An expedient, one-pot, stepwise sequential approach for the regioselective synthesis of pyrazolines

Article abstract of DOI:10.1177/1747519820977165

An efficient approach for the synthesis of pyrazoline/pyrazole-tethered pyridinyl methanones is described via a one-pot, stepwise, sequential methodology using chalcones and pyridine-4-carbohydrazide as substrates through a Michael addition followed by cy

Full text of DOI:10.1177/1747519820977165

977165CHL0010.1177/1747519820977165Journal of Chemical ResearchGanesan et al.
research-article2020
Research Paper
Journal of Chemical Research
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An expedient, one-pot, stepwise
sequential approach for the
regioselective synthesis of pyrazolines
https://doi.org/10.1177/1747519820977165
DOI: 10.1177/1747519820977165
journals.sagepub.com/home/chl
Suresh Ganesan1, Muniraj Sarangapani1
and Mukesh Doble2
Abstract
An efficient approach for the synthesis of pyrazoline/pyrazole-tethered pyridinyl methanones is described via a one-
pot, stepwise, sequential methodology using chalcones and pyridine-4-carbohydrazide as substrates through a Michael
addition followed by cyclization. The reaction proceeds via a catalyst-, solvent-, work-up-, and column-chromatography-
free method under melt conditions to provide the pyrazolines in short reaction times with high atom efficiency.
Keywords
chalcones, domino cyclization, ısoniazid, Michael addition, pyrazoline
Date received: 22 February 2020; accepted: 9 November 2020
An efficient construction of pyrazoline-based pyridinyl frameworks through Michael addition mediated domino cyclization
of chalcones with hydrazides. The two-step procedure generates four new C–C, C=C, C–N, and C=N bonds with
regioselectivity and high atom efficiency in excellent yields. Interestingly, the accomplishment of this reaction under melt
condition, the catalyst-, solvent-free synthesis in short time provided excellent yields is highly impressive.
Introduction
The synthesis of nitrogen-containing heterocyclic mole-
1Department of Chemistry, Ramakrishna Mission Vivekananda College,
cules through catalyst-, solvent-, and column-chromatogra-
phy-free conditions via melt-mediated reactions1 in the
solid state is very useful.2,3 Chalcones and pyridine-4-car-
bohydrazide (known as isoniazid) possess significant
medicinal properties4,5 and isoniazid is a valuable drug for
tuberculosis (TB).6 Pyrazoles exhibit a range of potent
activities such as antibacterial, antifungal,7 antidiabetic,8
and anti-inflammatory9 behavior, and are also active against
many mycobacteria.10,11 Examples of biologically active
chalcones, pyridine-4-carbohydrazides, and pyrazoline/
pyrazole motifs12–15 are shown in Figure 1. α,β-Unsaturated
Chennai, India
2Department of Biotechnology, Indian Institute of Technology Madras,
Chennai, India
Corresponding authors:
Muniraj Sarangapani, Department of Chemistry, Ramakrishna Mission
Vivekananda College, Mylapore, Chennai 600004, Tamil Nadu, India.
Email: smuniraj@rkmvc.ac.in
Mukesh Doble, Department of Biotechnology, Indian Institute of
Technology Madras, Chennai 600036, Tamil Nadu, India.
Email: mukeshd@iitm.ac.in
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Journal of Chemical Research 00(0)
Figure 1. Representative examples of chalcone-, isoniazid-, pyrazoline- and pyrazole unit comprising potential molecules.
carbonyl compounds, such as chalcones, are particularly that the use of meta-/para-substituted chalcones gives ben-
useful for their medicinal applications due to their easy zodiazepines rather than imidazoles.29 Owing to the presence
synthesis and wide-ranging pharmacological applications of the o-benzyl unit in chalcone 3m, steric hindrance may be
against many human diseases such as TB,16 cancer, and the reason for the failure to obtain benzodiazepine 7.
HIV.17,18 Significantly, the design of new drugs containing
In order to extend the applicability of the reaction, the
diverse pharmacophores in a single molecular scaffold may pyrazolines 5g–l were treated with FeCl3 in acetic acid
lead to new hybrid compounds with interesting biological which resulted in oxidation leading to the corresponding
profiles. By implementing this strategy, several research pyrazoles 8a–f (Table 2).
groups have developed numerous hybrid molecules by cou-
The structures of the compounds 5m and 6 were con-
pling chalcones with various bioactive molecules.19–22 firmed by single-crystal X-ray analysis (Figure 2). The spa-
Based on this approach, we have constructed pyrazolyl- tial orientations of the substituents present on the pyrazole
tethered (pyridin-4-yl)methanones that have both pyridinyl ring were established from the single-crystal X-ray diffrac-
and pyrazolyl motifs in a single molecular framework that tion (XRD) analysis of these pyrazoline and imidazole
may have biological significance.23
derivatives (5m and 6), and their Cambridge Crystallographic
Thus, we envisaged synthesizing the pyrazole-based Data Centre (CCDC) numbers are 1586980 and 1586981,
compounds by a Michael addition initiated domino cycliza- respectively.
tion. In continuation of our preliminary research studies24–27
and inspired by the efficient synthetic protocol accom-
Conclusion
plished by the Bakthadoss Research Group involving a
solid-state melt reaction (SSMR),2,3 we have utilized the
We have successfully constructed pyrazolines and pyrazoles
aforementioned SSMR protocol for the synthesis of pyra-
zole-containing molecules.
in a one-pot, stepwise approach with high regioselectivity.
Some of the notable features are as follows: (1) the reaction
creates new C–C, C=C, C–N, and C=N bonds in a unique
fashion through a domino process that includes a Michael
addition followed by a cyclization; (2) the reactions proceed
under eco-friendly, solvent-free reaction conditions via a
work-up-, catalyst-, chromatography-free method that pro-
vides excellent yields in short reaction times; (3) this protocol
provides the opportunity for the synthesis of libraries of tri-
substituted pyrazol(in)es with high atom efficiency (>96%);
and (4) the structures of the newly synthesized molecules
have been characterized by IR, NMR, and mass spectrometry,
and by single-crystal X-ray analyses. These pyrazoline/pyra-
zole products are currently undergoing biological screening.
Results and discussion
Thus, we combined the substituted chalcone 3 (1 mmol)
synthesized from various aldehydes and acetophenones and
isoniazid 4a (1 mmol) through a Michael addition mediated
cyclization.
Chalcones 3a–l and isoniazid 4a were ground thoroughly
in a round-bottom flask and allowed to melt at 160 to 180 °C
for 30 to 45min; this procedure led to the required products
5a–l in excellent yields (92%–98%). The isolated yields of
the products are given in Table 1. In order to extend the sub-
strate scope of the reaction, we also reacted isoniazid (4a) in
a melt with o-benzylated chalcone 3m at 170 °C for 45min,
which led to the pyrazoline 5m in 93% yield (Scheme 1).
We then decided to broaden the ring size, so we reacted
o-phenylenediamine (OPDA) (4b) in a melt at 200 °C for
45min with 3m. Unfortunately, the reaction was unsuccess-
ful in providing the expected product 7 and the imidazole 6
was obtained instead (Scheme 1).An earlier report28 revealed
Experimental
Materials and methods
All reagents and chemicals were obtained from Sigma-
Aldrich (St. Louis, MO, USA) and Merck (Bangalore,
Karnataka, India).

Ganesan et al.
3
Table 1. Synthesis of pyrazolines 5a–l from chalcone derivatives 3a–l.
Entry
1
Chalcone
Pyrazoline producta
Yield (%)b
96
3a
3b
3c
3d
5a
5b
5c
5d
2
3
4
92
94
96
5
6
92
90
3e
3f
5e
5f
7
8
9
95
97
96
3g
3h
3i
5g
5h
5i
(Continued)

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Journal of Chemical Research 00(0)
Table 1. (Continued)
Entry
Chalcone
Pyrazoline producta
Yield (%)b
10
11
12
95
96
98
3j
5j
3k
3l
5k
5l
aAll products were fully characterized by spectroscopic analysis.
bIsolated yields of pure products.
Scheme 1. Synthesis of 5m and 6 from 3m.
precipitate was filtered, and the crude sample was washed
with hot ethanol and dried.24,25
Physical and chemical characterization
A Perkin Elmer fourier transform infrared spectroscopy
(FTIR) (4000-400 cm−1) instrument was used to record the
1
IR spectra as KBr pellets. H and 13C NMR spectra were
Synthesis of isoniazid-containing
pyrazoline 5a: Typical procedure
obtained at 500 and 125 MHz (BRUKER AV-ΙΙΙ, fourier-
transform nuclear magnetic resonance (FT-NMR) spec-
trometer) using CDCl3 as the solvent and tetramethylsilane
(TMS) as an internal standard. The DEPT135 spectrum was
recorded in a standard manner (θ = 135 pulse program).
Mass spectra were recorded on a Thermo Scientific Orbitrap
Elite mass spectrometer. The XRD studies were conducted
on a Bruker Kappa APE XII diffractometer. Thin-layer
chromatography (TLC) was performed using pre-coated
silica gel sheets, and the spots were observed by ultraviolet
(UV) and iodine vapor absorption.
A mixture of substituted chalcone 3a (0.298 g, 1 mmole)
and pyridine-4-carboxylic acid hydrazide 4 (0.137 g, 1
mmol) in a round-bottomed flask was ground thoroughly to
make a homogeneous solid that was allowed to melt at 160
°C for 30min. After cooling, the crude mass was washed
with EtOAc/hexane mixture (1:3) to give the product 5a in
96% yield.30
Synthesis of isoniazid-containing pyrazole
8a
A solution of the pyrazoline 5e (1 mmol), ferric chloride
(0.2 mmol, 2 mol%), and acetic acid (10 mL) was stirred at
room temperature. The formation of the pyrazole was mon-
itored by TLC, and the reaction mixture was quenched with
aqueous NaHCO3 (30 mL). The reaction mixture was then
extracted with CHCl3. The organic phase was dried and
Synthesis of chalcones 3a
The aldehyde (1 mmol) and substituted acetophenone (1
mmol) were dissolved in ethanol (20 mL) in the presence of
40% NaOH. The reaction mixture was stirred at room tem-
perature for 4 h and neutralized with 1N HCl. The resulting

Ganesan et al.
5
Table 2. Synthesis of pyrazole derivatives 8a–f from pyrazolines 5e–j.
Entry
1
Pyrazoline
Pyrazole producta
Time (h)
Yield (%)b
4
81
82
82
85
83
85
5e
5f
8a
8b
8c
8d
8e
8f
2
3
4
5
6
4
3
2
3
2
5g
5h
5i
5j
aAll products were fully characterized by spectroscopic analysis.
bIsolated yields of pure products.
concentrated under reduced pressure to provide the pyra- (5-(4-(methylthio)phenyl)-3-(3-nitrophenyl)-4,5-dihydro-1H-pyr-
zole31 8a in good yield.
azol-1-yl)(pyridin-4-yl)methanone (5b). Mp = 153–154 °C;
Rf = 0.27 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 3043,
(3-(4-ethoxyphenyl)-5-(4-(methylthio)phenyl)-4,5-dihydro- 2919, 1663, 1532; 1H NMR (500 MHz, CDCl3) δ 8.81 (d, J
1H-pyrazol-1-yl)(pyridin-4-yl)methanone (5a). Mp = 145– = 6.0 Hz, 2H), 8.44 (t, J = 1.8 Hz, 1H), 8.32 (ddd, J1,2,3
=
146 °C; Rf = 0.40 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 8.2, 2.1, 0.8 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.89 (d, J =
1
3042, 2974, 2924, 1649; H NMR (500 MHz, CDCl3) δ 5.7 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 9.6 Hz,
8.76 (d, J = 6.1 Hz, 2H), 7.86 (d, J = 6.0 Hz, 2H), 7.65 4H), 5.84 (dd, J1,2 = 11.8, 5.0 Hz, 1H), 3.91 (dd, J1,2
=
(d, J = 8.8 Hz, 2H), 7.28 (d, J = 9.8 Hz, 2H), 7.26 (d, J 17.9, 11.8 Hz, 1H), 3.33 (dd, J1,2 = 17.9, 5.1 Hz, 1H), 2.48
= 2.2 Hz, 2H), 6.97 – 6.92 (m, 2H), 5.75 (dd, J1,2 = 11.6, (s, 3H); 13C NMR (126 MHz, CDCl3) δ 164.08, 154.03,
4.7 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 3.80 (dd, J1,2
=
148.62, 142.54, 138.99, 137.18, 132.53, 132.21, 130.14,
17.6, 11.6 Hz, 1H), 3.23 (dd, J1,2 = 14.0, 3.6 Hz, 1H), 130.06, 127.19, 126.25, 125.26, 124.02, 121.71, 61.32,
2.48 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H); 13C NMR (126 41.59, 15.71; HRMS (ESI): m/z [M]+1 calculated for
MHz, CDCl3) δ 161.17, 156.74, 149.67, 141.81, 138.26, C22H18N4O3S: 418.1100; found: 419.1187.
138.06, 128.52, 127.19, 126.35, 123.75, 122.53, 117.82,
114.76, 63.71, 60.76, 41.68, 15.94, 14.69; HRMS (ESI): (3-(4-fluorophenyl)-5-(4-(methylthio)phenyl)-4,5-dihydro-
m/z [M]+ calculated for C24H23N3O2S: 417.1511; found: 1H-pyrazol-1-yl)(pyridin-4-yl)methanone (5c). Mp = 156–
417.1540.
157 °C; Rf = 0.44 (hexane/EtOAc, 1:1); IR (KBr, cm−1):

6
Journal of Chemical Research 00(0)
Figure 2. ORTEP diagrams of compounds 5m and 6.
3034, 2993, 2946, 2921, 1644, 1328; 1H NMR (500 MHz,
CDCl3) δ 8.77 (d, J = 5.8 Hz, 2H), 7.86 (d, J = 5.8 Hz,
2H), 7.73 – 7.68 (m, 2H), 7.29 – 7.23 (m, 4H), 7.16 – 7.11
101.26, 61.18, 41.85; HRMS (ESI): m/z [M]+1 calculated
for C22H16FN3O3: 389.1176; found: 390.1251.
(m, 2H), 5.77 (dd, J1,2 = 11.7, 4.9 Hz, 1H), 3.82 (dd, J1,2
17.8, 11.7 Hz, 1H), 3.24 (dd, J1,2 = 17.8, 4.9 Hz, 1H), 2.47
(s, 3H); 13C NMR (126 MHz, CDCl3) δ 164.28 (1JC–F
253.2 Hz), 163.98, 163.28, 155.11, 149.07, 142.30, 138.59,
=
(5-(benzo[d][1,3]dioxol-5-yl)-3-(3-nitrophenyl)-4,5-dihydro-1H-
pyrazol-1-yl)(pyridin-4-yl)methanone (5f). Mp = 132–133 °C;
Rf = 0.29 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 3055,
3028, 2928, 1770, 1644, 1527; 1H NMR (500 MHz, CDCl3)
δ 8.81 (d, J = 5.5 Hz, 2H), 8.43 (s, 1H), 8.35 – 8.30 (m,
1H), 8.10 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 5.0 Hz, 2H),
7.66 (t, J = 8.0 Hz, 1H), 6.87 – 6.76 (m, 3H), 5.97 (s, 2H),
5.80 (dd, J1,2 = 11.7, 4.9 Hz, 1H), 3.89 (dd, J1,2 = 17.9,
11.8 Hz, 1H), 3.32 (dd, J1,2 = 17.9, 5.0 Hz, 1H); 13C NMR
(126 MHz, CDCl3) δ 164.10, 154.00, 148.62, 148.43,
147.62, 142.58, 134.40, 132.55, 132.19, 130.25, 130.05,
125.25, 124.02, 121.71, 119.41, 108.78, 105.91, 101.36,
61.53, 41.74; HRMS (ESI): m/z [M]+1 calculated for
C22H16N4O5: 416.1121; found: 417.1198.
=
137.75, 128.93 (3JC–F = 8.8 Hz),127.16, 127.05 (4JC–F
=
2.52 Hz), 126.31, 123.89, 116.12 (2JC–F = 22.6 Hz), 116.03,
60.99, 41.72; HRMS (ESI): m/z [M]+ calculated for
C22H18FN3OS: 391.1155; found: 391.1180.
(3-(3,4-dimethoxyphenyl)-5-(4-(methylthio)phenyl)-4,5-dihydro-
1H-pyrazol-1-yl)(pyridin-4-yl)methanone (5d). Mp = 140–
141 °C; Rf = 0.18 (hexane/EtOAc, 1:1); IR (KBr, cm−1):
1
3063, 2922, 1733, 1647; H NMR (500 MHz, CDCl3) δ
8.80 (d, J = 4.8 Hz, 2H), 8.01 (d, J = 5.5 Hz, 2H), 7.28 (dd,
J1,2 = 7.1, 3.9 Hz, 5H), 7.20 (dd, J1,2 = 8.3, 1.9 Hz, 1H),
6.91 (dd, J1,2 = 8.4, 2.0 Hz, 1H), 5.76 (dd, J1,2 = 11.6, 4.7
Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.84 (dd, J1,2 = 17.7,
11.6 Hz, 1H), 3.27 (dd, J1,2 = 17.7, 4.7 Hz, 1H), 2.48 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 162.93, 157.74,
151.83, 149.34, 148.99, 142.66, 141.22, 137.69, 127.16,
126.36, 124.72, 123.35, 120.99, 110.84, 108.90, 60.94,
55.99, 55.95, 41.78, 15.76; HRMS (ESI): m/z [M]+ calcu-
lated for C24H23N3O3S: 433.1460; found: 433.1490.
(5-(benzo[d][1,3]dioxol-5-yl)-3-(2-chlorophenyl)-4,5-dihydro-
1H-pyrazol-1-yl)(pyridin-4-yl)methanone (5g). Mp = 124–
125 °C; Rf = 0.46 (hexane/EtOAc, 1:1); IR (KBr, cm−1):
1
3031, 2919, 1713, 1644; H NMR (500 MHz, CDCl3) δ
8.73 (d, J = 4.7 Hz, 2H), 7.88 (d, J = 5.8 Hz, 2H), 7.65 (d,
J = 7.7 Hz, 1H), 7.44 (dd, J1,2 = 7.9, 1.2 Hz, 1H), 7.35 (td,
J = 7.7, 1.8 Hz, 1H), 7.33 – 7.28 (m, 1H), 6.85 (d, J = 8.0
Hz, 1H), 6.81 – 6.77 (m, 2H), 5.93 (s, 2H), 5.71 (dd, J1,2
=
11.6, 4.6 Hz, 1H), 3.98 (dd, J1,2 = 18.3, 11.7 Hz, 1H), 3.39
(dd, J1,2 = 18.3, 4.7 Hz, 1H); 13C NMR (126 MHz, CDCl3)
δ 164.18, 155.64, 148.76, 148.27, 147.40, 142.22, 134.82,
133.04, 131.33, 131.16, 130.44, 129.86, 127.12, 124.08,
119.44, 108.64, 106.07, 101.25, 61.29, 44.52; HRMS
(ESI): m/z [M]+ calculated for C22H16ClN3O3: 405.0880;
found: 405.0910.
(5-(benzo[d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-4,5-dihydro-1H-
pyrazol-1-yl)(pyridin-4-yl)methanone (5e). Mp = 143–144 °C;
Rf = 0.46 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 3065,
1
3043, 2945, 2922, 1749, 1646, 1332; H NMR (500 MHz,
CDCl3) δ 8.75 (d, J = 5.4 Hz, 2H), 7.83 (d, J = 5.8 Hz, 2H),
7.69 (dd, J1,2 = 8.7, 5.3 Hz, 2H), 7.12 (t, J = 8.5 Hz, 2H),
6.83 (dd, J1,2 = 8.0, 1.1 Hz, 1H), 6.78 (d, J = 7.9 Hz, 2H),
5.93 (s, 2H), 5.72 (dd, J1,2 = 11.6, 4.8 Hz, 1H), 3.78 (dd, J1,2
= 17.8, 11.7 Hz, 1H), 3.21 (dd, J1,2 = 17.8, 4.8 Hz, 1H); 13C
NMR (126 MHz, CDCl3) δ 164.24 (1JC–F = 253.2 Hz),
164.19, 155.00, 149.49, 148.29, 147.38, 141.90, 135.05,
128.91 (3JC–F = 8.8 Hz), 127.12 (4JC–F = 2.5 Hz), 123.72,
119.36, 116.26, 116.08 (2JC–F = 22.6 Hz), 108.65, 106.00,
(5-(benzo[d][1,3]dioxol-5-yl)-3-(4-ethoxyphenyl)-4,5-dihydro-
1H-pyrazol-1-yl)(pyridin-4-yl)methanone (5h). Mp = 129–
130 °C; Rf = 0.30 (hexane/EtOAc, 1:1); IR (KBr, cm−1):
3065, 3045, 2977, 2918, 1647; 1H NMR (500 MHz, CDCl3)
δ 8.77 (d, J = 5.9 Hz, 2H), 7.92 (d, J = 5.6 Hz, 2H), 7.64
(d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.85 (dd, J1,2

Ganesan et al.
7
2H), 7.29 (s, 1H), 7.19 (dd, J = 8.3, 2.0 Hz, 1H), 6.91 (d, J
= 8.4 Hz, 1H), 6.86 (dd, J1,2 = 8.0, 1.6 Hz, 1H), 6.81 (s,
1H), 6.80 – 6.78 (m, 1H), 5.96 (s, 1H), 5.72 (dd, J1,2 = 11.5,
4.6 Hz, 1H), 3.95 (s, 1H), 3.91 (s, 1H), 3.81 (dd, J1,2 = 17.7,
11.6 Hz, 1H), 3.25 (dd, J1,2 = 17.7, 4.7 Hz, 1H); 13C NMR
(126 MHz, CDCl3) δ 163.02, 156.50, 151.80, 149.32,
148.32, 147.43, 147.35, 144.18, 134.90, 124.64, 123.40,
120.97, 119.47, 110.83, 108.89, 108.67, 106.03, 101.28,
77.28, 77.02, 76.77, 61.14, 56.04, 55.98, 41.92; m/z [M]+
calculated for C24H21N3O5: 431.1481; found: 431.1512.
= 8.0, 1.6 Hz, 1H), 6.81 – 6.77 (m, 2H), 5.95 (s, 2H), 5.70
(dd, J1,2 = 11.5, 4.6 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.78
(dd, J1,2 = 17.7, 11.6 Hz, 1H), 3.22 (dd, J1,2 = 17.7, 4.7 Hz,
1H), 1.46 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3)
δ 163.55, 161.23, 156.09, 148.67, 148.26, 147.32, 142.85,
135.17, 128.54, 124.15, 123.10, 119.42, 114.77, 108.63,
106.06, 101.23, 63.71, 61.00, 41.85, 14.68; HRMS (ESI):
m/z [M]+1 calculated for C24H21N3O4: 415.1532; found:
416.1612.
(5-(benzo[d][1,3]dioxol-5-yl)-3-(3-bromophenyl)-4,5-dihydro-
1H-pyrazol-1-yl)(pyridin-4-yl)methanone (5i). Mp = 167–168
°C; Rf = 0.38 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 3027,
(5-(2-(benzyloxy)phenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-
pyrazol-1-yl)(pyridin-4-yl)methanone (5m). Mp = 148–149
°C; Rf = 0.45 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 3057,
1
3055, 2918, 1778, 1645; H NMR (500 MHz, CDCl3) δ
1
2983, 2919, 1725, 1607; H NMR (400 MHz, CDCl3) δ
8.80 (d, J = 5.6 Hz, 2H), 7.90 (d, J = 5.6 Hz, 2H), 7.81 (s,
1H), 7.64 (d, J = 7.8 Hz, 1H), 7.60 (ddd, J1,2,3 = 7.9, 1.8,
0.8 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 6.86 – 6.76 (m, 3H),
5.96 (s, 2H), 5.74 (dd, J1,2 = 11.7, 4.8 Hz, 1H), 3.80 (dd,
J1,2 = 17.9, 11.7 Hz, 1H), 3.23 (dd, J1,2 = 17.9, 4.9 Hz,
1H); 13C NMR (126 MHz, CDCl3) δ 163.88, 154.88,
148.51, 148.36, 147.50, 142.79, 134.68, 133.80, 132.75,
130.42, 129.78, 125.37, 124.11, 123.06, 119.40, 108.71,
105.97, 101.30, 61.26, 41.71; HRMS (ESI): m/z [M]+1
calculated for C22H16BrN3O3: 449.0375; found: 450.0454.
8.64 (d, J = 5.9 Hz, 2H), 7.68 (dd, J1,2 = 4.5, 1.6 Hz, 2H),
7.51 – 7.45 (m, 2H), 7.29 – 7.26 (m, 2H), 7.24 – 7.16 (m,
5H), 7.02 – 6.87 (m, 4H), 5.92 (dd, J1,2 = 11.8, 5.5 Hz, 1H),
5.01 (s, 2H), 3.63 (dd, J1,2 = 17.6, 11.9 Hz, 1H), 3.13 (dd,
J1,2 = 17.6, 5.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
163.18, 163.01 (1JC–F = 252.5 Hz), 154.60, 154.29, 148.60,
140.90, 135.43, 128.15, 127.73 (3JC–F = 8.0 Hz), 127.48,
127.32, 127.09, 126.67, 126.43, 126.37 (4JC–F = 6.0 Hz),
122.72, 120.04, 114.79 (2JC–F = 22.2 Hz), 111.22, 69.29,
57.34, 39.51; HRMS (ESI): m/z [M]+ calculated for
C28H22FN3O2: 451.1696; found: 451.1422.
(5-(benzo[d][1,3]dioxol-5-yl)-3-(3-methoxyphenyl)-4,5-dihydro-
1H-pyrazol-1-yl)(pyridin-4-yl)methanone (5j). Mp = 141–142
°C; Rf = 0.29 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 3063,
2912, 1731, 1643; 1H NMR (500 MHz, CDCl3) δ 8.76 (d, J
= 5.9 Hz, 2H), 7.86 (d, J = 6.0 Hz, 2H), 7.35 (t, J = 7.9
Hz, 1H), 7.29 – 7.23 (m, 2H), 7.01 (dd, J1,2 = 8.1, 2.5 Hz,
1H), 6.84 (dd, J1,2 = 8.0, 1.3 Hz, 1H), 6.81 – 6.77 (m, 2H),
5.94 (s, 2H), 5.71 (dd, J1,2 = 11.6, 4.7 Hz, 1H), 3.84 (s, 3H),
3.79 (dd, J1,2 = 17.8, 11.7 Hz, 1H), 3.22 (dd, J1,2 = 17.8,
4.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 164.13, 159.83,
156.03, 149.27, 148.27, 147.36, 142.05, 135.08, 132.11,
129.94, 123.88, 123.10, 119.46, 116.44, 112.18, 108.64,
106.05, 101.24, 61.14, 55.37, 41.87; HRMS (ESI): m/z
[M]+ calculated for C23H19N3O4: 401.1376; found:
401.1405.
2-(2-(benzyloxy)phenyl)-1H-benzo[d]imidazole (6). Mp
=
142–144 °C; Rf = 0.35 (hexane/EtOAc, 1:1); IR (KBr,
cm−1): 1346, 1680, 2998, 3174; 1H NMR (500 MHz,
CDCl3): δ 5.20 (s, 2H), 7.04 – 8.61 (m, 13H), 10.63 (br s,
1H); 13C NMR (125 MHz, CDCl3): δ 71.37, 112.96, 118.31,
122.09, 122.56, 127.84, 128.87, 129.11, 130.23, 131.22,
135.99, 149.79, 156.13; HRMS (ESI): m/z [M]+1 calcu-
lated for C20H16N2O: 300.1263; found: 301.1408.
(5-(benzo[d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-1H-pyrazol-
1-yl)(pyridin-4-yl)methanone (8a). Mp = 112–113 °C; Rf =
0.28 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 3034, 2922,
1734, 1635; 1H NMR (400 MHz, CDCl3) δ 8.86 – 6.77 (m,
12H), 5.93 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 164.31
(1JC–F = 254.5 Hz), 164.21, 155.14, 149.58, 148.40, 147.45,
145.51, 142.01, 135.16, 128.93 (3JC–F = 8.8 Hz), 127.13
(4JC–F = 3.7 Hz), 123.91, 119.49, 116.08 (1JC–F = 21.4 Hz),
108.87, 106.19, 103.71, 101.49; HRMS (ESI): m/z [M]+
calculated for C22H14FN3O3: 387.1019; found: 387.1009.
(3-(3-aminophenyl)-5-(benzo[d][1,3]dioxol-5-yl)-4,5-dihydro-
1H-pyrazol-1-yl)(pyridin-4-yl)methanone (5k). Mp = 181–
182 °C; Rf = 0.11 (hexane/EtOAc, 1:1); IR (KBr, cm−1):
3327, 3027, 2987, 2922, 1649; 1H NMR (500 MHz, CDCl3)
δ 8.76 (d, J = 5.9 Hz, 2H), 7.85 (d, J = 5.5 Hz, 2H), 7.22
(t, J = 7.8 Hz, 1H), 7.08 – 7.01 (m, 2H), 6.84 (dd, J1,2
=
(5-(benzo[d][1,3]dioxol-5-yl)-3-(3-nitrophenyl)-1H-pyrazol-
1-yl)(pyridin-4-yl)methanone (8b). Mp = 126–127 °C; Rf =
0.24 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 3212, 3116,
3036, 2922, 2854, 1649, 1595; 1H NMR (400 MHz, CDCl3)
δ 8.93 – 6.93 (m, 12H), 5.97 (s, 2H); 13C NMR (101 MHz,
8.0, 1.5 Hz, 1H), 6.80 – 6.77 (m, 3H), 5.95 (s, 2H), 5.69
(dd, J1,2 = 11.6, 4.7 Hz, 1H), 3.76 (dd, J1,2 = 17.8, 11.6 Hz,
1H), 3.28 (s, 2H), 3.20 (dd, J1,2 = 17.8, 4.7 Hz, 1H); 13C
NMR (126 MHz, CDCl3) δ 164.11, 156.38, 149.40, 148.25,
147.32, 146.79, 142.09, 135.16, 131.73, 129.77, 123.83,
119.39, 117.72, 117.44, 112.51, 108.62, 106.06, 101.23, CDCl3) δ 164.47, 154.66, 148.99, 148.51, 147.85, 144.93,
61.03, 41.88; HRMS (ESI): m/z [M]+ calculated for 142.79, 132.68, 134.52, 132.30, 130.25, 125.46, 124.28,
C22H18N4O3: 386.1379; found: 386.1408.
123.47, 121.87, 119.64, 109.23, 106.65, 104.06, 101.96;
HRMS (ESI): m/z [M]+ calculated for C22H14N4O5:
(5-(benzo[d][1,3]dioxol-5-yl)-3-(3,4-dimethoxyphenyl)-4,5-di- 414.0964; found: 414.0904.
hydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanone (5l). Mp
=
(5-(benzo[d][1,3]dioxol-5-yl)-3-(2-chlorophenyl)-1H-pyrazol-
1-yl)(pyridin-4-yl)methanone (8c). Mp = 130–131 °C; Rf =
0.24 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 3058, 3020,
122–123 °C; Rf = 0.14 (hexane/EtOAc, 1:1); IR (KBr,
cm−1): 3003, 2955, 2925, 1638, 1332; 1H NMR (500 MHz,
CDCl3) δ 8.79 (d, J = 5.9 Hz, 2H), 7.99 (d, J = 6.0 Hz,

8
Journal of Chemical Research 00(0)
1
study was supported by the Council of Scientific and Industrial
Research, New Delhi.
2959, 2923, 1724, 1642; H NMR (400 MHz, CDCl3) δ
8.96 – 7.05 (m, 12H), 5.93 (s, 2H); 13C NMR (101 MHz,
CDCl3) δ 164.37, 155.82, 148.90, 148.35, 147.48, 145.97,
142.30, 134.70, 133.20, 131.44, 131.22, 130.53, 129.92,
127.46, 124.30, 119.64, 108.79, 106.21, 104.04, 101.36;
HRMS (ESI): m/z [M]+ calculated for C22H14ClN3O3:
403.0724; found: 403.2350.
ORCID iD
Muniraj Sarangapani
https://orcid.org/0000-0003-4315-3069
Supplemental material
Supplemental material for this article is available online.
(5-(benzo[d][1,3]dioxol-5-yl)-3-(4-ethoxyphenyl)-1H-pyrazol-
1-yl)(pyridin-4-yl)methanone (8d). Mp = 116–117 °C; Rf =
0.45 (hexane/EtOAc, 1:1); IR (KBr, cm−1): 3236, 3064,
3033, 2919, 2851, 1782, 1611; 1H NMR (400 MHz, CDCl3)
δ 8.90 – 6.91 (m, 12H), 5.95 (s, 2H), 4.10 (q, J = 10.0 Hz,
2H), 1.46 (t, J = 5.0 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 163.51, 161.23, 156.21, 148.92, 148.15, 147.49, 145.39,
142.69, 135.17, 128.79, 124.33, 123.29, 119.65, 115.02,
108.91, 106.34, 104.16, 101.42, 64.08, 15.17; HRMS
(ESI): m/z [M]+ calculated for C24H19N3O4: 413.1376;
found: 413.2657.
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1
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Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
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The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This