Synthesis of new dihydropyrazoles of designed curcumin analogues

Article abstract of DOI:10.14233/ajchem.2019.22023

Present work demonstrates a facile synthesis of a series of 20 dihydropyrazole derivatives from well designed curcumin analogues by reaction of chalcone derivatives with phenylhydrazine. All the synthesized compounds were characterized by spectroscopic (¹H and ¹³C NMR, IR spectra), spectrometric (Mass spectra) data and elemental analysis. Synthesized dihydropyrazoles have diversity points on attached phenyl ring. Effect of substituent on reactivity was explained on the basis of electronic effect generated due to groups on phenyl ring. Presence of dd (double doublet) in ¹H NMR spectrum of dihydropyrazoles was also explained due to presence of optically active carbon of pyrazole ring.

Full text of DOI:10.14233/ajchem.2019.22023

Asian Journal of Chemistry; Vol. 31, No. 9 (2019), 1889-1894
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.22023
Synthesis of New Dihydropyrazoles of Designed Curcumin Analogues
VISHWA DEEPAK TRIPATHI
Department of Chemistry, M.K. College (Lalit Narayan Mithila University), Darbhanga-846003, India
Corresponding author: E-mail: vishwadeepak66@gmail.com
Received: 23 February 2019;
Accepted: 16 March 2019;
Published online: 31 July 2019;
AJC-19472
Present work demonstrates a facile synthesis of a series of 20 dihydropyrazole derivatives from well designed curcumin analogues by
reaction of chalcone derivatives with phenylhydrazine. All the synthesized compounds were characterized by spectroscopic (1H and 13
C
NMR, IR spectra), spectrometric (Mass spectra) data and elemental analysis. Synthesized dihydropyrazoles have diversity points on
attached phenyl ring. Effect of substituent on reactivity was explained on the basis of electronic effect generated due to groups on phenyl
ring. Presence of dd (double doublet) in 1H NMR spectrum of dihydropyrazoles was also explained due to presence of optically active
carbon of pyrazole ring.
Keywords: Dihydropyrazoles, Curcumin, Heterocycles, Phenylhydrazine, Chacone.
for treatment of various health problems. Apart from their
crucial role in medicinal chemistry pyrazoles have a great
significance in organometallic chemistry as ligands as well
as in catalysis. Their metal coordination complexes are also
reported to show anticancer and antimicrobial properties [15].
Being an essential pharmcophore in therapeutically
important molecules pyrazole moiety attached with some other
biologically important molecule create a new chemical space
in medicinal chemistry and drug discovery. Due to this reason
and in an attempt to get better biological profile several research
groups were interested in preparation of pyrazole analogues
of many biologically active natural compounds and investiga-
ting their biological potential. Moreover, pyrazole derivatives
of curcumin were synthesized and investigated for lipoxy-
genase inhibitory activity [16], cytotoxic activity [17,18] and
antioxidant activity [19]. In addition to this curcumin has been
shown to have synergistic effects with artemisinin against
Plasmodium berghei [20,21].Among the different drug mole-
cules as illustrated in Fig. 1 pyrazole nucleus is known to be a
crucial factor for showing biological activity. Furthermore, the
presence of enone function of chalcone moiety with pyrazole
ring also reported to get the enhanced the biological activity.
Our group have previously reported the synthesis of fabricated
curcumin based chalcone analogues and their biological
activity [22]. In continuation of the work this time we hypo-
INTRODUCTION
Pyrazoles constitutes one of the representative classes of
heterocycles and remains an attractive target for chemists in
the field of heterocyclic chemistry. After the first synthesis of
pyrazoles proposed by Buchner in 1889 via decarboxylation
of pyrazole-3,4,5-tricarboxylic acid, a number of methods have
been reported for their synthesis in literature [1]. Particularly
the importance of pyrazoles scaffolds are not only due to their
structural simplicity, but also because many natural products,
many drugs and many dyes belong to this group [2,3]. They
are crucial due to their theoretical implications, the diversity
of its synthetic procedures and the physiological as well as
industrial significance of heterocyclic compounds [4-6]. Pyra-
zole containing molecules posses an essential place in the drug
discovery domain because it is known to be most abundant
pharmacophore in synthetic as well as natural bioactive mole-
cules. These heterocycles continue to attract extensive attention
due to the broad range of biological activities they possess.
Pyrazoles are reported as potent bioactive molecules [7-11]
and are known to exhibit a wide range of pharmaceutical acti-
vities such as CNS depressant, neuroleptic, tuberculostatic,
antihypertensive, antileishmanial, analgesic, antidiabetic,
antitumor and antimicrobial [12-14]. Fig. 1 represents several
molecules bearing pyrazole nucleus which are used in clinics
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1890 Tripathi
Asian J. Chem.
thesize that the incorporation of the essential structural features
of pyrazoles with a curcumin moiety could provide new deriva-
tives with better biological activities since several curcumin
derivatives have already been shown to be active as potent
anticancer agents [23-25]. Prompted by all these observations,
here in we report the synthesis of dihydropyrazoles derivative
of curcumin based chalcones by utilizing condensation reaction
between chalcones and phenyl hydrazine. All the synthesized
heterocycles were characterized by 1H and 13C NMR, IR spectra,
mass spectra as well as elemental analysis measurements.
(1.5 mmol) were mixed with 10 mL of ethanol in a 100 mL
round bottom flask. To this solution catalytic amount of acetic
acid (10 mol %) was added followed by stirring under refluxing
condition upto completion of reaction. Progress of reaction
was monitored by thin layer chromatography.After completion
of reaction solvent was evaporated under the reduced pressure
in rotavapour. Solid residue was poured in ice water under
stirring and filtered off. After filtration the solid residue was
recrystallized with ethanol and dried under vacuum to afford
the pure dihydropyarazole derivatives (23-42) (Scheme-I),
which were further characterized by spectroscopic data.
F3C
Analytical data for compounds (23-42)
O
N
HN
N
3-(1,5-Diphenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-
hydroxy-6-methyl-2H-pyran-2-one (23):Yellow solid; m.p.
153 °C; IR (KBr, νmax, cm–1): 3452, 3022, 1640, 1526, 1216,
1022; 1H NMR (CDCl3, 300 MHz): 7.29-7.13 (m, 5H); 6.92-
6.78 (m, 3H); 6.71-6.67 (m, 2H); 5.20 (dd, J = 8 Hz, J = 12
Hz); 4.17 (dd, J = 12 Hz, J = 18 Hz); 3.48 (dd, J = 8 Hz, J =
22 Hz); 2.26 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ = 192.4,
183.7, 167.4, 153.6, 151.1, 136.1, 133.2, 131.1, 129.2, 126.4,
122.1, 116.4, 101.3, 98.4, 51.6, 33.8, 20.6. MS (ES): m/z (%)
= 347 (100) [M+1]+;Anal. calcd. (%) for C21H18N2O3: C, 71.82;
H, 5.24; N, 8.09; Found (%): C, 71.78; H, 5.21; N, 8.12.
4-Hydroxy-3-(5-(4-methoxyphenyl)-1-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)-6-methyl-2H-pyran-2-one (24):
Yellow solid; m.p. 164 °C; IR (KBr, νmax, cm–1): 3452, 3022,
1640, 1526, 1216, 1022; 1H NMR (CDCl3, 300 MHz): 7.23-
7.16 (m, 5H); 6.91 (d, J = 8.4 Hz, 2H); 6.86-6.81 (m, 2H);
6.04 (s, 1H); 5.22 (dd, J = 8.4 Hz, J = 12 Hz, 1H); 4.26 (dd, J
= 12.2 Hz, J = 19 Hz, 1H); 3.91 (s, 3H); 3.48 (dd, J = 8.4 Hz,
J = 12 Hz, 1H); 2.28 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ
192.7, 181.1, 169.0, 168.3, 153.7, 153.5, 141.4, 131.6, 129.3,
124.2, 123.9, 118.7, 113.3, 113.5, 101.4, 56.1, 20.6. MS (ES):
m/z (%) = 377 (100) [M+1]+;Anal. calcd. (%) for C22H20N2O4:
C, 70.20; H, 5.36; N, 7.44; Found (%): C, 70.16; H, 5.30; N,
7.50.
4-Hydroxy-3-(5-(3-methoxyphenyl)-1-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)-6-methyl-2H-pyran-2-one (25):
Yellow solid; m.p. 173 °C; IR (KBr, νmax, cm–1): 3452, 3022,
1640, 1526, 1216, 1022; 1H NMR (CDCl3, 300 MHz): 7.41-
7.21 (m, 5H); 6.93-6.86 (m, 3H); 6.85-6.83 (m, 1H); 6.06 (s,
1H); 5.18 (dd, J = 8.2 Hz, J = 11 Hz, 1H); 4.26 (dd, J = 11.2
Hz, J = 18 Hz, 1H); 3.89 (s, 3H); 3.48 (dd, J = 8.0 Hz, J = 18
Hz, 1H); 2.26 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 192.9,
182.4, 169.2, 167.2, 151.4, 150.5, 143.4, 132.6, 130.1, 128.2,
123.9, 115.4, 111.3, 103.6, 101.4, 56.4, 20.6. MS (ES): m/z
(%) = 377 (100) [M+1]+; Anal. calcd. (%) for C22H20N2O4: C,
70.20; H, 5.36; N, 7.44; Found (%): C, 70.16; H, 5.30; N,
7.50.
N
CH3
O
CH3
N
N
N
N
Cl
O
S
O
CN
H2N
Cl
Cl
Celecoxib
Anti-inflammatory
Rimonabant
antiobesity
CDPPB
Antipsychotic
CH3
HN
N
H3C
N
O
H3C
N
N
HN
N
H2N
N
H3C
N
H3C
Betazole
H2-receptor
Difenamizole
Analgesic
Fezolamine
Antidepressant
Fig. 1. Structures of some representative pyrazole containing drug molecules
EXPERIMENTAL
Unless otherwise specified all the reagents and catalysts
were purchased from Sigma-Aldrich and were used without
further any purification. The common solvents were purchased
from Ranbaxy. Organic solutions were concentrated under
reduced pressure on a Büchi rotary evaporator. Reactions were
monitored by thin-layer chromatography (TLC) on 0.25 mm
silica gel plates visualized under UV light, iodine or KMnO4
staining. 1H and 13C NMR spectra were recorded on a Brucker
DRX-200 MHz Spectrometer. Chemical shifts (δ) are given
in ppm relative to TMS and coupling constants (J) in Hz. IR
spectra were recorded on a FTIR spectrophotometer Shimadzu
8201 PC and are reported in terms of frequency of absorption
(cm-1). Mass spectra (ESIMS) were obtained by micromass
quattro II instrument.
General procedure for synthesis of dihydropyrazoles
(23-42): Chalcone analogues (1 mmol) and phenyl hydrazine
O
H
OH
O
O
OH
O
O
O
N
OH
O
N
O
Piperidine
Ethanol
R
Chloroform
Phenylhydrazine
O
R
R
(3-22)
2
(23-42)
1
Scheme-I: Synthesis of heterocyclic curcumin analogues and corresponding pyrazoles

Vol. 31, No. 9 (2019)
Synthesis of New Dihydropyrazoles of Designed Curcumin Analogues 1891
3-(5-(3,4-Dimethoxyphenyl)-1-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (26):
Yellow solid; m.p. 168 °C; IR (KBr, νmax, cm–1): 3430, 3022,
3H). 13C NMR (CDCl3, 75 MHz): δ = 192.6, 184.2, 167.4,
153.7, 151.2, 144.9, 136.3, 130.5, 129.1, 126.2, 122.6, 116.5,
101.5, 98.6, 51.3, 33.4, 20.4. MS (ES): m/z (%) = 381 (100)
[M+1]+;Anal. calcd. (%) for C21H17N2O3Cl: C, 66.23; H, 4.50;
N, 7.36; Found (%): C, 66.18; H, 4.46; N, 7.38.
1
2922, 1630, 1485, 1216; H NMR (CDCl3, 300 MHz): 13.4
(s, 1H); 7.22-7.19 (m, 3H); 6.92-6.83 (m, 5H); 6.06 (s, 1H);
5.07 (dd, J = 8.5 Hz, J = 12.1 Hz, 1H); 4.17 (dd, J = 12.1 Hz,
J = 18.9 Hz, 1H); 3.86 (s, 3H); 3.84 (s, 3H); 3.50 (dd, J = 8.4
Hz, J = 18.9 Hz, 1H); 2.28 (s, 3H). 13C NMR (CDCl3, 75
MHz): δ 190.8, 184.2, 168.2, 162.4, 158.7, 142.7, 133.6, 128.4,
123.6, 122.9, 121.8, 112.1, 103.3, 99.8, 62.4, 56.0, 20.6. MS
(ES): m/z (%) = 407 (100) [M+1]+; Anal. calcd. (%) for
C23H22N2O5: C, 67.97; H, 5.46; N, 6.89; Found (%): C, 67.94;
H, 5.41; N, 6.92.
3-(5-(4-Chlorophenyl)-1-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (31):
Yellow solid; m.p. 148 °C; IR (KBr, νmax, cm–1): 3406, 2880,
1717, 1590, 1418, 1353, 1173; 1H NMR (CDCl3, 300 MHz):
7.23-7.16 (m, 5H); 6.89-7.81 (m, 4H); 6.05 (s, 1H); 5.12 (dd,
J = 8 Hz, J = 12 Hz, 1H); 4.17 (dd, J = 12.2 Hz, J = 19 Hz,
1H); 3.51 (dd, J = 8.0 Hz, J = 11.9 Hz, 1H); 2.26 (s, 3H).13C
13
NMR (CDCl3, 75 MHz): δ C NMR: δ 191.4, 183.1, 166.8,
4-Hydroxy-6-methyl-3-(5-(4-nitrophenyl)-1-phenyl-
4,5-dihydro-1H-pyrazol-3-yl)-2H-pyran-2-one (27):Yellow
solid; m.p. 164 °C; IR (KBr, νmax, cm–1): 3406, 2880, 1717,
1590, 1418, 1353, 1173; 1H NMR (CDCl3, 300 MHz): 8.23-
8.19 (m, 2H); 7.51-7.47 (m, 2H); 7.26-7.18 (m, 2H); 6.91-
6.79 (m, 3H); 6.06 (s, 1H); 5.24 (dd, J = 7.9 Hz, J = 19.1 Hz,
1H); 4.24 (dd, J = 12.4 Hz, J = 19 Hz, 1H); 3.51 (dd, J = 7.9
Hz, J = 18.9 Hz, 1H); 2.27 (s, 3H). 13C NMR (CDCl3, 75 MHz):
δ = 191.8, 183.6, 167.8, 153.4, 151.2, 144.3, 136.1, 130.7,
129.5, 126.2, 122.2, 116.2, 101.3, 98.7, 51.3, 33.4, 20.7. MS
(ES): m/z (%) = 392 (100) [M+1]+; Anal. calcd. (%) for
C21H17N3O5: C, 64.45; H, 4.38; N, 10.74; Found (%): C, 64.40;
H, 4.33; N, 10.77.
162.3, 158.2, 142.1, 133.4, 128.4, 123.3, 121.7, 120.6, 112.1,
103.3, 99.8, 61.5, 56.2, 20.8; MS (ES): m/z (%) = 381 (100)
[M+1]+;Anal. calcd. (%) for C21H17N2O3Cl: C, 66.23; H, 4.50;
N, 7.36; Found (%): C, 66.18; H, 4.46; N, 7.38.
3-(5-(3,5-Dichlorophenyl)-1-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (32):
Yellow solid; m.p. 143 °C; IR (KBr, νmax, cm–1): 3430, 3022,
2922, 1630, 1485, 1216; 1H NMR (CDCl3, 300 MHz): 13.25
(s, 1H); 8.26 (d, J = 8.1 Hz, 2H) 7.54 (d, J = 8.2 Hz, 2H);
7.29-7.22 (m, 3H); 6.93-6.83 (m, 3H); 6.09 (s, 1H); 5.27 (dd,
J = 8.07 Hz, J = 12.3 Hz, 1H); 4.27 (dd, J = 12.7 Hz, J = 19.2
Hz, 1H); 3.49 (dd, J = 7.5 Hz, J = 18.9 Hz, 1H); 2.27 (s,
3H).13C NMR (CDCl3, 75 MHz): δ 191.6, 183.5, 168.2, 167.2,
163.1, 158.8, 144.6, 136.4, 135.3, 128.1, 121.9, 121.1, 113.4,
104.1, 99.6, 58.4, 37.6, 20.4. MS (ES): m/z (%) = 415 (100)
[M+1]+;Anal. calcd. (%) for C21H16Cl2N2O3: C, 60.74; H, 3.88;
N, 6.75; Found (%): C, 60.70; H, 3.83; N, 6.79.
4-Hydroxy-6-methyl-3-(5-(2-nitrophenyl)-1-phenyl-
4,5-dihydro-1H-pyrazol-3-yl)-2H-pyran-2-one (28):Yellow
solid; m.p. 144 °C; IR (KBr, νmax, cm–1): 3452, 3022, 1640,
1
1526, 1216, 1022; H NMR (CDCl3, 300 MHz): 8.20-8.17
(m, 2H); 7.48-7.44 (m, 2H); 7.17-7.06 (m, 2H); 6.90-6.82 (m,
3H); 6.05 (s, 1H); 5.18 (dd, J = 8 Hz, J = 18.6 Hz, 1H); 4.24
(dd, J = 11 Hz, J = 18.1 Hz, 1H); 3.51 (dd, J = 8 Hz, J = 18.4
Hz, 1H); 2.25 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 192.8,
185.6, 166.3, 158.8, 153.6, 142.4, 134.6, 131.2, 129.4, 124.7,
121.3, 116.5, 112.4, 103.8, 56.3, 37.4, 21.6. MS (ES): m/z
(%) = 392 (100) [M+1]+; Anal. calcd. (%) for C21H17N3O5: C,
64.45; H, 4.38; N, 10.74; Found (%): C, 64.40; H, 4.33; N,
10.78.
3-(5-(4-(Dimethylamino)phenyl)-1-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-
2-one (29): Yellow solid; m.p. 171 °C; IR (KBr, νmax, cm–1):
3406, 2880, 1717, 1590, 1418, 1353, 1173; 1H NMR (CDCl3,
300 MHz): 7.29-7.13 (m, 4H); 6.92-6.78 (m, 3H); 6.71-6.67
(m, 3H); 5.07 (dd, 1H, J = 8 Hz, J = 12 Hz); 4.12 (dd, 1H, J =
12 Hz, J = 18 Hz); 3.50 (dd, 1H, J = 8 Hz, J = 22 Hz); 2.93 (s,
6H); 2.26 (s, 3H).13C NMR (CDCl3, 75 MHz): δ 191.2, 183.3,
168.4, 159.6, 144.3, 132.6, 130.3, 128.7, 119.4, 104.6, 100.2,
98.9, 52.1, 35.4, 20.5 MS (ES): m/z (%) = 390 (100) [M+1]+;
Anal. calcd. (%) for C23H23N3O3: C, 70.93; H, 5.95; N, 10.79;
Found (%): C, 70.89; H, 5.91; N, 10.82.
4-Hydroxy-3-(5-(4-hydroxy-3-methoxyphenyl)-1-
phenyl-4,5-dihydro-1H-pyrazol-3-yl)-6-methyl-2H-pyran-
2-one (33): Yellow solid; m.p. 153 °C; IR (KBr, νmax, cm–1):
3328, 2917, 1684, 1597, 1423, 1270, 1127; 1H NMR (CDCl3,
300 MHz): 13.39 (s, 1H); 7.21-7.19 (m, 3H); 7.17 (t, J = 8.2
Hz, 2H); 6.91-6.79 (m, 3H); 6.05 (s, 1H); 5.03 (dd, J = 8 Hz,
J = 12 Hz, 1H); 4.31 (s, 1H); 4.16 (dd, J = 8 Hz, J = 12.4 Hz,
1H); 3.84 (s, 3H); 3.49 (dd, J = 12.2 Hz, J = 19 Hz, 1H); 2.27
(s, 3H).13C NMR (CDCl3, 75 MHz): δ 190.4, 184.6, 168.8
167.2, 162.6, 156.7, 148.2, 146.3, 138.3, 135.4, 127.3, 121.9,
122.2, 113.0, 103.8, 99.4, 57.6, 37.3, 20.6. MS (ES): m/z (%)
= 393 (100) [M+1]+;Anal. calcd. (%) for C22H20N2O5: C, 67.34;
H, 5.14; N, 7.14; Found (%): C, 67.29; H, 5.11; N, 7.41.
4-Hydroxy-3-(5-(3-hydroxyphenyl)-1-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)-6-methyl-2H-pyran-2-one (34):
Yellow solid; m.p. 168 °C; IR (KBr, νmax, cm–1): 3561, 3157,
1732, 1628, 1346, 1268; 1H NMR (CDCl3, 300 MHz): δ 10.04
(1H, s), 7.47-7.26 (m, 4H); 6.99-6.76 (m, 3H); 6.62-6.62 (m,
2H); 5.96 (1H, s), 5.26 (dd, J = 6 Hz, J = 14.2 Hz); 4.18 (dd,
J = 14.2 Hz, J = 16 Hz); 3.44 (dd, J = 6 Hz, J = 22 Hz); 2.26
13
(s, 3H); C NMR (CDCl3, 75 MHz): δ 189.8, 182.3, 163.2,
3-(5-(3-Chlorophenyl)-1-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (30):
Yellow solid; m.p. 157 °C; IR (KBr, νmax, cm–1): 3452, 3022,
1640, 1526, 1216, 1022; 1H NMR (CDCl3, 300 MHz): 7.26-
7.11 (m, 5H); 7 61 (d, J = 6.4 Hz, 1H); 6.91-6.80 (m, 4H);
6.06 (s, 1H); 5.44 (dd, J = 7.4 Hz, J = 12.0 Hz); 4.17 (dd, J =
12.0 Hz, J = 18 Hz); 3.42 (dd, J = 7.4 Hz, J = 18 Hz); 2.25 (s,
162.1, 150.6, 147.2, 136.4, 134.3, 129.8, 127.9, 126.7, 123.8,
114.1, 112.3, 111.5, 103.2, 97.6, 21.1; MS (ES): m/z (%) =
363 (100) [M+1]+; Anal. calcd. (%) for C21H18N2O4 C, 69.60;
H, 5.01; N, 7.73,; Found (%): C, 69.55; H, 4.98; N, 7.78.
4-Hydroxy-3-(5-(4-hydroxyphenyl)-1-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)-6-methyl-2H-pyran-2-one (35):
Bright yellow solid; m.p. 153 °C; IR (KBr, νmax, cm–1): 3541,

1892 Tripathi
Asian J. Chem.
3167, 1724, 1658, 1346, 1268; 1H NMR (CDCl3, 300 MHz):
δ 10.04 (1H, s), 7.46-7.29 (m, 4H); 6.98-6.74 (m, 3H); 6.68-
6.61 (m, 2H); 5.98 (1H, s), 5.24 (dd, J = 6 Hz, J = 14.2 Hz);
4.16 (dd, J = 14.2 Hz, J = 16 Hz); 3.42 (dd, J = 6 Hz, J = 22
Hz); 2.27 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 189.3, 182.2,
163.4, 162.4, 150.2, 147.6, 136.4, 134.2, 129.8, 127.3, 126.4,
123.2, 114.2, 112.6, 111.5, 103.2, 97.6, 21.0; MS (ES): m/z
(%) = 363 (100) [M+1]+; Anal. calcd. (%) for C21H18N2O4 C,
69.60; H, 5.01; N, 7.73,; Found (%): C, 69.57; H, 4.97; N,
7.77.
59.31; H, 4.03; N, 6.59; Found (%): C, 59.27; H, 3.98; N,
6.62.
3-(5-(2,5-Dimethoxyphenyl)-1-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (40):
Yellow solid; m.p. 146 °C; IR (KBr, νmax, cm–1): 3468, 3121,
1725, 1629, 1316, 1252; 1H NMR (CDCl3, 300 MHz): δ 10.10
(1H, s); 7.47-7.26 (m, 5H); 7.50-7.24 (2H, m); 7.21-6.86 (2H,
m), 5.94 (1H, s); 5.27 (dd, J = 8 Hz, J = 19 Hz); 4.18 (dd, J =
19 Hz, J = 18 Hz); 3.44 (dd, J = 8 Hz, J = 21 Hz); 3.89 (s,
3H), 3.86 (s, 3H); 2.31 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ
192.1, 183.4, 166.3, 161.9, 150.6, 147.3, 133.8, 131.8, 128.7,
126.6, 124.6, 123.2, 121.2, 116.4, 114.8, 112.5, 111.6, 103.8,
98.6, 56.4, 21.3; MS (ES): m/z (%) = 407 (100) [M+1]+;Anal.
calcd. (%) for C23H22N2O5: C, 67.97; H, 5.46; N, 6.89; Found
(%): C, 67.93; H, 5.42; N, 6.92.
4-Hydroxy-6-methyl-3-(1-phenyl-5-(2,3,5-trimethoxy-
phenyl)-4,5-dihydro-1H-pyrazol-3-yl)-2H-pyran-2-one
(41): Orange solid; m.p. 161 °C; IR (KBr, νmax, cm–1): 3436,
3148, 1718, 1658, 1350, 1261; 1H NMR (CDCl3, 300 MHz):
δ 9.84 (1H, s), 8.16 (1H, d, J= 15 Hz), 8.04 (1H, d, J= 15 Hz),
7.47-7.26 (m, 5H); 7.24 (1H, s), 7.13 (1H, s), 5.91 (1H, s),
5.28 (dd, J = 9 Hz, J = 16 Hz); 4.18 (dd, J = 16 Hz, J = 18
Hz); 3.44 (dd, J = 9 Hz, J = 22 Hz); 4.28 (3H, s), 4.19 (3H, s),
3.86 (3H, s,), 2.27 (3H, s); 13C NMR (CDCl3, 75 MHz): δ
190.8, 181.4, 168.4, 162.1, 153.2, 147.4, 136.8, 133.6, 132.8,
130.4, 129.7, 128.4, 126.5, 124.2, 116.8, 114.3, 112.4, 103.1,
96.5, 56.4, 21.0; MS (ES): m/z (%) = 437 (100) [M+1]+;Anal.
calcd. (%) for C24H24N2O6 C, 66.04; H, 5.54; N, 6.42; Found
(%): C, 66.00; H, 5.491; N, 6.45.
3-(5-(4-Fluorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-
3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (36): Yellow
solid; m.p. 126 °C; IR (KBr, νmax, cm–1): 3406, 2880, 1717,
1590, 1418, 1353, 1173; 1H NMR (CDCl3, 300 MHz): 13.31
(s, 1H); 7.31-7.18 (m, 4H); 7.07-7.02 (m, 2H); 6.89-6.85 (m,
3H); 6.07 (s, 1H); 5.15 (dd, J = 8.1 Hz, J = 12.2 Hz, 1H); 4.12
(dd, J = 12 Hz, J = 14 Hz, 1H); 3.50 (dd, J = 7.9 Hz, J = 17.1
Hz, 1H); 2.28 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 192.0,
184.1, 167.5, 154.1, 150.5, 144.6, 136.3, 131.6, 129.8, 127.5,
123.21 116.1, 101.4, 98.9, 51.4, 34.7, 20.7 MS (ES): m/z (%)
= 365 (100) [M+1]+; Anal. calcd. (%) for C21H17N2O3F: C,
69.22; H, 4.70; N, 7.69; Found (%): C, 69.18; H, 4.67; N, 7.85.
4-Hydroxy-3-(5-(2-methoxyphenyl)-1-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)-6-methyl-2H-pyran-2-one (37):
Yellow solid; m.p. 161 °C; IR (KBr, νmax, cm–1): 3452, 3022,
1
1640, 1526, 1216, 1022; H NMR (CDCl3, 300 MHz): 13.4
(s, 1H); 7.28-7.11 (m, 4H); 6 93 (d, J = 8.2 Hz, 1H); 6.92-
6.83 (m, 4H); 6.04 (s, 1H); 5.49 (dd, J = 7.28 Hz, J = 12.3 Hz,
1H); 4.17 (dd, J = 12.3 Hz, J = 19.1 Hz, 1H); 3.93 (s, 3H);
3.42 (dd, J = 7.6 Hz, J = 19.1 Hz, 1H); 2.27 (s, 3H).13C NMR
(CDCl3, 75 MHz): δ 192.9, 183.3, 168.3, 161.3, 159.1, 141.7,
132.6, 129.5, 123.7, 122.9, 120.8, 112.2, 102.5, 99.4, 55.5,
20.6. MS (ES): m/z (%) = 377 (100) [M+1]+; Anal. calcd. (%)
for C22H20N2O4: C, 70.20; H, 5.36; N, 7.44; Found (%): C,
70.16; H, 5.30; N, 7.50.
3-(5-(2-Chlorophenyl)-1-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (38):
Yellow solid; m.p. 151 °C; IR (KBr, νmax, cm–1): 3452, 3022,
1640, 1526, 1216, 1022; 1H NMR (CDCl3, 300 MHz): 8.20-
8.02 (m, 5H); 7.31-7.20 (m, 4H); 6.04 (s, 1H); 5.24 (dd, J =
7.4 Hz, J = 18.1 Hz, 1H); 4.18 (dd, J = 11 Hz, J = 19 Hz, 1H);
3.49 (dd, J = 7.4 Hz, J = 18.1 Hz, 1H); 2.26 (s, 3H). 13C NMR
(CDCl3, 75 MHz): δ = 192.2, 184.1, 167.6, 153.4, 151.5, 144.7,
136.1, 130.7, 129.2, 126.8, 122.1, 116.4, 101.5, 98.7, 51.3,
33.4, 20.6. MS (ES): m/z (%) = 381 (100) [M+1]+;Anal. calcd.
(%) for C21H17N2O3Cl: C, 66.23; H, 4.50; N, 7.36; Found (%):
C, 66.18; H, 4.46; N, 7.38.
3-(5-(4-Bromophenyl)-1-phenyl-4,5-dihydro-1H-
pyrazol-3-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (39):
Yellow solid; m.p. 148 °C; IR (KBr, νmax, cm–1): 3452, 3022,
1640, 1526, 1216, 1022; 1H NMR (CDCl3, 300 MHz): 13.25
(s,1H); 7.36-7.17 (m, 5H); 7.08-7.01 (m, 2H); 6.86-6.80 (m,
3H); 6.06 (s, 1H); 5.32 (dd, J = 8.4 Hz, J = 11.9 Hz); 4.08
(dd, J = 11.9 Hz, J = 14 Hz); 3.51 (dd, J = 7.9 Hz, J = 17.1
Hz); 2.26 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ = 191.8,
183.7, 167.2, 153.5, 148.4, 144.7, 136.2, 130.8, 129.2, 126.5,
122.1, 116.4, 101.5, 98.6, 51.7, 33.4, 20.5. MS (ES): m/z (%)
= 425 (100) [M+1]+; Anal. calcd. (%) for C21H17N2O3Br: C,
4-Hydroxy-6-methyl-3-(5-(3-nitrophenyl)-1-phenyl-
4,5-dihydro-1H-pyrazol-3-yl)-2H-pyran-2-one (42):Yellow
solid; m.p. 166 °C; IR (KBr, νmax, cm–1): 3452, 3022, 1640,
1
1526, 1216, 1022; H NMR (CDCl3, 300 MHz): 8.20-8.09
(m, 2H); 7.48-7.40 (m, 2H); 7.21-7.08 (m, 2H); 6.93-6.82 (m,
3H); 6.05 (s, 1H); 5.41 (dd, J = 8.4 Hz, J = 18 Hz); 4.24 (dd,
J = 12.4 Hz, J = 18 Hz); 3.51 (dd, J = 8.4 Hz, J = 16 Hz);
2.24 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 192.6, 185.6, 166.2,
158.8, 153.4, 142.1, 134.5, 131.2, 129.4, 124.7, 121.8, 116.5,
112.3, 103.8, 56.3, 37.4, 21.4. (ES): m/z (%) = 392 (100)
[M+1]+; Anal. calcd. (%) for C21H17N3O5: C, 64.45; H, 4.38;
N, 10.74; Found (%): C, 64.41; H, 4.33; N, 10.78.
RESULTS AND DISCUSSION
In this work, we developed a facile synthesis of a series of
20 substituted dihydropyrazoles. Dihydropyrazole analogues
were synthesized by reaction of various curcumin based chal-
cones having nitro, methoxy, chloro, bromo, flouro, benzyloxy,
methyl, amino functional groups at phenyl ring with phenylhy-
drazine. Designing and synthesis of curcumin based chalcone
analogues were reported [22,25]. Reaction of phenylhydrazine
with chalcone under neutral conditions leads to the formation
of corresponding dihydropyrazoles. The synthesis of designed
analogue is shown in Scheme-I. Chalcone analogues (3-22)
were synthesized from dehydroacetic acid (1) and substituted
benzaldehydes (2) via condensation reaction as earlier reported
procedure.
Further in an attempt to prepare corresponding dihydro-
pyrazole derivatives the chalcone analogues were reacted with

Vol. 31, No. 9 (2019)
Synthesis of New Dihydropyrazoles of Designed Curcumin Analogues 1893
phenyl hydrazine in refluxing condition to afford dihydro-
pyrazole derivatives. First we made our attempt in search of
optimum solvents and reaction conditions for this reaction.
To achieve this we selected reaction of unsubstituted chalcone
and phenyl hydrazine as model reaction and checked the feasi-
bility of various table solvents as methanol, ethanol, dichloro-
methane, chloroform, THF and DMF for the reaction and results
are summerized in Table-1. It is found that the use of ethanol
provides the desired heterocycle in best yield and minimum
time (Table-2). Hence we had chosen ethanol as solvent for
synthesis of dihydropyrazole nucleus.
spectrometric (mass) data. Prepared dihydropyrazole deriva-
tives were characterized by presence of an asymmetric carbon
adjacent to methylene carbon. Presence of optically active centre
adjacent to methylene carbon it made both the methylene
protons magnetically non-equivalent in nature which results
in presence of three different double doublets (dd) in proton
NMR spectra for each of three protons. Prepared dihydropyra-
zole derivatives also shown characteristic peaks in 13C NMR
at 192 ppm corresponding to carbonyl carbon in dihydro-
pyrazole structure. All of the prepared heterocycles shown
characterstic (M+1) peak in ESI mass spectra. In the process
of preparation of dihydropyrazoles library we have observed
a great deal of substituent effect on the rate and yield of
reaction. We have noticed that electron withdrawing substituent
like nitro and chloro groups reaction was taking longer time
for completion while with the substituent like methoxy and
N,N-dimethyl amino aromatic ring reaction time was short.
We have also noticed that dihydropyrazoles with nitro substi-
tution on phenyl ring were found to have poor solubility in
organic solvents. Possible explanation for this substituent effect
may be electronic displacement effect of substituent attached
with phenyl ring.
TABLE-1
SOLVENT OPTIMIZATION FOR SYNTHESIS
OF DIHYDROPYRAZOLE NUCLEUS
Entry No.
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
THF
DMF
Methanol
Ethanol
Dichloromethane
Chloroform
Acetonitrile
1,4-Dioxane
8
8
6
4
8
8
9
8
55
55
76
93
65
67
50
50
Conclusion
In summary, we have reported an efficient synthesis of
newly designed dihydropyrazoles. Synthetic methodology was
further established by synthesizing a series of 20 substituted
heterocyclic dihydropyrazoles. Structures of prepared hetero-
cycles were established by all the spectroscopic, spectrometric
and elemental analysis data. Appearance of double doublet
(dd) was also explained due to presence of asymmetric carbon
atom. The reported synthesis is an important finding in the
field of synthesis of heterocyclic compounds, which may be
useful for future drug discovery programme.
TABLE-2
SYNTHESIS OF CORRESPONDING PYRAZOLES
Compd.
23
R
H
Time (h)
Yield (%)
84
m.p. (°C)
167
155
152
150
200
205
180
141
130
162
158
164
162
138
157
153
149
161
166
145
7
6
6
6
7
7
9
4
4
4
7
5
5
4
6
4
7
4
6
7
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
4-OCH3
3- OCH3
3,4-(OCH3)2
4-NO2
87
85
85
84
2-NO2
89
N,N-(CH3)2
3-Cl
82
87
4-Cl
87
CONFLICT OF INTEREST
3,5-Cl2
3-OH,4-OCH3
3-OH
86
81
85
The authors declare that there is no conflict of interests
regarding the publication of this article.
4-OH
86
4-F
91
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2-OCH3
2-Cl
84
87
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