An eco-friendly synthesis of 2-pyrazoline derivatives catalysed by CeCl 3· 7 H 2O

Article abstract of DOI:10.1007/s12039-017-1327-x

Abstract: 1,3,5-triaryl-2-pyrazoline derivatives were synthesised by a condensation reaction between chalcones and phenyl hydrazine using cerium chloride heptahydrate as a catalyst. All these reactions were carried out in ethyl lactate (70%) as a green solvent. Easy and efficient work up, recyclability of solvent and catalyst are the key merits of this protocol. Graphical Abstract:: SYNOPSIS A facile protocol for the synthesis of 1,3,5-triaryl-2-pyrazolines is described. The solvent ethyl lactate, obtained from renewable sources, is biodegradable. The catalyst CeCl ₃· 7 H ₂O is a water-tolerant Lewis acid with low toxicity. Easy and clean work up, recyclable solvent and catalyst are merits of the protocol. The reaction works well for all systems giving good yields of the desired products.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-017-1327-x

J. Chem. Sci.
© Indian Academy of Sciences
DOI 10.1007/s12039-017-1327-x
REGULAR ARTICLE
An eco-friendly synthesis of 2-pyrazoline derivatives catalysed
by CeCl3 · 7H2O
PRABHAT BHATa, GOMATHI SHRIDHARb, SAVITA LADAGEc
and LAKSHMY RAVISHANKARd,∗
aNational Initiative on Undergraduate Science (NIUS) Chemistry Programme Fellow, Homi Bhabha Centre for
Science Education, Mankhurd, Mumbai, Maharashtra 400 088, India
bDepartment of Chemistry, V. K. Krishna Menon College of Commerce & S. S. Dighe College of Science,
Bhandup (E), Mumbai, Maharashtra 400 042, India
cHomi Bhabha Centre for Science Education (TIFR), Mankhurd, Mumbai, Maharashtra 400 088, India
dDepartment of Chemistry, K.E.T’s V.G. Vaze College of Arts, Science and Commerce, Mithagar Road,
Mulund- (E), Mumbai, Maharashtra 400 081, India
E-mail: lakshravi@yahoo.com
MS received 23 March 2017; revised 7 June 2017; accepted 14 June 2017
Abstract. 1,3,5-triaryl-2-pyrazoline derivatives were synthesised by a condensation reaction between
chalcones and phenyl hydrazine using cerium chloride heptahydrate as a catalyst. All these reactions were
carried out in ethyl lactate (70%) as a green solvent. Easy and efficient work up, recyclability of solvent and
catalyst are the key merits of this protocol.
Keywords. Cerium chloride heptahydrate; ethyl lactate; green solvent; chalcones;
1, 3, 5-Triaryl-2-pyrazoline.
1. Introduction
work in the late 19th century, Fischer and Knoeve-
α
nagel synthesised 2-pyrazolines by the reaction of , β-
Pyrazolines are a well-known class of five-membered
nitrogen heterocycles. Pyrazoline derivatives are attract-
ing a lot of interest amongst researchers in the field of
medicinal chemistry because of their bioactivity.1 They
have been shown to possess a broad range of physio-
logical activities such as antimicrobial,2 antiamoebic,3
antinociceptive,4 anticancer,5 antidepressant,6 and anti-
inflammatory.7 Pyrazolines have also shown promise
as a new type of highly active insecticide towards
coleopteran and lepidopteran insects.8 The bioassay of
some of these compounds have exhibited fungicidal and
plant growth regulatory activities.9 Further, these com-
pounds have been used in conjugated fluorescent dyes
that emit blue fluorescence with high quantum10 and
electroluminescence yields.11
unsaturated aldehydes and ketones (chalcones) with
hydrazine.12 This remains one of the most commonly
used methods for the synthesis of these compounds.
Some of the catalysts used for the synthesis include
glacial acetic acid under heating or ultrasound irra-
diation,13 K2CO3 – mediated microwave irradiation14
H3PW12O40,15 Amberlyst 15 in refluxing toluene,16 hot
propionic acid,17 triethanolamine,18 pyridine in reflux-
ing ethanol19 and ethanolic sodium hydroxide20/sodium
acetate.21
α
Chalcones are aromatic , β-unsaturated carbonyl
compounds that form the central core of a variety of
important naturally occurring compounds like
flavonoids, isoflavonoids and their derivatives.22 These
compounds have been receiving increased attention due
to numerous potential biological and pharmacological
activities.23 While the chalcone backbone itself has
physiological properties, the highly electrophilic three
In literature, 2-pyrazoline derivatives seem to be
frequently studied and a large number of methods
are reported for their synthesis. In their pioneering
*
For correspondence
Electronic supplementary material: The online version of this article (doi:10.1007/s12039-017-1327-x) contains supplementary material,
which is available to authorized users.

Prabhat Bhat et al.
carbon , β-unsaturated carbonyl system in them has without any further purification. The characterization of the
α
products was done by comparing their physical constants with
the literature values and by recording spectra. All the melting
points were recorded on Veego digital melting point apparatus
assumed further significance due to their utility in the
synthesis of many heterocyclic compounds. which are
biologically active.24 Thus, chalcones are useful syn-
thons for the synthesis of a large number of bioactive
molecules, primarily the nitrogen containing hetero-
cyclics.25
1
and are uncorrected. H and 13C NMR spectra were mea-
sured at ambient temperatures using CDCl3 as the solvent
on a 500 MHz MHz BRUKER AVANCE DRX-500 instru-
ment.
Solvents are an important constituent of any organic
synthesis and often account for the maximum amount of
waste that is generated.26 The conventional solvents like
benzene, DMSO, etc., have detrimental environmental
impacts.27 Hence, the use of green solvents in organic
synthesis is an area of extensive research and several
green solvents like water, ionic liquids, polyethylene
glycol and some biomass-based solvents in organic syn-
thesis have been reported in the literature.28 Ethyl lactate
is a versatile green solvent which can be easily obtained
from carbohydrate feedstock; it is cheap, non-toxic and
biodegradable and addition of a co-solvent like water
alters its polarity and the yields of the products.29
In the last few years, there has been substantial
interest in the organic reactions promoted by cerium
chloride.30 Unlike common Lewis acids, trivalent lan-
thanide salts are stable in aqueous solutions. Cerium
chloride heptahydrate (CeCl3 · 7H2O), the most com-
mon commercially available source of Ce+3, finds useful
application as a catalyst in heterocyclic synthesis.31 It is
amildLewisacidwhichhaslowtoxicityandisrelatively
inexpensive. Hence, it is a good candidate for green
organic transformations.32 Our studies have demon-
strated the effective use of CeCl3 · 7H2O as a catalyst in
the synthesis of imines33 as well as in reductive amina-
tion reactions.34 Further, we have synthesised 3-methyl
isoxazolone derivatives catalysed by CeCl3 ·7H2O using
ethyl lactate (70%) as a solvent.35 Recently we have
reported the use of low melting mixtures of sugars, urea
and CeCl3 ·7H2O as efficient green solvents for the syn-
thesis of 1,4-dihydropyridines.36
2.1 Synthesis of chalcones
All the chalcones were synthesised using a reported proce-
dure.37
2.2 General procedure for synthesis of
1,3,5-trisubstituted-2-pyrazolines
A mixture of phenyl hydrazine 4 (2.0 mmol, 0.20 mL),
CeCl3 · 7H2O (20 mol%) and chalcone 3 (1.0 mmol) was
refluxed in ethyl lactate (70%) for 5 h. The progress of the
reaction was monitored by thin layer chromatography (TLC)
using n-hexane:ethyl acetate (7:3) as the solvent system. The
solid precipitate formed during the reaction was filtered and
washed with cold water. In most of the cases, the product
obtained was pure, and when impure it was recrystallized
using ethanol.
2.2a Spectral data for 5-(4-methylphenyl)-1,3-di-
phenyl-2-pyrazoline (5a): Colour: light yellow; Time:
300 min; Yield: 82%; M.p.: 128–129 ◦C; H NMR (500 MHz,
1
Chloroform-d, δ, ppm): 2.30 (s, 3H, CH3), 3.08 (dd, J = 16.5
Hz, 12.0 Hz, 1H), 3.77 (dd, J = 16.5 Hz, 8.5 Hz 1H), 5.20
(dd, J = 12.0 Hz, 8.5 Hz, 1H), 7.71–6.74 (m, 14H, Ar-H).
13C NMR (125 MHz, Chloroform-d, , ppm): 21.1, 43.6,
δ
64.3, 113.4, 119.0, 125.7, 125.8, 128.5, 128.9, 129.8, 132.8,
137.2, 139.7, 144.9, 146.7.
In continuation with our previous work on the use
of Cerium chloride heptahydrate (CeCl3 · 7H2O) as a
mild, lowcostandhighperformancecatalystinthegreen
synthesis of heterocyclic compounds, we now report a
facile synthesis of a number of 1,3,5-trisubstituted -2-
pyrazolines from chalcones and phenyl hydrazine using
CeCl3 · 7H2O as catalyst and ethyl lactate (70%) as
a solvent. To the best of our knowledge, the use of
these conditions for the synthesis of pyrazolines is not
reported in the literature.
3. Results and Discussion
In our earlier work,35 we reported the synthesis of
isoxazole derivatives by the reaction of hydroxylamine
hydrochloride with substituted aldehydes and ethyl ace-
toacetate using CeCl3 · 7H2O as catalyst and ethyl
lactate (70%) as a solvent. To further our quest for
isoxazoles, we first synthesised a series of chalcones.
These chalcones were then reacted with hydroxylamine
hydrochloride using the standardised procedure. While
this reaction did not go to completion and resulted in a
mixture which consisted of unreacted chalcone and the
desired isoxazole (as demonstrated by GC-MS results),
it encouraged us to explore the reaction of the chalcones
with phenyl hydrazine.
2. Experimental
All the reagents were purchased from SD Fine Chem Lim-
ited (India) and Thomas Baker (India) and were used directly

CeCl3 · 7H2O catalysed synthesis of 2-pyrazoline derivatives
5-10°C
1
3
2
Scheme 1. Reaction of substituted acetophenones and benzaldehydes to form chalcones.
Table 1. Synthesis of different chalcones using substituted acetophenones and benzaldehydes.
Entry
Ar1
Ar2
Melting point (◦C)
Yield (%)
Found
Reported38–40
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4 − CH3C6H4
4 − ClC6H4
94 − 95
112 − 113
113 − 114
72 − 73
94 − 96
111 − 113
112 − 114
69 − 71
157
86
86
80
94
79
87
95
73
77
94
82
93
74
78
98
98
95
99
95
93
95
99
91
4 − (CH3)2NC6H4
4 − MeOC6H4
4 − NO2C6H4
3 − NO2C6H4
4 − CH3C6H4
4 − ClC6H4
156 − 158
133 − 135
126 − 127
143 − 144
128 − 129
95 − 96
133
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
126 − 127
145 − 147
129
94 − 96
155 − 157
148
4 − (CH3)2NC6H4
4 − MeOC6H4
4 − NO2C6H4
3 − NO2C6H4
C6H5
155 − 156
146 − 147
46 − 47
42 − 47
2 − ClC6H4
112 − 113
135 − 136
126 − 127
124 − 125
80 − 81
115
3, 4 − diMeOC6H3
4 − CH3C6H4
4 − ClC6H4
135 − 136
127
126 − 128
4 − (CH3)2NC6H4
4 − MeOC6H4
4 − NO2C6H4
3 − NO2C6H4
C6H5
80
3s
3t
3u
3v
3w
100 − 101
158 − 159
156 − 157
105 − 106
126 − 128
100 − 101
158
158
104 − 105
2 − ClC6H4
127
Reaction conditions: acetophenone derivative (25 mmol), substituted benzaldehyde (25 mmol), dissolved in 10 mL ethanol,
added NaOH (1.0 g in 2–3 mL water), stirred and kept overnight in the freezer.
4. Synthesis of chalcones
worked best when the latter was in excess. So, we fixed
the stoichiometry of chalcone to phenyl hydrazine to be
1:2. To further establish the optimal conditions, a model
reaction of chalcone, 3m with phenyl hydrazine 4 in the
ratio 1:2 was chosen (Scheme 2).
The synthesis of a series of chalcones was carried
out by using a reported procedure from literature.37
(Scheme 1).
The reaction of substituted acetophenones (1) with
the substituted benzaldehydes (2) occurred in a facile
manner to give the chalcones 3. Good yields of the
chalcones were obtained and their formation was con-
firmed by comparison of their melting points with
that reported in the literature. The results are listed in
Table 1.
For this heterocyclisation reaction, a series of exper-
iments were carried out by varying the solvent, the
amount of catalyst and the temperature to arrive at
the optimum conditions. The results are summarised in
Table 2.
Thereactiondidnotproceedinwaterandthiscouldbe
because phenyl hydrazine is insoluble in water (Table 2,
entries 1–3). In ethanol, the reaction mixture was faintly
turbid and the reaction failed to occur. (Table 2, entries
4, 5). However, no explanation can be attributed to
this experimental observation. Only trace amount of
the product was obtained in 70% ethyl lactate at R.T.
4.1 Synthesis of 1,3,5-trisubstituted-2-pyrazolines
An examination of the available literature revealed that
the condensation of chalcones and phenyl hydrazine

Prabhat Bhat et al.
Reflux
3m
4
5m
Scheme 2. Model reaction for the optimisation of reaction conditions.
Table 2. Optimisation of reaction conditions for the synthesis of 5m.
No.
Solvent
Catalyst (mol%)
Temperature
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Water
Water
Water
Ethanol
–
R.T.
R.T.
Reflux
Reflux
Reflux
R.T.
24
24
5
5
5
24
24
5
5
5
No product
No product
No product
No product
No product
Trace
20
20
15
20
–
20
5
10
15
20
20
20
Ethanol
Ethyl lactate (70%)
Ethyl lactate (70%)
Ethyl lactate (70%)
Ethyl lactate (70%)
Ethyl lactate (70%)
Ethyl lactate (70%)
Ethyl lactate (80%)
Ethyl lactate (100%)
R.T.
Trace
Trace
66
69
87
72
Trace
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
9
10
11
12
13
5
5
5
Reaction conditions: chalcone 3m (1.0 mmol), phenyl hydrazine 4 (2.0 mmol).
5
3
4
Scheme 3. Synthesis of 1,3,5-trisubstituted-2-pyrazoline derivatives.
in the presence and absence of a catalyst. (Table 2, substituent. However, inthecaseofchalcones3b, 3d, 3e,
entries 6, 7). As per the above results, the best yield 3f, 3k, 3r, 3t, 3u and 3w no product was obtained even
was obtained when the reaction was carried out in after prolonged heating. Table 3 gives the yields and
ethyl lactate (70%) at reflux using CeCl3 · 7H2O (20 melting points of the pyrazoline derivatives synthesised.
mol%) (Table 2, entry 11). Higher concentrations of
All the products were characterised by comparison
ethyl lactate reduced the yield considerably (Table 2, of their melting points with those available in litera-
entries 12, 13). On the basis of the above results, ture and by spectral analysis. The IR spectrum of all
several 1,3,5-triaryl pyrazoline derivatives were synthe- the synthesised 2-pyrazoline derivatives showed char-
sised using CeCl3 · 7H2O (20 mol%) in the presence of acteristic peaks in the following ranges viz. 1590 −
ethyl lactate (70%) as a solvent at reflux temperature 1620 cm−1(C=N stretch of the pyrazoline ring), 1495 −
(Scheme 3).
1520 cm−1(C=C stretch of aromatic ring) and 1120 −
The reactions proceeded well for several substrates, 1220 cm−1 (C-N stretch of pyrazoline ring). All these
but those with electron donating substituent generally values match well with the reported values for these
gave higher yields than those with electron withdrawing functional groups.

CeCl3 · 7H2O catalysed synthesis of 2-pyrazoline derivatives
Table 3. Synthesis of 1,3,5-trisubstituted-2-pyrazoline derivatives.
Entry
Ar1
Ar2
Yield %
Melting point (◦C)
Found
Reported
5a
5b
5c
5d
5e
5f
5g
5h
5i
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4 − CH3C6H4
4 − ClC6H4
82
128 − 129
128 − 13041
No product
–
–
4 − (CH3)2NC6H4
4 − MeOC6H4
4 − NO2C6H4
3 − NO2C6H4
4 − CH3C6H4
4 − ClC6H4
70
120 − 121
12042
–
–
–
No product
No product
No product
–
–
–
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − CH3C6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
4 − MeOC6H4
62
71
72
73
139 − 140
152 − 153
141 − 142
138 − 139
–
143 − 144
155 − 156
121 − 122
119 − 120
135 − 136
158 − 159
–
141 − 14243
155 − 15644
14042
4 − (CH3)2NC6H4
4 − MeOC6H4
4 − NO2C6H4
3 − NO2C6H4
C6H5
5j
5k
5l
140 − 14245
No product
–
38
86
74
68
75
144 − 14646
155 − 15747
123 − 12446
118 − 11948
136 − 13741
160 − 16114
–
5m
5n
5o
5p
5q
5r
5s
5t
5u
5v
5w
2 − ClC6H4
3, 4 − diMeOC6H3
4 − CH3C6H4
4 − ClC6H4
52
4 − (CH3)2NC6H4
4 − MeOC6H4
4 − NO2C6H4
3 − NO2C6H4
C6H5
No product
87
145 − 146
147 − 14849
No product
No product
66
–
–
–
–
113 − 114
110 − 11246
2 − ClC6H4
No product
–
–
Reaction conditions: chalcone 3 (1.0 mmol), phenyl hydrazine 4 (2.0 mmol), CeCl3 · 7H2O (20 mol%). Refluxed in ethyl
lactate (70%) for 5h.
The 1H NMR spectrum of product 5m shows a mul-
tiplet in the region 6.77–7.72 ppm integrating for 14
2
protons which is due to the protons of three phenyl rings,
1
3
one of which is monosubstituted with a methyl group in
the para position. A doublet of a doublet at 5.22 ppm is
attributed to the single proton at position 5 of the pyra-
zoline ring (Figure 1). The two protons in position 4
of this ring are diastereotopic and they appear as two
doublets of doublet at 3.11 ppm and 3.80 ppm. The two
geminally coupled protons have large coupling constant
(J = 12.5 Hz) which are very characteristic. The methyl
group on one of the phenyl rings appears as a singlet at
1.55 ppm. These values are in good agreement with liter-
ature values for this compound.47 The 1H NMR spectra
of all the products were analysed and found to show the
expected peaks corresponding to the above structural
features.
5
4
Figure 1. General structure of
the 2-pyrazoline derivatives.
To evaluate the recyclability of the solvent and cat-
alyst, the filtrate obtained after removal of the product
5m was reused as such for consecutive reactions. It was
confirmed that there is no product and reactant left in
the filtrate, with the help of thin layer chromatography
(TLC). Three consecutive trials were performed and the
yields at the end of each cycle were measured as follows:
86, 83 and 78% in 1st, 2nd and 3rd cycle, respectively.
Good yield at the end of the third cycle confirms the
recyclability of the solvent – catalyst mixture without
appreciable loss in activity.
The 13CNMR shows the characteristic peaks for the
aromatic carbons. The quaternary carbon at C-3 appears
intherange140–145ppm. Peaksintherange40–45ppm
and 60–64 ppm, which are attributed to the secondary
and tertiary carbons at C-4 and C-5, respectively, were
observed for all the compounds. Thus, the structures of
all the products were unambiguously established.

Prabhat Bhat et al.
..
..
..
chalcone
..
hydrogen bond
Phenyl hydrazine
hydrogen bond
ethyl lactate
2-pyrazoline
Scheme 4. Suggested mechanism for the reaction of chalcone with phenyl hydrazine in the presence of CeCl3 · 7H2O.
A reasonable pathway for the reaction between chal- is a biodegradable solvent and CeCl3 · 7H2O, which
cone and phenyl hydrazine in the presence of CeCl3 · is a water-tolerant Lewis acid. Further, the catalyst
7H2O is proposed based on the results obtained and and solvent are recyclable up to three times without
information in the literature. CeCl3 · 7H2O is a mild appreciable loss in activity. The reaction works well
Lewis acid capable of coordinating with carbonyl oxy- for all systems giving good to moderate yields of the
gen which enhances its reactivity. Liu and Wen have desired products. As compared to reported methods,
proposed the participation of ethyl lactate in increas- the current methodology provides a cleaner route to
ing the nucleophilicity of the amino group by hydrogen the synthesis of the target molecules with the addi-
bond formation.50 Based on mechanisms proposed tional advantage of recyclability of solvent and cata-
by Fazaeli et al., in the synthesis of 2-pyrazolines lyst.
by tungstophosphoric acid,46 by Kidwai and Jahan
in Mannich reaction catalysed by CeCl3 · 7H2O,51
aldoximes in the presence of ethyl lactate,50 we pro-
pose the following likely mechanism for this reaction
(Scheme 4).
Supplementary Information (SI)
and by Liu and Wen in the synthesis of keto and
The supplementary information gives the experimental
details, physical constants, 1H NMR and 13C NMR data
forallthesynthesised1,3,5-trisubstituted2-pyrazolines.
Supplementary Information is available at www.ias.ac.
in/chemsci.
5. Conclusions
Acknowledgements
This paper describes a facile protocol for the synthe-
sisof1,3,5-triaryl-2-pyrazolinederivativesusingcerium
chloride heptahydrate in ethyl lactate (70%). This pro-
tocol involves easy workup and fulfils some of the
Prabhat Bhat was a National Initiative on Undergraduate Sci-
ence (NIUS) chemistry fellow (Batch XI, 2014-2016) at Homi
Bhabha Centre for Science Education. The authors thank Tata
Institute of Fundamental Research (TIFR), for providing the
principles of green chemistry. It uses ethyl lactate which NMR spectra.

CeCl3 · 7H2O catalysed synthesis of 2-pyrazoline derivatives
16. Holla B S, Mahalinga M, Poojary B, Ashok M and
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