Synthesis and Antioxidant Activity of Some New Thiazolyl–Pyrazolone Derivatives

Article abstract of DOI:10.1002/jhet.2588

3-Methyl-1-thiocarbamoyl-2-pyrazolin-5-one has been utilized as a core for the synthesis of some 1-(thiazol-2-yl)-pyrazolin-5-one derivatives through diazo-coupling reaction and/or Knoevenagel condensation followed by heterocyclization with some α-halogen

Full text of DOI:10.1002/jhet.2588

Month 2016
Synthesis and Antioxidant Activity of Some New
Thiazolyl–Pyrazolone Derivatives
H. E. Gaffer, S. Abdel-Fattah, H. A. Etman, and E. Abdel-Latif
a
b
b
b
*
aTextile Research Division, National Research Centre, 12622 Dokki, Giza, Egypt
bDepartment of Chemistry, Faculty of Science, Mansoura University, ET-35516 Mansoura, Egypt
*
E-mail: ehabattia00@gmx.net
Additional Supporting Information may be found in the online version of this article.
Received July 14, 2015
DOI 10.1002/jhet.2588
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
3-Methyl-1-thiocarbamoyl-2-pyrazolin-5-one has been utilized as a core for the synthesis of some
1-(thiazol-2-yl)-pyrazolin-5-one derivatives through diazo-coupling reaction and/or Knoevenagel condensa-
tion followed by heterocyclization with some α-halogenated reagents such as bromoacetone, phenacyl
bromide, and ethyl bromoacetate. Base prompted addition of the core compound to an equimolar amount
of phenyl isothiocyanate furnished 3-methyl-4-phenylthiocarbamoyl-1-thiocarbamoyl-2-pyrazolin-5-one
which undergoes heterocyclization with α-halogenated reagents at the more reactive phenylthiocarbamoyl
moiety to afford the corresponding 4-(thiazol-2-yl)-1-thiocarbamoyl-2-pyrazolin-5-ones. The new
synthesized thiazolyl–pyrazolone compounds were evaluated for their potential antioxidant activity by using
(ABTS Radical Cation Decolorization Assay).
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
antioxidant properties that revealed interesting results by
using (ABTS Radical Cation Decolorization Assay).
The synthesis of various heterocyclic compounds having
more than one heteroatom with structural and functional
novelty has been increased in the recent years. The wide
variety of these heterocycles have been explored for devel-
oping pharmaceutically important molecules like chalcones
and their derivatives like pyrazoles and thiazoles. Pyrazole
derivatives have gained great interest because of their phar-
macological activities such as antidepressant [1], antioxidant
[2], antiinflammatory [3], anticancer [4], antiviral [5], anti-
bacterial [6], and antifungal [7] properties. Pyrazole deriva-
tives containing thiazole ring have attracted the researchers
because of their varied biological activities [8–12]. There-
fore, several methods have been reported for the synthesis
of thiazolyl–pyrazole derivatives [13,14]. In the literature,
pyrazole derivatives are of interest principally for antioxidant
properties because of the presence of conjugated π-system,
which delocalize after donation of hydrogen atom and stabi-
lize the antioxidant molecule; activity is also related to the
concentration and type of substituent present [15]. In the
present study, we report on the synthesis of some new
thiazolyl–pyrazolone derivatives, their characterization by
spectral data (IR, 1H NMR and MS) and evaluation of their
RESULTS AND DISCUSSION
Synthesis and reactions. The key compound 3-methyl-1-
thiocarbamoyl-2-pyrazolin-5-one (1) was prepared by the
reaction of ethyl acetoacetate with thiosemicarbazide
according to the previously reported methodology [16]. The
reactivity of methylene group in compound 1 was
investigated toward the electrophilic diazocoupling reaction
with the aromatic diazonium chloride of ethyl 4-amino
benzoate (2); the reaction proceeded in pyridine to afford
the corresponding 4-arylhydrazono-1-thiocarbamoyl-2-
pyrazolin-5-one derivative 3 (Scheme 1). The chemical
structure of 3 was secured by its correct elemental and
spectral analyses. The IR spectrum of 3 showed absorption
bands at 3370, 3252, and 3162cmꢀ1 corresponding to the
NH2 and NH groups and revealed the presence of two
absorption bands at 1707 and 1691cmꢀ1 corresponding to
1
the two carbonyl groups. The H NMR spectrum showed
triplet and quartet signals at 1.30 and 4.30ppm because of
ethyl group (COOCH2CH3), a singlet signal at 2.15ppm
© 2016 HeteroCorporation

H. E. Gaffer, S. Abdel-Fattah, H. A. Etman, and E. Abdel-Latif
Vol 9999
Scheme 1. Synthesis of 4-(arylhydrazono)-1-(thiazol-2-yl)-2-pyrazolin-5-ones 7–10.
because of methyl protons (CH3), two doublet signals at 7.55
and 8.00ppm corresponding to the aromatic protons, in
addition to two singlet signals at 9.55 and 11.55 ppm
corresponding to the NH2 and NH groups, respectively.
Heterocyclization of 4-arylhydrazono-1-thiocarbamoyl-2-
pyrazolin-5-one derivative 3 with variety of α-halogenated re-
agents 4–6 was employed to synthesize the target thiazolyl–
pyrazole derivatives 7, 8, and 9. Treatment of 3 with ethyl
bromoacetate under reflux in ethanol containing sodium ace-
tate for 4h afforded the corresponding thiazolyl-pyrazol-5-
one 7. The structure of 7 was established on the basis of its el-
emental analysis and spectral data. The reaction of compound
3 with chloroacetonitrile in ethanol containing a catalytic
amount of triethylamine furnished the corresponding 4-
aminothiazolyl-pyrazol-5-one 8. The structure of 8 was con-
firmed by its correct elemental analysis and spectral data.
The IR spectrum exhibited absorption bands at 3374, 3293,
and 3166 cmꢀ1 corresponding to the NH2 and NH functions,
while the absorption bands at 1701 and 1671cmꢀ1 were at-
tributed to the two carbonyl groups (ester and pyrazole ring).
is carried out in hot ethanol containing drops of triethylamine
to afford the corresponding 4-substitutedthiazolyl-pyrazol-5-
one derivatives 9. The chemical structure of compounds 9a,b
was confirmed on the basis of their elemental analysis and
spectral data. An attempt to synthesis arylazothiazolyl-
arylhydrazonopyrazol-5-one derivatives 11 was failed, 1-
thiocarbamoyl-2-pyrazolin-5-one compound 1 was reacted
with α-bromoketones 6 (e.g. bromoacetone and phenacyl
bromide) to furnish the corresponding thiazol-pyrazol-5-one deriv-
atives 6 which underwent diazocoupling reaction with aromatic
diazonium salt gave the corresponding 4-substitutedthiazolyl-
pyrazol-5-one derivatives
9
and did not give the
arylazothiazolyl-arylhydrazonopyrazol-5-one derivatives 11.
1,3-Diphenyl-1H-pyrazole-4-carbaldehyde (12) was
synthesized previously [17] by heating of acetophenone
phenyl hydrazone with Vilsmer–Haack reagent (DMF-
POCl3). The reactivity of our starting material, 3-
methyl-1-thiocarbamoyl-2-pyrazolin-5-one (1) toward
Knoevenagel condensation was also examined. Thus,
condensation of equimolar amounts of pyrazolin-5-one
compound 1 with 4-formylpyrazole 12 in acetic acid and
fused sodium acetate yielded the corresponding condensa-
tion product 13 which underwent further heterocyclization
reaction with α-bromoketones 6 (namely, bromoacetone
and phenacyl bromide) furnished the corresponding
thiazolyl–pyrazole derivatives 14. The chemical structures
of 14a,b were confirmed by its spectral data and alternative
synthesis from the reaction of thiazolyl-pyrazolin-5-one 10
with 4-formylpyrazole derivative 12 (Scheme 2). The IR
spectrum of 14a revealed the absence of NH2 function and
1
The H NMR spectrum displayed triplet signal at 1.30 ppm
because of the protons of methyl group (ester), singlet signal
at 2.15 ppm for the protons of methyl group, quartet signal
at 4.30 ppm for the protons of methylene group (ester), singlet
signal at 7.07 ppm for the proton of thiazole C-5, two doublet
signals at 7.60 and 7.98ppm because of the aromatic protons,
and two signals at 8.50 and 11.60 corresponding to the protons
of NH2 and ¼NNH groups.
In addition, heterocyclization of compound 3 with α-
bromoketones 6 (e.g. bromoacetone and phenacyl bromide)
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Synthesis of Thiazolyl-Pyrazolin-5-One Derivatives as Antioxidant Agents
Scheme 2. Synthesis of 1-(thiazol-2-yl)-4-[(1,3-diphenyl-1H-pyrazol-4-
yl)methylene]-2-pyrazolin-5-ones 14.
18 (Scheme 3). The chemical structure of 18 was inferred
from its elemental analysis and spectral data. Thus, its IR
spectrum showed absorption bands at 3239 and 3208cmꢀ1
corresponding to the NH2 function and bands at 1753 and
1657cmꢀ1 referring to the two carbonyl groups and
1591cmꢀ1 for the (C¼N) function. The 1H NMR spectrum
showed two singlet signals at 2.35 and 4.25ppm referring
to the protons of methyl and methylene groups, a multiplet
signal in the region 7.15–7.60ppm because of the aromatic
protons, and a singlet signal at 9.65ppm for the protons of
amino (NH2) group. The mass spectrum showed the molec-
ular ion peak at m/z=332 corresponding to the molecular
weight of the molecular formula C14H12N4O2S2.
On the other hand, in situ treatment of the potassium salt
16 with equimolar amount of ethyl bromoacetate (4)
afforded the isomeric 4-oxothiazolyl-pyrazolin-5-one de-
rivative 19. The IR spectrum of 19 showed absorption
bands at 3247 and 3190cmꢀ1 because of the (NH2) group
and bands at 1743 and 1655 cmꢀ1 corresponding to the two
showed absorption band at 1671cmꢀ1 referring to the car-
bonyl group (C¼O). 1H NMR spectrum of 14b displayed a
singlet signal at 2.35ppm because of the protons of the
methyl group (CH3), a singlet signal at 6.60ppm because
of the methine proton (CH¼C), a singlet signal at 7.10
because of the proton of thiazole C-5, and a multiplet signal
at the region 7.20–7.85ppm for the aromatic and the
pyrazole C-5 protons.
The base prompted addition of our starting compound 1 to
equimolar amount of phenyl isothiocyanate (15) in DMF
containing potassium hydroxide afforded the corresponding
potassium sulfide salt 16 that was not isolated. In situ subse-
quent treatment of the non-isolable potassium salt 16 with
chloroacetyl chloride (17) at room temperature furnished
the corresponding 5-oxothiazolyl-pyrazolin-5-one derivative
1
carbonyl functions. The H NMR spectrum showed a sin-
glet signal at 2.35ppm referring to the three protons of
methyl group, a singlet signal at 4.05ppm corresponding
to the protons of methylene (CH2) function, a multiplet sig-
nal in the region 7.10–7.55ppm because of the aromatic
protons, and a singlet signal at 9.55 ppm for the protons
of (NH2) function. The mass spectrum of the compound
showed the molecular ion peak at m/z =332 corresponding
to the molecular weight of its formula C14H12N4O2S2.
Further heterocyclization of the 4-oxothiazolyl-1-
thiocarbamoyl-2-pyrazolin-5-one derivative 19 with α-
bromoketone compounds 6 including phenacyl bromide
Scheme 3. Synthesis of 3-methyl-4-(thiazolidin-2-ylidene)-2-pyrazolin-5-ones 18–20.
Journal of Heterocyclic Chemistry
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H. E. Gaffer, S. Abdel-Fattah, H. A. Etman, and E. Abdel-Latif
Vol 9999
and bromoacetone was achieved by reflux in hot ethanol and
drops of triethylamine as a basic catalyst to furnish the corre-
sponding 4-(4-oxothiazolyl)-1-(4-substitutedthiazolyl)-2-
pyrazolin-5-one derivatives 20a and 20b. Also the structure
of 20 was further confirmed by an independent synthesis
via thiocarbamoylation of compound 10 by the reaction with
phenyl isothiocyanate in DMF containing solid potassium
hydroxide followed by neutralization with dilute HCl to give
the corresponding thiazolyl-4-thiocarbamoyl-2-pyrazolin-5-
one derivatives 21 which underwent cyclization reaction
with ethyl bromoacetate (4) by heating in ethanol containing
anhydrous sodium acetate to afford the target compounds 20.
The IR spectrum of 20a (as an example) showed an absorp-
tion band at 1718cmꢀ1 because of the (C¼O) function of
thiazole ring besides one amidic carbonyl absorption band
(pyrazole ring) at 1661cmꢀ1, while the stretching band of
(C¼N) function absorbed at 1601cmꢀ1. The 1H NMR spec-
trum of the same compound showed two singlet signals at
2.15 and 2.40ppm referring to the protons of two methyl
groups, a singlet signal at 3.95ppm for the protons of meth-
ylene group, a singlet signal at 6.65ppm for the proton of thi-
azole C-5, and a multiplet signal in the region 7.15–7.60ppm
for the aromatic protons. The chemical structure of 21 was
also established on the basis of elemental analysis and spec-
tral data. The IR spectrum of 21b (as an example) showed
absorption bands at 3106 and 1649cmꢀ1 corresponding to
the (NH) and (C¼O) functions, respectively. Also 1H
NMR spectrum in CDCl3/CF3COOD displayed a singlet sig-
nal at 2.15ppm referring to the protons of methyl group, a
singlet signal at 6.65ppm for the proton of thiazole C-5,
and a multiplet signal in the region 6.90–7.65 ppm because
of the aromatic protons. The mass spectrum displayed mo-
lecular ion peak at 392 (7.6%) corresponding to the molecu-
lar weight of the molecular formula C20H16N4OS2.
Treatment of the non-isolable potassium salt 16 with di-
lute HCl afforded the corresponding thiocarbamoyl-2-
pyrazolin-5-one derivative 22 with new active phenyl-
thiocarbamoyl function group at 4-position for further
derivatization (Scheme 4). The chemical structure of 22
was secured by its correct elemental and spectral analyses.
The IR spectrum of 22 revealed the presence of absorption
bands at 3338, 3241, and 3185cmꢀ1 referring to the NH2
and NH functions, while the absorption at 1662 cmꢀ1 was
1
attributed to the carbonyl group. The H NMR spectrum
in CDCl3/CF3COOD showed a singlet signal at 2.15ppm
because of the protons of methyl group and a multiplet sig-
nal in the region 7.10–7.55ppm because of the aromatic
protons. Treatment of 22, which has two different
thiocarbamoyl moieties, with equimolar amount of α-
bromoketone compounds 6 (namely, bromoacetone and
phenacyl bromide) in hot ethanol containing triethylamine
as a basic catalyst afforded the corresponding 4-(3-phenyl-
4-substituted-thiazol-2-ylidene)-1-thiocarbamoyl-2-
pyrazolin-5-one derivatives 23. The formation of thiazole
ring proceeds through heterocyclization of the more reac-
tive phenylthiocarbamoyl moiety with α-bromoketone
rather than the less reactive thiocarbamoyl moiety.
Moreover, heterocyclization reaction of 23, which has
only one thiocarbamoyl moiety as a single choice, with
α-bromoketone compounds was achieved by heating in
ethanol containing triethylamine as a basic catalyst to
form 3-methyl-4-(4-substituted-3-phenylthiazol-2-ylidene)-
1-(4-substituted-thiazol-2-yl)-2-pyrazolin-5-one derivatives
24a–c. Assignment of these products was based on elemen-
tal analyses, spectral data, and an independent synthesis via
further reaction of thiazolyl-4-thiocarbamoyl-2-pyrazolin-5-
one derivatives 21 with bromoacetone and/or phenacyl
bromide.
Scheme 4. Synthesis of 3-methyl-4-(thiazol-2-yl)-2-pyrazolin-5-ones 23 and 24.
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Synthesis of Thiazolyl-Pyrazolin-5-One Derivatives as Antioxidant Agents
Table 1
Antioxidant activity of the synthesized thiazolyl–pyrazole derivatives.
ABTS Abs (control) ꢀ Abs (test) / Abs (control) × 100
Method compounds
Absorbance of samples
% inhibition
Control of ABTS
Ascorbic acid
1
3
7
8
9a
9b
10a
10b
14a
14b
18
0.510
0.060
0.408
0.435
0.358
0.379
0.216
0.225
0.177
0.058
0.182
0.110
0.169
0.267
0.282
0.254
0.138
0.073
0.391
0.375
0.413
0.352
0.411
0%
88.20%
20.00%
14.70%
29.80%
25.70%
57.60%
55.90%
65.30%
88.60%
64.30%
78.40%
66.90%
47.60%
44.70%
50.20%
72.90%
85.70%
23.30%
26.50%
19.00%
31.00%
19.40%
19
20a
20b
21a
21b
23a
23b
24a
24b
24c
Antioxidant activity. The newly synthesized thiazolyl–
pyrazole compounds 7–10, 14, 18–21, 23, and 24 (Table 1)
were tested for their antioxidant activities by using (ABTS
Radical Cation Decolorization Assay) [18,19]. The results
(Table 1) indicated that most of the examined compounds
(except 1, 3, 7, 8, 23, and 24) exhibited moderate to very
strong antioxidant activity. The compounds 10a, 14b, 18,
and 21a displayed strong antioxidant activity. Compounds
10b and 21b displayed the best antioxidant property
(88.60%) and (85.70%) respectively. Compound 10b was
even more active than the standard inhibitor (L-ascorbic
acid 88.20%).
Structure–activity study. The antioxidant potential of
thiazolyl–pyrazole compounds is connected with the posi-
tioning and forms of substituents on the thiazole and
pyrazole rings. The enhancement in antioxidant activity
of compounds 10b and 21b may be because of the
presence of phenyl ring on the thiazole ring and
phenylthiocarbamoyl group along with core pyrazolin-5-
one moiety. Structure–activity relationship (SAR) points
out two major properties of the most active thiazolyl–
pyrazoles. 4-Phenyl substitution on the thiazole ring is
generally more beneficial than the methyl substitution.
The link of thiazolyl ring at position 1 of the pyrazole ring
increased the activity whereas at position 4 hindered the
activity.
CONCLUSIONS
Nineteen substituted thiazolyl-pyrazolin-5-one derivatives
were synthesized from the readily available 3-ethyl-1-
thiocarbamoyl-2-pyrazolin-5-one by diazo-coupling reaction,
Knoevenagel condensation, or thiocarbamoylation reaction
with phenyl isothiocyanate followed by heterocyclization
with various α-halogenated reagents such as bromoacetone,
phenacyl bromide, and ethyl bromoacetate. Their structures
were clearly confirmed by spectroscopy data (IR, 1H NMR,
and MS) and elemental analysis. The target compounds were
evaluated for their potential antioxidant activity by using
ABTS Radical Cation Decolorization Assay. Among the an-
alogue compounds, 10b and 21b showed the excellent activ-
ity in comparison to the standard inhibitor.
EXPERIMENTAL
All melting points (uncorrected) were determined on an
electrothermal Gallenkamp melting point apparatus. The
completion of reaction was checked by thin-layer chroma-
tography using silica gel-G (0.5-mm thickness, petroleum
ether and ethyl acetate solvent system). The IR spectra
were recorded in KBr disks on a Thermo Scientific Nicolet
iS 50 FT-IR spectrometer (not all frequencies are reported).
Journal of Heterocyclic Chemistry
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H. E. Gaffer, S. Abdel-Fattah, H. A. Etman, and E. Abdel-Latif
Vol 9999
The NMR spectra were acquired using a Bruker WP 300
spectrometer at 300 MHz using TMS as an internal stan-
dard and CDCl3 or DMSO-d6 as solvent. The mass spectra
were performed using a Shimadzu Qp-2010 mass spec-
trometer at 70 eV. Elemental analyses were carried out at
the Microanalytical Unit, Cairo University, Giza, Egypt;
the results were in satisfactory agreement with the calculated
values. Antioxidant activities were carried out at Drugs
Department, Faculty of Pharmacy, Mansoura University,
Egypt.
11.35 (s, 1H, ¼NNH); MS (EI, 70eV): m/z (%) = 373
(21.6), 320 (21.8), 289 (21.2), 223 (30.4), 200 (26.3),
179 (18.7), 133 (47.6), 91 (88.3), 80 (100), 64 (64.7), 55
(28.8). Anal. Calcd. for C16H15N5O4S (373.08): C, 51.47;
H, 4.05; N, 18.76. Found: C, 51.62; H, 4.14; N, 18.68.
Synthesis of thiazolyl-pyrazolin-5-one derivatives 8 and 9.
Method (A): A mixture of the 1-thiocarbamoyl-2-pyrazolin-
5-one derivative 3 (0.005mol, 1.66g), appropriate α-
halogenated reagents, chloroacetonitrile bromoacetone
and/or phenacyl bromide, (0.005mol), and 0.5-mL
triethylamine was refluxed in 20-mL ethanol–DMF
mixture (2:1) for 6h. The reaction mixture was poured
into cooled water, and the resulting precipitate was
collected by filtration, washed several times with water,
and crystallized from EtOH–DMF mixture (5:1). to afford
8, 9a, and/or 9b.
Synthesis of 4-(4-ethoxycarbonyl-phenylhydrazono)-3-
methyl-1-thiocarbamoyl-2-pyrazolin-5-one (3).
In a 100-
mL conical flask, a well-stirred solution of ethyl 4-amino
benzoate (2, 0.01 mol, 1.65 g) in 3.0-mL concentrated
hydrochloric acid (3.0 mL) and 2.0-mL H2O was cooled
in an ice-bath at 0–5°C and then diazotized with a
solution of NaNO2 (0.7 g in 10-mL H2O). The freshly
prepared diazonium solution was added dropwise to a
well-stirred cold solution of the pyrazolin-5-one
compound 1 (0.01 mol, 1.57g) in 15-mL pyridine. The
reaction mixture was allowed to stir at 0–5°C for 2h until
complete coupling reaction was achieved. The reaction
mixture was diluted with cold water, and the solid
product that deposited was collected by filtration, washed
with cold water, dried, and recrystallized from ethanol.
Orange crystals, yield 77%; mp 242–244°C; Rf value:
0.62 petroleum ether:ethyl acetate (5:1); IR ( ν /cmꢀ1):
3370, 3252, 3162, (NH2 and NH), 1707 (C¼O, ester),
Method (B): A well-stirred solution of ethyl 4-
aminobenzoate (2, 0.005mol, 0.82g) in 1.5-mL
concentrated HCl and 3-mL water was cooled in an ice-bath
at 0–5°C and diazotized with a solution of 0.35-g NaNO2 in
5-mL H2O. Then, the freshly cold diazonium solution was
added dropwise to
a well-stirred cold solution of
compound 10 (0.005mol) in 25-mL pyridine. The reaction
mixture was stirred for 2h until complete coupling reac-
tion was achieved. The solid product which deposited
was collected by filtration, washed with cold water, and
recrystallized from a mixture of EtOH:DMF (5:1) to give
9a and 9b.
1
1691 (C¼O, ring), 1606 (C¼N); H NMR (DMSO-d6):
4-(4-Ethoxycarbonyl-phenylhydrazono)-3-methyl-1-(4-aminothiazol-
2-yl)-2-pyrazolin-5-one (8). Yellowish green crystals, yield 79%,
mp 210–212°C; Rf value: 0.68 petroleum ether:ethyl acetate
(3:1); IR (ν/cmꢀ1): 3374, 3293, 3166 (NH2 and NH), 1701
δ/ppm =1.30 (t, 3H, CH3, J= 7.15 Hz), 2.15 (s, 3H,
CH3), 4.30 (q, 2H, CH2, J= 7.15 Hz), 7.55 (d, 2H,
Ar―H), 8.00 (d, 2H, Ar―H), 9.55 (s, 2H, NH2), 11.55
(s, 1H, ¼NNH); MS (EI, 70 eV): m/z (%) = 333 (19.6),
304 (30.2), 266 (45.6), 246 (77.8), 190 (65.4), 172
(29.2), 133 (18.6), 91 (100), 77 (36.5). Anal. Calcd. for
C14H15N5O3S (333.09): C, 50.44; H, 4.54; N, 21.01.
Found: C, 50.37; H, 4.48; N, 21.05.
1
(C¼O, ester), 1671 (C¼O, ring), 1608 (C¼N); H NMR
(DMSO-d6): δ/ppm =1.30 (t, 3H, CH3, J= 7.15 Hz), 2.15 (s,
3H, CH3), 4.30 (q, 2H, CH2, J= 7.15 Hz), 7.07 (s, 1H, thiazole
H-5), 7.60 (d, 2H, Ar―H), 7.98 (d, 2H, Ar―H), 8.50 (s, 2H,
NH2), 11.60 (s, 1H, ¼NNH); MS (EI, 70eV): m/z (%)=372
(11.6), 274 (49.8), 229 (11.6), 165 (24.8), 137 (9.8), 125 (100),
108 (12.6), 97 (28.6). Anal. Calcd. for C16H16N6O3S (372.10):
C, 51.60; H, 4.33; N, 22.57. Found: C, 51.76; H, 4.40; N, 22.67.
4-(4-Ethoxycarbonyl-phenylhydrazono)-3-methyl-1-(4-methy
Synthesis of 4-(4-ethoxycarbonyl-phenylhydrazono)-1-(4,5-
dihydro-4-oxothiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (7).
A
mixture
of
the
1-thiocarbamoyl-2-pyrazolin-5-one
derivative
3
(0.005mol, 1.66g), ethyl bromoacetate
(0.005mol, 0.55mL), and 0.5-g anhydrous sodium acetate
in absolute ethanol (25mL) was refluxed for 4h. The
reaction mixture was allowed to cool at room temperature,
poured into cooled water, and neutralized by dilute HCl.
The solid that formed after neutralization was collected by
filtration, dried, and recrystallized from ethanol.
Red crystals, yield 82%, mp 201–203°C; Rf value: 0.44
petroleum ether:ethyl acetate (3:1); IR ( ν /cmꢀ1): 3174
(¼NNH), 1741 (C¼O, thiazole ring), 1704 (C¼O, ester),
1665 (C¼O, pyrazole ring), 1610 (C¼N); 1H NMR
(DMSO-d6): δ/ppm =1.30 (t, 3H, CH3, J =7.15 Hz), 2.15
(s, 3H, CH3), 4.10 (s, 2H, CH2), 4.30 (q, 2H, CH2,
J =7.15 Hz), 7.58 (d, 2H, Ar―H), 7.98 (d, 2H, Ar―H),
lthiazol-2-yl)--2-pyrazolin-5-one (9a).
Orange crystals,
yield 75%, mp 184–186°C; Rf value: 0.52 petroleum
ether:ethyl acetate (3:1); IR (ν/cmꢀ1): 3228 (NH), 1714
1
(C¼O, ester) 1671 (C¼O, ring), 1608 (C¼N); H NMR
(DMSO-d6): δ/ppm= 1.30 (t, 3H, CH3, J =7.15 Hz), 2.15
(s, 3H, CH3), 2.45 (s, 3H, CH3), 4.30 (q, 2H, CH2,
J = 7.15 Hz), 7.52 (s, 1H, thiazole H-5), 7.59 (d, 2H,
Ar―H), 7.99 (d, 2H, Ar―H), 11.56 (s, 1H, ¼NNH); MS
(EI, 70eV): m/z (%) =371 (19.5), 345(20.8), 329 (31.5),
311 (40.7), 253 (100), 236 (64.3), 133 (26.8), 107 (34.1),
93 (61.2), 77 (66.2). Anal. Calcd. for C17H17N5O3S
(371.11): C, 54.97; H, 4.61; N, 18.86. Found: C, 54.86;
H, 4.68; N, 18.95.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Thiazolyl-Pyrazolin-5-One Derivatives as Antioxidant Agents
4-(4-Ethoxycarbonyl-phenylhydrazono)-3-methyl-1-(4-pheny
lthiazol-2-yl)--2-pyrazolin-5-one (9b).
Calcd. for C21H17N5OS (387.12): C, 65.10; H, 4.42; N,
18.08. Found: C, 65.26; H, 4.49; N, 18.17.
Red powder, yield
66%, mp 195–197°C; Rf value: 0.46 petroleum ether:ethyl
Synthesis of 4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-
methyl-1-(4-substituted-thiazol-2-yl)-2-pyrazolin-5-one (14).
Method (A): To a mixture of compound 13 (0.002mol,
0.77g) and bromoacetone or phenacyl bromide
(0.002mol) in absolute ethanol (20mL), few drops of
triethylamine were added as a catalyst. The mixture was
refluxed for 4 h and then left to cool at room temperature.
The solid that formed was collected by filtration, dried,
and recrystallized from ethanol.
Method (B): A mixture of the thiazolyl–pyrazole com-
pound 10 (0.003mol) and 4-formylpyrazole 12 (0.003mol,
0.75g) in 15-mL glacial acetic acid containing 1.0-g fused
sodium acetate was refluxed for 2h. The reaction mixture
was allowed to cool at room temperature and then poured
into ice water. The resulting precipitated solid was collected
by filtration, dried, and recrystallized from ethanol.
acetate (3:1); IR (ν/cmꢀ1): 3118 (NH), 1715 (C¼O, ester),
1
1667 (C¼O, ring), 1608 (C¼N); H NMR (DMSO-d6):
δ/ppm=1.30 (t, 3H, CH3, J= 7.15 Hz), 2.15 (s, 3H, CH3),
4.35 (q, 2H, CH2, J=7.15 Hz), 7.15 (s, 1H, thiazole H-5),
7.25–8.00 (m, 9H, Ar―H), 11.25 (s, 1H, ¼NNH); MS (EI,
70eV): m/z (%)=433 (13.5), 420(17.7), 407 (26.4), 392
(44.7), 381 (15.6), 372 (23.3), 344 (25.8), 311 (33.4), 258
(100), 243 (42.2), 200 (56.5), 174(35.8), 149 (28.5), 134
(19.7), 102 (18.3), 91 (38.7), 77 (24.7). Anal. Calcd. for
C22H19N5O3S (433.12): C, 60.96; H, 4.42; N, 16.16.
Found: C, 61.12; H, 4.53; N, 16.05.
Synthesis
of
3-methyl-1-(4-substituted-thiazol-2-yl)-2-
pyrazolin-5-ones (10). A mixture of the pyrazolin-5-one
compound 1 (0.01mol, 1.57g) and bromoacetone and/or
phenacyl bromide (0.01mol) in absolute ethanol (25mL)
containing five drops of triethylamine was refluxed for 2h.
The reaction mixture was allowed to cool at room
temperature and the solid that formed was collected by
filtration, dried, and recrystallized from ethanol.
3-Methyl-1-(4-methylthiazol-2-yl)-4-[(1,3-diphenyl-1H-pyrazol-
4-yl)methylene]-2-pyrazolin-5-one (14a).
Yellowish brown
crystals, yield 55%, mp 213–215°C; Rf value: 0.46
petroleum ether:ethyl acetate (5:1); IR ( ν /cmꢀ1): 1671
1
3-Methyl-1-(4-methyl-thiazol-2-yl)-2-pyrazolin-5-one (10a).
White crystals, yield 61%, mp 202–204°C; Rf value: 0.46
petroleum ether:ethyl acetate (5:1); IR ( ν /cmꢀ1): 1646
(C¼O), 1599 (C¼N); H NMR (DMSO-d6): δ/ppm =2.15
(s, 3H, CH3), 2.35 (s, 3H, CH3), 6.55 (s, 1H, HC¼C), 6.95
(s, 1H, thiazole H-5), 7.15–7.80 (m, 11H, Ar―H and
pyrazole H-5); MS (EI, 70eV): m/z (%)= 425 (9.4), 374
(2.8), 257 (34.5), 177 (4.7), 134 (53.8), 118 (69.3), 102
(47.8), 93 (50.1), 77 (100), 64 (47.2). Anal. Calcd. for
(425.13): C, 67.74; H, 4.50; N, 16.46. Found: C, 67.87; H,
4.58; N, 16.41.
1
(C¼O), 1594 (C¼N); H NMR (DMSO-d6): δ/ppm=2.15
(s, 3H, CH3), 2.40 (s, 3H, CH3), 3.85 (s, 2H, CH2), 6.72
(s, 1H, thiazole H-5); MS (EI, 70eV): m/z (%)=195 (8.4),
181 (22.8), 173 (15.5), 167 (41.7), 155 (59.3), 139 (6.3),
114 (37.8), 91 (100), 83 (23.3), 65 (40.2). Anal. Calcd. for
C8H9N3OS (195.05): C, 49.21; H, 4.65; N, 21.52. Found:
C, 49.08; H, 4.72; N, 21.61.
3-Methyl-4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-1-(4-
phenylthiazol-2-yl)-2-pyrazolin-5-one (14b).
Brown crystals,
3-Methyl-1-(4-phenyl-thiazol-2-yl)-2-pyrazolin-5-one (10b).
White crystals, yield 72%, mp 188–189°C (Lit. mp 190–
191°C) [20].
yield 63%, mp 261–263°C; Rf value: 0.41 petroleum ether:
ethyl acetate (3:1); IR (ν/cmꢀ1): 1668 (C¼O), 1603 (C¼N);
1H NMR (DMSO-d6): δ/ppm=2.35 (s, 3H, CH3), 6.60 (s,
1H, HC¼C), 7.10 (s, 1H, thiazole H-5), 7.20–7.85 (m, 16H,
Ar―H and pyrazole H-5); MS (EI, 70 eV): m/z (%)=487
(12.0), 456 (20.4), 307 (2.1), 257 (38.9), 203 (72.5), 176
(27.7), 148 (28.7), 134 (79.3), 102 (100), 91 (39.1), 77
(29.8). Anal. Calcd. for C29H21N5OS (487.15): C, 71.44; H,
4.34; N, 14.36. Found: C, 71.29; H, 4.24; N, 14.46.
Synthesis of 4-[(1,3-diphenyl-1H-pyrazol-4-yl)methylene]-
3-methyl-1-thiocarbamoyl-2-pyrazolin-5-one
(13).
A
mixture of compound 1 (0.003 mol, 0.47 g) and 4-
formylpyrazole 12 (0.003mol, 0.75g) in 15-mL glacial
acetic acid containing fused sodium acetate (1.0g) was
refluxed for 2h. The reaction mixture was allowed to cool
at room temperature and then poured into ice water. The
resulting precipitated solid was collected by filtration,
dried, and crystallized from ethanol. The isolated product
was tested by TLC, one spot, Rf =0.47, petroleum ether:
ethyl acetate (3:1).
Synthesis of 4-(oxo-thiazolidin-2-ylidene)-1-thiocarbamoyl-
2-pyrazolin-5-one derivatives 18 and 19.
To a cooled
suspension of finely grounded potassium hydroxide
(0.01 mol, 0.56g) in 20-mL dimethylformamide, the
pyrazolin-5-one compound 1 (0.01mol, 1.57 g) was
added and subsequently phenyl isothiocyanate (0.01 mol,
1.2 mL). The mixture was stirred at room temperature for
12h, then treated with chloroacetyl chloride and/or ethyl
bromoacetate (0.012 mol), and the stirring was continued
for further 4 h. The reaction mixture was poured into ice-
cooled water, and the resulting precipitated solid was
collected by filtration, washed several times with water,
and crystallized from ethanol to obtain 18 and 19.
Yellow crystals, yield 70%, mp 171–173°C; Rf value:
0.34 petroleum ether:ethyl acetate (5:1); IR ( ν /cmꢀ1):
1
3240, 3120 (NH2), 1674 (C¼O), 1599 (C¼N); H NMR
(DMSO-d6): δ/ppm = 2.35 (s, 3H, CH3), 6.45 (s, 1H,
HC¼C), 7.25–7.77 (m, 11H, Ar―H and pyrazole H-5),
9.48 (s, 2H, NH2); MS (EI, 70 eV): m/z (%) = 387 (20.4),
374 (44.8), 259 (14.5), 250 (16.9), 177 (30.2), 129
(62.3), 93 (61.8), 77 (84.1), 69 (95.3), 55 (100). Anal.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. E. Gaffer, S. Abdel-Fattah, H. A. Etman, and E. Abdel-Latif
Vol 9999
3-Methyl-4-(5-oxo-3-phenylthiazolidin-2-ylidene)-1-thiocarbamoyl-
2-pyrazolin-5-one (18). Orange crystals, yield 78%, mp 185–
187°C; Rf value: 0.66 petroleum ether:ethyl acetate (3:1); IR (ν
/cmꢀ1): 3239, 3208 (NH2), 1753 (C¼O thiazole ring), 1657
Synthesis of 3-methyl-4-phenylthiocarbamoyl-2-pyrazolin-
5-one derivatives 21 and 22.
To a cold suspension of
finely divided KOH (0.01mol, 0.56 g) in DMF (20-mL)
were added the pyrazolin-5-one derivatives 10 and/or 3
(0.01 mol) followed by phenyl isothiocyanate (0.01mol,
1.20-mL). The mixture was stirred at room temperature
overnight, poured into ice-cold water, and then
neutralized with dilute HCl. The resultant solid product
was collected by filtration, washed with water, dried, and
recrystallized from ethanol to afford the corresponding
1
(C¼O pyrazole ring), 1591 (C¼N); H NMR (DMSO-d6):
δ/ppm =2.35 (s, 3H, CH3), 4.25 (s, 2H, CH2), 7.15–7.60 (m,
5H, Ar―H), 9.65 (s, 2H, NH2); MS (EI, 70 eV): m/z (%)
=332 (60.1), 298 (21.1), 273 (27.11), 200 (55.2), 142 (17.2),
93 (86.1), 77 (100). Anal. Calcd. for C14H12N4O2S2 (332.04):
C, 50.59; H, 3.64; N, 16.86. Found: C, 50.72; H, 3.73; N, 16.77.
3-Methyl-4-(4-oxo-3-phenylthiazolidin-2-ylidene)-1-thiocarbamoyl-
2-pyrazolin-5-one (19). Orange powder, yield 65%, mp 253–
255°C; Rf value: 0.54 petroleum ether:ethyl acetate (3:1); IR (ν
/cmꢀ1): 3247, 3190 (NH2), 1743 (C¼O, thiazole ring), 1655
thiocarbamoyl derivatives 21 and/or 22, respectively.
3-Methyl-1-(4-methyl-thiazol-2-yl)-4-phenylthiocarbamoyl-2-
pyrazolin-5-one (21a).
Yellow crystals, yield 64%, mp
178–179°C; Rf value: 0.32 petroleum ether:ethyl acetate
(3:1); IR ( ν /cmꢀ1): 3123 (NH), 1656 (C¼O), 1598
(C¼N); 1H NMR (CDCl3/CF3COOD): δ/ppm = 2.15 (s,
3H, CH3), 2.45 (s, 3H, CH3), 6.65 (s, 1H, thiazole H-5),
6.90–7.45 (m, 5H, Ar―H); MS (EI, 70eV): m/z (%)
= 330 (16.8), 311 (16.2), 300 (23.6), 260 (19.2), 246
(47.2), 243 (18.4), 172 (20.8), 177 (21.6), 133 (19.9),
107 (31.5), 91 (100), 77 (31.4), 65 (42.7). Anal. Calcd.
for C15H14N4OS2 (330.06): C, 54.52; H, 4.27; N, 16.96.
1
(C¼O, pyrazole ring), 1595 (C¼N); H NMR (DMSO-d6):
δ/ppm = 2.35 (s, 3H, CH3), 4.05 (s, 2H, CH2), 7.10–7.55 (m,
5H, Ar―H), 9.55 (s, 2H, NH2); MS (EI, 70eV): m/z (%)
=332 (3.5), 289 (8.1), 200 (100.0), 170 (6.3), 142 (7.2), 93
(10.4), 77 (21.8). Anal. Calcd. for C14H12N4O2S2 (332.04): C,
50.59; H, 3.64; N, 16.86. Found: C, 50.43; H, 3.70; N, 16.92.
Synthesis of 3-methyl-1-(4-substituted-thiazol-2-yl)-4-(4-
oxo-3-phenyl-thiazolidin-2-yl)-2-pyrazolin-5-one derivatives
20a and 20b.
A mixture of the 1-thiocarbamoyl-2-
Found: C, 54.66; H, 4.19; N, 16.89.
pyrazolin-5-one derivative 19 (0.002 mol, 0.66g), the
appropriate α-halogenated reagents, bromoacetone and/or
phenacyl bromide (0.005 mol), and 0.5-mL triethylamine
was refluxed in 20-mL ethanol for 4 h. The reaction
mixture was poured into cooled water, and the resulting
precipitated solid was collected by filtration, washed
several times with water, and crystallized from EtOH to
give 20a and 20b, respectively.
3-Methyl-1-(4-phenyl-thiazol-2-yl)-4-phenylthiocarbamoyl-2-
pyrazolin-5-one (21b).
Yellow crystals, yield 80%, mp
190–192°C; Rf value: 0.49 petroleum ether:ethyl acetate
(3:1); IR ( ν /cmꢀ1): 3106 (NH), 1649 (C¼O), 1591
(C¼N); 1H NMR (CDCl3/CF3COOD): δ/ppm = 2.15 (s,
3H, CH3), 6.65 (s, 1H, thiazole H-5), 6.90–7.65 (m, 10H,
Ar―H); MS (EI, 70eV): m/z (%) = 392 (7.6), 359 (20.7),
300 (10.4), 257 (79.1), 174 (15.5), 134 (39.5), 102
(27.6), 93 (100), 76 (55.4). Anal. Calcd. for
C20H16N4OS2 (392.08): C, 61.20; H, 4.11; N, 14.27.
3-Methyl-1-(4-methyl-thiazol-2-yl)-4-(4-oxo-3-phenylthiazolidin-
2-ylidene)-2-pyrazolin-5-one (20a).
Orange powder, yield
58%, mp 181–182°C; Rf value: 0.36 petroleum ether:ethyl
Found: C, 60.32; H, 4.18; N, 14.18.
acetate (2:1); IR (ν/cmꢀ1): 1718 (C¼O, thiazole ring), 1661
3-Methyl-4-phenylthiocarbamoyl-1-thiocarbamoyl-2-pyrazolin-
1
5-one (22). White crystals, yield 75%, mp 110–111°C; Rf
value: 0.38 petroleum ether:ethyl acetate (3:1); IR (ν/cmꢀ1):
3338, 3241, 3185 (NH2 and NH), 1662 (C¼O), 1630
(C¼N); 1H NMR (CDCl3/CF3COOD): δ/ppm=2.15 (s, 3H,
CH3), 7.10–7.55 (m, 5H, Ar―H); MS (EI, 70eV): m/z (%)
= 292 (11.8), 265 (7.8), 217 (8.1), 199 (56.2), 182 (19.7),
143 (58.4), 134 (23.4), 115 (32.9), 84 (46.6), 80 (50.5), 77
(50.8), 64 (100), 55 (43.7). Anal. Calcd. for C12H12N4OS2
(292.05): C, 49.29; H, 4.14; N, 19.16. Found: C, 49.41; H,
(C¼O, pyrazole ring), 1601 (C¼N); H NMR (DMSO-d6):
δ/ppm=2.15 (s, 3H, CH3), 2.40 (s, 3H, CH3), 3.95 (s, 2H,
CH2), 6.65 (s, 1H, thiazole H-5), 7.15–7.60 (m, 5H,
Ar―H); MS (EI, 70eV): m/z (%)= 370(11.8), 344 (16.2),
257 (16.6), 236 (16.1), 149 (32.2), 129 (39.4), 102 (70.8),
91 (75.6), 77 (100), 64 (76.1). Anal. Calcd. for
C17H14N4O2S2 (370.06): C, 55.12; H, 3.81; N, 15.12.
Found: C, 55.21; H, 3.77; N, 15.18.
3-Methyl-1-(4-phenyl-thiazol-2-yl)-4-(4-oxo-3-phenylthiazolidin-2-
ylidene)-2-pyrazolin-5-one (20b). Orange powder, yield 64%,
4.07; N, 19.11.
mp 195–197°C; Rf value: 0.51 petroleum ether:ethyl
acetate (2:1); IR ( ν /cmꢀ1): 1722 (C¼O, thiazole), 1658
(C¼O, pyrazole), 1595 (C¼N); 1H NMR (DMSO-d6):
δ/ppm=2.15 (s, 3H, CH3), 3.95 (s, 2H, CH2), 6.60 (s, 1H,
thiazole H-5), 7.14–7.71 (m, 10H, Ar―H); MS (EI,
70eV): m/z (%) = 432 (16.8), 419 (8.2), 380 (15.6), 330
(27.2), 257 (34.2), 243 (18.4), 195 (17.8), 177 (21.6), 134
(35.6), 102 (47.5), 91 (25.3), 77 (100), 64 (47.7). Anal.
Calcd. for C22H16N4O2S2 (432.07): C, 61.09; H, 3.73; N,
12.95. Found: C, 61.26; H, 3.65; N, 12.84.
Synthesis of 4-(3-phenyl-4-substitutedthiazol-2-ylidene)-1-
thiocarbamoyl-2-pyrazolin-5-one derivatives 23.
A
mixture of 22 (0.003mol, 0.87g) and the appropriate α-
bromoketone (namely, bromoacetone and phenacyl
bromide) (0.003 mol) in 20-mL ethanol containing 0.5mL
of triethylamine was refluxed for 4–6h (monitored by
TLC, petroleum ether:ethyl acetate (2:1)). The separated
solid on cooling was collected by filtration, washed
several times with ethanol, and crystallized from EtOH:
DMF mixture (5:1).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Thiazolyl-Pyrazolin-5-One Derivatives as Antioxidant Agents
4-(4-Methyl-3-phenylthiazol-2-ylidene)-3-methyl-1-thiocarbamoyl-
2-pyrazolin-5-one (23a). Yellowish white crystals, yield 70%,
mp 198–199°C; Rf value: 0.46 petroleum ether:ethyl acetate
(3:1); IR ( ν /cmꢀ1): 3122, 3167 (NH2), 1641 (C¼O), 1589
3-Methyl-4-(3,4-diphenylthiazol-2-ylidene)-1-(4-phenylthiazol-
2-yl)-2-pyrazolin-5-one (24c). Yellow powder, yield 70%,
mp 295–297°C.; Rf value: 0.53 petroleum ether:ethyl
1
acetate (2:1); IR (ν/cmꢀ1): 1667 (C¼O), 1616 (C¼N); H
1
(C¼N); H NMR (DMSO-d6): δ/ppm=2.09 (s, 3H, CH3),
NMR (DMSO-d6): δ/ppm=2.15 (s, 3H, CH3), 5.20 (s, 1H,
thiazoline H-5), 6.75 (s, 1H, thiazole H-5), 7.20–7.86 (m,
15H, Ar―H); MS (EI, 70eV): m/z (%)=492 (35.9) 407
(35.9), 308 (35.4), 267 (41.0), 234 (36.8), 214 (37.3), 158
(39.1), 98 (40.5), 80 (100.0). Anal. Calcd. for
C28H20N4OS2 (492.11): C, 68.27; H, 4.09; N, 11.37.
Found: C, 68.16; H, 4.01; N, 11.44.
2.50 (s, 3H, CH3), 5.21 (s, 1H, thiazole H-5), 7.02–7.35 (m,
5H, Ar―H), 9.45 (s, 2H, NH2); MS (EI, 70eV): m/z (%)
=330 (10.1), 319 (11,3), 303 (11.2), 271 (31.1), 214 (17.4),
200 (85.2), 170 (7.1), 142 (17.6), 118 (34.7), 93 (29.4), 77
(100). Anal. Calcd. for C15H14N4OS2 (330.06): C, 54.52; H,
4.27; N, 16.96. Found: C, C, 54.71; H, 4.20; N, 17.07.
4-(3,4-Diphenylthiazol-2-ylidene)-3-methyl-1-thiocarbamoyl-
2-pyrazolin-5-one (23b). Yellow powder, yield 75%, mp
301–305°C; Rf value: 0.28 petroleum ether:ethyl acetate
(3:1); IR (ν/cmꢀ1): 3125, 3104 (NH2), 1655 (C¼O), 1599
Antioxidant activity screening assay by the ABTS
method. This assay employs the radical cation derived
from 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)
(ABTS) as stable free radical. The advantage of ABTS-
derived free radical method over other methods is that the
produced color remains stable for more than 1 h, and the
reaction is stoichiometric [18,19]. Thus, our reported
compounds in this work were screened for antioxidant
activity by the latter method. For each of the investigated
compounds, 2 mL of ABTS solution (60 μM) was added
to 3 mL MnO2 suspension (25 mg/mL), all prepared in
5 mL aqueous phosphate buffer solution (pH 7, 0.1M).
The mixture was shaken, centrifuged, and filtered, and
the absorbance of the resulting green blue solution
(ABTS radical solution) at 734nm was adjusted to
approx. ca. 0.5. Then, 50 μL of (2mM) solution of the
1
(C¼N); H NMR (DMSO-d6): δ/ppm=2.15 (s, 3H, CH3),
5.20 (s, 1H, thiazole H-5), 7.20–7.70 (m, 10H, Ar―H),
9.55 (s, 2H, NH2); MS (EI, 70eV): m/z (%)=392 (12.4),
355 (18.9), 304 (23.4), 259 (55.3), 177 (31.2), 134 (44.2),
108 (29.2), 91 (100), 77 (62.4). Anal. Calcd. for
C20H16N4OS2 (392.08): C, 61.20; H, 4.11; N, 14.27.
Found: C, 61.13; H, 4.16; N, 14.34.
Synthesis of 3-methyl-4-(4-substituted-3-phenylthiazol-2-
ylidene)-1-(4-substituted-thiazol-2-yl)-2-pyrazolin-5-one derivatives
24a–c. To a mixture of 23 (0.002mol) and the appropriate
α-bromoketone (0.002mmol), e.g. bromoacetone and
phenacyl bromide in 20-mL ethanol, few drops of
triethylamine were added as a catalyst and allowed to reflux
for 4h. The resulting solid that formed during heating was
filtered, dried, and recrystallized from DMF:H2O mixture
(3:1).
tested
compound
in
spectroscopic
grade
MeOH/phosphate buffer (1:1) was added. The absorbance
was measured and the reduction in color intensity was
expressed as inhibition percentage. L-Ascorbic acid was
used as standard antioxidant (Positive control). Blank
sample was run without ABTS and using
MeOH/phosphate buffer (1:1) instead of tested
compounds. Negative control was run with ABTS and
MeOH/phosphate buffer (1:1) only [21,22].
3-Methyl-4-(4-methyl-3-phenylthiazol-2-ylidene)-1-(4-methylthiazol-
2-yl)-2-pyrazolin-5-one (24a). Brown powder, yield 67%, mp
215–217°C; Rf value: 0.43 petroleum ether:ethyl acetate
1
(2:1); IR (ν/cmꢀ1): 1641 (broad, C¼O), 1598 (C¼N); H
NMR (DMSO-d6): δ/ppm= 1.95 (s, 3H, CH3), 2.15 (s, 3H,
CH3), 2.25 (s, 3H, CH3), 5.35 (s, 1H, thiazoline H-5), 6.75
(s, 1H, thiazole H-5), 7.05–7.40 (m, 5H, Ar―H); MS (EI,
70eV): m/z (%) =368 (18.2), 350 (38.5), 320 (11.2), 272
(14.2), 217 (22.5), 190 (73.3), 177 (100), 145 (91.0), 117
(32). Anal. Calcd. for C18H16N4OS2 (368.08): C, 58.67; H,
4.38; N, 15.21. Found: C, 58.86; H, 4.46; N, 15.14.
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2010, 45, 3692.
3-Methyl-4-(4-methyl-3-phenylthiazol-2-ylidene)-1-(4-phenylthiazol-
2-yl)-2-pyrazolin-5-one (24b). Brown powder, yield 56%, mp
230–232°C; Rf value: 0.38 petroleum ether:ethyl acetate (2:1);
1
IR ( ν /cmꢀ1): 1651 (broad, C¼O), 1595 (C¼N); H NMR
(DMSO-d6): δ/ppm = 1.95 (s, 3H, CH3), 2.15 (s, 3H, CH3),
5.40 (s, 1H, thiazoline H-5), 7.25 (s, 1H, thiazole H-5), 7.05–
7.75 (m, 10H, Ar―H); MS (EI, 70eV): m/z (%) = 430 (15.2),
415 (14.9), 404 (19.4), 379 (34.3), 353 (22.7) 338 (41.2), 299
(33.5), 254 (53.6), 215 (56.4), 174 (100), 148 (34.4), 134
(25.3), 102 (17.2), 91 (29.8), 77 (21.4). Anal. Calcd. for
C23H18N4OS2 (430.09): C, 64.16; H, 4.21; N, 13.01. Found:
C, 64.23; H, 4.19; N, 13.08.
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