Synthesis and biological evaluation of 3-(2,4-dichlorophenoxymethyl)-1-phenyl-1H-pyrazole derivatives as potential antitumor agents

Article abstract of DOI:10.1007/s13738-020-01951-w

Series of novel 3-(2,4-dichlorophenoxymethyl)-1-phenyl-1H-pyrazole derivatives with various substituents at positions 4 and 5 were synthesized. Antitumor activity of all the synthesized compounds was evaluated by using SRB assay on four cell lines: lung c

Full text of DOI:10.1007/s13738-020-01951-w

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-01951-w
ORIGINAL PAPER
Synthesis and biological evaluation
of 3‑(2,4‑dichlorophenoxymethyl)‑1‑phenyl‑1H‑pyrazole derivatives
as potential antitumor agents
Mohamed F. El Shehry1 · Samir Y. Abbas2 · Amel M. Farrag3 · Sawsan A. Fouad4 · Yousry A. Ammar5
Received: 22 March 2020 / Accepted: 4 May 2020
© Iranian Chemical Society 2020
Abstract
Series of novel 3-(2,4-dichlorophenoxymethyl)-1-phenyl-1H-pyrazole derivatives with various substituents at positions 4
and 5 were synthesized. Antitumor activity of all the synthesized compounds was evaluated by using SRB assay on four
cell lines: lung carcinoma (A549), human hepatocellular carcinoma (HepG2), colon carcinoma (HCT116) and mammary
gland breast cancer (MCF-7) cell lines. Some of the synthesized compounds showed promising activity in comparison with
doxorubicin against lung carcinoma cell lines. Incorporating arylidene moiety at position-4 in pyrazole ring improved and
displayed strong efect on the cytotoxic activity. Compound 9c incorporating 4-chlorophenyl moiety was the most potent
toward all tested cell lines.
Keywords Pyrazoles · Schif’s bases · Hydrazones · Vinyl derivative · Antitumor agents
Introduction
agents [1–3]. Pyrazoles have important roles among anti-
tumor agents; they play as good inhibitor against EGFR,
BRAFV600E, ROS receptor tyrosine kinase, telomerase, and
Aurora-A kinase. There are many of drugs incorporating
pyrazole moiety such as antipyrine, celecoxib, novalgine,
phenylbutazone, apixaban, ramifenazone, rimonabant,
fpronil, pyrazofurin [4–6]. Moreover, many of pyrazole
derivatives have another broad spectra of biological activi-
ties, such as antimicrobial [7] antiviral [8] and herbicidal
activities [9].
Pyrazole is one of the important moieties of heterocyclic
compounds. The frst pyrazole was synthesized by Knorr in
1883, which led to discovery of antipyrine and its deriva-
tives. Great attention has been focused on pyrazole deriva-
tives as potent anti-infammatory, analgesic, antipyretic
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-020-01951-w) contains
supplementary material, which is available to authorized users.
Dichlorophenoxy moiety showed systemic herbicide.
(2,4-Dichlorophenoxy) acetic acid (2,4-D) are used in the
control of broadleaf weeds. During the last six decades,
many research were carried out on (2,4-dichlorophenoxy)
acetic acid [10]. Schif’s base derivatives are interesting in
medicinal chemistry due to their diverse biological prop-
erties, including antitumor activity [11]. Many articles
reported that, the high electronegativity of halogens in the
drug molecules plays an important role in enhancing their
biological activity [12].
* Samir Y. Abbas
samiryoussef98@yahoo.com
* Yousry A. Ammar
yossry@yahoo.com
1
Pesticide Chemistry Department, National Research Centre,
Cairo 12622, Egypt
2
3
4
5
Organometallic and Organometalloid Chemistry Department,
National Research Centre, Cairo, Egypt
Treatment of cancer is a signifcant challenge for medici-
nal chemists over the past 100 years. Nevertheless, cancer is
still the causing leader of death; so, there are pressing needs
for novel and efective agents. Most of known chemotherapy
has toxic prosperity, So, we are in need to discover novel
agents that have selectively to kill tumor cells or inhibit their
Pharmaceutical Chemistry Department, Faculty of Pharmacy
(Girls), Al-Azher University, Nasr City, Cairo, Egypt
Chemistry Department, Faculty of Science, Al-Azhar
University (Girls), Cairo, Egypt
Chemistry Department, Faculty of Science, Al-Azhar
University, Cairo, Egypt
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
proliferation without being generally toxic as well as they
are more active [13, 14].
in ethanol led to the formation of Schif’s bases 4a–d in
high yield. By the similar way, the scope of the reaction of
pyrazole-4-carbaldehyde 3 with the same selected amines
was carried out and the corresponding Schif’s bases 5a–d
were obtained in moderate yields. IR spectra of 4a–d and
5a–d showed disappearance of bands for carbonyl group and
the presence of bands around 1614 cm−1 region for CH=N
group. Their 1H NMR spectra showed absence of aldehydic
group and revealed signal for azomethine about 8.50 ppm.
1H NMR spectrum of 4d, as an example, exhibited char-
acteristic signals for aromatic protons, beside three singlet
signals for CH3, OCH2and CH=N protons at δ=2.32, 5.55
and 8.56 ppm. Moreover, its 13C NMR spectrum revealed
24 carbon types, the most important signal displayed at
δ = 21.0 and 64.7 corresponding to CH3 and OCH2. For
obtain biologically active compounds, the reaction of pyra-
zole-4-carbaldehyde derivatives 2 and 3 with isonicotinichy-
drazide was carried out in dioxane and led to the forma-
tion of the hydrazone derivative 6a and 6b, respectively,
in good yields. 1H NMR spectrum of hydrazone derivative
6b revealed signal at δ=11.82 ppm (D2O-exchangeable) for
NH proton, aromatic protons were appeared in the range of
7.35–8.80 ppm, and also, aliphatic protons of pyrrolidine
moiety were observed as expected positions.
As view in Fig. 1, we have focused on the design of novel
structural entities that incorporate 1-phenyl-1H-pyrazole,
2,4-dichlorophenoxymethyl, azomethine (or olefn), chlorine
(or pyrrolidine) into a single molecular scafold to evalu-
ate the potential additive anticancer efect of these systems
on anticancer activity with the aim to obtain newer better-
tolerated antitumor drugs and more efcacious as well as
avoiding toxicity drawbacks.
Results and discussion
Chemistry
Three diferent types of pyrazole derivatives 1–3 were syn-
thesized and used as starting materials for synthesizing
more varieties of 4,5-disubstituted pyrazole derivatives. The
frst type of the aimed pyrazole derivative 1 was prepared
according to the reported method [15] through treatment
of ethyl 4-(2,4-dichlorophenoxy)-3-oxo-butanoate with
phenylhydrazine in acetic acid. The pyrazolone derivative
1 was used as a precursor for the synthesis second type of
pyrazole derivative. Thus, the pyrazolone 1 was subjected to
a Vilsmeir–Haack chloroformylation and aforded product
which was identifed as 5-chloro-pyrazole-4-carbaldehyde
derivative 2 [15]. The third type of pyrazole derivative was
obtained by nucleophilic substitution reaction of 2 with
pyrrolidine in DMSO, to aford pyrazole-4-carbaldehyde
Nitrovinyl derivative 7 was obtained by condensation
reaction of pyrazole-4-carbaldehyde 3 with nitrometh-
ane in dioxane in the presence few drops of piperidine
1
(Scheme 2). Its H NMR spectrum displayed doublet
signal at δ = 8.41 ppm with a coupling constant indicat-
ing trans-olefinic protons. Condensation of the pyrazol-
3-aldehyde derivative 3 with malononitrile afforded the
corresponding vinyl derivative 8. Its IR spectrum exhib-
ited absorption bands at 2219 cm−1 for nitrile functional
1
derivative 3 (Scheme 1). H NMR spectrum of the alde-
hyde 3 displayed signals at δ = 1.80, 3.09 and 3.23 ppm
characteristic for the protons of pyrrolidinyl moiety as well
as signal at δ=9.94 ppm characteristic for the proton of for-
myl group. Furthermore, its 13C NMR spectrum revealed
signals at δ=24.2, 25.8, 44.9 and 52.6 ppm characteristic
for the carbons of pyrrolidinyl moiety as well as signal at:
δ=183.1 ppm characteristic for the carbon of formyl group.
The scope of the reaction of pyrazole-4-carbaldehyde 2 with
various nitrogen nucleophile was studied with the objective
of obtaining biologically active compounds. Thus, the reac-
tion of pyrazole-4-carbaldehyde 2 with the selected amines
1
group. H NMR spectrum exhibited a singlet signal at
8.41 ppm for olefinic proton. 13C NMR spectrum showed
two signals at 25.8 and 51.6 ppm for pyrrolidine carbons
as well as signal at 66.0 ppm for methylene carbon.
Finally, aiming to reach new biologically active com-
pounds, some arylidene derivatives were synthesized.
Treatment of the pyrazolone derivative 1 with aromatic
aldehydes in glacial acetic acid containing catalytic
amount of sodium acetate under reflux, condensation
Fig. 1 Design of novel hybrid
molecular scafold
Cl
O
X
Azomethine or olefin substituents
for better biological activity
N
Cl
N
Dichlorophenoxy
moiety for better
Ph
biological activity
Pyrazole backbone
with drug like properties
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Journal of the Iranian Chemical Society
Scheme 1 Syntheses of pyra-
zolone 1, formylpyrazoles 2,3,
Schif’s bases 4,5 and hydra-
zone derivatives 6
Cl
O
N
Cl
O
N
Ph
1
Vilsmeir
reagent
Cl
R
H2N
R
O
N
Cl
N
Cl
X
CHO
X
N
Ph
O
CONHNH2
4a-d
5a-d
N
Cl
N
Cl
N
H
N
Ph
N
2,
X = Cl
O
N
X
pyrrolidine
3,
X = pyrrolidin-1-yl
N
Cl
O
N
Ph
4a
5a:
: X = Cl, R = H
: X = Cl, R = F
: X = Cl, R = Cl
X = pyrrolidin-1-yl, R = H
: X = pyrrolidin-1-yl, R = F
: X = pyrrolidin-1-yl, R = Cl
6a,
X = Cl
4b
4c
5b
5c
6b, X = pyrrolidin-1-yl
4d: X = Cl, R = CH3 5d: X = pyrrolidin-1-yl, R = CH3
Scheme 2 Syntheses of vinyl
derivatives 7 and 8
Cl
NO2
H3C NO2
O
N
Cl
Cl
N
N
CHO
N
Ph
7
O
N
Cl
Cl
N
Ph
3
CN
CN
O
NC
CN
N
Cl
N
N
Ph
8
reaction was occurred and afforded the corresponding
arylidene derivatives 9a–d (Scheme 3). Moreover, con-
densation of pyrazolone derivative 1 with pyrazole-4-car-
baldehyde 2 afforded the corresponding vinyl derivative
10.
substituent at C-(4) and those at C-(5) on these activities
was studied and make a comparative study between them to
deduce a structure activity relationship.
Antitumor properties of the synthesized compounds
in comparison with the standard drug, doxorubicin, were
evaluated by using sulforhodamine B colorimetric (SRB)
assay [16] on four cancer cell lines: lung carcinoma cell line
(A549), human hepatocellular carcinoma cell line (HepG2),
colon carcinoma cell line (HCT116) and mammary gland
breast cancer cell line (MCF-7). IC50 values for the tested
compounds are reported in Table 1. As general, all synthe-
sized compounds exhibited good to excellent efect toward
the tested cancer cell lines. The tested compounds in general
Anticancer activity
The aim of the present investigation was synthesizing new
series of pyrazole derivatives which bearing 3-((2,4-dichlo-
rophenoxy)methyl) at C-(3), phenyl at N-(1) and various
substituent at C-(4) and others at C-(5). The antitumor activ-
ity of these derivatives was measured. The efect of each
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Scheme 3 Syntheses of
arylidene derivatives 9a–d and
10
Cl
Cl
R
OHC
R
O
O
N
Cl
N
Cl
O
O
N
Ph
N
Ph
1
9a: R = H 9c: R = Cl
9b: R = F 9d: R = CH3
Cl
Cl
2
O
O
Cl
N
N
Cl
N
Ph
N
Ph
Cl
10
O
showed to be more selective toward A549 then HepG2 then
HCT116 than MCF-7.
efect, where compounds 6a and 6b showed good activity
against most of the tested cell lines but less than most of
their analogues.
The key precursor, 5-chloro-1H-pyrazole-4-carbaldehyde
2 displayed weak antitumor activity. Replacing the chlorine
atom in compound 2 by pyrrolidine moiety as in the key
precursor 3 improved the activity compared to its analogue
2. Structure 4 has at position-4 azomethine side chain end-
ing with aryl moiety (aryl: phenyl, 4a; 4-fuorophenyl, 4b;
4-chlorophenyl, 4c; 4-methylphenyl, 4d). The efect of each
substituent on benzene ring on the activity of the Schif’s
bases 4a–d was studied. The obtained IC50 values for these
compounds suggest that all of the evaluated Schif’s bases
(except 4c) displayed about 50% less activity compared to
doxorubicin against A549 cell line. Generally, phenyl moiety
(4a) showed the best result toward all cell lines followed
by methylphenyl moiety (4d). Changing the substituent on
C-(5) from chlorine atom to pyrrolidine was carried out
to show the diference between Cl and pyrrolidine on the
efect of the biological activities. Like structure 4, changing
the substituent at C-(4) from phenyl to 4-fuorophenyl to
4-chlorophenyl to 4-methylphenyl (5a/5b/5c/5d) was carried
out for the same reason. The obtained IC50 values for these
compounds suggest that all of the evaluated Schif’s bases 5b
and 5c possess signifcant cytotoxic activity against most of
the tested cell lines used in these assays. Interestingly, unlike
4a, its analogue 5a showed activity less than its analogue.
Pointing to the reinforcing and opposing efects of Y groups,
a clear diference in cytotoxic activity is noted between
compounds within this series, which may be augmented or
reduced depending on whether a matching or mismatching
relationship exists with other groups. So, the type of the
substitutions on the benzene ring of aryl moiety is important.
Structure 6 has at position-4 isonicotinohydrazide moi-
ety. Compounds 6a, b showed weak activities against all
tested cell lines. Replacement the substituent at position-4
from azomethine side chain moiety at structures 4 and 5 to
isonicotinohydrazide moiety at structure 6 has a detrimental
Structures 7 and 8 have at position-4 olefnic side chain
bond ending with nitro group (7), dicyano (8). The presence
of nitro group displayed strong efect on the cytotoxic activ-
ity and is one of the highest cytotoxic compounds among all
the compounds investigated in this study, where 7 showed
results near to the reference drug against all tested cell lines.
The presence of dicyano has a detrimental efect where com-
pound 8 displayed weak efects on the cytotoxic activity. For
searching for newer antitumor, series of arylidene deriva-
tives 9a–d were synthesized. Arylidene derivatives 9a–d
has at position-4 olefnic side chain bond ending with aryl
moiety (aryl: phenyl, 9a; 4-fuorophenyl, 9b; 4-chlorophe-
nyl, 9c; 4-methylphenyl, 9d). The obtained IC50 values for
these compounds suggest that all of the evaluated arylidenes
9a–d possess signifcant cytotoxic activity against most of
the tested cell lines used in these assays. In general, incorpo-
rating arylidene moiety at position-4 improved the cytotoxic
activity. Thus, arylidene moiety displayed strong efect on
the cytotoxic activity. The latter series is the highest cyto-
toxic compounds among all the series investigated in this
study, where 9b–d showed potency near todoxorubicin in
inhibiting the growth of most of cell lines.
Increasing the size of the substituent as in structure 10
had a good efect on antitumor activity. Structure 10, which
has olefnic bond ending with pyrazole moiety showed good
activity against all tested cell lines (except MCF-7). Com-
parison between the anticancer activity of our potent syn-
thesized compounds and doxorubicin as standard antican-
cer reference drug against the used cell lines is represented
graphically in Fig. 2.
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Journal of the Iranian Chemical Society
Table 1 Antitumor of all compounds and doxorubicin against the tested cancerous cell lines
compound 7 showed the highest cytotoxic activity among
Conclusions
all the investigated compounds. Incorporating arylidene
moiety at position-4 as in compounds 9b, c improved the
cytotoxic activity. Thus, arylidene moiety showed potency
near to doxorubicin in inhibiting the growth of the cell lines.
In general, it can be concluded that treatment of pyrazole-
4-carbaldehyde derivative with active methylene and
nitromethane improved the antitumor properties against the
tested cell lines. Also, treatment of the pyrazolone derivative
1 with aromatic aldehydes improved the antitumor proper-
ties against the tested cell lines. The obtained IC50 values
for these compounds suggest that incorporation at posi-
tion-4 olefnic side chain bond ending with nitro group as in
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Journal of the Iranian Chemical Society
16
14
12
10
8
Synthesis of Schif’s bases derivatives 4a–d
A549
and 5a–d
HEPG-2
HCT 116
MCF-7
A solution of the aldehyde 2 or 3 (0.01 mol) in 50 mL etha-
nol was treated with the requisite amine (0.01 mol) (namely
aniline, 4-fuoroaniline, 4-chloroaniline or 4-methylani-
line). The reaction mixture was heated under refux for 3 h.
The solution was left to cool. The solid product obtained
was fltered of and crystallized from THF to give the fnal
products.
6
4
2
0
7
9b
9c
9d
Doxorubicin
Compound No.
Fig. 2 Comparison between the antitumor activity of our potent syn-
thesized compounds and doxorubicin
N‑((5‑Chloro‑3‑((2,4‑dichlorophenoxy)
methyl)‑1‑phenyl‑1H‑pyrazol‑4‑yl)methylene)ani‑
line (4a)
Experimental section
Yield 85%; m.p. 126–128 °C; IR: ν/cm−1 = 3061
(CH–Ar.), 2941, 2866 (CH-aliph.), 1626 (C=N); 1H NMR:
δ/ppm=5.55 (s, 2H, OCH2), 7.1 (d, 1H, J=7.70 Hz, Ar–H),
7.19–7.30 (m, 1H, Ar–H), 7.38–7.50 (m, 5H, Ar–H),
7.56–7.68 (m, 5H, Ar–H), 8.02 (d, 1H, J=8.10 Hz, Ar–H),
8.56 (s, 1H, CH=N); 13C NMR: 64.7 (OCH2), 116.2 (CH),
118.5 (CH), 121.2 (2CH), 123.0 (C), 125.3 (C), 125.9
(2CH), 126.5 (CH), 128.5 (CH), 129.4 (CH), 129.7 (2CH),
129.8 (CH), 129.9 (2CH), 130.2 (CH), 137.4 (C), 148.4 (C),
151.1 (CH=N); 152.0 (C), 153.4 (C); MS, m/z (%): 456
(M+; 48.2); Anal. Calcd for C23H16Cl3N3O (456.75): C,
60.48; H, 3.53; N, 9.20; Found: C, 60.56; H, 3.42; N, 9.13%.
All melting points are recorded on digital Gallen Kamp
MFB-595 instrument and may be uncorrected. The IR
spectra (KBr) (cm−1) were measured on a JASCO spec-
trophotometer. 1H NMR spectra were recorded on Bruker
spectrometers (at 500 MHz) and are reported relative to
deuterated solvent signals in deuterated dimethylsulfoxide
(DMSO-d6).13C NMR spectra were recorded on Bruker
Spectrometers (at 125 MHz) in deuterated dimethylsul-
foxide (DMSO-d6).
Synthesis of 3‑((2,4‑dichlorophenoxy)
methyl)‑1‑phenyl‑5‑(pyrrolidin‑1‑yl)‑1H‑pyra‑
zole‑4‑carbaldehyde (3)
N‑((5‑Chloro‑3‑((2,4‑dichlorophenoxy)
methyl)‑1‑phenyl‑1H‑pyrazol‑4‑yl)
methylene)‑4‑fuoroaniline (4b)
To a solution of 2 (0.01 mol) in 25 mL DMSO, pyrrolidine
(0.01 mol) was added and the reaction mixture was stirred
for 24 h at room temperature. The solution was diluted
with H2O (100 mL) and extracted with Et2O (3 × 50 mL).
The organic phase was washed with H2O (100 mL), after
which it was dried (Na2SO4). Removal of the solvent left
a solid residue, which was purifed by column chroma-
tography (ethyl acetate: n-hexane\4:1). Yield 75%; m.p.
138–140 °C; IR: ν/cm−1 = 3065 (CH–Ar.), 2952, 2923,
Yield 81%; m.p. 120–122 °C; IR: ν/cm−1 =3071 (CH–Ar.),
2923 (CH-aliph.), 1629 (C=N); 1H NMR: δ/ppm=5.54 (s,
2H, OCH2), 7.21–7.25 (m, 4H, Ar–H), 7.39- 7.47 (m, 3H,
Ar–H), 7.58–7.68 (m, 5H, Ar–H), 8.57 (s, 1H, CH=N); 13
C
NMR: 64.7 (OCH2), 116.1 (CH), 116.3 (d, JC-F =22.3 Hz,
CH), 123.0 (CH), 123.1 (CH), 125.3 (C), 125.9 (CH),
128.5 (CH), 129.8 (d, JC-F = 9.3 Hz, CH), 129.9 (CH),
130.0 (CH), 130.1 (CH), 130.3 (C), 137.3 (C), 148.4 (d,
JC-F =2.7 Hz, C–N), 151.2 (CH=N), 153.4 (C), 161.03 (d,
JC-F =242.7 Hz, C-F); MS, m/z (%): 474 (M+; 39.6); Anal.
Calcd for C23H15Cl3FN3O (474.74): C, 58.19; H, 3.18; N,
8.85; Found: C, 58.23; H, 3.07; N, 8.76%.
1
2883 (CH-aliph.), 1603 (C=N); H NMR: δ/ppm = 1.80
(s, 4H, 2CH2-pyrrolidinyl), 3.23 (s, 2H, CH2-pyrrolidinyl),
5.28 (s, 2H, OCH2), 7.31 (d, 2H, J = 8.92 Hz, Ar–H), 7.39
(d, 2H, J = 8.70 Hz, Ar–H), 7.44–7.54 (m, 3H, Ar–H),
7.57 (s, 1H, Ar–H), 9.94 (br, 1H, CHO); 13C NMR: 24.2
(CH2), 25.8 (CH2), 44.9 (CH2), 52.6 (CH2), 65.4 (OCH2),
108.8 (C), 115.9 (CH), 122.8 (C), 125.0 (C), 126.8 (2CH),
128.5 (CH), 129.0 (CH), 129.5 (2CH), 129.7 (CH), 140.2
(C), 149.0 (C), 151.5 (C), 153.5 (CH), 183.1 (CHO); MS,
m/z (%): 416 (M+; 55.6); Anal. Calcd for C21H19Cl2N3O2
(416.30): C, 60.59; H, 4.60; N, 10.09; Found: C, 60.72;
H, 4.57; N, 9.87%.
4‑Chloro‑N‑((5‑chloro‑3‑((2,4‑dichlorophenoxy)
methyl)‑1‑phenyl‑1H‑pyrazol‑4‑yl)methylene)ani‑
line (4c)
Yield 85%; m.p. 116–118 °C; IR: ν/cm−1 = 3072
(CH–Ar.), 2921, 2851 (CH-aliph.), 1627 (C=N); 1H NMR:
δ/ppm=5.55 (s, 2H, OCH2), 7.19 (d, 2H, J=8.6 Hz, Ar–H),
7.39–7.46 (m, 4H, Ar–H), 7.56–7.68 (m, 6H, Ar–H), 8.58
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Journal of the Iranian Chemical Society
(s, 1H, CH=N); 13C NMR: 64.7 (OCH2), 116.1 (CH), 116.3
(CH), 123.0 (CH), 123.1 (2CH), 125.3 (C), 125.9 (2CH),
128.6 (CH), 129.6 (2CH), 129.8 (CH), 129.9 (CH), 130.0
(2CH), 130.5 (C), 130.8 (C), 137.3 (C), 148.5 (C), 150.8 (C),
151.9 (CH=N), 153.4 (C); MS, m/z (%): 491 (M+; 82.1);
Anal. Calcd for C23H15Cl4N3O (491.19): C, 56.24; H, 3.08;
N, 8.55; Found: C, 56.37; H, 2.99; N, 8.43%.
(CH), 128.5, 129.6 (d, JC-F =8.9 Hz, CH), 129.7, 140.2, 5
149.5 (d, JC-F =2.7 Hz, C–N), 150.0 (CH=N), 153.7, 160.3
(d, JC-F = 240.9 Hz, C-F); MS, m/z (%): 509 (M+; 55.2);
Anal. Calcd for C27H23Cl2FN4O (509.40): C, 63.66; H, 4.55;
N, 11.00; C, 64.25; H, 4.81; N, 10.70; Found: C, 63.73; H,
4.42; N, 10.87%.
4‑Chloro‑N‑((3‑((2,4‑dichlorophenoxy)
methyl)‑1‑phenyl‑5‑(pyrrolidin‑1‑yl)‑1H‑pyra‑
zol‑4‑yl)methylene)aniline (5c)
N‑((5‑Chloro‑3‑((2,4‑dichlorophenoxy)
methyl)‑1‑phenyl‑1H‑pyrazol‑4‑yl)
methylene)‑4‑methylaniline (4d)
Yield 75%; m.p. 146–148 °C; IR: ν/cm−1 =3065 (CH–Ar.),
Yield 81%; m.p. 145–147 °C; IR: ν/cm−1 =3022 (CH–Ar.),
2952, 2923, 2883 (CH-aliph.), 1603 (C=N); H NMR: δ/
1
1
2920 (CH-aliph.), 1627 (C=N); H NMR: δ/ppm = 2.32
ppm=1.83 (s, 4H, pyrrolidinyl-H), 3.27 (s, 4H, pyrrolidi-
nyl-H), 5.41 (s, 2H, OCH2), 7.09 - 7.17 (m, 4H, Ar–H),
7.30–7.80 (m, 8H, Ar–H), 8.70 (s, 1H, CH=N); 13C NMR:
δ=25.4 (CH2), 51.5 (CH2), 65.2 (OCH2), 107.4 (CH), 116.1
(CH), 116.5, 122.2, 122.4, 122.5, 124.7, 125.6 (2CH), 128.7,
129.2 (2CH), 129.4, 140.0, 148.1, 149.5, 153.1; MS, m/z
(%): 525 (M+; 33.6); Anal. Calcd for C27H23Cl3N4O (525.9):
C, 61.67; H, 4.41; N, 10.65; Found: C, 61.45; H, 4.39; N,
10.54%.
(s, 3H, CH3), 5.55 (s, 2H, OCH2), 7.06 (d, 2H, J=8.1 Hz,
Ar–H), 7.20 (d, 2H, J=7.8 Hz, Ar–H), 7.41 (s, 2H, Ar–H),
7.76–7.50 (m, 6H, Ar–H), 8.56 (s, 1H, CH=N); 13C NMR:
21.0 (CH3), 64.7 (OCH2), 116.1 (CH), 116.3 (CH), 121.2
(2CH), 123.0 (C), 125.3 (C), 125.9 (2CH), 128.6 (CH),
129.6 (CH), 129.8 (CH), 129.9 (2CH), 130.0 (2CH), 130.5
(C), 130.8 (C), 137.3 (C), 148.5 (C), 150.8 (C), 151.9
(CH=N), 153.4 (C); MS, m/z (%): 470 (M+; 72.2); Anal.
Calcd for C24H18Cl3N3O (470.78): C, 61.23; H, 3.85; N,
8.93; Found: C, 61.42; H, 3.74; N, 8.72%.
N‑((3‑((2,4‑dichlorophenoxy)methyl)‑1‑phe‑
nyl‑5‑(pyrrolidin‑1‑yl)‑1H‑pyrazol‑4‑yl)
methylene)‑4‑methylaniline (5d)
N‑((3‑((2,4‑Dichlorophenoxy)methyl)‑1‑phe‑
nyl‑5‑(pyrrolidin‑1‑yl)‑1H‑pyrazol‑4‑yl)methylene)
aniline (5a)
Yield 70%; m.p. 140–142 °C; IR: ν/cm−1 =3065 (CH–Ar.),
1
2952, 2923, 2883 (CH-aliph.), 1603 (C=N); H NMR: δ/
Yield 76%; m.p. 144–146 °C; IR: ν/cm−1 =3057 (CH–Ar.),
ppm=1.81 (s, 4H, 2CH2), 2.21 (s, 3H, CH3), 3.27 (s, 4H,
2CH2), 5.41 (s, 2H, OCH2), 7.00–7.80 (m, 8H, Ar–H), 8.63
(s, 1H, CH=N); 13C NMR: 20.2 (CH3), 25.4 (CH2), 51.5
(CH2), 65.2 (OCH2), 107.4, 116.1, 116.5,122.2, 122.4,
122.5, 124.7, 125.6, 126.4, 128.7, 129.2, 129.3, 129.4,
140.0, 148.1, 149.3, 153.0; MS, m/z (%): 505 (M+; 45.6);
Anal. Calcd for C28H26Cl2N4O (505.4): C, 66.54; H, 5.18;
N, 11.08; Found: C, 66.62; H, 5.23; N, 10.98%.
1
2975, 2927, 2875 (CH-aliph.), 1634 (C=N); H NMR: δ/
ppm=1.80 (s, 4H, pyrrolidinyl-H), 3.27 (s, 4H, pyrrolidinyl-
H), 5.41 (s, 2H, OCH2), 7.00 7.22 (m, 5H, Ar–H), 7.34–7.73
(m, 8H, Ar–H), 8.68 (s, 1H, CH=N); 13C NMR: 25.7 (CH2),
51.7 (CH2), 65.8 (OCH2), 107.7 (CH), 116.1 (CH), 116.3,
122.0, 122.4, 123.1, 125.0, 125.6 (2CH), 128.4, 129.2
(2CH), 129.4, 140.0, 147.7, 150.1 (CH=N), 153.8; MS,
m/z (%): 491 (M+; 63.2); Anal. Calcd for C27H24Cl2N4O
(491.4): C, 65.99; H, 4.92; N, 11.40; Found: C, 66.12; H,
4.89; N, 11.34%.
Synthesis of hydrazide derivatives 6a and 6b
A mixture of aldehyde 1 or 2 (0.01 mol) and isonicotinichy-
drazide (0.01 mol) in dioxane (30 mL) was heated under
refux for 1 h. The reaction mixture was concentrated under
vacuum, left to cool. The solid product obtained was fltered
of and crystallized from ethanol to give the fnal products.
N‑((3‑((2,4‑Dichlorophenoxy)methyl)‑1‑phe‑
nyl‑5‑(pyrrolidin‑1‑yl)‑1H‑pyrazol‑4‑yl)
methylene)‑4‑fuoroaniline(5b)
Yield 73%; m.p. 158–160 °C; IR: ν/cm−1 =3064 (CH–Ar.),
1
2954, 2924, 2884 (CH-aliph.), 1607 (C=N); H NMR: δ/
N’‑((5‑chloro‑3‑((2,4‑dichlorophenoxy)
methyl)‑1‑phenyl‑1H‑pyrazol‑4‑yl)methylene)isoni‑
cotinohydrazide (6a)
ppm=1.82 (s, 4H, pyrrolidinyl-H), 3.26 (s, 4H, pyrrolidinyl-
H), 5.43 (s, 2H, OCH2), 7.09 (dd, 2H, J=8.7, 5.2 Hz, Ar–H),
7.17 (t, 2H, J=8.7 Hz, Ar–H), 7.34–7.43 (m, 2H, Ar–H),
7.61–7.83 (m, 6H, Ar–H), 8.68 (s, 1H, CH=N); 13C NMR:
25.8 (CH2), 51.8 (CH2), 65.7 (OCH2), 107.5 (CH), 116.0
(d, JC-F =22.3 Hz, CH), 116.2, 122.6, 122.9, 124.9, 125.7
Yield 80%; m.p. 199–201 °C; IR: ν/cm−1 =3065 (CH–Ar.),
1
2952, 2923, 2883 (CH-aliph.), 1603 (C=N); H NMR: δ/
ppm=5.51 (s, 2H, OCH2), 7.35- 8.03 (m, 10H, Ar–H), 8.57
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Journal of the Iranian Chemical Society
(s, 1H, CH=N), 8.81 (m, 2H, Ar–H), 12.12 (br, 1H, NH);
13C NMR: 64.7, 100.4, 116.1, 116.2, 118.5, 121.1, 121.2
(2C), 123.0, 125.5, 125.9 (2C), 126.5, 128.5, 129.4, 129.7
(2C), 130.2, 130.3, 137.4, 148.4, 151.1, 152.0, 153.4; MS,
m/z (%): 500 (M+; 34.5); Anal. Calcd for C23H16Cl3N5O2
(500.76): C, 55.16; H, 3.22; N, 13.99; Found: C, 55.23; H,
3.17; N, 13.87%.
product was collected by fltration and crystallized from
dioxane. Yield 85%; m.p. 152–154 °C; IR: ν/cm−1 =2984,
2945, 2833 (CH-aliph.), 2219 (C≡N); 1H NMR: δ/
ppm=1.82 (s, 4H, pyrrolidinyl-H), 3.17 (s, 4H, pyrrolidinyl-
H), 5.34 (s, 2H, OCH2), 7.32 (d, 1H, J=6.1 Hz, Ar–H), 7.41
(dd, 1H, J=6.2 Hz, Ar–H), 7.50–7.59 (m, 5H, Ar–H), 7.64
(s, 1H, Ar–H), 8.41 (s, 1H, CH-olefnic); 13C NMR: 25.8
(2CH2), 51.6 (2CH2), 66.0 (OCH2), 75.6 (C), 102.8 (2C≡N),
115.1, 115.9, 116.1, 122.9, 125.5, 126.6 (2CH), 128.6,
129.4, 129.7 (2CH), 139.8, 147.3, 150.8, 152.6, 153.4; MS,
m/z (%): 464 (M+; 46.6); Anal. Calcd for C24H19Cl2N5O
(464.35): C, 62.08; H, 4.12; N, 15.08; Found: C, 62.17; H,
4.04; N, 15.23%.
N’‑((3‑((2,4‑dichlorophenoxy)methyl)‑1‑phe‑
nyl‑5‑(pyrrolidin‑1‑yl)‑1H‑pyrazol‑4‑yl)methylene)
isonicotinohydrazide (6b)
Yield 72%; m.p. 124–126 °C; IR: ν/cm−1 = 3444, 3205
(NH), 3046 (CH–Ar.), 2975, 2952, 2874 (CH-aliph.), 1666
(C=O); 1H NMR (500 MHz, CDCl3): δ/ppm=1.88 (s, 4H,
pyrrolidinyl-H), 3.20 (s, 4H, pyrrolidinyl-H), 5.39 (s, 2H,
OCH2), 7.35–7.71 (m, 9H, Ar–H), 7.82 (s, 1H, Ar–H), 8.68
Reaction of pyrazol‑5(4H)‑one 1 with aldehydes
Solution of 1 (0.01 mol) in glacial acetic acid (20 mL) was
treated with the requisite aldehydes (0.01 mL) and fused
sodium acetate (0.5 gm). The reaction mixture was heated
under refux for 2 h, poured into crashed ice. The obtained
product was fltered and crystallized from ethanol.
(s, 1H, CH=N), 8.80 (s, 2H, Ar–H), 11.82 (br, 1H, NH); 13
C
NMR (126 MHz,, CDCl3): δ=25.8, 51.8, 65.7, 25.9, 51.5,
64.7, 101.8, 116.6, 121.9,125.1,125.8, 128.6,129.6, 129.7,
143.1, 146.9, 150.8, 161.3; MS, m/z (%): 535 (M+; 43.6);
Anal. Calcd for C27H24Cl2N6O2 (535.4): C, 60.57; H, 4.52;
N, 15.70; Found: C, 60.38; H, 4.44; N, 15.47%.
4‑Benzylidene‑3‑((2,4‑dichlorophenoxy)
methyl)‑1‑phenyl‑1H‑pyrazol‑5(4H)‑one (9a)
Synthesis of 3‑((2,4‑dichlorophe‑
noxy)methyl)‑4‑(2‑nitrovinyl)‑1‑phe‑
nyl‑5‑(pyrrolidin‑1‑yl)‑1H‑pyrazole (7)
Yield 77%; IR: ν/cm−1 = 1650 (C=O); 1H NMR: δ/
ppm = 5.53 (s, 2H, OCH2), 7.02–7.50 (m, 8H, Ar–H),
7.60–7.70 (m, 5H, Ar–H), 8.11 (d, 1H, J=8.10 Hz, Ar–H);
13C NMR: 64.7, 116.2, 118.5, 121.2, 123.0, 125.3, 125.9,
126.5, 128.5, 129.4, 129.7, 129.1, 129.9, 130.2, 137.4,
148.4, 151.1, 152.0, 153.4, 166.3; MS, m/z (%): 423 (M+;
62.0); Anal. Calcd for C23H16Cl2N2O2 (423.29): C, 65.26; H,
3.81; N, 6.62; Found: C, 65.41; H, 3.78; N, 6.57%.
To equimolar amount of the aldehyde derivative 3 (0.01 mol)
and nitromethane (0.01 mol) in dioxane (30 mL), few drops
of piperidine was added. The reaction mixture was heated
under refux for 2 h., then allowed to cool. The obtained
product was collected by fltration and crystallized from
ethanol. Yield 67%; m.p. 133–135 °C; IR: ν/cm−1 = 3076
(CH–Ar.), 2938, 2884, 2846 (CH-aliph.), 1606 (C=N); 1H
NMR: δ/ppm = 1.82 (m, 4H, 2CH2), 3.26 (s, 4H, 2CH2),
5.28 (s, 2H, OCH2), 7.46 (d, 1H, Ar–H), 7.47–7.58 (m, 7H,
Ar–H), 7.65 (s, 1H, Ar–H), 8.41 (d, 1H, J=13.0 Hz, olefnic
CH); 13C NMR: 25.8 (2CH2), 52.0 (2CH2), 64.9 (OCH2),
100.1, 116.2, 123.0, 125.7, 126.5 (2CH), 128.6, 129.1, 129.6
(2CH), 130.0, 132.0 (2C), 140.0, 146.6, 151.3, 152.4; MS,
m/z (%): 459 (M+; 49.3); Anal. Calcd for C22H20Cl2N4O3
(459.33): C, 57.53; H, 4.39; N, 12.20; Found: C, 57.42; H,
4.42; N, 12.08%.
3‑((2,4‑Dichlorophenoxy)methyl)‑4‑(4‑fuorobenzyli
dene)‑1‑phenyl‑1H‑pyrazol‑5(4H)‑one (9b)
Yield 81%; IR: ν/cm−1 = 1651 (C=O); 1H NMR: δ/
ppm = 5.51 (s, 2H, OCH2), 7.20–7.50 (m, 6H, Ar–H),
7.58–7.70 (m, 7H, Ar–H); 13C NMR: 64.7, 116.1, 116.2,
116.4, 123.0, 123.1, 125.3, 125.9, 128.5, 129.8, 129.9,
130.0, 130.1, 130.3, 137.3, 148.4, 151.2, 166.4; MS, m/z
(%): 441 (M+; 37.5); Anal. Calcd for C23H15Cl2FN2O2
(441.28): C, 62.60; H, 3.43; N, 6.35; Found: C, 62.54; H,
3.41; N, 6.41%.
Synthesis of2‑((3‑((2,4‑dichlorophenoxy)
methyl)‑1‑phenyl‑5‑(pyrrolidin‑1‑yl)‑1H‑pyra‑
zol‑4‑yl)methylene)malononitrile (8)
4‑(4‑Chlorobenzylidene)‑3‑((2,4‑dichlorophenoxy)
methyl)‑1‑phenyl‑1H‑pyrazol‑5(4H)‑one (9c)
To equimolar amount of the aldehyde derivative 3 (0.01 mol)
and malononitrile (0.01 mol) in dioxane (30 mL), few drops
of piperidinewas added. The reaction mixture was heated
under refux for 1 h. then allowed to cool, the obtained
Yield 83%; IR: ν/cm−1 = 1648 (C=O); 1H NMR: δ/
ppm = 5.52 (s, 2H, OCH2), 7.19–7.46 (m, 6H, Ar–H),
7.56–8.84 (m, 7H, Ar–H);13C NMR: 64.7, 116.1, 116.3,
123.0, 123.1, 125.3, 125.9, 128.6, 129.6, 129.8, 129.9, 130.0,
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Journal of the Iranian Chemical Society
130.5, 130.8, 137.3, 148.5, 150.8, 151.9, 153.4, 166.5; MS,
m/z (%): 457 (M+; 55.6); Anal. Calcd for C23H15Cl3N2O2
(457.74): C, 60.35; H, 3.30; N, 6.12; Found: C, 60.44; H,
3.28; N, 6.04%.
References
1. A.A. Farag, M.F. El Shehry, S.Y. Abbas, S.N. Abd-Alrahman,
A.A. Atrees, H.Z. Al-basheer, Y.A. Ammar, Z. Naturforsch. B
70, 519–526 (2015)
2. M.F. Khan, M.M. Alam, G. Verma, W. Akhtar, M. Akhter, M.
Shaquiquzzaman, Eur. J. Med. Chem. 120, 170–201 (2016)
3. S. Ganguly, S.K. Jacob, Mini Rev. Med. Chem. 17, 959–983
(2017)
3‑((2,4‑Dichlorophenoxy)methyl)‑4‑(4‑methylbenzyl
idene)‑1‑phenyl‑1H‑pyrazol‑5(4H)‑one (9d)
4. S. Küçükgüzel, S. Senkardes, Eur. J. Med. Chem. 97, 786–815
(2015)
Yield 72%; IR: ν/cm−1 = 1652 (C=O); 1H NMR: δ/
ppm = 2.31 (s, 3H, CH3), 5.52 (s, 2H, OCH2), 7.06–7.50
(m, 13H, Ar–H); 13C NMR: 21.0, 64.7, 116.1, 116.3, 121.2,
123.0, 125.3, 125.9, 128.6, 129.6, 129.8, 129.9, 130.0, 130.5,
130.8, 137.3, 148.5, 150.8, 153.4, 165.9; MS, m/z (%): 437
(M+; 29.8); Anal. Calcd for C24H18Cl2N2O2 (437.32): C,
65.91; H, 4.15; N, 6.41; Found: C, 66.02; H, 4.11; N, 6.34%.
5. I. Desai, K. Sinha, W. Null, M.A. Wolter, T. Suckow, S. King, R.
Amin, Sinha. Int. J. Cancer 127, 230–238 (2010)
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17, 1479–1492 (2020)
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(2002)
Synthesis of 4‑((5‑chloro‑3‑((2,4‑dichloro‑
phenoxy)methyl)‑1‑phenyl‑1H‑pyrazol‑4‑yl)
methylene)‑3‑((2,4‑dichlorophenoxy)methyl)‑1‑phe‑
nyl‑1H‑pyrazol‑5(4H)‑one (10)
10. J. Pernak, A. Syguda, K. Materna, E. Janus, P. Kardasz, T. Prac-
zyk, Tetrahedron 68, 4267–4273 (2012)
11. S.Y. Abbas, K.A.M. El-Bayouki, W.M. Basyouni, E.A. Mostafa,
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Mohamed, A.A. El-Henawy, Monatsh. Chem. 144, 1725–1733
(2013)
Solution of 1 (0.01 mol) in glacial acetic acid (20 mL)
was treated with the pyrazole-4-carbaldehyde 2 (0.01 mL)
and fused sodium acetate (0.5 g). The reaction mixture
was heated under refux for 2 h, poured into crashed ice.
The obtained product was fltered and crystallized from
DMF, Yield 68%; IR: ν/cm−1 =1656 (C=O); 1H NMR: δ/
ppm=5.34 (s, 4H, 2OCH2), 7.20–8.30 (m, 17H, Ar–H); MS,
m/z (%): 698 (M+; 14.6); Anal. Calcd for C33H21Cl5N4O3
(698.81): C, 56.72; H, 3.03; N, 8.02; Found: C, 56.83; H,
2.98; N, 7.89%.
13. R.A.K. Al-Harbi, M.A.M.S. El-Sharief, S.Y. Abbas, Bioorg.
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Vistica, J.T. Warren, H. Bokesch, S. Kenny, M.R. Boyd, J. Nat.
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