A controlled reaction conducted under identical condi-
tions and devoid of hydrotrope only in water gave no
corresponding product despite the prolonged reaction time,
123

Hydrotrope: green and rapid approach
1215
are expected to contribute to the development of a green
strategy for the construction of biologically active pyra-
zoles. The present protocol allows a fast and general
synthesis of inaccessible pyrazoles offering very attractive
features such as no use of catalyst, reduced reaction times,
easy workup procedure, and a non-toxic and safer reaction
medium giving high yields.
Scheme 1
O
O
50% aq. NaPTS
RT, 2-3 min
R-NHNH2
+
N
N
R
indicating that the role of the hydrotrope is decisive
(Table 1, entry 4).
Experimental
To explore the generality and the scope of this method, a
wide variety of hydrazines/hydrazides were reacted with
various 1,3-diketones under the optimized conditions to
afford the corresponding pyrazole derivatives (Scheme 1),
and the results are listed in Table 2. The results suggest
that, irrespective of the nature of substituents, all these
reactions proceeded well in the optimized condition giving
good to excellent yields within a very short reaction time
under mild reaction conditions in aqueous medium. Sepa-
ration of the products involved simple filtration or
extraction of the reaction mixture. After the isolation, the
crude products were purified by column chromatography
using petroleum ether/ethyl acetate (7/3) as eluent. The
identity of all the compounds was ascertained on the basis
of IR, 1H NMR, 13C NMR spectroscopy as well as by mass
spectrometry. The physical and spectroscopic data are
consistent with the proposed structures and are in harmony
with the literature values.
Solvents and reagents were commercially sourced and used
without further purification. Melting points were deter-
mined in an open capillary. Infrared spectra were obtained
on a Perkin-Elmer FT-IR spectrometer. The samples were
1
examined as KBr discs (*5 %w/w). H NMR and 13C
NMR spectra were recorded on a Bruker Avance 300-MHz
spectrometer using CDCl3 as a solvent and TMS as internal
reference. Mass spectra were recorded on a Shimadzu
QP2010 GCMS. NaBS, NaXS, and NaPTS were synthe-
sized by the following procedures reported in the literature
[34].
General procedure for synthesis of pyrazoles
In a 100-cm3 round bottom flask, the 1,3-diketone
(1 mmol) and hydrazines/hydrazides (1.2 mmol) were
placed. To this 5 cm3 of 50 % aqueous NaPTS solution
was added and stirred at room temperature for a few
minutes until the completion of the reaction as indicated by
TLC. The solid products were separated by adding 50 cm3
water followed by simple filtration. In case of liquids,
products were separated by extraction in ethyl acetate.
After isolation, products were purified by column chro-
matography using petroleum ether/ethyl acetate (7/3) as
eluent.
The mechanism of the pyrazole formation is conceptu-
alized in Fig. 3. The water molecules hydrate the
hydrotrope head groups, decreasing the electrostatic inter-
action between these groups. The two head groups move
apart and displace the water molecules interacting with
hydrophobic chains containing reactants. This may be the
driving force for the hydrazine/hydrazide to interact with
diketone, enhancing the reaction rate. The eliminated water
molecules then are easily absorbed by the hydrophilic head
groups, which shift the equilibrium toward the product side
accelerating the reaction rate.
All synthesized products were characterized by spectral
analysis, and the spectroscopic data of the reported com-
pounds are in accordance with the literature. The
characteristic peak in the range d = 5.87–6.08 ppm in each
product is of –CH of the five-membered aromatic pyrazole
ring, indicating complete conversion of reactants into the
product.
Although the higher concentration of hydrotrope (50 %)
is needed for the reactions to occur, the most important
advantage while using hydrotrope is that it can be reused.
Reusability of the hydrotrope for a model reaction by
recovering the aqueous hydrotropic solution after the
reaction was screened in new runs, and it was found that
the recycled aqueous hydrotropic solution in subsequent
experiments gave almost similar yields (Fig. 2).
(4-Chlorophenyl)(3,5-dimethyl-1H-pyrazol-1-yl)metha-
none (6, C12H11ClN2O)
ꢀ
Colourless oil; IR (KBr): m = 3,094, 2,930, 1,698, 1,584,
1,342, 1,084, 916 cm-1 1H NMR (300 MHz, CDCl3):
;
d = 2.24 (s, 3H), 2.63 (s, 3H), 6.04 (s, 1H), 7.44 (dd,
J = 1.8, 6.6 Hz, 2H), 7.97 (dd, J = 1.8, 6.6 Hz, 2H) ppm;
13C NMR (75 MHz, CDCl3): d = 13.8, 14.3, 111.1, 128.0,
131.6, 132.8, 138.7, 145.0, 152.0, 166.9 ppm; MS (EI): m/
z = 234 (M?).
Conclusion
In summary, the use of a simple experimental procedure
and ease of recovery and reuse of this novel reaction media
123

1216
M. Barge et al.
Table 2 Synthesis of pyrazoles in 50 % aq. NaPTS solutiona
Compound
1
Hydrazine/hydrazide
Product
Yieldb/%
90
M.p./°C
References
[24]
Oil
NHNH2
N
N
2
3
92
78
120–122
108–110
122–123 [19]
O2N
NHNH2
NO2
O2N
N
N
N
O2
H2NNH2ÁH2O
108 [24]
HN
N
4
89
231–233
230–233 [24]
NHNH2
N
N
O
O
5
80
Oil
[19]
Cl
O
Cl
NHNH2
N
N
O
6
88
Oil
–
Cl
Cl
N
NHNH2
N
O
O
7
73
53–55
–
Br
O
Br
O
NHNH2
N
N
123

Hydrotrope: green and rapid approach
1217
Table 2 continued
Compound
8
Hydrazine/hydrazide
Product
Yieldb/%
90
M.p./°C
References
153–155
155 [35]
N
N
NHNH2
N
N
O
O
9
91
Oil
–
N
N
NHNH2
N
N
O
O
10
85
51–53
–
CH3
CH3
N
N
O
NHNH2
O
O
O
11
90
Oil
[24]
H3C
NHNH2
N
H3C
N
O
O
a
1
All products were characterized by IR, H NMR, 13C NMR, and mass spectroscopy
b
Isolated yields after purification
NMR (300 MHz, CDCl3): d = 2.17 (s, 3H), 2.68 (s,3H),
6.03 (s, 1H), 7.30–7.59 (m, 3H), 7.60 (d, J = 7.8 Hz, 1H)
ppm; 13C NMR (75 MHz, CDCl3): d = 13.8, 14.1, 111.6,
120.1, 126.7, 129.1, 131.0, 132.6, 137.3, 144.2, 152.8,
167.7 ppm; MS (EI): m/z = 279 (M?).
(3,5-Dimethyl-1H-pyrazol-1-yl)(pyridin-4-yl)methanone
(9, C11H11N3O)
ꢀ
Yellow oil; IR (KBr): m = 2,926, 2,849, 1,691, 1,581,
1,336, 1,271, 1,088, 918 cm-1 1H NMR (300 MHz,
;
CDCl3): d = 2.25 (s, 3H), 2.64 (s, 3H), 6.04 (s, 1H),
7.43 (dd, J = 1.8, 6.9 Hz, 2H), 7.96 (dd, J = 1.8, 6.6 Hz,
2H) ppm; 13C NMR (75 MHz, CDCl3): d = 13.8, 14.4,
111.2, 126.1, 131.6, 132.8, 138.7, 145.1, 152.0, 166.9 ppm;
MS (EI): m/z = 201 (M?).
Fig. 2 Recyclability of 50 % aq. NaPTS solution
1-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(3-methylphenyl-
oxy)ethanone (10, C14H16N2O2)
(2-Bromophenyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone
ꢀ
White solid; m.p.: 51–53 °C; IR (KBr): m = 3,101, 2,922,
2,845, 1,745, 1,615, 1,584, 1,398, 1,328, 1,257, 1,161,
(7, C12H11BrN2O)
ꢀ
Pale yellow solid; m.p.: 53–55 °C; IR (KBr): m = 3,056,
1,093, 964, 839, 774 cm-1; H NMR (300 MHz, CDCl3):
1
2,928, 1,717, 1,586, 1,343, 1,023, 918, 783, 689 cm-1; H
1
123

1218
M. Barge et al.
Fig. 3 Mechanistic picture of
pyrazole formation
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Acknowledgments We gratefully acknowledge the financial sup-
port from the Department of Science Technology and University
Grants Commission for FIST and SAP, respectively. One of the
authors (Madhuri S. Barge) thanks the Department of Science
Technology, New Delhi, India, for the award of the PURSE
fellowship.
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