Synthesis of 1-substituted 3-aryl-5-aryl(hetaryl)-2-pyrazolines and study of their antitumor activity

Article abstract of DOI:10.1002/ardp.201100170

Three series of novel 1,3,5-trisubstituted 2-pyrazoline derivatives containing thiophene and benzodioxol moieties as potential antitumor agents were synthesized. The in vitro antitumor activity of the obtained compounds was determined at the National Canc

Full text of DOI:10.1002/ardp.201100170

Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
275
Full Paper
Synthesis of 1-Substituted 3-Aryl-5-aryl(hetaryl)-2-
pyrazolines and Study of Their Antitumor Activity
1
1
1
1
Braulio Insuasty , Leidy Chamizo , Jhon Munoz , Alexis Tigreros , Jairo Quiroga ,
1
˜
1
Rodrigo Abonıa , Manuel Nogueras , and Justo Cobo
2
2
´
1 Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, Cali, Colombia
2
´
Department of Inorganic and Organic Chemistry, Universidad de Jaen, Jaen, Spain
´
Three series of novel 1,3,5-trisubstituted 2-pyrazoline derivatives containing thiophene and
benzodioxol moieties as potential antitumor agents were synthesized. The in vitro antitumor
activity of the obtained compounds was determined at the National Cancer Institute (NCI). The 5-
(benzo[d][1,3]dioxol-5-yl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (9a) is the
most prominent of the compounds due to its remarkable activity toward leukemia (RPMI-8226),
renal cancer (UO-31) and prostate cancer (DU-145) cell lines with GI50 values of 1.88, 1.91 and 1.94 mM,
respectively.
Keywords: Antitumor activity / Chalcones / Hydrazine hydrate / N-Substituted pyrazolines / Thiosemicarbazide
Received: May 4, 2011; Revised: October 6, 2011; Accepted: October 14, 2011
DOI 10.1002/ardp.201100170
Introduction
As part of our ongoing research in the discovery of new active
anticancer compounds [9, 15, 20, 21], in this work we report the
synthesis and characterization of new N-substituted 2-pyrazo-
lines bearing benzodioxole and thiophene substituents and
the in vitro anticancer profiles of the selected compounds deter-
mined by the National Cancer Institute (NCI), USA.
Pyrazolines constitute an important heterocyclic family con-
taining nitrogen in their five-membered ring, and several
methods have been worked out for their synthesis [1–5].
Several pyrazoline derivatives have been found to possess
considerable biological activities, which have stimulated
the research activity in medicinal chemistry or chemical Results and discusion
biology. Recently, different authors worldwide have reported
pyrazoline derivatives with antiproliferative properties for
antitumor applications [6–11].
Chemistry
Since the milestone work of Fischer and Knoevenagel pub-
lished in the late 19th century, the reaction of a,b-unsatu-
rated carbonyl derivatives with hydrazines became a simple
and convenient procedure of general use for the synthesis of
2-pyrazolines [22–25].
On the other hand, the formation of the 1-substituted
derivatives is beneficial since the 1-substituted 2-pyrazolines
are stable compounds and can be used for biological and
pharmaceutical trials without the risk of undesirable
decomposition [12]. It is important to note that the introduc-
tion of a substituent group at the N-1 position has resulted in
increasing their antitumor activity [13]. In addition, hetero-
cyclic rings such as benzodioxole or thiophene are important
pharmacophores in the search for molecules with antitumor
activity [14–19].
In order to obtain the target pyrazolinic compounds the
starting 1-aryl-3-aryl(hetaryl)-2-propen-1-ones (chalcones) (1–3)
were previously synthesized by a Claisen–Schmidt conden-
sation between substituted arylketones and appropriate sub-
stituted aryl or heteroaryl aldehydes in NaOH/EtOH and under
reflux. Then, these intermediates 1–3 were treated with hydra-
zine hydrate (molar ratio 1:2) in acetic or formic acid and
thiosemicarbazide (molar ratio 1:2) in KOH/EtOH to afford the
desired products (4–11) in good yields (50–98%) (see Scheme 1).
In the 13C-NMR spectra of all new pyrazolines 4–11, the
chemical shift values of carbon atoms C-3 (167.6–149.9 ppm),
C-4 (41.3–42.9 ppm) and C-5 (55.2–63.7 ppm) confirm the
Correspondence: Braulio Insuasty, Heterocyclic Compounds Research
Group, Department of Chemistry, Universidad del Valle, A. A. 25360, Cali,
Colombia.
E-mail: braulio.insuasty@correounivalle.edu.co
Fax: þ57 2 33392440
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

276
B. Insuasty et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
Scheme 1. The structures of all new compounds 4–11 were elucidated by IR, 1H- and 13C-NMR and MS measurements. In the 1H-NMR
spectra of 2-pyrazolines 4–9, the three hydrogen atoms attached to the C-4 and C-5 carbon atoms of the heterocyclic ring gave an AMX
and the 2-pyrazolines 10, 11 showed an ABX spin system.
1
formation of the 2-pyrazoline framework. H- and 13C-NMR
chemical shifts of the N-acetyl, N-thiocarbamoyl and N-formyl
fragments have also been assigned in all cases. Finally, the
mass spectra of compounds 4–11 showed well-defined mol-
ecular ions with a characteristic fragmentation pattern
involving the loss of the arylnitrile (Ar-CN) molecule group
in all cases, involving the N-1 and C-3 atoms.
growth of that cell line by 50% (relative to untreated cells), TGI
as the molar concentration that causes total growth inhi-
bition, and LC50 which is a parameter of cytotoxicity and
reflects the molar concentration needed to kill 50% of the
cells [26]. The compounds were evaluated at five concentration
levels (100, 10, 1.0, 0.1, and 0.01 mM) and the test consisted of a
48 h continuous drug exposure protocol using the sulforho-
damide B (SRB) protein assay to estimate cell growth. Details of
this evaluation method, and the complementary information
related with the activity pattern over all cell lines, have been
published [27–29]. As shown in Table 2, compound 9a pre-
sented outstanding activity against the 60 human tumor cell
lines, being the most sensitive to growth inhibition of RPMI-
8226 of the leukemia panel with GI50 value of 1.88 mM, UO-31
of the renal cancer panel displaying a GI50 value of 1.91 mM
and DU-145 of prostate cancer with GI50 value of 1.94 mM
(cytotoxicity expressed as LC50 with values >100 mM for three
cell lines), where most of the GI50 values of the screening
process resulted in a sensitive range under 9.33 mM denoting
an outstanding activity. The values of cytotoxicity associated
with compound 9a measured as LC50 are in most of the cell
lines >100 mM (Table 1).
Preliminary in-vitro antitumor screening
The two-stage screening process started with the evaluation
of 18 compounds (4c, 4d, 4e, 4f, 5a, 5c, 5f, 6b, 7a, 7d, 7e, 7f, 9a,
9c, 9d, 9f, 10d and 10g) selected by the NCI, against 60 cell
lines at a single dose of 1.0 mM. The output from the single
dose screen was reported as a mean graph available for
analysis by the COMPARE program. The results of the primary
assay showed that compound 9a was declared active, while
the other compounds were essentially inactive.
Subsequently, a secondary screening process was per-
formed, in order to determine the cytostatic activity of this
compound, against the 60-cell panel representing leukemia,
melanoma and cancers of the lung, colon, ovary, breast, pros-
tate, CNS and kidney; where the testing results were expressed
according to the following three parameters: GI50 which is the
molar concentration of the compounds required to inhibit the
The antitumor activity related to this compound 9a could
be associated to the structural similitude with CA-4 and
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Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
Antitumor Activity of 1-Substituted 3-Aryl-5-aryl(hetaryl)-2-pyrazolines
277
Table 1. (continued )
Table 1. In vitro testing expressed as growth inhibition of cancer
cell lines for compound 9aa.
Panel/cell line
GI50b (mM)
LC50c (mM)
Panel/cell line
GI50b (mM)
LC50c (mM)
RXF 393
SN 12C
TK-10
4.28
3.37
2.47
1.91
>100
>100
>100
>100
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
2.50
2.42
2.89
3.02
1.88
3.08
>100
>100
>100
>100
>100
>100
UO-31
Prostate cancer
PC-3
DU-145
4.33
1.94
>100
>100
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
BT-549
Non-small-cell lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
3.23
4.71
2.82
2.89
3.22
2.68
>100
>100
>100
>100
>100
>100
3.19
2.54
3.56
2.12
2.49
3.71
2.51
2.60
2.40
>100
>100
>100
>100
>100
>100
>100
>100
>100
T-47D
MDA-MB-468
a
Data obtained from the in vitro disease-oriented human tumor
cell lines of the NCI screen [27–29].
b
GI50 was the drug concentration resulting in a 50% reduction in
the net protein increase (as measured by SRB staining) in control
cells during the drug incubation. Determined at five concen-
tration levels (100, 10, 1.0, 0.1, and 0.01 mM).
LC50 is a parameter of cytotoxicity and reflects the molar
concentration needed to kill 50% of the cells.
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
3.39
2.30
2.96
2.88
3.13
2.27
2.29
90.3
64.1
c
>100
>100
>100
>100
>100
analogues (Figure 1), which have shown important properties
as antitumor agents [6].
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
2.79
2.64
2.12
3.13
2.27
3.05
>100
>100
51.7
>100
>100
>100
Conclusion
We described herein the synthesis and biological activity
of new 2-pyrazoline derivatives bearing a benzodioxole or
thiophene moiety and with various substituted aryl groups
forming part of their structures. The anticancer screening
reveals that among the 18 2-pyrazolines evaluated, derivative
9a showed important activity against different cancer cell
lines with remarkable values in leukemia, renal and prostate
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
2.19
3.62
3.77
2.39
3.12
9.33
2.47
3.96
3.79
16.0
>100
>100
>100
>100
>100
>100
>100
>100
Ovarian cancer
IGROV1
2.42
2.07
3.40
2.79
3.29
2.90
2.35
>100
23.4
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
>100
>100
>100
>100
>100
Renal cancer
786-0
A498
ACHN
CAKI-1
3.80
2.24
3.58
2.60
>100
>100
>100
>100
continued
Figure 1. Molecular structures of CA-4, CA-4 PA and 9a.
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278
B. Insuasty et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
0
(Co -B), 108.9 (Cm-B), 122.3 (Co-B), 125.8 (Cm-A), 125.9 (Co-A), 129.6
cancer panels. Owing to the significant results obtained,
chemical studies are being conducted to modify structures
in order to improve the antitumor activity of such com-
pounds, as well as other biological studies focusing on anti-
viral and antifungal activities.
0
(Cp-A), 136.8 (Ci-A), 148.3 (Ci-B), 149.6 (Cm -B), 154.3 (Cp-B), 167.6
þ
–
(C-3), 168.4 (C O) ppm. MS (EI, 70 eV), m/z (%): 322 (28, M ), 279
–
(20), 205 (100), 148 (8). Anal. Calcd. for C19H18N2O3: C, 70.79; H,
5.63; N, 8.69. Found: C, 70.70; H, 5.71; N, 8.60.
1-Acetyl-3-(benzo[d][1,3]dioxol-5-yl)-5-(4-fluorophenyl)-
4,5-dihydro-1H-pyrazole (4c)
Experimental
Yield: 95%; m.p.: 1558C; FTIR (KBr) nmax/cmꢀ1: 3072 (C–H), 1657.89
1
(C O), 1596 (C N), 1485 (C C, Ar), 1222 (C–O). H NMR (400 MHz,
–
–
–
–
–
–
Melting points were determined in a Buchi melting point
apparatus and are uncorrected. The 1H and 13C NMR spectra
were run on a Bruker DPX 400 spectrometer operating at 400
and 100 MHz, respectively, using dimethyl sulfoxide-d6 and
chloroform-d1 as solvents and tetramethylsilane as internal
CDCl3) d: 2.41 (s, 3H, CH3), 3.09 (dd, 1H, H-4A, J4A-4M ¼ 17.57 Hz,
J4A-5 ¼ 4.52 Hz), 3.71 (dd, 1H, H-4M, J4M-4A ¼ 17.44 Hz, J4M-5
¼
11.92 Hz), 5.56 (dd, 1H, H-5, J5-4A ¼ 4.52 Hz, J5-4M ¼ 11.80 Hz),
0
6.04 (s, 2H, CH2), 6.84 (d, 1H, Ho -B, J ¼ 1.51 Hz), 7.01 (m, 2H,
standard. The mass spectra were obtained on
a Hewlett
Hm-A), 7.10 (d, 1H, Hm-B, J ¼ 8.03 Hz), 7.22 (m, 2H, Ho-A), 7.38
(dd, 1H, Ho-B, J ¼ 8.03 Hz, J ¼ 1.51 Hz) ppm. 13C NMR (100 MHz,
Packard HP Engine-5989 spectrometer (equipped with a direct
inlet probe) operating at 70 eV. The IR spectra (KBr disks) were
recorded on a Perkin Elmer 1650 spectrometer (USA). The
elemental analyses were obtained using a LECO CHNS-900
elemental analyzer.
0
CDCl3) d: 21.9 (CH3), 42.4 (C-4), 59.3 (C-5), 101.6 (CH2), 106.2 (Co -B),
2
108.3 (Co-B), 115.7 (Cm-B, JC-F ¼ 88 Hz), 121.7 (Cm-B), 125.6 (Cp-A,
1JC-F ¼ 251 Hz), 127.4 (Co-A, 3JC-F ¼ 32 Hz), 137.7 (Ci-A), 148.3 (Ci-B),
–
0
149.7 (Cm -B), 153.4 (C -B), 163.4 (C-3), 168.7 (C O) ppm. MS
–
p
(EI, 70 eV), m/z (%): 326 (73, Mþ), 283 (100), 205 (1), 148 (19).
Anal. Calcd. for C18H15FN2O3: C, 66.25; H, 4.63; N, 8.58. Found:
C, 66.17; H, 4.68; N, 8.51.
General procedure for the synthesis of derivatives 4, 7, 10
The appropriate chalcone 1, 2 or 3 (1.0 mmol) was dissolved
in 10.0 mL of acetic acid and vigorously stirred under
reflux with hydrazine hydrate (2.0 mmol) for 24 h. The desired
product precipitated from the reaction mixture. After cooling,
the solid was filtered off under vacuum and crystallized from
ethanol.
1-Acetyl-3-(benzo[d][1,3]dioxol-5-yl)-5-(4-chlorophenyl)-
4,5-dihydro-1H-pyrazole (4d)
Yield: 98%; m.p.: 1358C; FTIR (KBr) nmax/cmꢀ1: 2979 (C–H), 1654
1
(C O), 1560 (C N), 1430 (C C, Ar), 1241 (C–O). H NMR (400 MHz,
–
–
–
–
–
–
CDCl3) d: 2.40 (s, 3H, CH3), 3.08 (dd, 1H, H-4A, J4A-4M ¼ 17.44 Hz,
1-Acetyl-3-(benzo[d][1,3]dioxol-5-yl)-5-
(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole (4a)
J4A-5 ¼ 4.64 Hz), 3.70 (dd, 1H, H-4M, J4M-4A ¼ 17.57 Hz, J4M-5
¼
11.80 Hz), 5.55 (dd, 1H, H-5, J5-4A ¼ 4.64 Hz, J5-4M ¼ 11.67 Hz),
Yield: 94%; m.p.: 1418C; FTIR (KBr)nmax/cmꢀ1: 3098 (C–H), 1663
0
6.03 (s, 2H, CH2), 6.84 (d, 1H, Ho -B, J ¼ 1.51 Hz), 7.12 (d, 1H,
1
(C O), 1592 (C N), 1478 (C C, Ar), 1215 (C–O); H NMR (400 MHz,
Hm-B, J ¼ 8.03 Hz), 7.18 (d, 2H, Hm-A, J ¼ 8.53 Hz), 7.30 (d, 2H,
Ho-A, J ¼ 8.53 Hz), 7.37 (dd, 1H, Ho-B, J ¼ 8.03 Hz, J ¼ 1.76 Hz)
ppm. 13C NMR (100 MHz, CDCl3) d: 20.5 (CH3), 42.3 (C-4), 59.5
–
–
–
–
–
–
CDCl3) d: 2.39 (s, 3H, CH3), 3.10 (dd, 1H, H-4A, J4A-4M ¼ 17.44 Hz,
J4A-5 ¼ 4.57 Hz), 3.67 (dd, 1H, H-4M, J4M-4A ¼ 17.44 Hz, J4M-5
¼
0
(C-5), 101.5 (CH2), 106.3 (Co -B), 108.2 (Co-B), 121.6 (Cm-B), 125.6
11.67 Hz), 3.78 (s, 3H, CH3O), 5.54 (dd, 1H, H-5, J5-4A ¼ 4.52 Hz,
(Cp-A), 127.1 (Cm-A), 129.0 (Co-A), 140.4 (Ci-B), 148.3 (Ci-A), 153.4
0
0
J5-4M ¼ 11.54 Hz), 6.02 (s, 2H, CH2), 6.83 (d, 1H, H0 -B, J ¼ 1.51 Hz),
–
(Cm -B), 154.2 (C -B), 159.9 (C-3), 167.6 (C O) ppm. MS (EI, 70 eV),
–
6.84 (d, 2H, Hm-A, J ¼ 8.53 Hz), 7.13 (d, 1H, Hm-B, J ¼ 8.28 Hz),
7.14 (d, 2H, Ho-A, J ¼ 8.53 Hz), 7.37 (dd, 1H, Ho-B, J ¼ 8.03 Hz,
J ¼ 1.76 Hz) ppm; 13C NMR (100 MHz, CDCl3) d: 21.8 (CH3), 42.4
p
m/z (%): 342 (18, Mþ), 344 (6, Mþ2), 299 (100), 205 (10.0), 148 (7).
Anal. Calcd. for C18H15ClN2O3: C, 63.07; H, 4.41; N, 8.17. Found: C,
63.14; H, 4.49; N, 8.23.
0
(C-4), 55.2 (CH3O), 59.5 (C-5), 101.4 (CH2), 106.3 (Co -B), 108.2 (Cm-B),
114.3 (Co-B), 121.5 (Cp-A), 125.9 (Cm-A), 126.9 (Co-A), 134.2 (Ci-B),
0
ppm; MS (EI, 70 eV), m/z (%): 338 (97, Mþ), 295 (19), 205 (100), 148
(23). Anal. Calcd. for C19H18N2O4: C, 67.44; H, 5.36; N, 8.28. Found:
C, 67.35; H, 5.27; N, 8.33.
–
148.3 (Ci-A), 147.1 (Cm -B), 148.1 (C -B), 152.6 (C-3), 168.9 (C O)
–
p
1-Acetyl-3-(benzo[d][1,3]dioxol-5-yl)-5-
(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole (4e)
Yield: 85%; m.p.: 1018C; FTIR (KBr) nmax/cmꢀ1: 2998 (C-H), 1657.9
(C O), 1561 (C N), 1416.8 (C C, Ar), 1256.7 (C–O); 1H NMR
–
–
–
–
–
–
(400 MHz, CDCl3) d: 2.41 (s, 3H, CH3), 3.07 (dd, 1H, H-4A,
J4A-4M ¼ 17.57 Hz, J4A-5 ¼ 4.77 Hz), 3.73 (dd, 1H, H-4M,
1-Acetyl-3-(benzo[d][1,3]dioxol-5-yl)-5-p-tolyl-4,5-dihydro-
1H-pyrazole (4b)
J4M-4A ¼ 17.57 Hz, J4M-5 ¼ 12.05 Hz), 5.60 (dd, 1H, H-5, J5-4A
¼
Yield: 97%; m.p.: 1488C; FTIR (KBr) nmax/cmꢀ1: 3040.91 (C–H), 1656
4.77 Hz, J5-4M ¼ 11.80 Hz), 6.02 (s, 2H, CH2), 6.82 (d, 1H, H0 -B,
J ¼ 1.76 Hz), 7.08 (dd, 1H, Ho-B, J ¼ 8.03 Hz, J ¼ 1.76 Hz), 7.37
(d, 1H, Hm-B, J ¼ 8.03 Hz), 7.39 (d, 2H, Hm-A, J ¼ 8.28 Hz), 7.58
(d, 2H, Ho-A, J ¼ 8.28 Hz) ppm; 13C NMR (100 MHz, CDCl3) d: 21.9
0
(C O), 1599 (C N), 1462 (C C, Ar), 1260.5 (C–O). 1H NMR
–
–
–
–
–
–
(400 MHz, CDCl3) d: 2.20 (s, 3H, CH3), 2.27 (s, 3H, CH3), 3.06
(dd, 1H, H-4A, J4A-4M ¼ 18.07 Hz, J4A-5 ¼ 4.80 Hz), 5.48 (dd, 1H,
H-4M, J4M-4A ¼ 18.07 Hz, J4M-5 ¼ 11.92 Hz), 5.53 (dd, 1H, H-5,
J5-4A ¼ 4.27 Hz, J5-4M ¼ 11.80 Hz), 6.09 (s, 2H, CH2), 6.99 (d, 1H,
0
(CH3), 42.3 (C-4), 59.6 (C-5), 101.6 (CH2), 106.2 (Co -B), 108.3 (Co-B),
121.7 (Cm-A), 125.9 (Cm-B), 125.9 (Co-A),129.8 (Cp-A), 130.1 (Ci-B),
0
0
H0 -B, J ¼ 1.51 Hz), 7.05 (d, 2H, Hm-A, J ¼ 8.03 Hz), 7.12 (d, 2H,
145.7 (Ci-A), 148.3 (Cm -B), 149.0 (CF3), 149.8 (Cp-B), þ153.7 (C-3),
–
Ho-A, J ¼ 8.03 Hz), 7.24 (d, 1H, Hm-B, J ¼ 8.16 Hz), 7.36 (dd, 1H,
Ho-B, J ¼ 8.16 Hz, J ¼ 1.63 Hz) ppm. 13C NMR (100 MHz, CDCl3)
d: 20.9 (CH3), 21.0 (Ac-CH3), 42.6 (C-4), 59.6 (C-5), 102.1 (CH2), 106.4
168.8 (C O) ppm; MS (EI, 70 eV), m/z (%): 376 (100, M ), 333 (20),
–
205 (6), 148 (11). Anal. Calcd. for C19H15F3N2O3: C, 60.64; H, 4.02;
N, 7.44. Found: C, 60.56; H, 4.10; N, 7.36.
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Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
Antitumor Activity of 1-Substituted 3-Aryl-5-aryl(hetaryl)-2-pyrazolines
279
0
5.89 (s, 2H, CH2), 6.70 (m, 3H, Ho -A, Ho-A, Hm-A), 7.09 (m, 2H,
1-Acetyl-3-(benzo[d][1,3]dioxol-5-yl)-5-phenyl-4,5-
dihydro-1H-pyrazole (4f)
Hm-B), 7.71 (m, 2H, Ho-B) ppm; 13C NMR (100 MHz, CDCl3) d: 21.8
0
(CH3), 42.4 (C-4), 59.9 (C-5), 101.1 (CH2), 106.0 (Co -A), 108.5 (Co-A),
Yield: 89%; m.p.: 1148C; FTIR (KBr) nmax/cmꢀ1: 3042.5 (C–H),
115.8 (Cm-B, 2JC-F ¼ 88 Hz), 119.1 (Cm-A), 127.8 (Cp-B,
1651.2 (C O), 1597.1 (C N), 1456 (C C, Ar), 1260 (C–O); 1H
NMR (400 MHz, CDCl3) d: 2.41 (s, 3H, CH3), 3.11 (dd, 1H, H-4A,
–
–
–
–
–
–
1JC-F ¼ 259 Hz), 128.5 (Co-B, JC-F ¼ 32 Hz), 135.9 (Ci-A), 147.1
3
–
–
0
(Ci-B), 148.2 (Cm -A), 152.7 (C -A), 162.8 (C-3), 168.8 (C O) ppm;
p
J4A-4M ¼ 17.44 Hz, J4A-5 ¼ 4.64 Hz), 3.71 (dd, 1H, H-4M, J4M-4A
¼
MS (EI, 70 eV), m/z (%): 326 (100, Mþ), 283 (20), 205 (2), 148 (21).
Anal. Calcd. for C18H15FN2O3: C, 66.25; H, 4.63; N, 8.58. Found:
C, 66.19; H, 4.70; N, 8.50.
17.44 Hz, J4M-5 ¼ 11.67 Hz), 5.59 (dd, 1H, H-5, J5-4A ¼ 4.64 Hz,
0
J5-4M ¼ 11.67 Hz), 6.02 (s, 2H, CH2), 6.83 (d, 1H, H0 -B,
J ¼ 1.70 Hz), 7.11 (d, 1H, Hm-B, J ¼ 8.05 Hz), 7.22 (dd, 1H, Ho-B,
J ¼ 8.05 Hz, J ¼ 1.73 Hz), 7.30 (m, 5H, Ph-A) ppm; 13C NMR
(100 MHz, CDCl3) d: 21.7 (CH3), 42.5 (C-4), 60.0 (C-5), 101.5
1-Acetyl-5-(benzo[d][1,3]dioxol-5-yl)-3-(4-chlorophenyl)-
4,5-dihydro-1H-pyrazole (7d)
0
(CH2), 106.3 (Cm-B), 108.2 (Co -B), 121.6 (Co-B), 125.8 (Co-A), 127.6
Yield: 95%; m.p.: 1858C; FTIR (KBr) nmax/cmꢀ1: 3065 (C–H), 1649
(Cp-A), 128.8 (Cm-A), 141.9 (Ci-A), 148.3 (Ci-B), 149.6 (Cp-B), 153.5
–
1
(C O), 1597 (C N), 1497 (C C, Ar), 1241 (C–O); H NMR (400 MHz,
0
(Cm -B), 167.4 (C-3), 168.7 (C O) ppm; MS (EI, 70 eV), m/z (%): 308
–
–
–
–
–
–
–
(75, Mþ), 265 (100), 205 (25), 148 (25). Anal. Calcd. for C18H16N2O3:
C, 70.12; H, 5.23; N, 9.09. Found: C, 70.19; H, 5.15; N, 9.13.
CDCl3) d: 2.42 (s, 3H, CH3), 3.12 (dd, 1H, H-4A, J4A-4M ¼ 17.69 Hz,
J4A-5 ¼ 4.64 Hz), 3.72 (dd, 1H, H-4M, J4M-4A ¼ 17.69 Hz,
J4M-5 ¼ 11.92 Hz), 5.53 (dd, 1H, H-5, J5-4A ¼ 4.52 Hz, J5-4M
¼
0
11.80 Hz), 5.94 (s, 2H, CH2), 6.69 (s, 1H, H0 -A), 6.75 (m, 2H,
Ho-A, Hm-A), 7.41 (d, 2H, Hm-B, J ¼ 8.53 Hz), 7.68 (d, 2H, Ho-B,
J ¼ 8.53 Hz) ppm; 13C NMR (100 MHz, CDCl3) d: 21.9 (CH3),
1-Acetyl-5-(benzo[d][1,3]dioxol-5-yl)-3-
(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole (7a)
Yield: 98%; m.p.: 1398C; FTIR (KBr) nmax/cmꢀ1: 2925 (C–H), 1658
0
1
(C O), 1596 (C N), 1447 (C C, Ar), 1242 (C–O); H NMR (400 MHz,
42.3 (C-4), 60.0 (C-5), 101.1 (CH2), 106.0 (Co -A), 108.5 (Co-A),
–
–
–
–
–
–
108.9 (Co-B), 119.1 (Cm-A), 127.0 (Cm-B), 129.0 (Cp-B), 135.8 (Ci-A),
0
CDCl3) d: 2.42 (s, 3H, CH3), 3.12 (dd, 1H, H-4A,
J4A-4M ¼ 17.57 Hz, J4A-5 ¼ 4.52 Hz), 3.70 (dd, 1H, H-4M,
J4M-4A ¼ 17.57 Hz, J4M-5 ¼ 11.80 Hz), 3.74 (s, 3H, CH3O), 5.51
(dd, 1H, H-5, J5-4A ¼ 4.52 Hz, J5-4M ¼ 11.80 Hz), 5.93 (s, 2H,
–
–
136.3 (Ci-B), 147.1 (Cm -A), 148.10 (C -A), 152.60 (C-3), 168.90 (C O)
p
ppm; MS (EI, 70 eV), m/z (%): 342 (46, Mþ), 344 (15, Mþ2), 299 (100),
205 (49.0), 148 (33.2); Anal. Calcd. for C18H15ClN2O3: C, 63.07; H,
4.41; N, 8.17. Found: C, 63.13; H, 4.49; N, 8.25.
0
CH2), 6.73 (m, 3H, H0 -A, Ho-A, Hm-A), 6.96 (d, 2H, Hm-B,
J ¼ 8.78 Hz), 7.70 (d, 2H, Ho-B, J ¼ 8.78 Hz) ppm; 13C NMR
(100 MHz, CDCl3) d: 21.9 (CH3), 42.5 (C-4), 53.4 (C-5), 59.6 (CH3),
0
101.1 (CH2), 106.0 (Co -A), 108.5 (Co-A), 114.2 (Cm-B), 119.1 (Cm-A),
1-Acetyl-5-(benzo[d][1,3]dioxol-5-yl)-3-
(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole (7e)
0
124.1 (Cp-B), 128.2 (Co-B), 136.1 (Ci-A), 146.9 (Ci-B), 148.1 (Cm -A),
Yield: 82%; m.p.: 1348C; FTIR (KBr) nmax/cmꢀ1: 2999 (C H), 1672
–
–
(C O), 1594 (C N), 1459 (C C, Ar), 1253 (C–O); H NMR (400 MHz,
–
153.6 (C -A), 161.4 (C-3), 168.7 (C O) ppm; MS (EI, 70 eV), m/z (%):
1
–
p
–
–
–
–
–
–
338 (100, Mþ), 299 (30), 295 (15), 148 (25). Anal. Calcd. for
C19H18N2O4: C, 67.44; H, 5.36; N, 8.28. Found: C, 67.36; H,
5.29; N, 8.36.
CDCl3) d: 2.46 (s, 3H, CH3), 2.99 (dd, 1H, H-4A, J4A-4M ¼ 17.82 Hz,
J4A-5 ¼ 4.50 Hz), 3.76 (dd, 1H, H-4M, J4M-4A ¼ 17.82 Hz, J4M-5
¼
12.05 Hz), 5.96 (dd, 1H, H-5, J5-4A ¼ 4.89 Hz, J5-4M ¼ 11.67 Hz),
0
6.00 (s, 2H, CH2), 6.86 (d, 1H, H0 -A, J ¼ 1.70 Hz), 7.21 (d, 1H,
1-Acetyl-5-(benzo[d][1,3]dioxol-5-yl)-3-p-tolyl-4,5-dihydro-
1H-pyrazole (7b)
Hm-A, J ¼ 8.10 Hz), 7.56 (m, 4H, Hm-B, Ho-B) 7.72 (dd, 1H, Ho-A,
J ¼ 8.00 Hz, J ¼ 1.72 Hz) ppm; 13C NMR (100 MHz, CDCl3) d: 21.8
(CH3), 42.9 (C-4), 56.6 (C-5), 101.6 (Cm-B), 106.2 (CH2), 107.9 (Co-B),
Yield: 97%; m.p.: 1688C; FTIR (KBr) nmax/cmꢀ1: 3065 (C–H), 1649
1
(C O), 1595 (C N), 1494 (C C, Ar), 1241 (C–O); H NMR (400 MHz,
0
108.2 (Co -A), 121.7 (Co-A), 128.6 (Cm-A), 131.9 (Cp-A), 132.8 (Ci-A),
–
–
–
–
CDCl3) d: 2.19 (s, 3H, CH3), 2.43 (s, 3H, CH3), 3.12 (dd, 1H,
–
–
0
141.8 (Ci-B), 148.3 (Cm -A), 149.7 (CF3), 153.2 (Cp-A), þ156.8 (C-3),
–
168.5 (C O) ppm; MS (EI, 70 eV), m/z (%): 376 (75, M ), 333 (25),
–
205 (100), 148 (13); Anal. Calcd. for C19H15F3N2O3: C, 60.64; H,
4.02; N, 7.44. Found: C, 60.55; H, 4.08; N, 7.39.
H-4A, J4A-4M ¼ 17.57 Hz, J4A-5 ¼ 4.52 Hz), 3.71 (dd, 1H, H-4M,
J4M-4A ¼ 17.57 Hz, J4M-5 ¼ 11.80 Hz), 5.53 (dd, 1H, H-5, J5-4A
¼
0
4.39 Hz, J5-4M ¼ 11.67 Hz), 5.94 (s, 2H, CH2), 6.69 (d, 1H, H0 -A,
J ¼ 1.40 Hz), 6.75 (m, 2H, Ho-A, Hm-A), 7.40 (d, 2H, Hm-B,
J ¼ 8.53 Hz), 7.43 (d, 2H, J ¼ 8.53 Hz) ppm; 13C NMR
(100 MHz, CDCl3) d: 21.9 (CH3), 42.5 (CH3), 55.4 (C-4), 59.6 (C-5),
1-Acetyl-5-(benzo[d][1,3]dioxol-5-yl)-3-phenyl-4,5-
dihydro-1H-pyrazole (7f)
0
101.1 (CH2), 106.0 (Co -A), 108.5 (Co-A), 114.2 (Cm-B), 119.1 (Cm-A),
0
124.1 (Cp-B), 128.2 (Co-B), 136.1 (Ci-A), 146.9 (Ci-B), 148.1 (Cm -A),
Yield: 91%; m.p.: 1498C; FTIR (KBr) nmax/cmꢀ1: 3071 (C–H),
1654 (C O), 1590 (C N), 1414 (C C, Ar), 1243 (C–O); 1H NMR
(400 MHz, CDCl3) d: 2.44 (s, 3H, CH3), 3.16 (dd, 1H, H-4a,
–
–
–
–
–
–
–
153.6 (C -A), 161.4 (C-3), 168.7 (C O) ppm; MS (EI, 70 eV), m/z (%):
–
p
322 (100, Mþ), 279 (24), 205 (4), 148 (12). Anal. Calcd. for
C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.72; H,
5.69; N, 8.63.
J4A-4M ¼ 17.69 Hz, J4A-5 ¼ 4.64 Hz), 3.74 (dd, 1H, H-4M, J4M-4A
¼
17.57 Hz, J4M-5 ¼ 11.80 Hz), 5.53 (dd, 1H, H-5, J5-4A ¼ 4.52 Hz,
0
J5-4M ¼ 11.80 Hz), 6.03 (s, 2H, CH2), 6.71 (d, 1H, H0 -A,
J ¼ 1.04 Hz), 6.76 (m, 2H, Ho-A, Hm-A), 7.60 (m, 5H, H-Ph) ppm;
13C NMR (100 MHz, CDCl3) d: 21.9 (CH3), 42.4 (C-4), 59.8 (C-5),
1-Acetyl-5-(benzo[d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-
4,5-dihydro-1H-pyrazole (7c)
0
101.1 (CH2), 106.0 (Co -A), 108.5 (Co-A), 119.1 (Cm-A), 126.6 (Cm-B),
128.7 (Co-B), 130.3 (Cp-B), 131.4 (Ci-A), 135.9 (Ci-B), 147.0 (Cm -A),
Yield: 90%; m.p.: 1478C; FTIR (KBr) nmax/cmꢀ1: 3092 (C–H), 1654
0
1
(C O), 1593 (C N), 1442 (C C, Ar), 1233 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
–
–
148.1 (C -A), 153.8 (C-3), 168.9 (C O) ppm; MS (EI, 70 eV), m/z (%):
p
CDCl3) d: 2.38 (s, 3H, CH3), 3.09 (dd, 1H, H-4A, J4A-4M ¼ 17.57 Hz,
308 (78, Mþ), 265 (100), 205 (40), 148 (24); Anal. Calcd. for
C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 70.18; H,
5.15; N, 9.15.
J4A-5 ¼ 4.52 Hz), 3.67 (dd, 1H, H-4M, J4M-4A ¼ 17.57 Hz, J4M-5
¼
11.80 Hz), 5.50 (dd, 1H, H-5, J5-4A ¼ 4.64 Hz, J5-4M ¼ 11.67 Hz),
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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280
B. Insuasty et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
6.79 (d, 1H, H-3’, J ¼ 3.4 Hz), 7.56 (d, 2H, Ho-B, J ¼ 8.7 Hz), 7.61
(d, 2H, Hm-B, J ¼ 8.6 Hz) ppm; 13C NMR (100 MHz, CDCl3) d: 15.3
(CH3-thiophene), 22.0 (CH3-Ac), 41.6 (C-4), 56.1 (C-5), 124.6 (Ci-B),
124.7 (C-4’), 124.7 (C-3’), 128.0 (Co-B) 130.3 (Cp-B), 132.0 (Cm-B),
1-Acetyl-5-(5-methylthiophen-2-yl)-3-(4-methoxyphenyl)-
4,5-dihydro-1H-pyrazole (10a)
Yield: 52%; m.p.: 968C, FTIR (KBr) nmax/cmꢀ1: 1648 (C O), 1601
–
–
(C N); 1H NMR (400 MHz, CDCl3) d: 2.37 (s, 3H, CH3-Ac), 2.39
–
–
–
139.3 (C-5’), 141.4 (C-2’), 152.7 (C-3), 169.1 (C O) ppm; MS
–
(d, 3H, CH3–thiophene, 4J ¼ 0.9 Hz), 3.29 (dd, 1H, H-4A,
(EI, 70 eV), m/z (%): 362 (22, Mþ), 364 (21, Mþ2þ), 319/321
(47/56), 287/289 (16/17), 181 (65); Anal. Calcd. for
C16H15BrN2OS: C, 52.90; H, 4.16; N, 7.71. Found: C, 52.82; H,
4.17; N, 7.80.
J4A-4B ¼ 17.1 Hz,
J4A-5 ¼ 3.9 Hz),
3.63
(dd,
1H,
H4B,
J4B-5 ¼ 11.3 Hz, J4B-4A ¼ 17.4 Hz), 3.85 (s, 3H, OCH3), 5.79
(dd, 1H, H-5, J5-4A ¼ 3.8 Hz, J5-4B ¼ 11.3 Hz), 6.54 (dd, 1H, H-4’,
4J ¼ 1.0 Hz, J ¼ 3.4 Hz), 6.79 (d, 1H, H-3’, J ¼ 3.4 Hz), 6.94 (d, 2H,
Hm-B, J ¼ 8.8 Hz), 7.69 (d, 2H, Ho-B, J ¼ 8.8 Hz) ppm; 13C NMR
(100 MHz, CDCl3) d: 15.3 (CH3-thiophene), 22.0 (CH3-Ac), 41.8
(C-4), 55.3 (C-5), 55.4 (OCH3) 114.2 (Cm-B), 124.0 (Ci-B), 124.5
(C-4’), 124.7 (C-3’), 128.2 (Co-B), 139.1 (C-5’), 141.8 (C-2’), 153.7
1-Acetyl-5-(5-methylthiophen-2-yl)-3-(benzo[d][1,3]dioxol-
5-yl)-4,5-dihydro-1H-pyrazole (10h)
Yield: 52%; m.p.: 1348C, IR (KBr) nmax/cmꢀ1: 1654 (C O), 1589
–
–
(C N); H NMR (400 MHz, CDCl ) d: 2.36 (s, 3H, CH -thiophene),
1
–
(C-3), 161.4 (C -B), 168.8 (C O) ppm; MS (EI, 70 eV), m/z (%):
–
–
p
–
3
3
314 (87, Mþ), 271 (100), 256 (30), 239 (28); Anal. Calcd.
for C17H18N2O2S: C, 64.94; H, 5.77; N, 8.91. Found: C, 64.91;
H, 5.70; N, 8.99.
2.39 (s, 3H, CH3-Ac), 3.26 (dd, 1H, H-4A, J4A-5 ¼ 3.9 Hz, J4A-4B
¼
17.4 Hz), 3.61 (dd, 1H, H4-B, J4B-5 ¼ 11.3 Hz, J4B-4A ¼ 17.4 Hz),
5.79 (dd, 1H, H-5, J5-4A ¼ 3.8 Hz, J5-4B ¼ 11.3 Hz), 6.02 (s, 2H,
CH2), 6.54 (d, 1H, H-4’, J ¼ 3.4 Hz), 6.78 (d, 1H, H-3’,
J ¼ 3.4 Hz), 6.83 (d, 1H, Hm-B, J ¼ 8.0 Hz), 7.11 (dd, 1H, Ho-B,
4J ¼ 1.6 Hz, 3J ¼ 8.1 Hz), 7.36 (d, 1H, Ho’-B, J ¼ 1.5 Hz) ppm;
13C NMR (100 MHz, CDCl3) d: 15.3 (CH3-thiophene), 22.0
1-Acetyl-5-(5-methylthiophen-2-yl)-3-p-tolyl-4,5-dihydro-
1H-pyrazole (10b)
Yield: 56%; m.p.: 1098C, FTIR (KBr) nmax/cmꢀ1: 1648 (C O), 1588
–
–
0
(CH3-Ac), 41.9 (C-4), 55.4 (C-5), 101.6 (CH2), 106.2 (Co -B) 108.3
(C N); 1H NMR (400 MHz, CDCl3) d: 2.38 (s, 3H, CH3–Ar), 2.39
–
–
(s, 6H, CH3–Ac, CH3-thiophene), 3.30 (dd, 1H, H-4A, J4A-4B
(Cm-B), 121.6 (Co-B), 124.6 (C-4’), 124.7 (C-3’), 125.7 (Ci-B), 139.2
(C-5’), 141.7 (Cm‘-B), 148.3 (Cp-B), 149.6 (C-2‘), 153.5 (C-3), 168.7
¼
17.1 Hz, J4A-5 ¼ 3.9 Hz), 3.64 (dd, 1H, H4-B, J4B-5 ¼ 11.4 Hz,
þ
–
(C O) ppm; MS (EI, 70 eV), m/z (%): 328 (100, M ), 285 (97), 270
–
J4B-4A ¼ 17.5 Hz), 5.79 (dd, 1H, H-5, J5-4A ¼ 3.9 Hz, J5-4B
¼
(31); Anal. Calcd. for C17H16N2O3S: C, 62.18; H, 4.91; N, 8.53.
Found: C, 62.11; H, 4.94; N, 8.59.
11.3 Hz), 6.54 (d, 1H, H-4’, J ¼ 3.4 Hz), 6.79 (d, 1H,
H-3’, J ¼ 3.4 Hz), 7.23 (d, 2H, Hm-B, J ¼ 8.0 Hz), 7.63 (d, 2H,
Ho-B, J ¼ 8.2 Hz) ppm; 13C NMR (100 MHz, CDCl3) d: 15.3
(CH3-thiophene), 21.5 (CH3-Ar), 22.0 (CH3-Ac), 41.8 (C-4), 55.3
(C-5), 124.6 (C-4’), 124.7 (C-3’), 126.6 (Cm-B), 128.6 (Ci-B), 129.5
1-Acetyl-5-(5-methylthiophen-2-yl)-3-(4-nitrophenyl)-4,5-
dihydro-1H-pyrazole (10i)
Yield: 84%; m.p.: 1478C, FTIR (KBr) nmax/cmꢀ1: 1661 (C O), 1598
(Co-B), 139.2 (C-5’), 140.7 (C-2’), 141.8 (Cp-B), 154.0 (C-3), 168.8
þ
–
–
(C N), 1510 and 1346 (NO ); 1H NMR (400 MHz, CDCl3) d: 2.40
–
(C O) ppm; MS (EI, 70 eV), m/z (%): 298 (45, M ), 255 (100), 223
–
–
–
(s, 6H, CH3 Ac, CH3-thiophene), 3.35 (dd, 1H, H-4A, J4A-4B
2
(35), 181 (38); Anal. Calc. for C17H18N2OS: C, 68.42; H, 6.08; N,
9.39. Found: C, 68.49; H, 6.17; N, 9.30.
¼
17.6 Hz, J4A-5 ¼ 3.9 Hz), 3.71 (dd, 1H, H-4B, J4B-4A ¼ 17.6 Hz,
J4B-5 ¼ 11.5 Hz), 5.87 (dd, 1H, H-5, J5-4A ¼ 4.1 Hz, J5-4B ¼ 11.5 Hz),
6.56 (d, 1H, H-4’, J ¼ 3.6 Hz), 6.81 (d, 1H, H-3’, J ¼ 3.4 Hz), 7.90
(d, 2H, Ho-B, J ¼ 8.8 Hz) 8.28 (d, 2H, Hm-B, J ¼ 8.8 Hz) ppm;
13C NMR (100 MHz, CDCl3) d: 15.3 (CH3-thiophene), 22.0
(CH3-Ac), 41.5 (C-4), 56.1 (C-5), 124.0 (Cm-B), 124.9 (C-4’), 125.0
(C-3’), 127.2 (Co-B), 137.4 (Cp-B), 139.6 (C-5’), 141.0 (C-2’), 148.5
1-Acetyl-5-(5-methylthiophen-2-yl)-3-(4-chlorophenyl)-
4,5-dihydro-1H-pyrazole (10d)
Yield: 52%; m.p.: 1078C, FTIR (KBr) nmax/cmꢀ1: 1648 (C O), 1590
–
–
(C N); 1H NMR (400 MHz, CDCl3) d: 2.37 (s, 3H, CH3-Ac), 2.39
–
–
(s, 3H, CH3-thiophene), 3.29 (dd, 1H, H-4A, J4A-5 ¼ 4.0 Hz, J4A-4B
¼
–
(C -B), 151.4 (C-3), 169.1 (C O) ppm; MS (EI, 70 eV), m/z (%): 329
–
i
17.5 Hz), 3.64 (dd, 1H, H4-B, J4B-5 ¼ 11.4 Hz, J4B-4A ¼ 17.6 Hz),
5.81 (dd, 1H, H-5, J5-4A ¼ 3.9 Hz, J5-4B ¼ 11.4 Hz), 6.55 (dd, 1H,
H-4’, 4J ¼ 0.8 Hz, J ¼ 3.4 Hz), 6.79 (d, 1H, H-3’, J ¼ 3.4 Hz), 7.40
(d, 2H, Ho-B, J ¼ 8.6 Hz), 7.67 (d, 2H, Hm-B, J ¼ 8.5 Hz) ppm;
13C NMR (100 MHz, CDCl3) d: 15.2 (CH3-thiophene), 22.0
(CH3-Ac), 41.6 (C-4), 55.6 (C-5), 124.7 (C-4’), 124.8 (C-3’), 127.8
(Co-B), 129.0 (Cm-B), 129.9 (Ci-B), 136.3 (Cp-B), 139.3 (C-5’), 141.5
–
(17, Mþ), 286 (82), 254 (40), 181 (100); Anal. Calcd. for
C16H15N3O3S: C, 58.34; H, 4.59; N, 12.76. Found: C, 58.39; H,
4.50; N, 12.79.
General procedure for the synthesis of derivatives 5 and 8
The appropriate chalcone 1 or 2 (1.0 mmol) was dissolved in
5.0 mL of formic acid and vigorously stirred at reflux with
hydrazine hydrate (2.0 mmol) for 24 h. The desired product
precipitated from the reaction mixture after cooling, was filtered
off under vacuum and crystallized from ethanol.
(C-2’), 152.7 (C-3), 168.8 (C O) ppm; MS (EI, 70 eV), m/z (%): 318 (36,
–
Mþ), 320 (13, Mþ2þ), 275 (100), 260 (33), 243 (41), 181 (77); Anal.
Calcd. for C16H15ClN2OS: C, 60.28; H, 4.74; N, 8.79. Found: C,
60.22; H, 4.83; N, 8.81.
3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-methoxyphenyl)-4,5-
dihydro-1H-pyrazole-1-carbaldehyde (5a)
1-Acetyl-5-(5-methylthiophen-2-yl)-3-(4-bromophenyl)-
4,5-dihydro-1H-pyrazole (10g)
Yield: 86%; m.p.: 1698C; FTIR (KBr) nmax/cmꢀ1: 3009 (C–H), 1666
Yield: 53%; m.p.: 1168C, FTIR (KBr) nmax/cmꢀ1: 1648 (C O) 1601
–
–
1
(C O), 1598 (C N), 1442 (C C, Ar), 1219 (C–O); H NMR (400 MHz,
(C N); 1H NMR (400 MHz, CDCl3) d: 2.38 (s, 3H, CH3-Ac), 2.39
–
–
–
–
–
–
–
–
(d, 3H, CH3-thiophene, 4J ¼ 0.8 Hz), 3.29 (dd, 1H, H-4A,
CDCl3) d: 3.16 (dd, 1H, H-4A, J4A-4M ¼ 18.07 Hz, J4A-5 ¼ 4.77 Hz),
3.81 (s, 3H, CH3), 3.84 (dd, 1H, H-4M, J4M-4A ¼ 18.07 Hz, J4M-5
¼
J4A-5 ¼ 4.0 Hz, J4A-4B ¼ 17.5 Hz), 3.65 (dd, 1H, H4-B, J4B-5
¼
11.54 Hz), 5.43 (dd, 1H, H-5, J5-4A ¼ 4.64 Hz, J5-4M ¼ 11.67 Hz),
11.4 Hz, J4B-4A ¼ 17.6 Hz), 5.82 (dd, 1H, H-5, J5-4A ¼ 4.0 Hz,
J5-4B ¼ 11.4 Hz), 6.55 (dd, 1H, H-4’, 4J ¼ 1.1 Hz, J ¼ 3.4 Hz),
0
5.99 (s, 2H, CH2), 6.71 (d, 1H, Ho -B, J ¼ 1.50 Hz), 6.78 (dd, 1H,
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Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
Antitumor Activity of 1-Substituted 3-Aryl-5-aryl(hetaryl)-2-pyrazolines
281
Hm-B, J ¼ 8.03 Hz, J ¼ 1.51 Hz), 6.86 (d, 1H, Hm-B, J ¼ 8.03 Hz),
7.78 (d, 2H, Ho-A, J ¼ 8.58 Hz), 7.89 (d, 2H, Hm-A, J ¼ 8.58 Hz), 8.85
(s, 1H, CHO) ppm; 13C NMR (100 MHz, CDCl3) d: 42.6 (C-4), 55.3
Anal. Calcd. for C17H13ClN2O3: C, 62.11; H, 3.99; N, 8.52. Found: C,
62.16; H, 4.05; N, 8.61.
0
(C-5), 58.6 (CH3), 101.5 (CH2), 106.4 (Co -B), 108.3 (Cm-B), 114.4
(Co-A), 121.7 (Co-B), 125.4 (Ci-B), 127.0 (Cm-A), 132.9 (Cp-A), 148.3
3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-(trifluoromethyl)phenyl)-
4,5-dihydro-1H-pyrazole-1-carbaldehyde (5e)
–
0
(Ci-A), 149.8 (Cm -B), 155.2 (C -B), 159.4 (C-3), 159.9 (C O) ppm; MS
–
p
Yield: 81%; m.p.: 1578C; FTIR (KBr) nmax/cmꢀ1: 2932 (C–H), 1625
(EI, 70 eV), m/z (%): 324 (89, Mþ), 295 (2), 189 (21), 148 (39).
Anal. Calcd. for C18H16N2O4: C, 66.66; H, 4.97; N, 8.64. Found:
C, 66.61; H, 4.91; N, 8.70.
1
(C O), 1600 (C N), 1454 (C C, Ar), 1217 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
CDCl3) d: 3.21 (dd, 1H, H-4A, J4A-4M ¼ 17.82 Hz, J4A-5 ¼ 5.27 Hz),
3.92 (dd, 1H, H-4M, J4M-4A ¼ 18.20 Hz, J4M-5 ¼ 11.92 Hz), 5.62
(dd, 1H, H-5, J5-4A ¼ 4.89 Hz, J5-4M ¼ 11.67 Hz), 6.08 (s, 2H,
CH2), 6.98 (s, 1H, Ho‘-B), 7.26 (m, 2H, Ho-B, Hm-B), 7.61 (d, 2H,
Ho-A, J ¼ 8.03 Hz), 7.70 (d, 2H, Hm-A, J ¼ 8.03 Hz), 8.93 (s, 1H,
CHO) ppm; 13C NMR (100 MHz, CDCl3) d: 42.7 (C-4), 58.6 (C-5),
3-(Benzo[d][1,3]dioxol-5-yl)-5-p-tolyl-4,5-dihydro-1H-
pyrazole-1-carbaldehyde (5b)
Yield: 95%; m.p.: 1708C; FTIR (KBr) nmax/cmꢀ1: 2919 (C–H), 1652
1
(C O), 1604 (C N), 1461 (C C, Ar), 1221 (C–O); H NMR (400 MHz,
0
101.5 (CH2), 102.1 (Co -B), 106.6 (Co-B), 108.9 (Cm-B), 122.5 (Co-A),
0
125.4 (Ci-B), 126.0 (Cp-A), 127.2 (Cm-A), 148.4 (Ci-A), 149.9 (Cm -B),
–
–
–
–
–
–
CDCl3) d: 2.43 (s, 3H, CH3), 3.16 (dd, 1H, H-4A, J4A-4M ¼ 17.57 Hz,
–
156.2 (C -B), 159.2 (CF ), 160.0 (C-3), 166.9 (C O) ppm; MS
–
p
3
J4A-5 ¼ 4.77 Hz), 3.75 (dd, 1H, H-4M, J4M-4A ¼ 17.57 Hz,
(EI, 70 eV), m/z (%): 362 (78, Mþ), 333 (100), 148 (17); Anal.
Calcd. for C18H13F3N2O3: C, 59.67; H, 3.62; N, 7.73. Found: C,
59.61; H, 3.68; N, 7.79.
J4M-5 ¼ 11.54 Hz), 5.50 (dd, 1H, H-5, J5-4A ¼ 4.77 Hz, J5-4M
¼
11.54 Hz), 6.04 (s, 2H, CH2), 6.85 (d, 1H, Ho‘-B, J ¼ 1.70 Hz),
7.11 (dd, 1H, Hm-B, J ¼ 8.03 Hz, J ¼ 1.76 Hz), 7.16 (s, 4H, H-A),
7.38 (d, 1H, Ho B, J ¼ 8.15 Hz), 8.94 (s, 1H, CHO) ppm; 13C NMR
(100 MHz, CDCl3) d: 21.1 (CH3), 42.8 (C-4), 58.9 (C-5), 101.6 (CH2),
3-(Benzo[d][1,3]dioxol-5-yl)-5-phenyl-4,5-dihydro-1H-
pyrazole-1-carbaldehyde (5f)
0
106.3 (Co -B), 108.3 (Cm-B), 121.8 (Co-A), 125.3 (Co-B), 125.6 (Ci-B),
0
129.7 (Cm-A), 137.7 (Cp-A), 137.8 (Ci-A), 148.3 (Cm -B), 149.8 (Cp-þB),
Yield: 93%; m.p.: 1588C; FTIR (KBr) nmax/cmꢀ1: 2921 (C–H), 1706
–
155.5 (C-3), 159.9 (C O) ppm; MS (EI, 70 eV), m/z (%): 308 (29, M ),
1
(C O), 1610 (C N), 1464 (C C, Ar), 1225 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
–
279 (100), 189 (22), 148 (14); Anal. Calcd. for C18H16N2O3: C, 70.12;
H, 5.23; N, 9.09. Found: C, 70.05; H, 5.16; N, 9.04.
CDCl3) d: 3.18 (dd, 1H, H-4A, J4A-4M ¼ 17.57 Hz, J4M-5 ¼ 4.77 Hz),
3.76 (dd, 1H, H-4M, J4M-4A ¼ 17.57 Hz, J4M-5 ¼ 11.54 Hz), 5.52 (dd,
1H, H-5, J5-4A ¼ 4.77 Hz, J5-4M ¼ 11.54 Hz), 6.03 (s, 2H, CH2), 6.84
0
(dd, 1H, Ho -B, J ¼ 1.51 Hz), 7.14 (dd, 1H, Hm-B, J ¼ 8.16 Hz,
3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-fluorophenyl)-4,5-
dihydro-1H-pyrazole-1-carbaldehyde (5c)
J¼ 1.63 Hz), 7.30 (m, 6H, Ho-B, H-A), 8.95 (s, 1H, CHO) ppm;
13C NMR (100 MHz, CDCl3) d: 42.7 (C-4), 59.1 (C-5), 101.1 (CH2),
Yield: 87%; m.p.: 1878C; FTIR (KBr) nmax/cmꢀ1: 2916 (C–H), 1659
0
106.4 (Co -B), 108.3 (Cm-B), 121.8 (Co-B), 125.2 (Ci-B), 125.4 (Co-A),
1
(C O), 1600 (C N), 1479 (C C, Ar), 1228 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
0
126.8 (Cp-A), 127.8 (Cm-A), 140.7 (Ci-A), 148.4 (Cm -B), 149.8 (Cp-þB),
CDCl3) d: 3.16 (dd, 1H, H-4A, J4A-4M ¼ 17.69 Hz, J4A-5 ¼ 4.89 Hz),
3.78 (dd, 1H, H-4M, J4M-4A ¼ 17.69 Hz, J4M-5 ¼ 11.67 Hz), 5.52
(dd, 1H, H-5, J5-4A ¼ 4.77 Hz, J5-4M ¼ 11.54 Hz), 6.05 (s, 2H,
CH2), 6.86 (d, 1H, Ho‘-B, J ¼ 1.52 Hz), 7.05 (t, 2H, Hm-A,
J ¼ 8.66 Hz), 7.13 (dd, 1H, Hm-B, J ¼ 8.16 Hz, J ¼ 1.63 Hz), 7.25
(dd, 2H, Hm-A, J ¼ 8.78 Hz, J ¼ 5.02 Hz), 7.37 (d, 1H, Ho-B,
J ¼ 1.51 Hz), 8.99 (s, 1H, CHO) ppm; 13C NMR (100 MHz,
–
155.2 (C-3), 159.9 (C O) ppm; MS (EI, 70 eV), m/z (%): 294 (100, M ),
–
191 (28), 148 (12); Anal. Calcd. for C17H14N2O3: C, 69.38; H, 4.79;
N, 9.52. Found: C, 69.30; H, 4.77; N, 9.47.
5-(Benzo[d][1,3]dioxol-5-yl)-3-(4-methoxyphenyl)-4,5-
dihydro-1H-pyrazole-1-carbaldehyde (8a)
Yield: 92%; m.p.: 1678C; FTIR (KBr) nmax/cmꢀ1: 2988 (C–H), 1674
0
CDCl3) d: 42.7 (C-4), 58.4 (C-5), 101.7 (CH2), 106.3 (Co -B), 108.3
(Cm-B), 115.9 (Co-A, 3JC-F¼ 84), 121.9 (Co-B), 125.1 (Ci-B), 127.2 (Cm-A,
1
(C O), 1587 (C N), 1435 (C C, Ar), 1210 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
2
1
0
JC-F ¼ 32), 136.5 (Cp-A, JC-F ¼ 259 Hz), 148.4 (Ci-A), 149.9 (Cm -B),
CDCl3) d: 3.17 (dd, 1H, H-4A, J4A-4M ¼ 18.07 Hz, J4A-5 ¼ 4.77 Hz),
–
–
155.2 (C -B), 159.9 (C-3), 163.6 (C O) ppm; MS (EI, 70 eV), m/z (%):
p
3.82 (s, 3H, CH3), 3.84 (dd, 1H, H-4M, J4M-4A ¼ 18.09 Hz,
312 (100, Mþ), 283 (28), 148 (35); Anal. Calcd. for C17H13FN2O3: C,
65.38; H, 4.20; N, 8.97. Found: C, 65.35; H, 4.27; N, 8.89.
J4M-5 ¼ 11.55 Hz), 5.47 (dd, 1H, H-5, J5-4A ¼ 4.64 Hz, J5-4M
¼
11.67 Hz), 6.02 (s, 2H, CH2), 6.73 (dd, 1H, Ho-A, J ¼ 8.05 Hz,
0
J ¼ 1.49 Hz), 6.77 (d, 1H, Ho -A, J ¼ 1.76 Hz), 6.89 (d, 1H, Hm-A,
J ¼ 8.00 Hz), 7.02 (d, 2H, Ho-B, J ¼ 8.78 Hz), 7.23 (d, 2H, Hm-B,
J ¼ 8.78 Hz), 8.88 (s, 1H, CHO) ppm; 13C NMR (100 MHz, CDCl3) d:
3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-chlorophenyl)-4,5-
dihydro-1H-pyrazole-1-carbaldehyde (5d)
0
42.8 (C-4), 55.8 (C-5), 58.6 (CH3O), 101.5 (CH2), 106.7 (Co -A), 108.8
Yield: 94%; m.p.: 1618C; FTIR (KBr) nmax/cmꢀ1: 3079 (C–H), 1655
(Cm-A), 114.7 (Co-B), 119.5 (Co-A), 123.7 (Ci-A), 128.9 (Cm-B), 135.8
0
1
(C O), 1598 (C N), 1461 (C C, Ar), 1222 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
(Cp-B), 143.1 (Ci-B), 146.9 (Cm -A), 147.9 (Cp-A), 1þ59.9 (C-3), 161.6
CDCl3) d: 3.14 (dd, 1H, H-4a, J4A-4M ¼ 17.57 Hz, J4A-5 ¼ 5.02 Hz),
3.78 (dd, 1H, H-4M, J4M-4A ¼ 17.57 Hz, J4M-5 ¼ 11.80 Hz), 5.50
(dd, 1H, H-5, J5-4A ¼ 4.77 Hz, J5-4M ¼ 11.80 Hz), 5.94 (s, 2H,
–
(C O) ppm; MS (EI, 70 eV), m/z (%): 324 (100, M ), 189 (18), 148
–
(38); Anal. Calcd. for C18H16N2O4: C, 66.66; H, 4.97; N, 8.64. Found:
C, 66.59; H, 4.92; N, 8.72.
0
CH2), 6.07 (d, 1H, Ho -B, J ¼ 1.51 Hz), 6.85 (d, 1H, Hm-B,
J ¼ 8.14 Hz), 7.11 (dd, 1H, Ho-B, J ¼ 8.03 Hz, J ¼ 1.51 Hz), 7.21
(d, 2H, Hm-A, J ¼ 8.53 Hz), 7.30 (d, 2H, Ho-A, J ¼ 8.53 Hz), 8.94
(s, 1H, CHO) ppm; 13C NMR (100 MHz, CDCl3) d: 42.9 (C-4), 58.4
5-(Benzo[d][1,3]dioxol-5-yl)-3-p-tolyl-4,5-dihydro-1H-
pyrazole-1-carbaldehyde (8b)
Yield: 87%; m.p.: 1708C; FTIR (KBr) nmax/cmꢀ1: 2978 (C–H), 1679
0
(C-5), 101.7 (CH2), 106.3 (Co -B), 108.3 (Cm-B), 121.9 (Co-B), 125.0
1
(C O), 1589 (C N), 1433 (C C, Ar), 1209 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
(Ci-B), 127.2 (Cm-A), 129.2 (Co-A) 133.8 (Cp-A), 139.0 (Ci-A), 148.4
–
0
(Cm -B), 150.1 (C -B), 155.2 (C-3), 159.9 (C O) ppm; MS (EI, 70 eV),
–
CDCl3) d: 2.40 (s, 3H, CH3), 3.10 (dd, 1H, H-4A, J4A-4M ¼ 17.47 Hz,
p
m/z (%): 328 (100, Mþ), 330 (37, Mþ2), 299 (37), 189 (51), 148 (56);
J4A-5 ¼ 4.55 Hz), 3.71 (dd, 1H, H-4M, J4M-4A ¼ 17.49 Hz,
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282
B. Insuasty et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
J4M-5 ¼ 11.48 Hz), 5.52 (dd, 1H, H-5, J5-4A ¼ 4.69 Hz, J5-4M
¼
(EI, 70 eV), m/z (%): 362 (100, Mþ), 333 (13), 148 (15); Anal.
Calcd. for C18H13F3N2O3: C, 59.67; H, 3.62; N, 7.73. Found: C,
59.60; H, 3.61; N, 7.76.
0
11.51 Hz), 6.00 (s, 2H, CH2), 6.88 (d, 1H, Ho -A, J ¼ 1.47 Hz),
7.20 (d, 1H, Hm-A, J ¼ 8.11 Hz), 7.26 (s, 4H, H-Ar), 7.41 (dd, 1H,
Ho-A, J ¼ 8.15 Hz, J ¼ 1.53 Hz), 8.90 (s, 1H, CHO) ppm; 13C NMR
(100 MHz, CDCl3) d: 21.1 (CH3), 41.6 (C-4), 58.7 (C-5), 101.4 (CH2),
5-(Benzo[d][1,3]dioxol-5-yl)-3-phenyl-4,5-dihydro-1H-
pyrazole-1-carbaldehyde (8f)
0
106.4 (Co -A), 108.1 (Cm-A), 122.1 (Co-B), 124.4 (Co-A), 125.6 (Ci-A),
0
129.8 (Cm-B), 136.6 (Cp-B), 137.6 (Ci-B), 148.1 (Cm -A), 149.2 (Cp-A),
Yield: 92%; m.p.: 1568C; FTIR (KBr) nmax/cmꢀ1: 2934 (C–H), 1658
þ
–
154.4 (C-3), 159.8 (C O) ppm; MS (EI, 70 eV), m/z (%): 308 (54, M ),
–
1
(C O), 1598 (C N), 1421 (C C, Ar), 1210 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
279 (26), 189 (100), 148 (25); Anal. Calcd. for C18H16N2O3: C, 70.12;
H, 5.23; N, 9.09. Found: C, 70.09; H, 5.18; N, 9.04.
CDCl3) d: 3.20 (dd, 1H, H-4A, J4A-4M ¼ 18.20 Hz, J4A-5 ¼ 4.84 Hz),
3.88 (dd, 1H, H-4m, J4M-4A ¼ 18.32 Hz, J4M-5 ¼ 11.80 Hz), 5.44
(dd, 1H, H-5, J5-4A ¼ 4.89 Hz, J5-4M ¼ 11.42 Hz), 5.99 (s, 2H,
0
5-(Benzo[d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-4,5-
dihydro-1H-pyrazole-1-carbaldehyde (8c)
CH2), 6.72 (d, 1H, Ho -A, J ¼ 1.51 Hz), 6.78 (dd, 1H, Ho-A,
J ¼ 1.63 Hz, J ¼ 7.91 Hz), 6.87 (d, 1H, Hm-A, J ¼ 8.00 Hz), 7.48
(m, 3H, H-Ar), 7.79 (m, 2H, H-Ar), 8.88 (s, 1H, CHO) ppm;
13C NMR (100 MHz, CDCl3) d: 42.7 (C-4), 58.8 (C-5), 101.5 (CH2),
Yield: 83%; m.p.: 1528C; FTIR (KBr) nmax/cmꢀ1: 2918 (C–H), 1621
1
(C O), 1580 (C N), 1366 (C C, Ar), 1228 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
0
106.7 (Co -A), 108.8 (Cm-A), 119.6 (Co-A), 127.2 (Co-B), 129.3 (Cm-B),
CDCl3) d: 3.12 (dd, 1H, H-4A, J4A-4M ¼ 17.53 Hz, J4A-5 ¼ 4.55 Hz),
3.82 (dd, 1H, H-4M, J4M-4A ¼ 17.53 Hz, J4M-5 ¼ 11.26 Hz), 5.56
(dd, 1H, H-5, J5-4A ¼ 4.65 Hz, J5-4M ¼ 11.29 Hz), 6.02 (s, 2H,
0
131.0 (Ci-A), 135.7 (Cp-B), 144.5 (Ci-B), 147.0 (Cm -A), 148.0 (CpA),
þ
–
156.6 (C-3), 160.2 (C O) ppm; MS (EI, 70 eV), m/z (%): 294 (86, M ),
–
265 (29), 191 (100), 148 (73); Anal. Calcd. for C17H14N2O3: C, 69.38;
H, 4.79; N, 9.52. Found: C, 69.32; H, 4.71; N, 9.48.
0
CH2), 6.82 (d, 1H, Ho -A, J ¼ 1.53 Hz), 7.11 (t, 2H, Hm-B,
J ¼ 8.60 Hz), 7.16 (d, 1H, Hm-A, J ¼ 8.03 Hz), 7.35 (dd, 2H,
Hm-B, J ¼ 8.69 Hz, JF ¼ 4.86 Hz), 7.47 (dd, 1H, Ho-A,
J ¼ 8.11 Hz, J ¼ 1.57 Hz), 8.94 (s, 1H, CHO) ppm; 13C NMR
General procedure for the synthesis of derivatives 6, 9
and 11
The appropriate chalcone 1, 2 and 3 (1.0 mmol) was dissolved in
10.0 mL of a mixture of NaOH in ethanol and vigorously stirred
at reflux with thiosemicarbazide (2.0 mmol) for 24 h. The
desired product precipitated from the reaction mixture after
cooling, was filtered off and crystallized from ethanol.
(100 MHz, CDCl3) d: 42.5 (C-4), 58.4 (C-5), 101.7 (CH2), 106.4
3
0
(Co -A), 108.4 (Cm-A), 115.8 (Co-B, JC-F ¼ 87 Hz), 121.1 (Co-A),
2
1
123.1 (Ci-A), 127.4 (Cm-B, JC-F ¼ 33 Hz), 132.5 (Cp-B, JC-F
¼
0
253 Hz), 148.1 (Ci-B), 149.2 (Cm -A), 154.2 (Cp-A), 158.7 (C-3),
þ
–
–
162.8 (C O) ppm; MS (EI, 70 eV), m/z (%): 312 (30, M ), 283
(20), 191 (100), 148 (30); Anal. Calcd. for C17H13FN2O3: C,
65.38; H, 4.20; N, 8.97. Found: C, 65.33; H, 4.26; N, 8.93.
3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-methoxyphenyl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide (6a)
5-(Benzo[d][1,3]dioxol-5-yl)-3-(4-chlorophenyl)-4,5-
dihydro-1H-pyrazole-1-carbaldehyde (8d)
Yield: 86%; m.p.: 1148C; FTIR (KBr) nmax/cmꢀ1: 3001 (C–H), 1606
Yield: 84%; m.p.: 1748C; FTIR (KBr) nmax/cmꢀ1: 2916 (C–H), 1655
(C N), 1417 (C C, Ar), 1233 (C–O); 1H NMR (400 MHz, DMSOd6)
–
–
–
–
1
(C O), 1592 (C N), 1440 (C C, Ar), 1230 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
d: 3.08 (dd, 1H, H-4A, J4A-4M ¼ 17.94 Hz, J4A-5 ¼ 3.14 Hz), 3.72
CDCl3) d: 3.18 (dd, 1H, H-4A, J4A-4M ¼ 17.82 Hz, J4A-5 ¼ 5.02 Hz),
3.86 (dd, 1H, H-4M, J4M-4A ¼ 17.94 Hz, J4M-5 ¼ 11.67 Hz), 5.46
(dd, 1H, H-5, J5-4A ¼ 5.14 Hz, J5-4M ¼ 11.67 Hz), 5.97 (s, 2H,
(s, 3H, CH3), 3.79 (dd, 1H, H-4M, J4M-4A ¼ 17.94 Hz, J4M-5
¼
11.17 Hz), 5.83 (dd, 1H, H-5, J5-4A ¼ 3.01 Hz, J5-4M ¼ 11.29 Hz),
6.09 (s, 2H, CH2), 6.86 (d, 2H, Ho-A, J ¼ 8.78 Hz), 6.97 (d, 1H,
Hm-B, J ¼ 8.03 Hz), 7.04 (d, 2H, Hm A, J ¼ 8.78 Hz), 7.24
0
CH2), 6.80 (m, 3H, H0 -A, Ho-A, Hm-A), 7.28 (d, 2H, Ho-B,
J ¼ 8.28 Hz), 7.67 (d, 2H, Hm-B, J ¼ 8.28 Hz), 8.03 (s, 1H, CHO)
0
(dd, 1H, HoB, J ¼ 8.03 Hz, J ¼ 1.51 Hz), 7.63 (d, 1H, Ho -B,
ppm; 13C NMR (100 MHz, CDCl3) d: 42.8 (C-4), 59.1 (C-5), 101.5
J ¼ 1.76 Hz), 7.91 (1s, 1H, NH), 8.12 (1s, 1H, NH) ppm;
13C NMR (100 MHz, DMSOd6) d: 42.9 (C-4), 55.5 (C-5), 62.8 (CH3),
0
(CH2), 106.7 (Co -A), 108.7 (Cm-A), 119.6 (Co-A), 127.1 (Co-B), 128.8
0
(Ci-A), 129.7 (Cm-B), 135.8 (Cp-B), 140.8 (Ci-B), 147.1 (Cm -A), 148.2
0
102.1 (CH2), 106.8 (Co-B), 108.7 (Co -B), 114.3 (Co-A), 123.1 (Cm-B),
0
125.6 (Ci-A), 127.1 (Cm-A), 136.5 (Cm -B), 148.3 (Cp-B), 149.9
–
(C -A), 156.5 (C-3), 159.9 (C O) ppm; MS (EI, 70 eV), m/z (%):
–
p
359 (100, Mþ), 361 (37, Mþ2þ) 299 (22), 189 (62), 148 (56);
Anal. Calcd. for C17H13ClN2O3: C, 62.11; H, 3.99; N, 8.52.
Found: C, 62.17; H, 4.06; N, 8.59.
–
(C -B), 155.1 (C -A), 158.7 (C-3),176.3 (C S) ppm; MS (EI, 70 eV),
–
i
p
m/z (%): 355 (34, Mþ), 322 (53), 295 (100); Anal. Calcd. for
C18H17N3O3S: C, 60.83; H, 4.82; N, 11.82. Found: C, 60.89; H,
4.84; N, 11.90.
5-(Benzo[d][1,3]dioxol-5-yl)-3-(4-(trifluoromethyl)phenyl)-
4,5-dihydro-1H-pyrazole-1-carbaldehyde (8e)
3-(Benzo[d][1,3]dioxol-5-yl)-5-p-tolyl-4,5-dihydro-1H-
pyrazole-1-carbothioamide (6b)
Yield: 90%; m.p.: 1688C; FTIR (KBr) nmax/cmꢀ1: 2918 (C–H), 1627
1
(C O), 1592 (C N), 1365 (C C, Ar), 1227 (C–O); H NMR (400 MHz,
Yield: 88%; m.p.: 1228C; FTIR (KBr) nmax/cmꢀ1: 2985 (C–H), 1600
–
–
–
–
–
–
(C N), 1404 (C C, Ar), 1223 (C–O); 1H NMR (400 MHz, DMSOd6)
–
–
–
–
CDCl3) d: 3.24 (dd, 1H, H-4A, J4A-4M ¼ 17.53 Hz, J4A-5 ¼ 5.02 Hz),
3.95 (dd, 1H, H-4M, J4M-4A ¼ 17.53 Hz, J4M-5 ¼ 11.84 Hz), 5.67 (dd,
1H, H-5, J5-4A ¼ 5.00 Hz, J5-4M ¼ 11.76 Hz), 6.02 (s, 2H, CH2), 7.10
d: 2.26 (s, 3H, CH3), 3.05 (dd, 1H, H-4A, J4A-4M ¼ 17.94 Hz,
J4A-5 ¼ 3.14 Hz), 3.80 (dd, 1H, H-4M, J4M-4A ¼ 17.94 Hz,
0
(d, 1H, Ho -A, J ¼ 1.52 Hz), 7.31 (m, 2H, Ho-A, Hm-A), 7.76 (d, 2H,
J4M-5 ¼ 11.42 Hz), 5.85 (dd, 1H, H-5, J5-4A ¼ 2.89 Hz, J5-4M ¼
Ho-B, J ¼ 8.01 Hz), 7.81 (d, 2H, Hm-B, J ¼ 8.01 Hz), 8.91 (s, 1H,
11.17 Hz), 6.09 (s, 2H, CH2), 6.96 (d, 2H, Ho-A, J ¼ 8.03 Hz), 7.00
(d, 1H, Hm-B, J ¼ 7.78 Hz), 7.10 (d, 2H, Hm-A, J ¼ 8.03 Hz), 7.23
CHO) ppm; 13C NMR (100 MHz, CDCl3) d: 41.3 (C-4), 59.1 (C-5),
0
101.9 (CH2), 101.9 (Co -A), 106.6 (Co-A), 108.6 (Cm-A), 122.1 (Co-B),
0
125.2 (Ci-A), 126.0 (Cp-B), 127.1 (Cm-B), 128.3 (Ci-B), 148.4 (Cm -A),
0
(dd, 1H, Ho-B, J ¼ 8.04 Hz, J ¼ 1.51 Hz), 7.63 (d, 1H, Ho -B,
J ¼ 1.25 Hz), 7.90 (1s, 1H, NH), 8.15 (1s, 1H, NH) ppm;
13C NMR (100 MHz, DMSOd6) d: 21.1 (CH3), 42.9 (C-4), 63.1 (C-5),
–
149.9 (C -A), 159.1 (CF ), 160.0 (C-3), 166.8 (C O) ppm; MS
–
p
3
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
Antitumor Activity of 1-Substituted 3-Aryl-5-aryl(hetaryl)-2-pyrazolines
283
0
102.1 (CH2), 106.8 (Co-B), 108.7 (Co -B), 123.0 (Cm-B), 125.6 (Ci-A),
0
125.7 (Co-A), 129.5 (Cm-A), 136.4 (Cm -B), 140.5 (Cp-B), 148.3
3-(Benzo[d][1,3]dioxol-5-yl)-5-phenyl-4,5-dihydro-1H-
pyrazole-1-carbothioamide (6f)
–
(C -B), 149.9 (C -A), 155.1 (C-3), 176.3 (C S) ppm. MS (EI, 70 eV),
Yield: 70%; m.p.: 1318C; FTIR (KBr) nmax/cmꢀ1: 2987 (C–H), 1614
–
i
p
m/z (%): 339 (62, Mþ), 306 (100), 279 (37); Anal. Calcd. for
C18H17N3O2S: C, 63.70; H, 5.05; N, 12.38. Found: C, 63.76; H,
4.97; N, 12.31.
(C N), 1479 (C C, Ar), 1203 (C–O); 1H NMR (400 MHz, DMSOd6)
–
–
–
–
d: 3.24 (dd, 1H, H-4a, J4A-4M ¼ 18.11 Hz, J4A-5 ¼ 3.56 Hz), 3.84
(dd, 1H, H-4M, J4M-4A ¼ 18.11 Hz, J4M-5 ¼ 11.23 Hz), 5.97
(dd, 1H, H-5, J5-4A ¼ 3.77 Hz, J5-4M ¼ 11.27 Hz), 6.03 (s, 2H,
CH2), 6.83 (d, 1H, Hm-B, J ¼ 8.03 Hz), 7.20 (m, 5H, H-A), 7.40
3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-fluorophenyl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide (6c)
0
(d, 1H, Ho -B, J ¼ 1.25 Hz), 7.59 (dd, 1H, Ho-B, J¼ 8.03 Hz,
J ¼ 1.51 Hz), 7.84 (1s, 1H, NH), 8.16 (1s, 1H, NH) ppm; 13C NMR
Yield: 74%; m.p.: 2038C; FTIR (KBr) nmax/cmꢀ1: 3110 (C–H), 1610
(C N), 1481 (C C, Ar), 1220 (C–O); 1H NMR (400 MHz, DMSOd6)
(100 MHz, DMSOd6) d: 42.6 (C-4), 54.6 (C-5), 102.4 (CH2), 124.8
0
(Co-B), 126.6 (Co -B), 124.8 (Co-A), 126.6 (Cm-B), 128.1 (Cm-A) 128.6
–
–
–
–
d: 3.11 (dd, 1H, H-4A, J4A-4M ¼ 17.94 Hz, J4A-5 ¼ 3.39 Hz), 3.83
(dd, 1H, H-4M, J4M-4A ¼ 18.07 Hz, J4M-5 ¼ 11.29 Hz), 5.89
(dd, 1H, H-5, J5-4A ¼ 3.26 Hz, J5-4M ¼ 11.29 Hz), 6.09 (s, 2H,
CH2), 6.97 (d, 1H, Hm-B, J ¼ 8.03 Hz), 7.13 (1s, 1H, NH), 7.16
(1s, 1H, NH), 7.15 (m, 4H, H-A), 7.25 (dd, 1H, Ho-B,
0
(Ci-A), 131.9 (Cm -B), 143.3 (Cp-B), 144.7 (Ci-B), 148.3 (þCp-A), 151.8
–
(C-3), 177.1 (C S); MS (EI, 70 eV), m/z (%): 325 (100, M ), 392 (70),
–
265 (9); Anal. Calcd. for C17H15N3O2S: C, 62.75; H, 4.65; N, 12.91.
Found: C, 62.69; H, 4.61; N, 12.98.
0
J ¼ 8.16 Hz, J ¼ 1.63 Hz), 7.63 (d, 1H, Ho -B, J ¼ 1.25 Hz) ppm;
13C NMR (100 MHz, DMSOd6) d: 42.9 (C-4), 62.7 (C-5), 102.1
5-(Benzo[d][1,3]dioxol-5-yl)-3-(4-methoxyphenyl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide (9a)
3
0
(CH2), 106.9 (Co-B), 108.7 (Co -B), 115.7 (Co-A, JC-F ¼ 88 Hz),
2
Yield: 85%; m.p.: 1208C; FTIR (KBr) nmax/cmꢀ1: 3010 (C–H), 1612
0
123.1 (Cm-B), 125.5 (Cm-A, JC-F ¼ 35) 126.7 (Ci-A), 139.7 (Cm -B),
1
(C N), 1408 (C C, Ar), 1222 (C–O); 1H NMR (400 MHz, DMSOd6)
148.3 (Cp-B), 149.9 (Ci-B), 155.1 (C-3), 162.8 (Cp-A, JC-F ¼ 243 Hz),
–
–
–
–
þ
–
–
176.3 (C S) ppm; MS (EI, 70 eV), m/z (%): 343 (100, M ), 310 (79),
d: 3.10 (dd, 1H, H-4A, J4A-4M ¼ 17.95 Hz, J4A-5 ¼ 3.19 Hz), 3.76
283 (15); Anal. Calcd. for C17H14FN3O2S: C, 59.46; H, 4.11; N,
12.24. Found: C, 59.52; H, 4.13; N, 12.32.
(s, 3H, CH3), 3.81 (dd, 1H, H-4M, J4M-4A ¼ 17.94 Hz, J4M-5
¼
11.20 Hz), 5.84 (dd, 1H, H-5, J5-4A ¼ 3.12 Hz, J5-4M ¼ 11.23 Hz),
5.99 (s, 2H, CH2), 6.87 (d, 2H, Ho-B, J ¼ 8.58 Hz), 6.99 (d, 1H,
Hm-A, J ¼ 8.09 Hz), 7.04 (d, 2H, Hm-B, J ¼ 8.59 Hz), 7.28
3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-chlorophenyl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide (6d)
0
(dd, 1H, Ho-A, J ¼ 8.05 Hz, J ¼ 1.51 Hz), 7.66 (d, 1H, Ho -A,
J ¼ 1.76 Hz), 8.02 (1s, 1H, NH), 8.03 (1s, 1H, NH) ppm;
Yield: 80%; m.p.: 2098C; FTIR (KBr) nmax/cmꢀ1: 3162 (C–H), 1607
13C NMR (100 MHz, DMSOd6) d: 42.9 (C-4), 55.9 (C-5), 62.9 (CH3),
(C N), 1498 (C C, Ar), 1250 (C–O); 1H NMR (400 MHz, DMSOd6)
–
–
–
–
0
101.4 (CH2), 106.4 (Co-A), 108.7 (Co -A), 114.6 (Co-B), 118.9 (Cm-A),
0
123.8 (Ci-B), 129.3 (Cm-B), 137.5 (Cm -A), 146.5 (Cp-A), 147.7 (Ci-A),
d: 3.13 (dd, 1H, H-4A, J4A-4M ¼ 18.07 Hz, J4A-5 ¼ 3.51 Hz), 3.84
(dd, 1H, H-4M, J4M-4A ¼ 17.94 Hz, J4M-5 ¼ 11.42 Hz), 5.84
(dd, 1H, H-5, J5-4a ¼ 3.26 Hz, J5-4m ¼ 11.29 Hz), 5.97 (s, 2H,
CH2), 6.60 (dd, 1H, Ho-B, J ¼ 8.03 Hz, J ¼ 1.76 Hz), 6.65 (d, 1H,
–
155.4 (C -B), 161.7 (C-3), 176.2 (C S) ppm; MS (EI, 70 eV), m/z (%):
p
–
355 (100, Mþ), 322 (12), 295 (15); Anal. Calcd. for C18H17N3O3S:
C, 60.83; H, 4.82; N, 11.82. Found: C, 60.90; H, 4.88; N, 11.88.
0
Ho -B, J ¼ 1.51 Hz), 6.83 (d, 1H, Hm-B, J ¼ 8.03 Hz), 7.52 (d, 2H,
Ho-A, J ¼ 8.53 Hz), 7.90 (d, 2H, Hm-A, J ¼ 8.53 Hz), 7.94 (1s, 1H,
NH), 8.06 (1s, 1H, NH) ppm; 13C NMR (100 MHz, DMSOd6) d: 42.8
5-(Benzo[d][1,3]dioxol-5-yl)-3-p-tolyl-4,5-dihydro-1H-
pyrazole-1-carbothioamide (9b)
0
(C-4), 63.3 (C-5), 101.4 (CH2), 106.4 (Co-B), 108.7 (Co -B), 118.9 (Cm-B)
0
129.2 (Co-A), 129.3 (Cm-A), 130.4 (Ci-A), 135.6 (Cm -B), 137.4 (Cp-B),
Yield: 85%; m.p.: 1258C; FTIR (KBr) nmax/cmꢀ1: 3089 (C–H), 1599
1
(C N), 1501 (C N), 1434 (C C, Ar), 1209 (C–O); H NMR (400 MHz,
–
–
–
–
146.6 (C -A), 147.7 (C -B), 154.4 (C-3), 176.7 (C S) ppm; MS
–
p
i
–
–
–
DMSOd6) d: 2.51 (s, 3H, CH3), 3.13 (dd, 1H, H-4A, J4A-4M
(EI, 70 eV), m/z (%): 359 (74, Mþ), 361 (25, Mþ2), 326 (79) 299
(76), 60 (100); Anal. Calcd. for C17H14ClN3O2S: C, 56.74; H,
3.92; N, 11.68. Found: C, 56.68; H, 3.93; N, 11.74.
¼
18.07 Hz, J4A-5 ¼ 3.51 Hz), 3.84 (dd, 1H, H-4M, J4M-4A ¼ 18.07 Hz,
J4M-5 ¼ 11.54 Hz), 5.83 (dd, 1H, H-5, J5-4A ¼ 11.42 Hz, J5-4M
¼
3.39 Hz), 5.97 (s, 2H, CH2), 6.61 (dd, 1H, Ho-A, J ¼ 8.03 Hz,
0
J ¼ 1.76 Hz), 6.65 (d, 1H, Ho -A, J ¼ 1.51 Hz), 6.83 (d, 1H, Hm-A,
3-(Benzo[d][1,3]dioxol-5-yl)-5-(4-(trifluoromethyl)phenyl)-
4,5-dihydro-1H-pyrazole-1-carbothioamide (6e)
J ¼ 6.83 Hz), 7.52 (d, 2H, Ho-B, J ¼ 8.78 Hz), 7.86 (d, 1H, Hm-B,
J ¼ 8.78 Hz), 8.02 (1s, 1H, NH), 8.10 (1s, 1H, NH) ppm; 13C NMR
(100 MHz, DMSOd6) d: 21.3 (CH3), 42.8 (C-4), 63.3 (C-5), 101.4 (CH2),
Yield: 71%; m.p.: 1998C; FTIR (KBr) nmax/cmꢀ1: 3091 (C–H), 1620
(C N), 1423 (C C, Ar), 1210 (C–O); 1H NMR (400 MHz, DMSOd6)
–
–
–
–
0
106.4 (Co-A), 108.7 (Co -A), 118.9 (Cm-A), 129.2 (Ci-B), 130.4 (Co-B),
d: 3.15 (dd, 1H, H-4A, J4A-4M ¼ 18.07 Hz, J4A-5 ¼ 3.76 Hz), 3.87
(dd, 1H, H-4m, J4M-4A ¼ 18.07 Hz, J4M-5 ¼ 11.54 Hz), 5.98
(dd, 1H, H-5, J5-4A ¼ 3.51 Hz, J5-4M ¼ 11.54 Hz), 6.09 (s, 2H,
CH2), 6.96 (d, 1H, Hm-B, J ¼ 8.06 Hz), 7.25 (dd, 1H, Ho-B,
J ¼ 8.03 Hz, J ¼ 1.51 Hz), 7.34 (d, 2H, Ho-A, J ¼ 8.28 Hz), 7.64
(1s, 1H, NH), 8.06 (1s, 1H, NH) ppm; 13C NMR (100 MHz,
DMSOd6) d: 42.7 (C-4), 63.1 (C-5), 102.1 (CH2), 106.9 (Co-B), 108.7
0
135.6 (Cm-B), 137.4 (Cm -A), 146.6 (Cp-A), 147.8 (Ci-A), 147.9 (Cp-þB),
–
154.4 (C-3), 176.8 (C S) ppm; MS (EI, 70 eV), m/z (%): 339 (100, M ),
–
306 (37), 279 (22); Anal. Calcd. for C18H17N3O2S: C, 63.70; H, 5.05;
N, 12.38. Found: C, 63.79; H, 5.09; N, 12.44.
0
(d, 1H, Ho -B, J ¼ 1.51 Hz), 7.69 (d, 2H, Hm-A, J ¼ 8.28), 7.99
5-(Benzo[d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide (9c)
Yield: 72%; m.p.: 2008C; FTIR (KBr) nmax/cmꢀ1: 3113 (C–H), 1609
0
(Co -B), 123.2 (Co-A), 125.4 (Cm-B), 125.9 (Cp-A), 126.0 (Cm-A), 126.7
1
(C N), 1573 (C N), 1489 (C C, Ar), 1219 (C–O); H NMR (400 MHz,
–
–
–
–
–
0
(Ci-A), 127.6 (Ci-B), 148.1 (Cp-B), 148.3 (Cm -B), 149.9 (CF3), 155.1
–
þ
–
(C-3), 176.3 (C S) ppm; MS (EI, 70 eV), m/z (%): 393 (22, M ), 360
DMSOd6) d: 3.14 (dd, 1H, H-4A, J4A-4M ¼ 18.07 Hz, J4A-5 ¼ 3.26 Hz),
3.85 (dd, 1H, H-4M, J4M-4A ¼ 18.07 Hz, J4M-5 ¼ 11.54 Hz), 5.84
(dd, 1H, H-5, J5-4A ¼ 3.26 Hz, J5-4M ¼ 11.29 Hz), 5.98 (s, 2H,
–
(100), 333 (17); Anal. Calcd. for C18H14F3N3O2S: C, 54.96; H, 3.59;
N, 10.68. Found: C, 54.95; H, 3.53; N, 10.73.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

284
B. Insuasty et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
þ
–
CH2), 6.60 (dd, 1H, Ho-A, J ¼ 8.03 Hz, J ¼ 1.51 Hz), 6.65 (d, 1H,
(C-3), 176.7 (C S) ppm; MS (EI, 70 eV), m/z (%): 325 (70, M ), 392
–
0
Ho -A, J ¼ 1.25 Hz), 6.83 (d, 1H, Hm-A, J ¼ 8.03 Hz), 7.30 (t, 2H,
(100), 265 (21); Anal. Calcd. for C17H15N3O2S: C, 62.75; H, 4.65; N,
12.91. Found: C, 62.70; H, 4.71; N, 12.97.
Ho-B, J ¼ 8.78 Hz), 7.93 (m, 2H, Hm-B), 8.01 (1s, 1H, NH), 8.03
(1s, 1H, NH) ppm; 13C NMR (100 MHz, DMSOd6) d: 42.9 (C-4),
0
63.7 (C-5), 101.4 (CH2), 106.4 (Co-A), 108.7 (Co -A), 116.1 (Co-B,
2
3-(4-Methoxyphenyl)-5-(5-methylthiophen-2-yl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide (11a)
3JC-F ¼ 88 Hz), 128.0 (Cm-A), 129.9 (Cm-B, JC-F ¼ 32 Hz), 137.4
0
(Ci-B), 146.6 (Cm -A), 147.7 (Cp-A), 154.5 (Ci-A), 162.7 (Cp-B,
Yield: 52%; m.p.: 1548C, FTIR (KBr) nmax/cmꢀ1: 3487, 3358 (N–H),
1
–
–
JC-F ¼ 242 Hz), 165.1 (C-3), 176.6 (C S) ppm; MS (EI, 70 eV), m/z
1
1357 (C S), 1572 (C N); H NMR (400 MHz, CDCl ) d: 2.40 (s, 3H,
–
–
–
–
(%): 343 (100, Mþ), 310 (82), 283 (17); Anal. Calcd. for
C17H14FN3O2S: C, 59.46; H, 4.11; N, 12.24. Found: C, 59.51; H,
4.19; N, 12.28.
3
CH3-thiophene), 3.34 (dd, 1H, H-4A, J4A-5 ¼ 2.8 Hz, J4A-4B
¼
17.4 Hz), 3.72 (dd, 1H, H-4B, J4B-4A ¼ 17.4 Hz, J4B-5 ¼ 10.8 Hz),
3.86 (s, 3H, OCH3), 6.03 (s, 1H, NH), 6.25 (dd, 1H, H-5,
J5-4A ¼ 2.6 Hz, J5-4B ¼ 10.8 Hz), 6.56 (dd, 1H, H-4’, 4J ¼ 0.8 Hz,
J ¼ 3.4 Hz), 6.83 (d, 1H, H-3’, J ¼ 3.4 Hz), 6.94 (d, 2H, Hm-B,
J ¼ 8.8 Hz), 6.98 (s, 1H, NH), 7.69 (d, 2H, Ho-B, J ¼ 8.8 Hz) ppm;
13C NMR (100 MHz, CDCl3) d: 15.3 (CH3-thiophene), 42.7 (C-4),
55.5 (CH3O), 59.2 (C-5), 114.3 (Cm-B), 123.1 (Ci-B), 124.7 (C-4’), 124.9
5-(Benzo[d][1,3]dioxol-5-yl)-3-(4-chlorophenyl)-4,5-
dihydro-1H-pyrazole-1-carbothioamide (9d)
Yield: 89%; m.p.: 2018C; FTIR (KBr) nmax/cmꢀ1: 3019 (C–H), 1599
1
(C N), 1512 (C N), 1445 (C C, Ar), 1217 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
DMSOd6) d: 3.11 (dd, 1H, H-4A, J4A-4M ¼ 17.94 Hz, J4A-5 ¼ 3.39 Hz),
3.83 (dd, 1H, H-4M, J4M-4A ¼ 17.94 Hz, J4M-5 ¼ 11.42 Hz), 5.83
(dd, 1H, H-5, J5-4A ¼ 3.39 Hz, J5-4M ¼ 11.17 Hz), 5.97 (s, 2H,
CH2), 6.60 (dd, 1H, Ho-A, J ¼ 8.03 Hz, J ¼ 1.76 Hz), 6.64 (d, 1H,
(C-3’), 128.7 (Co-B), 129.6 (Cp-B), 139.2 (C-5’), 156.1 (C-3), 162.0 (C-2‘),
þ
–
176.1 (C S) ppm; MS (EI, 70 eV), m/z (%): 331 (80, M ), 298 (25), 183
–
(100); Anal. Calcd. for C16H17N3OS2: C, 57.98; H, 5.17; N, 12.68.
Found: C, 58.04; H, 5.24; N, 12.63.
0
Ho -A, J ¼ 1.51 Hz), 6.84 (d, 2H, Ho-B, J ¼ 8.28 Hz), 7.27 (d, 1H,
Hm-A, J ¼ 8.03 Hz), 7.76 (d, 2H, Hm-B, J ¼ 8.28 Hz), 7.82 (1s, 1H,
5-(5-Methylthiophen-2-yl)-3-p-tolyl-4,5-dihydro-1H-
pyrazole-1-carbothioamide (11b)
NH), 7.97 (1s, 1H, NH) ppm; 13C NMR (100 MHz, DMSOd6) d: 42.9
0
(C-4), 63.0 (C-5), 101.4 (CH2), 106.4 (Co-A), 108.7 (Co -A), 118.9 (Cm-A),
0
127.6 (Co-B), 128.6 (Ci-B), 129.7 (Cm-B), 137.5 (Cm -A), 140.9 (Cp-A),
Yield: 58%; m.p.: 1938C, FTIR (KBr) nmax/cmꢀ1: 3488, 3360 (N–H),
1
1358 (C S), 1580 (C N); H NMR (400 MHz, CDCl ) d: 2.40 (s, 6H,
–
–
–
–
–
3
146.5 (C -A), 147.7 (C -B), 155.6 C-3), 176.5 (C S) ppm; MS (EI,
–
i
p
70 eV), m/z (%): 359 (100, Mþ) 361 (37, Mþ2), 326 (38) 299 (21);
Anal. Calcd. for C17H14ClN3O2S: C, 56.74; H, 3.92; N, 11.68. Found:
C, 56.69; H, 3.97; N, 11.75.
CH3-Ar, CH3-thiophene), 3.34 (dd, 1H, H-4A, J4A-5 ¼ 2.9 Hz,
J4A-4B ¼ 17.5 Hz), 3.72 (dd, 1H, H-4B, J4B-4A ¼ 17.5 Hz, J4B-5
¼
10.8 Hz), 6.07 (s, 1H, NH), 6.26 (dd, 1H, H-5, J5-4A ¼ 2.8 Hz,
J5-4B ¼ 10.8 Hz), 6.55 (d, 1H, H-4’, J ¼ 3.5 Hz), 6.83 (d, 1H, H-3’,
J ¼ 3.5 Hz), 6.92 (s, 1H, NH), 7.24 (d, 2H, Hm-B, J ¼ 8.0 Hz) 7.63
(d, 2H, Ho-B, J ¼ 8.2 Hz) ppm; 13C NMR (100 MHz, CDCl3) d: 15.3
(CH3-thiophene), 21.6 (CH3-Ar), 42.7 (C-4), 59.3 (C-5), 124.7 (C-4’),
125.0 (C-3’), 127.0 (Cm-B), 127.9 (Ci-B), 129.6 (Co-B), 139.2 (C-5’),
5-(Benzo[d][1,3]dioxol-5-yl)-3-(4-(trifluoromethyl)phenyl)-
4,5-dihydro-1H-pyrazole-1-carbothioamide (9e)
Yield: 75%; m.p.: 1898C; FTIR (KBr) nmax/cmꢀ1: 3110 (C–H), 1608
1
(C N), 1511 (C N), 1473 (C C, Ar), 1254 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
–
141.4 (C-2’), 141.6 (C -B), 156.4 (C-3), 176.4 (C S) ppm; MS (EI,
–
p
DMSOd6) d: 3.06 (dd, 1H, H-4a, J4A-4M ¼ 17.94 Hz, J4A-5 ¼ 3.14 Hz),
3.46 (dd, 1H, H-4M, J4M-4A ¼ 17.94 Hz, J4M-5 ¼ 11.23 Hz), 5.07
(dd, 1H, H-5, J5-4A ¼ 3.57 Hz, J5-4M ¼ 11.54 Hz), 6.09 (s, 2H,
CH2), 6.95 (d, 1H, Hm-A, J ¼ 8.28 Hz), 7.24 (dd, 1H, Ho-A,
70 eV), m/z (%): 315 (25, Mþ), 282 (22), 197 (23), 183 (100); Anal.
Calc. for C16H17N3S2: C, 60.92, H, 5.43; N, 13.32. Found: C, 60.83;
H, 5.44; N, 12.99.
0
J ¼ 8.03 Hz, J ¼ 1.51 Hz) 7.42 (d, 1H, Ho -A, J ¼ 1.51 Hz), 7.50
3-(4-Fluorophenyl)-5-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide (11c)
(m, 4H, H-ArB), 8.03 (1s, 1H, NH), 8.08 (1s, 1H, NH) ppm;
13C NMR (100 MHz, DMSOd6) d: 42.3 (C-4), 60.5 (C-5), 102.1
Yield: 56%; m.p.: 1868C; FTIR (KBr) nmax/cmꢀ1: 3486, 3358 (N–H),
0
(CH2), 106.9 (Co-A), 108.7 (Co -A), 123.2 (Co-B), 124.9 (Cm-A), 127.0
(Cp-B), 128.9 (Cm-B),131.8 (Ci-B), 133.6 (Ci-A), 148.3 (Cp-A), 149.9
1
1361 (C S), 1591 (C N); H NMR (400 MHz, CDCl ) d: 2.40 (s, 3H,
–
–
–
–
3
–
0
(Cm -A), 151.9 (CF ), 154.6 (C-3), 176.2 (C S) ppm; MS (EI, 70 eV),
CH3-thiophene), 3.34 (dd, 1H, H-4A, J4A-5 ¼ 2.9 Hz, J4A-4B ¼
–
3
m/z (%): 393 (43, Mþ), 360 (58), 333 (100); Anal. Calcd. for
C18H14F3N3O2S: C, 54.96; H, 3.59; N, 10.68. Found: C, 54.99; H,
3.52; N, 10.75.
17.5 Hz), 3.74 (dd, 1H, H-4B, J4B-4A ¼ 17.5 Hz, J4B-5 ¼ 10.9 Hz),
6.09 (s, 1H, NH), 6.28 (dd, 1H, H-5, J5-4A ¼ 2.7 Hz,
J5-4B ¼ 10.8 Hz), 6.56 (dd, 1H, H-4’, 4J ¼ 1.0 Hz, J ¼ 3.3 Hz),
6.83 (d, 1H, H-3’, J ¼ 3.4 Hz), 6.99 (s, 1H, NH), 7.13 (t, 2H, Hm-B,
J ¼ 8.6 Hz), 7.74 (dd, 2H, Ho-B, JHF ¼ 5.3 Hz, J ¼ 8.8 Hz) ppm;
13C NMR (100 MHz, CDCl3) d: 15.3 (CH3-thiophene), 42.7 (C-4),
59.4 (C-5), 116.2 (d, Cm-B, 2JCF ¼ 22.0 Hz), 124.8 (C-4’), 125.1 (C-3’),
5-(Benzo[d][1,3]dioxol-5-yl)-3-phenyl-4,5-dihydro-1H-
pyrazole-1-carbothioamide (9f)
Yield: 84%; m.p.: 1428C; FTIR (KBr) nmax/cmꢀ1: 2997 (C–H), 1624
4
3
126.9 (d, Ci-B, JCF¼ 3.7 Hz), 129.1 (d, Co-B, JCF ¼ 8.8 Hz), 139.3
1
(C N), 1510 (C N), 1426 (C C, Ar), 1201 (C–O); H NMR (400 MHz,
–
–
–
–
–
–
1
(C-5’), 141.2 (C-2’), 155.2 (C-3), 164.4 (d, Cp-B, JCF ¼ 253.1 Hz),
DMSOd6) d: 3.14 (dd, 1H, H-4A, J4A-4M ¼ 18.07 Hz, J4A-5 ¼ 3.26 Hz),
3.86 (dd, 1H, H-4M, J4M-4A ¼ 18.07 Hz, J4M-5 ¼ 11.29 Hz), 5.85
(dd, 1H, H-5, J5-4A ¼ 3.26 Hz, J5-4M ¼ 11.29 Hz), 5.97 (s, 2H,
CH2), 6.62 (dd, 1H, Ho-A, J ¼ 8.03 Hz, J ¼ 1.51 Hz), 6.66 (d, 1H,
þ
–
–
176.6 (C S) ppm; MS (EI, 70Ev) m/z (%): 319 (23, M ), 286 (18),
197 (24), 183 (100), 123 (56); Anal. Calcd. for C15H14FN3S2: C,
56.40; H, 4.42; N, 13.16. Found: C, 56.49; H, 4.44; N, 13.23.
0
Ho -A, J ¼ 1.51 Hz), 6.83 (d, 1H, Hm-A, J ¼ 7.78 Hz), 7.66 (m, 5H,
H-ArB), 7.99 (1s, 1H, NH), 8.03 (1s, 1H, NH) ppm; 13C NMR
(100 MHz, DMSOd6) d: 42.9 (C-4), 63.1 (C-5), 101.4 (CH2), 106.4
3-(4-Chlorophenyl)-5-(5-methylthiophen-2-yl)-4,5-dihydro-
1H-pyrazole-1-carbothioamide (11d)
Yield: 52%; m.p.: 1988C, FTIR (KBr) nmax/cmꢀ1: 3487, 3359 (N–H),
0
(Co-A), 108.7 (Co -A), 118.9 (Cm-A), 127.6 (Co-B), 129.1 (Cm-B) 131.0
0
(Ci-B), 131.4 (Cm -A), 137.5 (Cp-A), 146.6 (Ci-A), 147.7 (Cp-B), 155.5
1
1358 (C S), 1571 (C N); H NMR (400 MHz, CDCl ) d: 2.40 (s, 3H,
–
–
–
–
3
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2012, 345, 275–286
Antitumor Activity of 1-Substituted 3-Aryl-5-aryl(hetaryl)-2-pyrazolines
285
CH3-thiophene), 3.33 (dd, 1H, H-4A, J4A-4B ¼ 17.5 Hz, J4A-5
¼
References
2.9 Hz), 3.73 (dd, 1H, H-4B, J4B-4A ¼ 17.5 Hz, J5-4B ¼ 10.9 Hz),
6.15 (s, 1H, NH), 6.28 (dd, 1H, H-5, J5-4A ¼ 2.8 Hz, JBX
10.9 Hz), 6.56 (d, 1H, H-4’, J ¼ 3.4 Hz), 6.83 (d, 1H, H-3’,
J ¼ 3.4 Hz), 7.01 (s, 1H, NH), 7.41 (d, 2H, Ho-B, J ¼ 8.6 Hz) 7.67
(d, 2H, Hm-B, J ¼ 8.6 Hz) ppm; 13C NMR (100 MHz, CDCl3) d: 15.3
(CH3-thiophene), 42.6 (C-4), 59.4 (C-5), 124.7 (C-4’), 125.1 (C-3’),
128.1 (Co-B), 129.1 (Ci-B), 129.2 (Cm-B), 137.1 (Cp-B), 139.3 (C-5’),
¼
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–
141.1 (C-2’), 155.0 (C-3), 176.4 (C S) ppm; MS (EI, 70 eV), m/z (%):
–
335 (15, Mþ), 337 (5, Mþ2þ), 302 (14), 183 (100), 123 (51); Anal.
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1357 (C S), 1571 (C N); H NMR (400 MHz, CDCl ) d: 2.40 (s, 3H,
–
–
–
–
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3
CH3-thiophene), 3.33 (dd, 1H, H-4A, J4A-5 ¼ 2.9 Hz, J4A-4B
¼
17.5 Hz), 3.74 (dd, 1H, H-4B, J4B-4A ¼ 17.5 Hz, J4B-5 ¼ 10.9 Hz),
´
[9] B. Insuasty, A. Tigreros, F. Orozco, J. Quiroga, R. Abonıa,
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¼
10.9 Hz), 6.56 (d, 1H, H-4’, J ¼ 3.4 Hz), 6.83 (d, 1H, H-3’,
J ¼ 3.4 Hz), 7.00 (s, 1H, NH), 7.57 (d, 2H, Ho-B, J ¼ 8.7 Hz), 7.60
(d, 2H, Hm-B, J ¼ 8.7 Hz) ppm; 13C NMR (100 MHz, CDCl3) d: 15.3
(CH3-thiophene), 42.5 (C-4), 59.4 (C-5), 124.7 (C-4’), 125.1 (C-3’),
125.5 (Ci-B), 128.3 (Co-B), 129.5 (Cp-B), 132.1 (Cm-B), 139.3 (C-5’),
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–
141.1 (C-2’), 155.1 (C-3), 176.4 (C S) ppm; MS (EI, 70 eV), m/z (%):
–
381 (12), 379 (11, Mþ), 197 (25), 183 (100), 123 (53); Anal. Calcd.
for C15H14BrN3S2: C, 47.37; H, 3.71; N, 11.05. Found: C, 47.48;
H, 3.74; N, 11.08.
´
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4,5-dihydro-1H-pyrazole-1-carbothioamide (11h)
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1
–
–
1354 (C S), 1586 (C N); H NMR (400 MHz, CDCl ) d: 2.40 (d, 3H,
–
–
3
CH3-thiophene, 4J ¼ 0.9 Hz), 3.30 (dd, 1H, H-4A, J4A-5 ¼ 2.8 Hz,
J4A-4B ¼ 17.4 Hz), 3.69 (dd, 1H, H-4B, J4B-4A ¼ 17.4 Hz,
J4B-5 ¼ 10.8 Hz), 6.03 (s, 2H, CH2), 6.07 (s, 1H, NH), 6.25 (dd, 1H,
H-5, J5-4A ¼ 2.7 Hz, J5-4B ¼ 10.8 Hz), 6.55 (dd, 1H, H-4’,
4J ¼ 1.0 Hz, J ¼ 3.5 Hz), 6.82 (d, 1H, H-3’ J ¼ 3.4 Hz), 6.84
(d, 1H, Hm-B, J ¼ 8.2 Hz), 6.92 (s, 1H, NH), 7.13 (dd, 1H, Ho-B,
4J ¼ 1.7 Hz, 3J ¼ 8.1 Hz), 7.33 (d, 1H, Ho’-B, J ¼ 1.7 Hz) ppm;
13C NMR (100 MHz, CDCl3) d: 15.3 (CH3-thiophene), 42.8 (C-4),
´
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59.3 (C-5), 101.7 (CH2), 106.4 (Cm-B), 108.4 (Co-B), 122.5 (Co -B), 124.1
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`
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–
150.3 (C-2’), 156.0 (C-3), 176.2 (C S) ppm; MS (EI, 70 eV), m/z (%):
–
345 (26, Mþ), 312 (19), 285 (13), 197 (30), 183 (100); Anal. Calcd. for
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´
´
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The authors wish to credit The Developmental Therapeutics Program (DTP)
of the National Cancer Institute of the United States (US) for performing the
screening of compounds. This work was supported by Colciencias,
Universidad del Valle, Consejer´ıa de Econom´ıa, Innovacio´n y Ciencia
(Junta de Andaluc´ıa, Spain) and the Universidad de Jae´n. The authors
thank ‘Centro de Instrumentacio´n Cient´ıfico-Te´cnica de la Universidad de
Jae´n’ and the staff for data collection.
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The authors have declared no conflict of interest.
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www.archpharm.com

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ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com