Et3N-Prompted Efficient Synthesis of Anthracenyl Pyrazolines and Their Cytotoxicity Evaluation against Cancer Cell Lines

Article abstract of DOI:10.1002/jhet.3636

A series of anthracenyl pyrazoline derivatives (3a–o) were synthesized with an aim to evaluate their in vitro anticancer activities. Anthracenyl pyrazoline compounds were prepared by the reaction between various anthracenyl chalcones (1a–o) and hydrazine

Full text of DOI:10.1002/jhet.3636

Month 2019 Et3N-Prompted Efficient Synthesis of Anthracenyl Pyrazolines and Their
Cytotoxicity Evaluation against Cancer Cell Lines
a
a
Thechano Merry, Prabhakar Maddela,
Kiran Devaraya,b Anand K. Kondapi,b and Chullikkattil P. Pradeepc
*
aDepartment of Chemistry, Nagaland University, Lumami, Nagaland 798627, India
bDepartment of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad 500046,
India
cSchool of Basic Sciences, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh 175001, India
*E-mail: prab.chem@gmail.com
Received March 25, 2019
DOI 10.1002/jhet.3636
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A series of anthracenyl pyrazoline derivatives (3a–o) were synthesized with an aim to evaluate their
in vitro anticancer activities. Anthracenyl pyrazoline compounds were prepared by the reaction between var-
ious anthracenyl chalcones (1a–o) and hydrazine hydrate (2). The reactions were carried out under reflux in
the presence of triethylamine and ethanol for 24 h, and the obtained yields were from good to excellent (90–
97%). The structure of each compound is well characterized by IR, 1H-NMR, 13C-NMR, elemental analyses,
and mass spectroscopic technics, and the molecular structures of compounds 3d and 3e were solved by
single-crystal X-ray crystallographic methods. The newly synthesized compounds (3a–o) were evaluated
for their in vitro cytotoxic studies against four human cancer cell lines MCF-7 (breast cancer cell lines),
SK-N-SH (neuroblastoma cancer cell lines), HeLa (cervical cancer cell lines), and HepG2 (liver cancer cell
lines), and the screening results show strong cytotoxic effects for most of the synthesized compounds against
the three cell lines except SK-N-SH cells. Notably, compounds 3a, 3j, 3l, 3m, 3n, and 3o showed a highly
potential activity against HeLa cells (IC50: 0.22, 0.3, 0.3, 0.10, 0.25, and 0.25 μM), while compounds 3i, 3k,
3l, and 3m showed a significant cytotoxic activity in HepG2 cells (IC50: 0.22, 0.44, 0.40, and 0.22 μM),
whereas compounds 3a, 3b, 3d, and 3e exhibit a promising cytotoxicity against MCF-7 cells (IC50: 0.73,
0.495, 0.493, and 0.66 μM).
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
Various naturally occurring and synthetic compounds
have been reported for their anticancer activity, and most
of them consist of pyrazole unit as the core structure.[9]
In particular, pyrazoles are important in medicinal
chemistry and were exclusively reported to exhibit wide
range of biological properties.[10–12] In the past few
decades, extensive research has been carried out on the
pyrazole nucleus and its anticancer activity.[13]
Therefore, pyrazole is a versatile lead compound to
design potent bioactive molecules for drug discovery and
development, especially in cancer therapy. Pyrazolines
can be considered as intermediate compound for
synthesis of various heterocyclic compounds of high
biological activity. The well-established methods for the
synthesis of substituted pyrazoles are based either on the
condensations of substituted hydrazines with dicarbonyl
or on intermolecular [3+2] cycloaddition reaction of
Cancer, certainly cancer has become one of the most
major health problems in the world, and it affects people
at all ages. The World Health Organization reported that
70% or more of all cancer deaths happen in low-income
as well as in middle-income nations.[1] All-inclusive, the
most noticeable types of cancer are lung, bronchus,
prostate, breast, colon, and rectum,[2,3] and it is because
of the common environmental factors like use of tobacco,
other dietary habits, obesity, infections, radiation, stress,
lack of physical activity, and environmental pollutants
leading to cancer deaths.[4] Despite extensive
research and advances in cancer therapy, cancer is
reported to be the second leading cause of death in the
world next to cardiovascular disorders.[5–8] Therefore,
search for the new potent anticancer agents remains a
challenge and need of the hour to fight against cancer
disease.
alkynes
1 to 3-dipoles.[14,15] The addition of a
pyrazoline ring between the two aryl rings of chalcone
© 2019 Wiley Periodicals, Inc.

T. Merry, P. Maddela, K. Devaraya, A. K. Kondapi, and C. P. Pradeep
Vol 000
gives more scope for the synthesis of the new heterocyclic
compounds from diverse chalcones.
yields are not improved much under this methods
(Table 1, entries 1–5).
In view of the aforementioned findings in cancer
research and in continuation with our ongoing research in
designing and synthesizing natural products-based new
scaffolds synthesis and their biological activity, in this
article, we report the synthesis of a series of anthracenyl
pyrazoline derivatives (3a–o) and their anticancer activity
evaluation against the MCF-7, SK-N-SH, HeLa, and
HepG2 cancer cell lines.
The aforementioned catalysts and conditions were not
attained up to satisfactory yields of the product 3a
monitored by thin-layer chromatography (TLC) on time
intervals. Then we proceed to carry out the reactions in
the presence of base catalysts, such as Et3N (Table 1,
entry 6), piperidine (Table 1, entry 7), and pyridine
(Table 1, entry 8) under the refluxing conditions in
ethanol for 24 h and microwave conditions, and we
found that the better yields (96%) were achieved only in
the presence of Et3N under the refluxing conditions in
ethanol for 24 h (Table 1, entry 6). Thus, in order to
standardize the reaction, we examined the mole ratio of
the reactants (1:1, 1:2, 1:5, and 1:10) for better
conversion of the reactant 1a to the product 3a in the
presence of Et3N (10 mol %), and we found that the
better yields (96%) of the product 3a were obtained at
1:10 mole ratio of reactants anthracenyl chalcone (1a)
and hydrazine hydrate (2) in ethanol at reflux temperature
for 24 h (Table 1, entry 6). To test the generality and
scope of this method, we then examined the reactions
with a series of anthracenyl chalcones (1a–o) and
hydrazine hydrate (2) under the aforementioned
standardized reaction conditions for the synthesis of
anthracenyl pyrazoline derivatives (3a–o) as revealed in
Scheme 1 and Figure 1. All the reactions showed to be a
good and quite efficient synthetic etiquette for aryl as
well as hetero-aryl group and irrespective of the presence
of electron-donating and electron-withdrawing functional
groups in phenyl ring system.
RESULTS AND DISCUSSION
Chemistry. The synthesis of anthracenyl pyrazoline
derivatives (3a–o) was carried out from the reaction of
anthracenyl chalcones (1a–o)[16] with hydrazine hydrate
(2) in the presence of triethylamine (Et3N) in ethanol
solution at refluxing temperature for 24 h. Initially,
attempts have made to synthesize the 3-anthracen-9-yl-
5-phenyl-4,5-dihydro-1H-pyrazole (3a) starting from
1:10 ratio of 1-anthracen-9-yl-3-phenyl-propenone (1a)
with hydrazine hydrate (2) in the presence of different
acid catalysts (AcOH, HCl, H2SO4, TsOH, and FeCl3)
in ethanol solution under reflux conditions for 24 h, and
we observed that the progress of the reactions was very
slow and obtained poor yields (Table 1, entries 1–5).
Further, we carry out the reaction under microwave
reaction conditions at 200°C for 30 min by using
different acid catalysts (AcOH, HCl, H2SO4, TsOH, and
FeCl3); here in this reaction also, the percentage of the
Table 1
Optimization of the reaction conditions and catalysts for the synthesis of anthracenyl pyrazoline (3a).a
Reaction methods, yields (%)
Entry
Catalyst
Reflux (24 h)
Microwave (200°C, 30 min)
1
2
3
4
5
6
7
8
AcOH
TsOH
HCl
H2SO4
FeCl3
Et3N
30
40
35
10
10
96
40
25
10
25
20
3
3
60
15
5
Piperidine
Pyridine
aReaction conditions: anthracenyl chalcone (1a) (1 mmol), hydrazine hydrate (2) (10 mmol), and catalyst (10 mol %) in 5 mL ethanol solution.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Et3N-Prompted Efficient Synthesis of Anthracenyl Pyrazolines and Their
Cytotoxicity Evaluation against Cancer Cell Lines
Scheme 1. Synthesis of anthracenyl pyrazoline derivatives (3a–o).
Figure 1. Structures of the anthracenyl pyrazoline derivatives (3a–o).
The structures of the newly synthesized anthracenyl
pyrazoline derivatives (3a–o) were elucidated by IR, H-
47.75–43.71 (C, CH2 pyrazoline), 64.73–57.48 (C, CH
pyrazoline), and 151.80–151.34 (C, C═N pyrazoline) that
agree the pyrazoline character deduced from the H-NMR
spectra. The proposed reaction mechanism for the
synthesis of anthracenyl pyrazolines is shown in Scheme 2.
1
NMR, 13C-NMR, and mass spectroscopy. The Fourier
transform infrared spectra of the compounds endorse that
the disappearance of two absorption bands of the
CH═CH and C═O groups of anthracenyl chalcones and
appearance of a new absorption bands of NH and C═N
groups at 3343 and 1591 cmÀ1 as well as the aliphatic
1
X-ray crystallography.
The molecular structures of
the anthracenyl pyrazoline compounds 3d and 3e were
unambiguously deduced by single-crystal X-ray diffrac-
tion analyses. The crystal structure refinement data of 3d
and 3e are listed in Table 2. The complete listing of the
bond distances and bond angles is presented in the
supporting information. ORTEP drawings of the crystal
structures of 3d and 3e with atomic numbering scheme
are shown in Figure 2. Compound 3d crystallized in
orthorhombic Pbca space group. The asymmetric unit of
3d consists of two independent molecules as shown in
Figure 2, which show almost identical structural features
C–H stretching vibrations appear at 2985–2930 cmÀ1
,
1
respectively. In the H-NMR spectra of the anthracenyl
pyrazolines, the CH2 protons of pyrazoline ring resonated
as a pair of doublet of doublets at δ 3.16–3.07 ppm,
3.60–3.51 ppm, and the CH proton of the compounds
appears as a triplet at δ 5.35–5.10 ppm because of the
protons of the methylene (CH2) group. In the 13C-NMR
spectra of the compounds, the characteristic chemical
shift values of the pyrazoline ring carbons appear at
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T. Merry, P. Maddela, K. Devaraya, A. K. Kondapi, and C. P. Pradeep
Vol 000
Scheme 2. Proposed reaction mechanism for the synthesis of anthracenyl pyrazolines (3a–o).
Table 2
The single-crystal X-ray molecular structures refinement data of anthracenyl pyrazolines 3d and 3e.
Parameters
3d
3e
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
α (°)
C
24H20N2
C23H17ClN2
356.84
293(2)
Orthorhombic
Pccn
23.7241(9)
15.2117(7)
10.1917(4)
90.00
336.42
293(2)
Orthorhombic
Pbca
18.3899(6)
16.2601(5)
25.0633(6)
90.00
β (°)
90.00
90.00
γ (°)
90.00
7494.5(4)
16
1.193
0.537
90.00
3678.0(3)
8
1.289
1.885
Volume (Å3)
Z
ρ
calc (g/cm3)
μ (mmÀ1
F(000)
)
2848.0
1488.0
Crystal size (mm3)
0.236 × 0.105 × 0.088
CuKα (λ = 1.54184)
8.54 to 133.62
0.656 × 0.088 × 0.069
CuKα (λ = 1.54184)
6.9 to 133.72
Radiation
2Θ range for data collection (°)
Index ranges
À21 ≤ h ≤ 13, À16 ≤ k ≤ 19, À22 ≤ l ≤ 29
À22 ≤ h ≤ 28, À14 ≤ k ≤ 18, À12 ≤ l ≤ 11
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
Final R indexes [I ≥ 2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole/e ÅÀ3
CCDC number
15250
6762
3077 [Rint = 0.0262, Rsigma = 0.0313]
3077/0/235
6476 [Rint = 0.0427, Rsigma = 0.0462]
6476/0/471
1.023
1.281
R1 = 0.0646, wR2 = 0.1773
R1 = 0.0982, wR2 = 0.2096
0.32/À0.29
R1 = 0.1089, wR2 = 0.2952
R1 = 0.1303, wR2 = 0.3278
1.42/À0.63
1891026
1891027
except some minor differences in the corresponding bond
lengths and angles. The angles between the planes of the
anthracene and benzene rings of the two molecules
present in the asymmetric unit are 76.42° and 79.80°.
The supramolecular analysis of 3d revealed that the
crystal structure is stabilized by a number of C–H···π
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Month 2019
Et3N-Prompted Efficient Synthesis of Anthracenyl Pyrazolines and Their
Cytotoxicity Evaluation against Cancer Cell Lines
Figure 2. X-ray crystal structure thermal ellipsoid plot (30% probability level) of anthracenyl pyrazolines 3d and 3e.
intermolecular interactions. The strongest interaction
among them is C47–H47···Cg1 with an angle of 161.62°
and an H···Cg1 distance of 2.718 Å. The other such
bonds include C9–H9···Cg1 with an angle of 162.06° and
an H···Cg1 distance of 2.798 Å, C46–H46···Cg2 with an
angle of 122.17° and an H···Cg2 distance of 3.161 Å, and
C19–H19···Cg3 with an angle of 171.87° and an H···Cg3
distance of 2.757 Å; see Table S.3.1 (Cg1 is the ring
centroid of the six-membered C25-38 ring, Cg2 of C25-
C30, and Cg3 of C1-C14; see Fig. 2 also). The amine-H
atom in 3d does not participate in hydrogen bonding
interactions. The inter-connection of molecules through
such weak bonding interactions leads to a supramolecular
sheet-like structure in the crystal lattice (Fig. S.3.1).
Meanwhile, compound 3e crystallized in orthorhombic
Pccn space group. The asymmetric unit consists of one
molecule of 3e as shown in Figure 2. The planes of the
anthracene and phenyl rings in this molecule make an
angle of 49° with each other. Structural analyses revealed
a number of weak bonding interactions in the crystal.
These include various C–H···Cl, N–H···N, and C–H···π
interactions (Table S.3.2). All these interactions stabilize
the crystal structure and lead to the formation of a
supramolecular arrangement as shown in Figure S.3.2.
Crystallographic data for the solved structures 3d and
3e were deposited to the Cambridge Crystallographic
Data Center as supplementary publication numbers
CCDC-1891026 and CCDC-1891027, respectively.
These data can be obtained free of charge from the
Cambridge Crystallographic Data Center via www.ccdc.
cam.ac.uk.
Biology. Anticancer activity. The anticancer activity of
the newly synthesized anthracenyl pyrazoline derivatives
(3a–o) was carried out against four human cancer cell
lines MCF-7 (breast cancer), SK-N-SH (neuroblastoma
cancer), HeLa (cervical cancer), and HepG2 (liver
cancer). Curcumin was used as a reference drug, and the
cell viability in the presence of test compounds was
measured by MTT (3-(4,5-dimethylthiazolyl-2)-2,5-
diphenyltetrazolium bromide) assay. The anticancer
Table 3
Anticancer inhibition values (IC50) of anthracenyl pyrazoline compounds (3a–o) on four human cell lines.
Anticancer activity (IC50; μM)
S. no.
Compounds
MCF-7
SK-N-SH
HeLa
HepG2
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
0.73
0.495
3.08
0.493
0.66
1.5
260.00
290.00
254.22
258.42
254.23
250.66
240.26
250.29
3.55
260.22
1.88
2.00
23.42
25.33
253.88
58.33
0.22
25.00
29.56
2.03
2.58
27.29
1.96
1.10
1.30
0.3
1.88
0.3
0.10
0.25
0.25
35.00
3.86
22.22
3.50
26.44
20.88
20.65
19.22
33.44
0.22
1.58
0.44
0.40
0.22
1.5
2.0
9
26.0
17.0
1.98
23.0
29.0
25.0
10
11
12
13
14
15
16
2.66
3.26
15.23
3o
Curcumin
2.50
50
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T. Merry, P. Maddela, K. Devaraya, A. K. Kondapi, and C. P. Pradeep
Vol 000
Figure 3. The survival curves of the human cancer cells (MCF-7 (a), SK-N-SH (b), HeLa (c), and HepG (d)) for anthracenyl pyrazoline compounds
(3a–o); curcumin was used as a positive control. [Color figure can be viewed at wileyonlinelibrary.com]
activity results revealed that compounds 3a, 3b, 3d, and 3e
exhibit a potential toxicity against MCF-7 cells (IC50: 0.73,
0.495, 0.493, and 0.66 μM) and 3i, 3k, and 3l showed a
good toxicity against SK-N-SH cells (IC50: 3.55, 1.88,
and 2.00 μM), whereas compounds 3a, 3j, 3l, 3m, 3n,
and 3o showed a highly potential toxicity against HeLa
cells (IC50: 0.22, 0.3, 0.3, 0.10, 0.25, and 0.25 μM) and
3i, 3k, 3l, and 3m showed a significant toxicity against
HepG2 cells (IC50: 0.22, 0.44, 0.40, and 0.22 μM)
(Table 3).
The overall anticancer activity screening results of the
anthracenyl pyrazoline compounds (3a–o) against four
human cancer cell lines demonstrate that the substitution
on phenyl ring showed marked effect on cytotoxic
activity. Index of nitrogen-containing groups and
electron-donating and electron-withdrawing groups on
phenyl ring led to enhanced anticancer activity apart from
SK-N-SH cell lines. The replacement of phenyl ring with
heterocyclic ring also shows good anticancer activity
against the MCF-7, HeLa, and HepG2 except for SK-N-
SH cell lines. The anticancer activity screening results
(IC50; μM) of compounds (3a–o) were represented in
Table 3, and percentage of cancer cells viability of four
cell lines were depicted in Figure 3.
A comparative analysis of results of the anticancer
activity shows a distinct properties of the target in three
cell lines with a common requirement of hydrophobic
methyl for interaction; thus, active site of target in MCF-
7 cells may have lower hydrophobic packet volume; thus,
–CH3 and –Cl could exhibit significant activity compared
with higher volume (–O–CH3) of the side chain. In
contrast, interacting target in HeLa cells possess larger
space facilitating interaction with two extended side
chains (–O–CH3) is symmetrically, while target in
HepG2 cell line is asymmetrically located to interact with
two –O–CH3 groups. In addition, polar oxygen may be
providing additional interactions in HeLa and HepG2,
while such interaction may be absent in MCF-7.
CONCLUSIONS
We have established and reported the Et3N-prompted
efficient synthesis of anthracenyl pyrazoline derivatives
(3a–o) and their anticancer activity. The present synthetic
protocol is quite simple, and obtained yields are good to
excellent as pure solids by simple filtration methods. The
single-crystal X-ray crystallographic structures show
Journal of Heterocyclic Chemistry
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Month 2019
Et3N-Prompted Efficient Synthesis of Anthracenyl Pyrazolines and Their
Cytotoxicity Evaluation against Cancer Cell Lines
intermolecular C–H···π interactions lead to the formation of
supramolecular sheet-like arrangement in 3d and C–H···Cl,
N–H···N, and C–H···π interactions in 3e. The anticancer
activity screening results revealed that compounds 3a,
3b, 3d, and 3e exhibit potential toxicity against MCF-7
cells and 3i, 3k, and 3l show significant toxicity against
SK-N-SH cells, whereas compounds 3a, 3j, 3l, 3m, 3n,
and 3o showed remarkable potential toxicity against
HeLa cells (IC50: 0.22, 0.3, 0.3, 0.10, 0.25, and 0.25 μM)
and 3i, 3k, 3l, and 3m showed highest toxicity against
HepG2 cells. In conclusion, the newly synthesized
anthracenyl pyrazoline derivatives were found to be a
more potent activity against cancer and some of them are
exclusively potent against breast cancer and cervical
cancer and have more scope to explore for further
investigations towards the clinical trials.
Nova diffractometer and equipped with multilayer optics,
monochromatic dual source (Cu and Mo), and Eos CCD
detector, using Mo-Kα (0.71073 Å) radiation at 293 K.
Data acquisition, reduction, and absorption correction
were performed by using CrysAlisPRO program.[17] The
structure was solved with ShelXS and refined on F2 by
full-matrix least-squares techniques using ShelXL
program provided in Olex2 (v.1.2) program package.
[18,19] Anisotropic displacement parameters were
applied for all the atoms, except hydrogen atoms. H
atoms were calculated into their positions or located from
the electron density map and refined as riding atoms
using isotropic displacement parameters. The data
collected for 3e were of poor quality, despite multiple
attempts of data collection. It exhibited relatively high R1
and wR2 values. The ratio of maximum/minimum
residual density was 2.24 in this case.
Biology and anticancer activity. Cytotoxicity of
compounds in cancer cell lines.
Cytotoxicity assay was
EXPERIMENTAL
performed with MTT in four human cancer cell lines
(MCF-7, SK-N-SH, HeLa, and HepG2 cells). Briefly,
cancer cell lines were grown in Dulbecco’s modified
Eagle media with 10% fetal bovine serum; approximately
0.02 × 106 cells were seeded in 100 μL of complete
media. After overnight incubation, cell viability was
determined by MTT reagent (5 mg/mL) assay. Test
compounds (3a–o) at different concentrations (25 and
250 nM and 2.5, 25, and 250 μM) were added and
incubated for a period of 48 h in cell culture incubator at
37°C. At the end of the treatment, the medium was
removed, and the cells were washed with 1 × phosphate-
buffered saline, and 20 μL of MTT was added to each
well and incubated for 4 h in cell culture incubator.
Finally, 200 μL of dimethyl sulfoxide was added to all
the wells, and plate was gently swirled and kept in dark
for 2 h at room temperature. Absorbance was measured
at 570 nm in a microtiter plate reader and compared with
that of the wells in which the drug is omitted (control).
Curcumin was used as a positive control. Each assay was
repeated at least three times and in triplicates. The IC50
(concentration of 50% inhibition) value was calculated
using Microsoft Excel sheet. All compounds were
showed potential anticancer activity (Fig. 3).
Chemistry, materials, and methods.
All the reagents
and solvents were purchased from commercially available
sources and used without further purification. Melting
points were recorded in open capillaries using IKON
melting point apparatus and are uncorrected. Fourier
transform infrared spectra of the compounds were
recorded on Perkin-Elmer spectrophotometer (Spectrum-
Two) using KBr disk, and values are expressed in cmÀ1
.
1H-NMR and 13C-NMR spectra for the compounds were
recorded using Bruker 300 MHz spectrometer in CDCl3
as a solvent and tetramethylsilane as an internal standard;
values are given in parts per million (ppm). Mass spectra
for the compounds were recorded on PE Sciex API 2000
system. Microanalytical (CHN) data were obtained with a
FLASH EA 1112 Series CHNS analyzer. Progress of the
reactions was monitored by TLC with silica gel plates
(Merck) using ethyl acetate and n-hexane (3:7) as a
solvent system and visualized under UV-light/iodine
vapors.
General procedure for the synthesis of anthracenyl
pyrazoline (3a). To a stirred solution of corresponding
anthracenyl chalcone (1a) (0.220 g, 1 mmol), hydrazine
hydrate (2) (0.500 g, 10 mmol) was added Et3N (10 mol
%) in ethanol (5 mL). The reaction mixture was refluxed
for 24 h with continuous stirring. After completion of the
reaction monitored by TLC, the solvent was removed and
added ice-cold water. The pure solid product anthracenyl
pyrazoline (3a) was collected by filtration, washed with
water (three to four times) and finally with 50% ethanol,
and dried. The same synthetic protocol was followed for
the synthesis of all other anthracenyl pyrazoline
Spectral
characterization
data. 3-Anthracen-9-yl-5-
phenyl-4,5-dihydro-1H-pyrazole (3a). Yellow solid. Yield:
96%. mp 94–97°C. IR (KBr) cmÀ1 3052.66 (Aromatic
C–H), 3336.68 (NH) and 1590.63 (C═N). 1H-NMR
(300 MHz, CDCl3) δ (ppm): 8.47 (s, 1H, Ar–H), 8.03–
8.01 (t, Hz, 4H, Ar–H), 7.60–7.57 (d, J = 7.38 Hz, 2H,
Ar–H), 7.48–7.45 (m, 6H, Ar–H), 7.39–7.36 (d,
J = 7.25 Hz, 1H, Ar–H), 6.41 (s, 1H, –NH), 5.29–5.23 (t,
1H, –CH), 3.62–3.53 (dd, 1H, –CH2), 3.23–3.14 (dd, 1H,
–CH2). 13C-NMR (300 MHz, CDCl3) δ (ppm): 151.54,
142.22, 134.14, 131.43, 130.24, 128.99, 128.76, 128.05,
derivatives (3a–o) (Scheme 1 and Fig. 1).
X-ray crystallography. Single-crystal X-ray diffraction
data of 3d and 3e were collected on an Agilent Super
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127.88, 127.67, 127.25, 126.54, 126.31, 125.38, 64.87,
47.62. MS (m/z): 323.2 (M+1). Elemental Anal. Calcd for
C23H18N2: C, 77.41; H, 4.80; N, 7.85. Found: C, 77.32;
5H, Ar–H), 6.76–6.73 (d, J = 8.16 Hz, 1H, Ar–H), 6.56–
6.48 (t, 1H, –NH), 5.35–5.10 (tt, 1H, –CH), 3.73–3.44
(m, 1H, –CH2), 3.18–3.04 (m, 1H, –CH2). 13C-NMR
(300 MHz, CDCl3) δ: 151.34, 149.48, 131.34, 130.08,
128.85, 128.70, 128.29, 127.53, 127.45, 126.50, 126.25,
125.45, 125.00, 124.01, 115.45, 64.16, 47.60. MS (m/z):
356.9 (M+). Elemental Anal. Calcd for C23H17N2Cl: C,
H, 4.85; N, 7.79.
3-Anthracen-9-yl-5-(4-chloro-phenyl)-4,5-dihydro-1H-
pyrazole (3b). Yellow solid. Yield: 95%. mp 50–53°C. IR
(KBr) cmÀ1 3052 (Aromatic C–H), 3343.44 (NH) and
1
1591.30 (C═N). H-NMR (300 MHz, CDCl3) δ (ppm):
77.41; H, 4.80; N, 7.85. Found: C, 77.32; H, 4.86; N, 7.81.
3-Anthracen-9-yl-5-(4-nitro-phenyl)-4,5-dihydro-1H-
8.48 (s, 1H, Ar–H), 8.01–8.00 (d, J = 3.46 Hz, 4H, Ar–
H), 7.53–7.40 (m, 8H, Ar–H), 6.37 (s, 1H, –NH), 5.26–
5.19 (t, 1H, –CH), 3.60–3.51 (dd, 1H, –CH2), 3.16–3.07
(dd, 1H, –CH2). 13C-NMR (300 MHz, CDCl3) δ (ppm):
151.56, 140.63, 133.54, 131.41, 130.18, 129.07, 128.82,
128.16, 128.01, 127.37, 126.41, 125.42, 125.22, 64.31,
47.65. MS (m/z): 357.0 (M+1). Elemental Anal. Calcd for
C23H17N2Cl: C, 85.68; H, 5.63; N, 8.69. Found: C,
pyrazole (3f). Yellow solid. Yield: 97%. mp 67–70°C. IR
(KBr) cmÀ1 3053.73 (Aromatic C–H), 3324.08 (NH), and
1
1591.85 (C═N). H-NMR (300 MHz, CDCl3) δ: 8.47 (s,
1H, Ar–H), 8.02–7.99 (t, 4H, Ar–H), 7.60 (s, 1H, Ar–H),
7.49–7.31 (m, 7H, Ar–H), 6.37 (s, 1H, –NH), 5.25–5.18
(t, 1H, –CH), 3.60–3.51 (dd, 1H, –CH2), 3.16–3.07 (dd,
1H, –CH2). 13C-NMR (300 MHz, CDCl3) δ: 151.51,
144.32, 134.86, 131.42, 130.27, 128.82, 128.17, 128.02,
126.87, 126.43, 125.44, 125.26, 124.81, 64.45, 47.61.
MS (m/z): 367.1 (M+). Elemental Anal. Calcd for
C23H17N3O2: C, 75.19; H, 4.66; N, 11.44. Found: C,
85.52; H, 5.68; N, 8.61.
3-Anthracen-9-yl-5-(4-fluoro-phenyl)-4,5-dihydro-1H-
pyrazole (3c). Yellow solid. Yield: 94%. mp 76–79°C. IR
(KBr) cmÀ1 3053.99 (Aromatic C–H), 3342.95 (NH) and
1
1600.83 (C═N). H-NMR (300 MHz, CDCl3) δ: 8.48 (s,
75.24; H, 4.71; N, 11.32.
1H, Ar–H), 8.02–8.00 (t, Hz, 4H, Ar–H), 7.57–7.46
(m, 6H, Ar–H), 7.16–7.10 (t, 2H, Ar–H), 5.27–5.21 (t,
1H, –CH), 3.59–3.50 (dd, 1H, –CH2), 3.17–3.08 (dd, 1H,
–CH2) ppm. 13C-NMR (300 MHz, CDCl3) δ: 151.69,
137.83, 134.23, 131.46, 128.85, 128.33, 128.22, 128.18,
126.42, 125.46, 125.28, 116.00, 115.71, 64.37,
47.77 ppm. MS (m/z): 341.1 (M+1). Elemental Anal.
Calcd for C23H17N2F: C, 81.16; H, 5.03; N, 8.23. Found:
3-Anthracen-9-yl-5-(4-bromo-phenyl)-4,5-dihydro-1H-
pyrazole (3g). Yellow solid. Yield: 94%. mp 57–59°C. IR
(KBr) cmÀ1 3052.47 (Aromatic C–H), 3343.23 (NH), and
1
1589.42 (C═N). H-NMR (300 MHz, CDCl3) δ: 8.47 (s,
1H, Ar–H), 8.00–7.99 (d, J = 3.16 Hz, 4H, Ar–H), 7.57–
7.43 (m, 8H, Ar–H), 6.37 (s, 1H, –NH), 5.23–5.16 (t,
1H, –CH), 3.58–3.49 (dd, 1H, –CH2), 3.14–3.05 (dd, 1H,
–CH2). 13C-NMR (300 MHz, CDCl3) δ: 151.56, 141.13,
132.00, 131.38, 130.14, 128.81, 128.34, 128.16, 127.27,
126.40, 125.40, 125.18, 121.60, 64.31, 47.59. MS (m/z):
402.0 (M+1). Elemental Anal. Calcd for C23H17N2Br: C,
C, 81.26; H, 5.09; N, 8.27.
3-Anthracen-9-yl-5-p-tolyl-4,5-dihydro-1H-pyrazole (3d).
Yellow color single crystals were obtained from
methanol solution on slow evaporation at room
temperature. Yield: 96%. mp 123–125°C. IR (KBr) cmÀ1
30544.09 (Aromatic C–H), 3326.74 (NH), and
1589.75 (C═N). 1H-NMR (300 MHz, CDCl3) δ: 8.47
(s, 1H, Ar–H), 8.03–8.02 (d, J = 2.03 Hz, 4H, Ar–H),
7.48–7.46 (t, 6H, Ar–H), 7.27–7.25 (d, J = 6.92 Hz,
2H, Ar–H), 6.34 (s, 1H, –NH), 5.25–5.19 (t, 1H, –CH),
3.59–3.50 (dd, 1H, –CH2), 3.20–3.12 (dd, 1H, –CH2),
2.40 (s, 3H, Ar–CH3) ppm. 13C-NMR (300 MHz, CDCl3)
δ: 151.58, 139.29, 137.65, 131.49, 130.30, 129.69,
128.79, 128.03, 127.86, 126.53, 126.31, 125.47, 125.41,
64.78, 47.68, 21.27 ppm. MS (m/z): 337.1 (M+1).
Elemental Anal. Calcd for C24H20N2: C, 85.68; H, 5.99;
68.84; H, 4.27; N, 6.98. Found: C, 68.75; H, 4.31; N, 6.92.
3-Anthracen-9-yl-5-(3-fluoro-phenyl)-4,5-dihydro-1H-
pyrazole (3h). Brown solid. Yield: 93%. mp 86–89°C. IR
(KBr) cmÀ1 3055.58 (Aromatic C–H), 3328.34 (NH), and
1
1587.74 (C═N). H-NMR (300 MHz, CDCl3) δ: 8.47 (s,
1H, Ar–H), 8.02–7.99 (t, 4H, Ar–H), 7.48–7.02 (m, 8H,
Ar–H), 6.37 (s, 1H, –NH), 5.27–5.20 (t, 1H, –CH), 3.60–
3.51 (dd, 1H, –CH2), 3.17–3.08 (dd, 1H, –CH2). 13C-
NMR (300 MHz, CDCl3) δ: 151.51, 131.40, 130.57,
130.46, 130.19, 128.79, 128.13, 126.39, 125.40, 125.23,
122.24, 114.88, 114.60, 113.75, 113.46, 64.44, 47.62.
MS (m/z): 341.1 (M+1). Elemental Anal. Calcd for
C23H17N2F: C, 81.16; H, 5.03; N, 8.23. Found: C, 81.23;
H, 5.08; N, 8.29.
N, 8.33. Found: C, 85.56; H, 5.91; N, 8.27.
3-Anthracen-9-yl-5-(3-chloro-phenyl)-4,5-dihydro-1H-
3-Anthracen-9-yl-5-(3-nitro-phenyl)-4,5-dihydro-1H-
pyrazole (3i). Yellow solid. Yield: 95%. mp 73–75°C. IR
pyrazole (3e). Brown color single crystals were obtained
from recrystallization in acetonitrile solution on slow
evaporation at room temperature. Yield: 90%. mp 104–
106°C. IR (KBr) cmÀ1 3053.07 (Aromatic C–H),
(KBr) cmÀ1 3049.76 (Aromatic C–H), 3339.50 (NH),
1
and 1589.69 (C═N). H-NMR (300 MHz, CDCl3) δ: 8.47
(s, 1H, Ar–H), 8.03–8.02 (d, J = 3.14 Hz, 4H, Ar–H),
7.48–7.45 (q, 5H, Ar–H), 7.25–7.19 (t, 2H, Ar–H), 7.25–
7.19 (t, 2H, Ar–H), 6.33 (s, 1H, –NH), 5.18–5.12 (t, 1H,
–CH), 3.58–3.49 (dd, 1H, –CH2), 3.21–3.13 (dd, 1H, –
CH2). 13C-NMR (300 MHz, CDCl3) δ: 151.73, 147.10,
1
3343.93 (NH), and 1587.78 (C═N). H-NMR (300 MHz,
CDCl3) δ: 8.48–8.45 (d, J = 8.69 Hz, 1H, Ar–H), 8.28–
8.25 (d, J = 8.59 Hz, 1H, Ar–H), 8.02–7.97 (m, 4H, Ar–
H), 7.74–7.72 (d, J = 8.46 Hz, 1H, Ar–H), 7.50–7.33 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Et3N-Prompted Efficient Synthesis of Anthracenyl Pyrazolines and Their
Cytotoxicity Evaluation against Cancer Cell Lines
143.62, 131.45, 130.27, 129.98, 128.77, 128.50, 128.03,
126.31, 126.15, 125.41, 116.61, 114.56, 112.89, 64.85,
47.52. MS (m/z): 367.3 (M+). Elemental Anal. Calcd for
C23H17N3O2: C, 75.19; H, 4.66; N, 11.44. Found: C,
134.96, 131.49, 130.30, 128.84, 128.58, 128.28, 128.11,
126.52, 126.35, 126.05, 125.67, 125.44, 118.78, 111.46,
109.36, 64.73, 56.12, 47.74. MS (m/z): 383.1 (M+1).
Elemental Anal. Calcd for C25H22N2O2: C, 78.51; H,
75.26; H, 4.59; N, 11.51.
5.80; N, 7.32. Found: C, 78.39; H, 5.75; N, 7.38.
3-Anthracen-9-yl-5-(4-methoxy-phenyl)-4,5-dihydro-1H-
pyrazole (3n). Yellow solid. Yield: 94%. mp 103–105°C.
[4-(5-Anthracen-9-yl-3,4-dihydro-2H-pyrazol-3-yl)-phenyl]-
dimethyl-amine (3j). Orange solid. Yield: 93%. mp 114–
116°C. IR (KBr) cmÀ1 3048.31 (Aromatic C–H),
IR (KBr) cmÀ1 3052.61 (Aromatic C–H), 3299.86 (NH),
1
1
3297.26 (NH), and 1588.02 (C═N). H-NMR (300 MHz,
and 1581.20 (C═N). H-NMR (300 MHz, CDCl3) δ: 8.47
CDCl3) δ: 8.51–8.47 (d, J = 12.45 Hz, 1H, Ar–H), 8.08–
7.94 (m, 4H, Ar–H), 7.48–7.44 (m, 5H, Ar–H), 7.32–
7.25 (t, 2H, Ar–H), 6.83–6.80 (d, J = 8.56, 1H, Ar–
H), 6.60–6.57 (d, J = 8.75, 1H, Ar–H), 5.21–5.14 (t,
1H, –CH), 3.55–3.46 (dd, 1H, –CH2), 3.22–3.13 (dd, 1H,
–CH2), 2.99 (s, 6H, Ar-N (CH3)2). 13C-NMR (300 MHz,
CDCl3) δ: 151.37, 149.38, 130.76, 128.74, 128.58,
127.92, 127.43, 126.38, 125.81, 125.50, 124.42, 112.96,
111.78, 64.65, 47.54, 40.79, 40.13. MS (m/z): 366.1 (M
+1). Elemental Anal. Calcd for C25H23N3: C, 82.16; H,
(s, 1H, Ar–H), 8.02–7.99 (d, J = 7.35 Hz, 4H, Ar–H),
7.51–7.45 (m, 6H, Ar–H), 6.99–6.96 (d, J = 8.53 Hz, 2H,
Ar–H), 5.24–5.17 (t, 1H, –CH), 3.84 (s, 3H, Ar–CH3),
3.56–3.47 (dd, 1H, –CH2), 3.19–3.10 (dd, 1H, –CH2).
13C-NMR (300 MHz, CDCl3) δ: 159.26, 151.53, 134.11,
131.40, 130.20, 128.73, 127.96, 127.82, 127.68, 126.26,
125.39, 125.35, 114.28, 64.43, 55.40, 47.57. MS (m/z):
353.1 (M+1). Elemental Anal. Calcd for C24H20N2O: C,
81.79; H, 5.72; N, 7.95. Found: C, 81.66; H, 5.67; N, 7.89.
4-(5-Anthracen-9-yl-3,4-dihydro-2H-pyrazol-3-yl)-pyridine
(3o). Brown solid. Yield: 90%. mp 57–60°C. IR (KBr)
6.34; N, 11.50. Found: C, 82.25; H, 6.38; N, 11.43.
3-Anthracen-9-yl-5-furan-2-yl-4,5-dihydro-1H-pyrazole
(3k). Yellow solid. Yield: 90%. mp 56–58°C. IR (KBr)
cmÀ1 3053.10 (Aromatic C–H), 3412.73 (NH), and
1599.03 (C═N). 1H-NMR (300 MHz, CDCl3) δ: 8.64–863
(d, J = 4.34 Hz, 2H, Ar–H), 8.48 (s, 1H, Ar–H), 8.05–7.94
(m, 3H, Ar–H), 7.80–7.79 (d, J = 4.89 Hz, 1H, Ar–H),
7.49–7.46 (q, 6H, Ar–H), 6.43 (s, 1H, –NH), 5.25–5.18 (t,
1H, –CH), 3.65–3.56 (dd, 1H, –CH2), 3.15–3.06 (dd, 1H,
–CH2). 13C-NMR (300 MHz, CDCl3) δ: 151.36, 150.18,
134.17, 131.37, 130.13, 128.86, 128.58, 128.32, 126.51,
125.45, 125.01, 121.72, 63.64, 47.26. MS (m/z): 324.2 (M
+1). Elemental Anal. Calcd for C22H17N3: C, 81.71; H,
5.30; N, 12.99. Found: C, 81.65; H, 5.36; N, 12.89.
cmÀ1 3053.20 (Aromatic C–H), 3410.42 (NH), and
1
1586.72 (C═N). H-NMR (300 MHz, CDCl3) δ: 8.49–
8.43 (d, J = 17.51 Hz, 1H, Ar–H), 8.02–8.01 (d,
J = 3.12 Hz, 4H, Ar–H), 7.50–7.46 (m, 7H, Ar–H),
6.43–6.41 (d, J = 4.11 Hz, 1H, –NH), 5.25–5.19 (q,
1H, –CH), 3.77–3.70 (m, 1H, –CH2), 3.58–3.47 (m, 1H,
–CH2). 13C-NMR (300 MHz, CDCl3) δ: 151.38, 142.64,
134.22, 131.10, 128.87, 128.76, 126.86, 126.37, 125.59,
125.45, 124.54, 110.55, 106.51, 57.48, 43.71. MS (m/z):
313.0 (M+1). Elemental Anal. Calcd for C21H16N2O: C,
80.75; H, 5.16; N, 8.97. Found: C, 80.65; H, 5.19; N,
8.91.
Acknowledgments. Dr. Prabhakar M. highly acknowledges the
SERB-DST, Govt. India, for the financial support (grant no.
SB/EMEQ-030/2014) towards his research work. Thechano M.
thanks the SERB-DST for the financial support and UGC, India,
for NFHE. We thank Nagaland University, University of Hyder-
abad, and IIT-Mandi for the instrumental facilities.
3-Anthracen-9-yl-5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-
1H-pyrazole (3l). Yellow solid. Yield: 95%. mp 62–64°C.
IR (KBr) cmÀ1 3053.05 (Aromatic C–H), 3333.35 (NH),
1
and 1590.28 (C═N). H-NMR (300 MHz, CDCl3) δ: 8.48
(s, 1H, Ar–H), 8.06–8.01 (q, 4H, Ar–H), 7.48–7.45 (q,
4H, Ar–H), 6.80 (s, 2H, Ar–H), 5.22–5.15 (t, 1H, –CH),
3.95–3.89 (t, 9H, Ar–OCH3), 3.62–3.53 (dd, 1H, –CH2),
3.23–3.14 (dd, 1H, –CH2). 13C-NMR (300 MHz, CDCl3)
δ: 153.77, 151.68, 138.29, 134.20, 131.46, 130.28,
128.86, 128.15, 127.30, 126.33, 125.43, 125.33, 103.26,
65.06, 61.03, 56.34, 47.75. MS (m/z): 413.0 (M+1).
Elemental Anal. Calcd for C26H24N2O3: C, 75.71; H,
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet