Synthesis and antimicrobial evaluation of some heterocyclic compounds from 3-Aryl-1-phenyl-1H-pyrazole-4-carbaldehydes

Article abstract of DOI:10.1515/znb-2018-0009

A new series of chalcones, pyrazolinyl-pyrazoles, pyrazole-4-carbaldehyde oximes, pyrazole-4-carbonitriles, 5-pyrazolyl-1,2,4-Triazolidine-3-Thiones, and Knoevenagel condensation products was synthesized from 3-Aryl-1-phenyl-1H-pyrazole-4-carbaldehydes. Most reactions were carried out either without solvent or in the presence of water as a green solvent. The structure of synthesized compounds was characterized by spectral and elemental analysis. The synthesized compounds were tested in vitro for their antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans in comparison with imipenem (intravenous β-lactam antibiotic) and clotrimazole (antifungal medication) as reference drugs by using the agar diffusion technique. 3-Aryl-1-phenyl-1H-pyrazole-4-carbonitriles 8b, 8c, and 8d showed significant antifungal activity against the fungus C. albicans.

Full text of DOI:10.1515/znb-2018-0009

Z. Naturforsch. 2018; aop
El Sayed Ramadan*, Essam M. Sharshira, Ramadan I. El Sokkary and Noussa Morsy
Synthesis and antimicrobial evaluation of some
heterocyclic compounds from 3-aryl-1-phenyl-1H-
pyrazole-4-carbaldehydes
https://doi.org/10.1515/znb-2018-0009
active compounds have been synthesized from pyrazole-
4-carbaldehydes. These compounds showed antimi-
crobial [7], antitumor, antiangiogenic [8], antiviral [9],
antitubercular [10], and antiparasitic activity [11]. On the
other hand, the use of water as environmentally benign
solvent and solvent-free reactions represent very powerful
green chemical procedures from both the economic and
synthetic points of view [12]. These methods may reduce
the burden of organic solvent disposal. The use of water
in organic synthesis represents a remarkable benefit
since it is an innocuous, non-flammable, inexhaustible,
and abundantly available solvent. Water as the reaction
medium is immiscible with most organic compounds and
thus offers ease of product isolation.
In combination with these findings, the aim of the
present work was to synthesize some heterocyclic com-
pounds from 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehydes
either in water or under solvent-free conditions with
evaluation of their antimicrobial activities against some
microorganisms.
Received January 7, 2018; accepted April 22, 2018
Abstract: A new series of chalcones, pyrazolinyl-pyra-
zoles, pyrazole-4-carbaldehyde oximes, pyrazole-4-car-
bonitriles, 5-pyrazolyl-1,2,4-triazolidine-3-thiones, and
Knoevenagel condensation products was synthesized
from 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehydes. Most
reactions were carried out either without solvent or in
the presence of water as a green solvent. The structure
of synthesized compounds was characterized by spec-
tral and elemental analysis. The synthesized compounds
were tested in vitro for their antimicrobial activity against
Escherichia coli, Staphylococcus aureus, and Candida albi-
cans in comparison with imipenem (intravenous β-lactam
antibiotic) and clotrimazole (antifungal medication) as
reference drugs by using the agar diffusion technique.
3-Aryl-1-phenyl-1H-pyrazole-4-carbonitriles 8b, 8c, and 8d
showed significant antifungal activity against the fungus
C. albicans.
Keywords: antimicrobial activity; chalcones; green
solvent; pyrazole-4-carbaldehyde; pyrazole-4-carboni-
triles; solvent-free.
2 Results and discussion
In our previous work, a number of chalcone derivatives
were obtained by Claisen-Schmidt condensation of ali-
phatic or aromatic ketones with aromatic aldehydes in
1 Introduction
Pyrazole nucleus is a unique structural scaffold that the presence of a base [13]. In this work 3-aryl-1-phenyl-
acts as an interesting template for combinatorial as well 1H-pyrazole-4-carbaldehydes (2) were prepared in good
as medicinal chemistry [1–6]. Many pyrazole derivatives yields by Vilsmeier-Haack reaction of 1-phenyl-2-(1-phe-
(Fig. 1) have already found their application as nonsteroi- nylethylidene)hydrazine (1) with POCl3 in dimethylfor-
dal anti-inflammatory drugs clinically, such as antipyrine mamide (DMF) (Scheme 1) [14–16]. Treatment of 2 with
or phenazone, metamizole or dipyrone, aminopyrine or substituted acetophenones in the presence of potassium
aminophenazone, phenylbutazone, sulfinpyrazone, and hydroxide gave chalcone derivatives 3a–3d in good yields.
oxyphenbutazone. Moreover, a number of biologically Their infrared (IR) spectra showed absorption bands at
1647–1660, 1583–1600, and 1506–1534 cm−1 due to C=O,
C=N, and C=C groups, respectively. The 1H NMR spectra of
*Corresponding author: El Sayed Ramadan, Department of
3a–3d showed a singlet at δꢀ=ꢀ8.34–8.41 ppm for the 5-H
Chemistry, Faculty of Science, Alexandria University, Alexandria
of pyrazole ring, a doublet at δꢀ=ꢀ7.87–8.00 ppm for the
β-vinylic proton, and the aromatic protons in the region of
δꢀ=ꢀ7.29–8.37 ppm. In case of 3d two geometrical isomers
(E and Z) were obtained in a ratio of 10:1. The β-vinylic
21524, A. R. Egypt, e-mail: elsayedramadan2008@yahoo.com
Essam M. Sharshira, Ramadan I. El Sokkary and Noussa Morsy:
Department of Chemistry, Faculty of Science, Alexandria University,
Alexandria 21524, A. R. Egypt
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ꢀE.S. Ramadan et al.: Synthesis and antimicrobial evaluation of heterocyclic compounds
O
proton of the E-isomer appeared at a relatively higher field
(δꢀ=ꢀ7.89 ppm) than the Z-isomer (δꢀ=ꢀ8.00 ppm).
HO
O
S
N
Solvent-free reaction of chalcone derivatives 3a–3d
with hydrazine hydrate in the presence of a catalytic
amount of glacial acetic acid was achieved at room tem-
perature to give 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-
5-yl)-1-phenyl-1H-pyrazoles (4a–4d) in 78–92% yields.
The reaction time was reduced from 9–10 to 4–6 h, when
it compared with the classical heating method [17]. The
1H NMR spectra of 4a–4d showed a singlet at δꢀ=ꢀ 7.78 –
8.35 ppm due to 5-H of pyrazole ring, two signals for two
diastereotopic protons of pyrazoline ring (CHA and CHB) at
δꢀ=ꢀ3.11–3.28 and 3.50–3.89 ppm, and a triplet or doublet
of doublets at δꢀ=ꢀ5.25–5.55 ppm for the CHX proton due
to vicinal coupling with two magnetically non-equivalent
protons of methylene group at position 4 of pyrazoline ring.
Compounds 2a–2e were easily converted into the
corresponding oximes 5a–5e by treatment with hydrox-
ylamine. The literature survey revealed that 1HꢀNMR
spectra is one of the most reliable methods for structure
N
N
N
N
O
O
Ph
Antipyrine
Ph
Metamizole
O
N
N
N
Ph
N
N
O
O
Ph
Ph
Aminophenazone
Phenylbutazone
O
O
S
O
Ph
N
Ph
OH
N
N
N
O
O
Ph
Ph
Sulfinpyrazone
Oxyphenbutazone
Fig. 1:ꢀSome examples of marketed drugs containing pyrazole moiety.
O
H
Ar1
Ar
O
O
Ar
Ar1
H3C
Ar
H3C
DMF/POCl3
heat
N
H
N
N
N
EtOH/KOH,
reflux
N
N
Ph
Ph
Ph
3a, Ar = Ar1 = C6H5
1a, Ar = C6H5
2a, Ar = C6H5
3b, Ar = 4-CH3C6H4, Ar1 = C6H5
3c, Ar = 4-CH3C6H4, Ar1 = 4-NO2C6H4
3d, Ar = 4-NO2C6H4, Ar1 = 4-BrC6H4
1b, Ar = 4-CH3C6H4
1c, Ar = 4-ClC6H4
1d, Ar = 4-BrC6H4
1e, Ar = 4-NO2C6H4
2b, Ar = 4-CH3C6H4
2c, Ar = 4-ClC6H4
2d, Ar = 4-BrC6H4
2e, Ar = 4-NO2C6H4
N2H4·H2O/
two drops AcOH,
stirring, r.t.
H
H
NH2
H2N
NH2
NH2
O
HN
O
O
HN
Ar1
Ar1
Ar1
Ar
Ar
Ar
− H+
+ H+
N
N
N
N
N
N
Ph
Ph
Ph
− H+
+ H+
H
N
OH
Ar1
H
H
N
N
N
Ar1
HX
Ar
Ar
4a, Ar = Ar1 = C6H5
HA
− H2O
HB
4b, Ar = 4-CH3C6H4, Ar1 = C6H5
N
N
4c, Ar = 4-CH3C6H4, Ar1 = 4-NO2C6H4
4d, Ar = 4-NO2C6H4, Ar1 = 4-BrC6H4
N
N
Ph
Ph
Scheme 1:ꢀSynthesis of pyrazolinyl-pyrazoles under solvent-free conditions.
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E.S. Ramadan et al.: Synthesis and antimicrobial evaluation of heterocyclic compoundsꢂ ꢂ3
determination of isomeric oximes since the difference
A very limited number of synthetic methods were
between chemical shifts of protons in the aldoxime group reported for the preparation of 5-aryl-1,2,4-triazolidine-
(δOH–δCH) is specifically for syn and anti isomers [18]. The 3-thiones [21–24]. However, 1,2,4-triazolidine-3-thiones
reported difference was ~3.0 ppm for syn and ~4.0 ppm bearing a pyrazole nucleus at position 5 have never
for anti isomers. In the 1H NMR spectrum of 1,3-diphenyl- been reported yet. In the present work, heating of 2 with
1H-pyrazole-4-carbaldehyde oxime (5a), there was only thiosemicarbazide in water as a green solvent afforded
one signal for OH group proton, and the δOH–δCH difference the 5-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1,2,4-triazolidine-
was found to be 2.59 ppm, which is typical of syn isomer. 3-thiones (9a–9d) in excellent yields. The respective thio-
On the other hand, it was reported that syn-aldoximes semicarbazones have never been isolated under these
reacted with acetic anhydride to form acetyl derivatives reaction conditions. This result was evidenced from
6, while anti isomers under similar conditions were con- spectral data. The IR spectrum of compound 9b showed
verted into nitriles via elimination of water [19]. Moreo- absorption bands at 3305, 3297, and 3158 cm−1 due to NH
ver, nitrone derivative 7 was obtained on treatment of syn groups; which were further confirmed by the presence
or anti-aldoxime with haloacetic acid [20]. However, we of three D2O-exchangeable protons at δꢀ=ꢀ7.78, 8.23, and
1
found that the reaction of oximes 5a–5e with either acetic 11.31 ppm in its HꢀNMR spectrum. It also showed two
anhydride or 2-chloroacetic acid gave exclusively pyra- singlet peaks at δꢀ=ꢀ8.18 and 9.14 ppm for the 5-H of tria-
zole-4-carbonitriles 8a–8e (Scheme 2). Thus, compound zolidine ring and 5-H of pyrazole ring, respectively. The
5 behaved like anti-aldoximes, and the assignment of structure of 9b was also proved by 13C NMR, which exhib-
1
oximes to be syn or anti isomers on the basis of HꢀNMR ited signals at δꢀ=ꢀ117.70 and 178.08 ppm due to C-5 of tria-
data is not absolutely reliable.
zolidine ring and thiocarbonyl (C=S) group, respectively.
H
H
Ar
O
Ar
NNHCSNH2
H2NNHCSNH2/H2O
2 drops AcOH
reflux
N
N
NC-CH2CO2C2H5
heat
N
N
Ph
NH2OH·HCl/
Ph
NaOAc/EtOH,
reflux
2
H
OH
N
H
N
S
COOC2H5
Ar
N
Ar
Ar
N
H
CN
N
N
N
N
N
N
Ph
Ph
Ph
5a, Ar = C6H5
10a, Ar = C6H5
9a, Ar = C6H5
5b, Ar = 4-CH3C6H4
5c, Ar = 4-ClC6H4
5d, Ar = 4-BrC6H4
5e, Ar = 4-NO2C6H4
10b, Ar = 4-CH3C6H4
10c, Ar = 4-BrC6H4
10d, Ar = 4-NO2C6H4
9b, Ar = 4-CH3C6H4
9c, Ar = 4-ClC6H4
9d, Ar = 4-BrC6H4
ClCH2CO2H/
NaOAc, reflux
ClCH2CO2H/
NaOAc, reflux
2
2
O
N
Ar
N
CN
OCOCH3
Ar
Ar
N
N
COOH
N
N
N
N
Ph
8a, Ar = C6H5
Ph
Ph
8b, Ar = 4-CH3C6H4
8c, Ar = 4-ClC6H4
8d, Ar = 4-BrC6H4
8e, Ar = 4-NO2C6H4
6
7
Scheme 2:ꢀSynthetic routes of pyrazole derivatives from pyrazole-4-carbaldehydes.
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4ꢀ ꢀE.S. Ramadan et al.: Synthesis and antimicrobial evaluation of heterocyclic compounds
The advantages of this eco-friendly reaction are the ease minimal inhibitory concentrations (MIC) in micrograms
of reaction work-up and excellent yield of products.
per milliliter (μgꢀmL−1), and percentage of inhibition.
Knoevenagel condensation is one of the most impor- The pyrazolinyl-pyrazole 4d and pyrazole-4-carbon-
tant C–C bond-forming reactions. The reaction is cata- itrile 8c exhibited low activity against E. coli. Com-
lyzed by bases or acids, and in many of these methods pound 8d showed moderate activity against S. aureus.
relatively harsh conditions and expensive reagents are On the other hand, the tested compounds showed
involved. We report herein a simple eco-friendly method growth IZ against C. albicans in the following ranking:
for Knoevenagel condensation of 2 with ethyl 2-cyanoac- 8dꢀ>ꢀ8bꢀ=ꢀ8cꢀ>ꢀ9dꢀ>ꢀ9cꢀ=ꢀ10d. It is clear that pyrazole-
etate without using a solvent and basic or acidic catalyst 4-carbonitriles 8b, 8c, and 8d have promising activity
to give ethyl 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-2-cyano- against C. albicans. Furthermore, 5-pyrazolyl-1,2,4-tri-
propenoate (10a–10d) in 83–97% yields. The IR spectra azolidine-3-thiones 9d bearing a bromophenyl sub-
of 10a–10d showed stretching vibrational bands at stituent at position 3 of the pyrazole ring possessed
2218–2219 and 1722–1724 cm−1 characteristic for Cꢀ≡ꢀN and moderate activity, while compounds 9c and 10d had the
1
C=O groups, respectively. The HꢀNMR spectrum of 10a lowest activity against this strain. The MICs and inhibi-
showed a singlet at δꢀ=ꢀ9.14 ppm for 5-H of pyrazole ring, a tion level of the active compounds ranged at 31.25–125
singlet at δꢀ=ꢀ8.13 ppm for an olefinic (CH=C) proton, and μgꢀmL−1 and 41.17–82.35%, respectively.
a triplet and quartet at δꢀ=ꢀ1.38 and 4.34 ppm for the ethyl
group in addition to aromatic protons which resonated
in δꢀ=ꢀ7.39–7.84 ppm. The structure of newly synthesized
3 Experimental section
compounds was supported by their analytical and spec-
tral data (Experimental section).
The synthesized compounds were tested in vitro for 3.1 Materials and measurements
their antimicrobial activities against Escherichia coli
(ATCC-8739), Staphylococcus aureus (ATCC-6538P), and Commercially available chemicals were purchased from
Candida albicans (ATCC-2091) by agar well-diffusion Sigma Aldrich. Melting points were measured in open
method using clotrimazole and imipenem as standard capillary tubes using an Electro-thermal apparatus
drugs [25, 26]. The results are shown in Tables 1 and 2 IA9100 and are uncorrected. Microanalyses were per-
as growth inhibition zones (IZ) in millimeters (mm), formed on an elemental Euro EA 3000 analyzer at the
Table 1:ꢀIn vitro antifungal activity of synthetic compounds against C. albicans.a
Compound
IZ (mm)
MIC (μg mLꢁ−ꢁ1
)
% Inhibition
Compound
IZ (mm)
MIC (μg mLꢁ−ꢁ1
)
% Inhibition
8b
25
25
27
13
125.0
62.5
62.5
–
70.58
70.58
82.35
–
9c
20
23
20
17
31.25
62.50
62.50
–
41.17
58.82
41.17
–
8c
9d
8d
DMF
10d
Clotrimazole
aThe diameter of growth inhibition zone (IZ) is accurately measured in three different directions, and its mean was calculated; % inhibi-
tionꢁ=ꢁ[IZ(testing compound)ꢁ−ꢁIZ(DMF)]/[IZ(clotrimazole)]ꢁ×ꢁ100.
Table 2:ꢀIn vitro antibacterial activity of synthetic compounds against S. aureus and E. coli.a
S. aureus
E. coli
Compound
IZ (mm)
MIC (μg mLꢁ−ꢁ1
)
% Inhibition
Compound
IZ (mm)
MIC (μg mLꢁ−ꢁ1
)
% Inhibition
8d
20
15
15
11
8.0
30
62.5
62.5
62.5
62.5
–
40.00
23.33
23.33
10.00
–
4d
16
18
10
26
62.5
62.5
–
23.07
30.76
–
9c
8c
9d
DMF
Imipenem
10d
DMF
Imipenem
–
–
–
–
aSee footnote a of Table 1 for growth inhibition zone and calculation of % inhibition.
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Regional Center for Mycology and Biotechnology, Al- 11 H, Ar-H and CH=CHCO), 2.43 (s, 3 H, CH3). – C25H20N2O
Azhar University, Egypt. IR spectra were recorded using (364.44): calcd. C 82.39, H 5.53, N 7.69; found C 82.44, H
the potassium bromide disk on a Perkin Elmer Spec- 5.46, N 7.71.
trum RX I and Bruker Tensor 37 FTIR spectrometers.
1HꢀNMR and 13CꢀNMR spectra were measured on a Jeol
EAC 500 MHz spectrophotometer. The chemical shifts are 3.2.3 1-(p-Nitrophenyl)-3-[1-phenyl-3-(p-tolyl)-1H-
reported in δ units, and coupling constants (J) are given in
hertz. Reaction time was monitored by thin layer chroma-
pyrazol-4-yl]prop-2-en-1-one (3c)
tography (TLC) using Alugram Sil G UV254 silica gel plates, Yellow crystals, yield 72% (1.473 g), m. p. 190–191°C.
and chloroform-ethanol (9:1 or 19:1) was used as eluents. – IR (KBr): νꢀ=ꢀ1660 (C=O), 1583 (C=N), 1525 (C=C) cm−1.
The spots were detected by using UV light absorption. – 1HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ8.37 (s, 1H, 5-H of pyrazole
Antimicrobial tests were measured in the Pharmaceutical ring), 8.30 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 8.06 (d, Jꢀ=ꢀ8 Hz, 2 H,
Microbiology Department, Faculty of Pharmacy, Alexan- Ar-H), 7.91 (d, Jꢀ=ꢀ15 Hz, 1 H, CHꢀ=ꢀCHCO), 7.78 (d, Jꢀ=ꢀ8 Hz,
dria University.
2 H, Ar-H), 7.57 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.48 (t, Jꢀ=ꢀ8 Hz, 2 H,
Ar-H), 7.34 (t, Jꢀ=ꢀ8 Hz, 1 H, Ar-H), 7.28–7.31 (m, 3 H, Ar-H
and CH=CHCO), 2.43 (s, 3 H, CH3). – C25H19N3O3 (409.44):
calcd. C 73.34, H 4.68, N 10.26; found C 73.33, H 4.67, N
10.24.
3.2 General procedure for synthesis of
chalcones 3a–3d
A mixture of carbaldehyde 2a, 2b, or 2e (5 mmol) and ace-
tophenone derivative (5 mmol) was dissolved in ethanol
(15 mL), and then aqueous potassium hydroxide (20%,
1.0 mL) was added. The reaction mixture was heated under
reflux for 3–5 h. It was kept to attain ambient temperature,
and the separated solid was filtered, washed with water,
dried, and recrystallized from a mixture of chloroform and
ethanol.
3.2.4 (E/Z)-1-(p-Bromophenyl)-3-[3-(p-nitrophenyl)-1-
phenyl-1H-pyrazol-4-yl]prop-2-en-1-one (3d)
Colorless – yellow crystals, yield 89% (2.11 g), m. p. 210–
212°C. – IR (KBr): νꢀ=ꢀ1659 (C=O), 1600 (C=N), 1506 (C=C)
cm−1. – 1HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ8.39, 8.41 (2s, 2 H, 5-H
of pyrazole ring), 7.89 (d, Jꢀ=ꢀ14 Hz, 1 H, CHꢀ=ꢀCHCO of E-iso-
mer), 8.00 (d, Jꢀ=ꢀ9 Hz, 1 H, CHꢀ=ꢀCHCO of Z-isomer), [8.35
(d, Jꢀ=ꢀ8 Hz, Ar-H), 8.28 (d, Jꢀ=ꢀ8 Hz, Ar-H), 8.06 (d, Jꢀ=ꢀ8 Hz,
Ar-H), 7.90 (d, Jꢀ=ꢀ8 Hz, Ar-H), 7.85–7.87 (m, Ar-H), 7.80 (d,
Jꢀ=ꢀ8 Hz, Ar-H), 7.74 (d, Jꢀ=ꢀ8 Hz, Ar-H), 7.68 (d, Jꢀ=ꢀ8 Hz, Ar-H),
7.62–7.65 (m, Ar-H), 7.54–7.57 (m, Ar-H), 7.52 (t, Jꢀ=ꢀ8 Hz,
Ar-H), 7.42–7.47 (m, Ar-H and CH=CHCO), 7.32–7.37 (m, Ar-H
and CH=CHCO), total integralꢀ=ꢀ28 H]. – 13CꢀNMR (125 MHz,
[D6]DMSO): δꢀ=ꢀ118.88, 119.43, 122.49, 124.70, 127.89, 128.15,
129.89, 130.04, 130.33, 130.80, 132.44, 134.33, 137.02, 138.82,
139.27, 147.90 (Ar-C, CH=CH, C-4 and C-5 of pyrazole ring),
151.08 (C-3 of pyrazole ring), 188.22 (C=O).
3.2.1 3-(1,3-Diphenyl-1H-pyrazol-4-yl)-1-phenylprop-2-
en-1-one (3a)
Yellow crystals, yield 77% (1.349 g), m. p. 140–141°C.
– IR (KBr): νꢀ=ꢀ1659 (C=O), 1592 (C=N), 1533 (C=C) cm−1.
1
– HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ8.36 (s, 1 H, 5-H of pyra-
zole ring), 7.95 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.88 (d, Jꢀ=ꢀ16 Hz,
1 H, CHꢀ=ꢀCHCO), 7.79 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.70–7.72
(m, 2 H, Ar-H), 7.34–7.58 (m, 12 H, Ar-H and CH=CHCO).
– C24H18N2O (350.41): calcd. C 82.26, H 5.18, N 7.99; found C
82.33, H, 5.09, N 8.04.
3.3 General procedure for synthesis of
pyrazolinyl-pyrazoles 4a–4d
3.2.2 1-Phenyl-3-[1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl]
prop-2-en-1-one (3b)
A mixture of chalcone derivatives 3a–3d (1.0 mmol),
Yellow crystals, yield 85% (1.548 g), m. p. 170–172°C. hydrazine hydrate (5 mL, 80%) and two drops of glacial
– IR (KBr): νꢀ=ꢀ1647 (C=O), 1591 (C=N), 1534 (C=C) cm−1. acetic acid was stirred at room temperature for 4–6 h until
1
– HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ8.34 (s, 1 H, 5-H of pyra- the reaction was completed; the reaction progress was
zole ring), 7.95 (d, Jꢀ=ꢀ7 Hz, 2 H, Ar-H), 7.87 (d, Jꢀ=ꢀ16 Hz, monitored by TLC using chloroform-ethanol (9:1). The
1 H, CHꢀ=ꢀCHCO), 7.79 (d, Jꢀ=ꢀ7 Hz, 2 H, Ar-H), 7.29–7.61 (m, resulting mixture was added to cold water (20 mL) with
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6ꢀ ꢀE.S. Ramadan et al.: Synthesis and antimicrobial evaluation of heterocyclic compounds
vigorous stirring for 5 min. The separated solid was fil- Ar-H), 7.41 (t, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.25–7.27 (m, 3 H, Ar-H),
tered and recrystallized from a mixture of chloroform and 7.17 (broad s, 1 H, NH), 5.25 (t, Jꢀ=ꢀ8 Hz, 1 H, pyrazoline-HX),
ethanol.
3.50–3.52 (m, 1 H, pyrazoline-HB), 3.11–3.13 (m, 1 H, pyrazo-
line-HA), 2.39 (s, 3 H, CH3). – C25H21N5O2 (423.47): calcd. C
70.91, H 5.00, N 16.54; found C 70.94, H 4.93, N 16.61.
3.3.1 1,3-Diphenyl-4-(3-phenyl-4,5-dihydro-1H-pyrazol-
5-yl)-1H-pyrazole (4a)
3.3.4 4-[3-(p-Bromophenyl)-4,5-dihydro-1H-pyrazol-5-
yl]-3-(p-nitrophenyl)-1-phenyl-1H-pyrazole (4d)
Yellow crystals, yield 92% (0.334 g), m. p. 218–220°C. – IR
(KBr): νꢀ=ꢀ3440 (NH), 1593 (C=N), 1497 (C=C) cm−1. – 1HꢀNMR
(500 MHz, CDCl3): δꢀ=ꢀ7.81 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.78 (s, Pale yellow crystals, yield 78% (0.380 g), m. p. 206–208°C.
1 H, 5-H of pyrazole ring), 7.73 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.64 – IR (KBr): νꢀ=ꢀ3308 (NH), 1595 (C=N), 1506 (C=C) cm−1.
1
(d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.51 (t, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.19–7.45 – HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ8.35 (s, 1 H, 5-H of pyra-
(m, 5 H, Ar-H and NH), 7.10 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 6.79 zole ring), 8.28 (d, Jꢀ=ꢀ9 Hz, 2 H, Ar-H), 7.95 (d, Jꢀ=ꢀ9 Hz, 2 H,
(t, Jꢀ=ꢀ8 Hz, 1 H, Ar-H), 5.52, 5.55 (dd, JAXꢀ=ꢀ6 Hz, JBXꢀ=ꢀ12 Hz, Ar-H), 7.71 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.28-7.69 (m, 8 H, Ar-H
1 H, pyrazoline-HX), 3.83, 3.89 (dd, JABꢀ=ꢀ16 Hz, JBXꢀ=ꢀ12 Hz, and NH), 5.31 (t, Jꢀ=ꢀ9 Hz, 1 H, pyrazoline-HX), 3.58, 3.63 (dd,
1 H, pyrazoline-HB), 3.24, 3.28 (dd, JABꢀ=ꢀ16 Hz, JAXꢀ=ꢀ6 Hz, 1 H, JABꢀ=ꢀ17 Hz, JBXꢀ=ꢀ10 Hz, 1 H, pyrazoline-HB), 3.19, 3.25 (dd,
pyrazoline-HA). – C24H20N4 (364.44): calcd. C 79.10, H 5.53, N JABꢀ=ꢀ17 Hz, JAXꢀ=ꢀ7 Hz, 1 H, pyrazoline-HA). – C24H18BrN5O2
15.37; found C 79.17, H 5.44, N 15.36.
(488.34): calcd. C 59.03, H 3.72, Br 16.36, N 14.34; found C
58.99, H 3.67, Br 16.37, N 14.31.
3.3.2 1-Phenyl-4-(3-phenyl-4,5-dihydro-1H-pyrazol-5-yl)-
3-(p-tolyl)-1H-pyrazole (4b)
3.4 General procedure for synthesis of
pyrazole-4-carbaldehyde oximes 5a–5e
Pale yellow crystals, yield 79% (0.298 g), m. p. 210–211°C.
– IR (KBr): νꢀ=ꢀ3438 (NH), 1597 (C=N), 1501 (C=C) cm−1. To a solution of 2a–2e (1.0 mmol) in ethanol (20 mL),
– 1HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ8.18 (s, 1 H, 5-H of pyrazole hydroxylamine hydrochloride (0.069 g, 1.0 mmol) and
ring), 7.71 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.67–7.69 (m, 2 H, Ar-H), anhydrous sodium acetate (0.082 g, 1.0 mmol) were added.
7.59 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.41 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.34– The mixture was heated under reflux for 5 h; the reaction
7.37 (m, 2 H, Ar-H), 7.24–7.27 (m, 4 H, Ar-H), 5.25 (t, Jꢀ=ꢀ10 Hz, progress was monitored by TLC using chloroform-ethanol
1 H, pyrazoline-HX), 3.75 (broad s, 1 H, NH), 3.53, 3.58 (dd, (9:1). The product that separated out on cooling was fil-
JABꢀ=ꢀ17 Hz, JBXꢀ=ꢀ10 Hz, 1 H, pyrazoline-HB), 3.16, 3.19 (dd, tered and recrystallized from ethanol.
JABꢀ=ꢀ17 Hz, JAXꢀ=ꢀ6 Hz, 1 H, pyrazoline-HA), 2.39 (s, 3H, CH3).
– 13CꢀNMR (125 MHz, [D6]DMSO): δꢀ=ꢀ21.42 (CH3), 40.08 (C-4
of pyrazoline ring), 56.58 (C-5 of pyrazoline ring), 113.84, 3.4.1 Anti-1,3-diphenyl-1H-pyrazole-4-carbaldehyde
118.63, 119.51, 123.33, 126.32, 126.80, 127.50, 128.38, 129.13,
129.26, 129.39, 129.89, 130.00, 130.38, 132.88, 138.13, 139.75,
oxime (5a) [27]
145.21 (Ar-C, C-4 and C-5 of pyrazole ring), 148.20 (C-3 of Colorless crystals, yield 88% (0.231 g), m. p. 155–157°C.
pyrazole ring), 150.24 (C-3 of pyrazoline ring). – C25H22N4 – IR (KBr): νꢀ=ꢀ3265 (OH), 1597 (C=N), 1534 (C=C) cm−1.
1
(378.47): calcd. C 79.34, H 5.86, N 14.80; found C 79.39, H – HꢀNMR (500 MHz, [D6]DMSO): δꢀ=ꢀ8.97 (s, 1 H, CH=N),
5.79, N 14.86.
7.79 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.68 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H),
7.58 (s, 1 H, 5-H of pyrazole ring), 7.43–7.51 (m, 5 H, Ar-H),
7.31–7.35 (m, 1 H, Ar-H), 6.38 (broad s, D2O-exchangeable,
13
3.3.3 4-[3-(p-Nitrophenyl)-4,5-dihydro-1H-pyrazol-5-yl]-
1-phenyl-3-(p-tolyl)-1H-pyrazole (4c)
1 H, OH). CꢀNMR (125 MHz, [D6]DMSO): δꢀ=ꢀ111.96, 119.59,
127.52, 129.18, 129.35, 130.17, 131.89, 132.46, 137.37 (Ar-C, C-4
and C-5 of pyrazole ring), 139.64 (CH=N), 152.53 (C-3 of
Pale yellow crystals, yield 81% (0.342 g), m. p. 213–215°C. pyrazole ring). – C16H13N3O (263.29): calcd. C 72.99, H 4.98,
– IR (KBr): νꢀ=ꢀ3341 (NH), 1595 (C=N), 1509 (C=C) cm−1. N 15.96; found C 73.05, H 5.01, N 15.92.
1
– HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ8.20 (d, Jꢀ=ꢀ8 Hz, 2 H,
Aldoximes 5b–5e [27] were formed as a mixture of syn
Ar-H), 8.06 (s, 1 H, 5-H of pyrazole ring), 7.77 (d, Jꢀ=ꢀ8 Hz, 2 and anti isomers. Their proton signals appeared in the
H, Ar-H), 7.70 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.57 (d, Jꢀ=ꢀ8 Hz, 2 H, region of δꢀ=ꢀ6.35–8.97 ppm, but the assignment was not
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1
possible because they were highly overlapped with each 1599 (C=N), 1530 (C=C) cm−1. – HꢀNMR (500 MHz, CDCl3):
other. They were used in the next step without further δꢀ=ꢀ8.36 (s, 1 H, 5-H of pyrazole ring), 8.02 (d, Jꢀ=ꢀ8 Hz,
purification.
2 H, Ar-H), 7.73 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.51 (t, Jꢀ=ꢀ8 Hz, 2 H,
Ar-H), 7.45 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.40 (t, Jꢀ=ꢀ8 Hz, 1 H,
Ar-H). – 13CꢀNMR (125 MHz, [D6]DMSO): δꢀ=ꢀ91.16 (C-4 of
pyrazole ring), 114.66 (Cꢀ≡ꢀN), 119.85, 128.59, 129.47, 129.75,
130.27, 134.98, 136.93, 138.80 (Ar-C, C-5 of pyrazole ring),
151.96 (C-3 of pyrazole ring). – C16H10ClN3 (279.72): calcd.
3.5 General procedure for synthesis of
pyrazole-4-carbonitriles 8a–8e
Method a. A solution of aldoximes 5a–5e (1.0 mmol) and C 68.70, H, 3.60, Cl 12.67, N 15.02; found C 68.61, H 3.54, Cl
anhydrous sodium acetate (0.164 g, 2 mmol) in acetic 12.91, N 14.93.
anhydride (10 mL) was heated on a boiling water bath for
3 h. The mixture was kept to cool and poured onto crushed
ice (20 g) with occasional stirring. The separated product 3.5.4 3-(p-Bromophenyl)-1-phenyl-1H-pyrazole-4-
was filtered off, washed repeatedly with water, and recrys-
tallized from a mixture of chloroform and ethanol.
carbonitrile (8d)
Colorless crystals, yield 80% (0.259 g, method a), 83%
Method b. A solution of 5a–5e (1.0 mmol), 2-chloroacetic (0.268 g, method b), m. p. 132–134°C. – IR (KBr): νꢀ=ꢀ2224
acid (0.094 g, 1.0 mmol) and anhydrous sodium acetate (Cꢀ≡ꢀN), 1639 (C=N), 1598 (C=C) cm−1. – H NMR (500 MHz,
1
(0.082 g, 1.0 mmol) in DMF (10 mL) was heated under CDCl3): δꢀ=ꢀ8.37 (s, 1 H, 5-H of pyrazole ring), 7.95 (d, Jꢀ=ꢀ8 Hz,
reflux for 17–21 h. The mixture was processed as above to 2 H, Ar-H), 7.73 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.61 (d, Jꢀ=ꢀ8 Hz, 2 H,
give identical products to that obtained from method a.
Ar-H), 7.51 (t, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.41 (t, Jꢀ=ꢀ8 Hz, 1 H, Ar-H).
– 13CꢀNMR (125 MHz, [D6]DMSO): δꢀ=ꢀ91.16 (C-4 of pyrazole
ring), 114.66 (Cꢀ≡ꢀN), 119.89, 123.71, 128.65, 128.84, 129.83,
130.31, 132.69, 136.98, 138.82 (Ar-C, C-5 of pyrazole ring),
152.06 (C-3 of pyrazole ring). – C16H10BrN3 (324.17): calcd.
3.5.1 1,3-Diphenyl-1H-pyrazole-4-carbonitrile (8a) [28]
Colorless crystals, yield 81% (0.198 g, method a), 76% C 59.28, H 3.11, Br 24.65, N 12.96; found C 59.24, H 3.03, Br
(0.186 g, method b), m. p. 125–127°C. – IR (KBr): νꢀ=ꢀ2227 24.71, N 13.01.
1
(Cꢀ≡ꢀN), 1597 (C=N), 1532 (C=C) cm−1. – HꢀNMR (500 MHz,
CDCl3): δꢀ=ꢀ8.36 (s, 1 H, 5-H of pyrazole ring), 8.07 (d,
Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.74 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.41–7.54 3.5.5 3-(p-Nitrophenyl)-1-phenyl-1H-pyrazole-4-
(m, 6 H, Ar-H). – C16H11N3 (245.28): calcd. C 78.35, H 4.52, N
17.13; found C 78.41, H 4.44, N 17.17.
carbonitrile (8e) [28]
Colorless crystals, yield 71% (0.205 g, method a), 73% (0.211
g, method b), m. p. 154–156°C. – IR (KBr): νꢀ=ꢀ2229 (Cꢀ≡ꢀN),
3.5.2 3-(p-Tolyl)-1-phenyl-1H-pyrazole-4-carbonitrile
(8b) [29]
1
1600 (C=N), 1534 (C=C) cm−1. – HꢀNMR (500 MHz, CDCl3):
δꢀ=ꢀ8.43 (s, 1 H, 5-H of pyrazole ring), 8.33 (d, Jꢀ=ꢀ8 Hz, 2 H,
Ar-H), 8.27 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.75 (d, Jꢀ=ꢀ8 Hz, 2 H,
Ar-H), 7.54 (t, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.44 (t, Jꢀ=ꢀ8 Hz, 1 H, Ar-H).
– C16H10N4O2 (290.28): calcd. C 66.20, H 3.47, N, 19.30; found
C 66.19, H 3.47, N 19.26.
Colorless crystals, yield 77% (0.199 g, method a), 67%
(0.173 g, method b), m. p. 102–104°C. – IR (KBr): νꢀ=ꢀ2223
1
(Cꢀ≡ꢀN), 1596 (C=N), 1530 (C=C) cm−1. – HꢀNMR (500 MHz,
CDCl3): δꢀ=ꢀ8.34 (s, 1H, 5-H of pyrazole ring), 7.96 (d, Jꢀ=ꢀ8 Hz,
2 H, Ar-H), 7.73 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.50 (t, Jꢀ=ꢀ8 Hz, 2
H, Ar-H), 7.38 (t, Jꢀ=ꢀ8 Hz, 1 H, Ar-H), 7.29 (d, Jꢀ=ꢀ8 Hz, 2 H,
Ar-H), 2.42 (s, 3 H, CH3). – C17H13N3 (259.31): calcd. C 78.74,
H 5.05, N 16.20; found C 78.91, H 5.07, N 16.21.
3.6 General procedure for synthesis of
5-pyrazolyl-1,2,4-triazolidine-3-thiones
9a–9d
3.5.3 3-(p-Chlorophenyl)-1-phenyl-1H-pyrazole-4-
carbonitrile (8c) [29]
A suspension of 2a–2d (1.0 mmol) in water (20 mL) was
treated with thiosemicarbazide (0.091 g, 1.0 mmol) and two
drops of glacial acetic acid. The mixture was heated under
Colorless crystals, yield 72% (0.2 g, method a), 75% (0.209 reflux for 3 h; the completion of the reaction was checked
g, method b), m. p. 138–140°C. – IR (KBr): νꢀ=ꢀ2224 (Cꢀ≡ꢀN), by TLC using chloroform-ethanol (9:1). The product that
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separated out on cooling was filtered, washed with water, (355.84): calcd. C 57.38, H 3.97, Cl 9.96, N 19.68, S 9.01;
dried, and recrystallized from a mixture of chloroform and found C 57.32, H 3.96, Cl 10.17, N 19.61, S 9.03.
ethanol.
3.6.4 5-[3-(p-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl]-
3.6.1 5-(1,3-Diphenyl-1H-pyrazol-4-yl)-1,2,4-triazolidine-
3-thione (9a)
1,2,4-triazolidine-3-thione (9d)
Colorless crystals, yield 96% (0.384 g), m. p. 215–217°C.
Colorless crystals, yield 95% (0.304 g), m. p. 195–196°C. – IR (KBr): νꢀ=ꢀ3341 (NH), 3155 (NH), 1618 (C=N), 1536 (C=C),
– IR (KBr): νꢀ=ꢀ3295 (NH), 3264 (NH), 3147 (NH), 1597 1220 (C=S) cm−1. – 1HꢀNMR (500 MHz, [D6]DMSO): δꢀ=ꢀ11.30
(C=N), 1537 (C=C), 1216 (C=S) cm−1. – HꢀNMR (500 MHz, (s, 1 H, NH, D2O-exchangeable), 9.15 (s, 1 H, 5-H of pyrazole
1
[D6]DMSO): δꢀ=ꢀ11.31 (s, 1 H, NH, D2O-exchangeable), ring), 8.24 (s, 1 H, NH, D2O-exchangeable), 8.15 (s, 1 H, 5-H
9.17 (s, 1 H, 5-H of pyrazole ring), 8.24 (s, 1 H, NH, D2O- of triazolidine ring), 7.85 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.77 (s, 1 H,
exchangeable), 8.19 (s, 1 H, 5-H of triazolidine ring), 7.86 NH, D2O-exchangeable), 7.68 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.60
(d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.78 (s, 1 H, NH, D2O-exchangeable), (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.52 (t, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.35 (t,
7.64 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.52 (t, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.48 Jꢀ=ꢀ8 Hz, 1 H, Ar-H). – C17H14BrN5S (400.30): calcd. C 51.01,
(t, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.42 (t, Jꢀ=ꢀ8 Hz, 1 H, Ar-H), 7.34 (t, H 3.53, Br 19.96, N 17.50, S 8.01; found C 50.89, H 3.53, Br
Jꢀ=ꢀ8 Hz, 1 H, Ar-H). – C17H15N5S (321.40): calcd. C 63.53, H 20.23, N 17.41, S 8.05.
4.70, N 21.79, S 9.98; found C 63.51, H 4.71, N 21.84, S 10.03.
3.7 General procedure for synthesis of
3.6.2 5-[1-Phenyl-3-(p-tolyl)-1H-pyrazol-4-yl]-1,2,4-
Knoevenagel condensation products
triazolidine-3-thione (9b)
10a–10d
Colorless crystals, yield 89% (0.298 g), m. p. 190–192°C. In a dry test tube, carbaldehyde 2a, 2b, 2d, or 2e (5 mmol)
– IR (KBr): νꢀ=ꢀ3305 (NH), 3297 (NH), 3158 (NH), 1598 (C=N), was added to ethyl 2-cyanoacetate (0.53 mL, 5 mmol), and
1541 (C=C), 1223 (C=S) cm−1. – 1HꢀNMR (500 MHz, [D6]DMSO): the mixture was heated over a boiling water bath for 2 h.
δꢀ=ꢀ11.31 (s, 1 H, NH, D2O-exchangeable), 9.14 (s, 1 H, 5-H of The separated product was collected by filtration, washed
pyrazole ring), 8.23 (s, 1 H, NH, D2O-exchangeable), 8.18 (s, with water, and dried. It was recrystallized from a mixture
1 H, 5-H of triazolidine ring), 7.85 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.78 of chloroform and ethanol.
(s, 1 H, NH, D2O-exchangeable), 7.51–7.54 (m, 4 H, Ar-H), 7.33
(t, Jꢀ=ꢀ8 Hz, 1 H, Ar-H), 7.28 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 2.35 (s,
3.7.1 Ethyl 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)
3 H, CH3). – 13CꢀNMR (125 MHz, [D6]DMSO): δꢀ=ꢀ21.40 (CH3),
propenoate (10a)
117.70 (C-5 of triazolidine ring), 119.00, 127.45, 128.11, 128.53,
129.85, 130.19, 135.61, 138.59, 139.60 (Ar-C, C-4 and C-5 of
Colorless crystals, yield 83% (1.425 g), m. p. 118–120°C.
pyrazole ring), 151.92 (C-3 of pyrazole ring), 178.08 (C=S).
– IR (KBr): νꢀ=ꢀ2218 (Cꢀ≡ꢀN), 1722 (C=O), 1591 (C=N), 1528
– C18H17N5S (335.43): calcd. C 64.45, H 5.11, N 20.88, S 9.56;
1
(C=C) cm−1. – HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ9.14 (s, 1 H,
found C 64.51, H 5.08, N 21.03, S 9.56.
5-H of pyrazole ring), 8.31 (s, 1 H, CH=C), 7.83–7.84 (m, 2 H,
Ar-H), 7.61–7.63 (m, 2 H, Ar-H), 7.49–7.54 (m, 5 H, Ar-H), 7.39
(t, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 4.34 (q, Jꢀ=ꢀ7 Hz, 2 H, CH2-CH3), 1.38
3.6.3 5-[3-(p-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-
(t, Jꢀ=ꢀ7 Hz, 3 H, CH2-CH3). – C21H17N3O2 (343.38): calcd. C
1,2,4-triazolidine-3-thione (9c)
73.45, H 4.99, N 12.24; found C 73.44, H 5.03, N 12.23.
Colorless crystals, yield 97% (0.344 g), m. p. 193–194°C.
– IR (KBr): νꢀ=ꢀ3334 (NH), 1602 (C=N), 1543 (C=C), 1221 (C=S) 3.7.2 Ethyl 2-cyano-3-[1-phenyl-3-(p-tolyl)-1H-pyrazol-
cm−1. – 1HꢀNMR (500 MHz, [D6]DMSO): δꢀ=ꢀ11.31 (s, 1 H, NH,
D2O-exchangeable), 9.16 (s, 1 H, 5-H of pyrazole ring), 8.24
4-yl]propenoate (10b)
(s, 1 H, NH, D2O-exchangeable), 8.17 (s, 1 H, 5-H of triazo- Colorless crystals, yield 95% (1.697 g), m. p. 132–133°C.
lidine ring), 7.85 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.77 (s, 1 H, NH, – IR (KBr): νꢀ=ꢀ2218 (Cꢀ≡ꢀN), 1724 (C=O), 1595 (C=N), 1536
1
D2O-exchangeable), 7.67 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.51–7.55 (C=C) cm−1. – HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ9.12 (s, 1 H,
(m, 4 H, Ar-H), 7.34 (t, Jꢀ=ꢀ7 Hz, 1 H, Ar-H). – C17H14ClN5S 5-H of pyrazole ring), 8.30 (s, 1 H, CH=C), 7.82 (d, Jꢀ=ꢀ8 Hz,
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[3] S. Du, Z. Tian, D. Yang, X. Li, H. Li, C. Jia, C. Che, M. Wang, Z.
Qin, Molecules 2015, 20, 8395.
2 H, Ar-H), 7.50–7.53 (m, 4 H, Ar-H), 7.38 (t, Jꢀ=ꢀ8 Hz, 1 H,
Ar-H), 7.32–7.34 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 4.35 (q, Jꢀ=ꢀ7 Hz, 2 H,
CH2-CH3), 2.44 (s, 3 H, CH3), 1.38 (t, Jꢀ=ꢀ7 Hz, 3 H, CH2-CH3).
– C22H19N3O2 (357.41): calcd. C 73.93, H, 5.36, N 11.76; found
C 73.91, H 5.37, N 11.81.
[4] S. Ghadbeigi, S. N. Ostad, A. Shafiee, M. Amini, Lett. Drug Des.
Discov. 2015, 12, 754.
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3.7.3 Ethyl 3-[3-(p-bromophenyl)-1-phenyl-1H-pyrazol-4-
yl]-2-cyanopropenoate (10c)
Pale yellow solid, yield 92% (1.942 g), m. p. 143–144°C. – IR
(KBr): νꢀ=ꢀ2219 (Cꢀ≡ꢀN), 1722 (C=O), 1591 (C=N), 1522 (C=C)
1
cm−1. – HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ9.12 (s, 1 H, 5-H of
pyrazole ring), 8.23 (s, 1 H, CH=C), 7.81–7.82 (m, 2 H, Ar-H),
7.65 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 7.49–7.54 (m, 4 H, Ar-H), 7.40
(t, Jꢀ=ꢀ8 Hz, 1 H, Ar-H), 4.35 (q, Jꢀ=ꢀ7 Hz, 2 H, CH2-CH3), 1.38
(t, Jꢀ=ꢀ7 Hz, 3 H, CH2-CH3). – C21H16BrN3O2 (422.27): calcd.
C 59.73, H 3.82, Br 18.92, N 9.95; found C 59.61, H 3.81, Br
19.11, N 9.94.
3.7.4 Ethyl 2-cyano-3-[3-(p-nitrophenyl)-1-phenyl-1H-
pyrazol-4-yl]propenoate (10d)
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Pale yellow solid, yield 97% (1.883 g), m. p. 164–165°C.
– IR (KBr): νꢀ=ꢀ2219 (Cꢀ≡ꢀN), 1723 (C=O), 1600 (C=N), 1529
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1
(C=C) cm−1. – HꢀNMR (500 MHz, CDCl3): δꢀ=ꢀ9.16 (s, 1 H,
5-H of pyrazole ring), 8.38 (d, Jꢀ=ꢀ8 Hz, 2 H, Ar-H), 8.24 (s,
1 H, CH=C), 7.82 (d, Jꢀ=ꢀ8 Hz, 4 H, Ar-H), 7.53 (t, Jꢀ=ꢀ8 Hz, 2 H,
Ar-H), 7.43 (t, Jꢀ=ꢀ8 Hz, 1 H, Ar-H), 4.36 (q, Jꢀ=ꢀ7 Hz, 2 H, CH2-
CH3), 1.41 (t, Jꢀ=ꢀ7 Hz, 3 H, CH2-CH3). – C21H16N4O4 (388.38):
calcd. C 64.94, H 4.15, N 14.43; found C 64.91, H 4.17, N 14.55.
References
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Z. Naturforsch.ꢂ
ꢂ2018 | Volume x | Issue x(b)
Graphical synopsis
El Sayed Ramadan, Essam M. Sharshira,
Ramadan I. El Sokkary and Noussa Morsy
Synthesis and antimicrobial evaluation
of some heterocyclic compounds from
3-aryl-1-phenyl-1H-pyrazole-4-carbalde-
hydes
https://doi.org/10.1515/znb-2018-0009
Z. Naturforsch. 2018; x(x)b: xxx–xxx
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