Synthesis, Antimicrobial Studies, and Docking Simulations of New Bis(4,5-dihydropyrazole) Derivatives

Article abstract of DOI:10.1002/jhet.2835

A novel series of bis(3-thienyl-4,5-dihydropyrazoles) has been synthesized by the cyclization reactions of bischalcones with phenyl hydrazine in basic medium. The O-alkylation reactions of chalcones with suitable 1,ω-dibromoalkanes in the presence of anhy

Full text of DOI:10.1002/jhet.2835

Month 2017
Synthesis, Antimicrobial Studies, and Docking Simulations of New
Bis(4,5-dihydropyrazole) Derivatives
a
a
b
*
Mohamad Yusuf, Amanpreet Kaur, and Mohammad Abid
aDepartment of Chemistry, Punjabi University, Patiala 147002, Punjab, India
bDepartment of Bio-Sciences, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India
*
E-mail: yusuf_sah04@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received August 29, 2016
DOI 10.1002/jhet.2835
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of bis(3-thienyl-4,5-dihydropyrazoles) has been synthesized by the cyclization reactions of
bischalcones with phenyl hydrazine in basic medium. The O-alkylation reactions of chalcones with suitable
1,ω-dibromoalkanes in the presence of anhydrous K2CO3, dry acetone, and Bu4N+Iꢀ as PTC lead to the
formation of bischalcones in good yields. The chalcone required was obtained from the Claisen–Schmidt
condensation reaction of 2-acetylthiophene with 3-hydroxybenzaldehyde. Structures of prepared compounds
were elucidated from their IR, 1H-NMR, 13C-NMR, and ESI-MS spectral data. Newly synthesized
compounds were screened for their antimicrobial potencies against Gram-positive, Gram-negative bacterial
strains, and fungal strains using serial tube dilution method. Docking simulations have also been carried out
to visualize the possible interaction of synthesized scaffold 2(a–g) and 3(a–g) at the active sites of
Escherichia coli.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
immense interest among the synthetic organic chemists
owing to their broad biological spectrum in terms of
The ever-increasing antibiotic resistance by the microbes
is a serious problem in contemporary medical science and
has emerged as one of the major concern to public health
in the present century [1–3]. A bacterial strain can acquire
resistance either by mutation or by the uptake of
exogenous genes by horizontal transfer from other
bacterial strains. So with the evolution of new microbial
strains resistant to many conventional antibiotics, there is
an enormous interest among the synthetic chemists to
come out with new novel antimicrobial agents [4–6]. The
literature studies have revealed that incorporation of
heteroatoms (N/O/S) in the five membered rings enhance
the activity of compounds, as a number of widely implied
drugs also consist of heterocyclic scaffold [7]. Chalcones
are key synthones as their cyclocondensation reactions
lead to the generation of many exotic heterocyclics, useful
in the construction of novel antimicrobial products [8,9].
Among these pyrazolines, five membered nitrogen-
containing heterocyclic compounds have attracted
antimicrobial,
antitumor,
antidepressant,
MAO-B
inhibitors, anti-amoebic, cyclooxygenase (COX-2)
inhibitors, immunosuppressive, and anti-inflammatory
agents [10–17]. Many pyrazoline derivatives like
antipyrene, morazone, famprofazone, and ramifonazone
are employed as leading non-steroidal anti-inflammatory
drugs [18–20]. It is quite evident from the literature that
pyrazole-containing pharmacoactive agents play important
role in discovery of new antimicrobial agents [21,22]. By
keeping these aspects in mind and also in continuation of
our investigations [23–25] upon the bisheterocyclic
compounds, we report herein the synthesis and
antimicrobial studies of new bis(4,5-dihydropyrazole)
derivatives. These bispyrazolines are prepared by the
cyclization of bischalcones. Further, to investigate
structural activity relationship, docking simulations of the
most active antimicrobial agents into the active sites of
Escherichia coli have been carried out and compared with
the standard.
© 2017 Wiley Periodicals, Inc.

M. Yusuf, A. Kaur, and M. Abid
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RESULTS AND DISCUSSION
J3 ,4 =3.8–3.9 Hz), 7.90–7.63 (dd, J5 ,3 = 0.6–1.0 Hz,
0
0
0
0
J5 ,4 = 4.8–5.0 Hz), and 7.24–7.18 (dd, J4 ,3 = 3.8–
0
0
This study describes the synthesis of bischalcones and
bispyrazolines as shown in Scheme 1. The bispyrazolines
3(a–g) were prepared from the cyclization reaction of
bischalcones 2(a–g) with phenyl hydrazine by refluxing
under alcoholic medium in the presence of sodium
hydroxide. The bischalcones were obtained in good
yields from the O-alkylation of hydroxy substituted
chalcone with suitable 1,ω-dibromoalkanens using
anhydrous K2CO3, dry acetone, and tetrabutyl ammonium
iodide as PTC. Claisen–Schmidt condensation reaction of
2-acetylthiophene with 3-hydroxybenzaldehyde provided
chalcone 1 in good yield. The structures of prepared
compounds (chalcone, bischalcone, and bispyrazoline)
were confirmed from the rigorous analysis of their
spectral data (IR, 1H-NMR, and 13C-NMR) and were
found fully in accordance with their proposed structure.
ESI-MS of these compounds were also performed. The
elemental analysis was also carried out to confirm the
purity of these products.
The IR spectra of compounds 2(a–g) exhibited major
adsorptions at 1649 (C = O), 1596–1580 (C = C), 1267,
1078 (C-O) and 1255, 1049 (C-O) respectively. In the
1H-NMR (400 MHz) spectra of 2(a–g), two broad
doublets centered at δ 7.83–7.43 and 7.68–7.63 were
easily assigned to H-3 and H-2. The coupling value of
J2,3 = 15.6 Hz describes the trans geometry around the
C-2 and C-3 double bond. The thiophen ring protons
H-30, H-50, and H-40 were found to be resonating in the
3.9 Hz, J4 ,5 =4.8–5.0 Hz), respectively. The OCH2 group
protons belonging to aliphatic linkers were placed at δ
4.27–4.03 (Jvic = 6.7 Hz) as four protons triplets. In the
13C-NMR (100 MHz) spectra of 2(a–g) presence of
carbonyl group was confirmed by the downfield
appearance of signals at δ 181.46–180.34 (C = O). The
carbon atoms belonging to the double bond C-3 and C-2
were found to be resonating at δ 144.09–142.97 and
121.66–120.11. The downfield placement of the former
could be explained because of its placement at the
β-position in the enone moiety. The carbon atoms C-3″
and OCH2 showed suitable resonances at δ 159.00–
157.70 and 68.12–64.26 respectively in their 13C-NMR
spectra.
The IR spectra of bispyrazoline 3(a–g) exhibited
strong absorption at 1590–1598 (C = N), which is a
characteristic of pyrazoline ring. In the 400 MHz 1H-
NMR spectra of 2(a–g), pyrazoline ring protons H-X,
H-M, and H-A furnished three distinctive doublets of
doublets at δ 5.42–5.13 (2H), 3.89–3.75 (2H), and
3.11–3.09 (2H), respectively. The sterochemical
disposition of these hydrogens was confirmed from
consideration of J parameters. The vicinal coupling
constant (3J) between H-X and H-M was found to be
12.4 Hz, which reflects that these hydrogens are cis to
each other while coupling value of JXA = 7.6–6.3 Hz
describes the trans relationship between H-X and H-A.
The coupling value of 17.3–16.9 Hz between H-M and
H-A suggests their geminal placement at C-4. The
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aromatic region at δ 8.22–7.84 (dd, J3 5 =1.1–0.8 Hz,
Scheme 1. Synthesis of bis(4, 5-dihydropyrazoles).
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Synthesis of New bis(4,5-dihydropyrazole) Derivatives
phenyl rings placed at N-1 and C-5 are evidently trans
oriented to avoid any intramolecular repulsion.
2(a–g) were found to inhibit the growth of E. coli
effectively at MIC of 8 and 16 μg/mL. Improved results
have been observed in the case of bispyrazolines 3(a–g).
Here, compounds 3b and 3c showed MIC of 4 μg/mL
against E. coli comparable with standard drug
Amoxicillin. Compounds 3b and 3c were also found to
inhibit the growth of P. aeruginosa, A. Janus, S. aureus,
S. Pyrogens, and A. Niger at MIC of 4 and 8 μg/mL,
respectively. Compounds 3e and 3f inhibited the growth
of tested strains at MIC of 8 and 16 μg/mL. Rest of
compounds showed effective antimicrobial behavior with
MIC of 8 and 16 μg/mL against all the tested bacterial
and fungal strains.
A
suitable resonance present at δ 144.87–144.08 in the
13C-NMR (100 MHz) spectra of 3(a–g) confirms the
presence of C = N moiety. The downfield resonance
placed at δ159.88–159.03 may be ascribed to C-3‴
because of its direct placement with electronegative
oxygen atom. The characteristic pyrazoline ring carbon
atoms C-3, C-5, and C-4 resulted in three signals at δ
144.88–144.08,
64.82–63.31,
and
44.72–43.699,
respectively, and internal chain OCH2 carbon atom was
found to be resonating at δ 67.89–64.72. Rest of the
carbon atoms belonging to internal chain could provide
suitable resonances in the aliphatic region at
δ
29.24–24.01 {(CH2)n}.
MATERIALS AND METHODS OF DOCKING
STUDIES
ANTIMICROBIAL ACTIVITY
Protein and ligand preparation. The three-dimensional
crystal structure of E. coli peptide deformylase, malate
synthase, and methionine aminopeptidase 1 at 1.9 Å
resolution (PDB ID: IDFF, 2JQX, and 2MAT),
determined by X-ray crystallography was retrieved from
the Protein Data Bank (http://www.rcsb.org/). Since,
PDB files suffer from a variety of potential problems,
for example, missing atoms, added waters, more than
one molecule, chain breaks, and alternate locations,
therefore, need to be corrected before use. Before
docking, the preparations of protein and ligands were
carried out, and subsequently, electron affinity grids
were generated.
The prepared compounds 2(a–g) and 3(a–g) were
subjected to the antimicrobial analysis by serial tube
dilution method as reported in the literature. Seven
bacterial and five fungal species were used as the
antimicrobial test strains, namely, Klubsellia pneumonia
(MTCC 3384), Pseudomonas aeruginosa (MTCC 424),
E. coli (MTCC 443), Straphylococcus aureus (MTCC 96),
Bacillius subtilis (MTCC 441), Pseudomonas fluorescens
(MTCC 103), Streptoccus pyrogens (MTCC 442) and
Aspergillius janus (MTCC 2751), Pencillium glabrum
(MTCC 4951), Fusarium oxysporum (MTCC 2480),
Aspergillus sclerotiorum (MTCC 1008), and Aspergillus
niger (MTCC 281), respectively. Amoxicillin and
Fluconazole were used as the standard drug against
bacteria and fungi, respectively. The minimum inhibitory
concentrations (MIC-μg/mL) were determined by using
various dilutions of the concerned compound. The results
were compared with positive controls, the standard drug
amoxicillin and fluconazole. Serial dilutions of the test
compounds previously dissolved in dimethyl sulfoxides
(DMSO) were prepared to final concentrations of 128, 64,
32, 16, 8, 4, and 2 μg/mL. All the bacterial strains were
grown at 37°C for 24 h in nutrient broth, and fungi were
grown in malt extract at 28°C for 72 h. Each test
compound was dissolved in DMSO, and minimum
inhibitory concentration (MIC-μg/ml) thus obtained were
compared with control.
Molecular docking studies. Auto Dock Vina 4.0 was
used for molecular docking screening of bischalcones
2(a–g) and bispyrazoline 3(a–g) binding to E. coli
peptide deformylase, malate synthase, and methionine
aminopeptidase [26]. Auto Dock Vina is a newly
developed program for molecular docking and virtual
screening. It achieves an approximately two orders of
magnitude speed-up in comparison with the molecular
docking software AutoDock4.0 [27] and can achieve
significantly improved accuracy of the binding mode
predictions. The program automatically calculates the
grid maps and clusters and uses a sophisticated gradient
optimization method in its local optimization. The ligands
designed for this study were drawn by Chem Draw Ultra
8.0, and their coordinate files were generated using
Online Smiles Translator. Polar hydrogen was added, and
Kollman charges were assigned to all atoms. Affinity
grids were centered on and encompassing the active site
was calculated with 44 × 46 × 44 points and a grid
spacing of 0.375 A°. Gasteiger charges were assigned to
all atoms, and rotatable bonds were assigned using Auto
Dock tools. Auto Dock was used to evaluate ligand-
All the bischalcones 2(a–g) were found to be potent
antimicrobial agents (Tables 1 and 2) against the tested
strains. Compounds 2b and 2c were found to be the most
active against
P aeruginosa, E. coli, S. aureus,
S. pyrogens, A. janus, and F. oxysporum with MIC of
8 μg/mL. Compounds 2e and 2f showed MIC of
8 μg/mL against E. coli, P. Fluorescen, S. aureus,
P. glabrum, and A. Niger. Interestingly, the compounds
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Synthesis of New bis(4,5-dihydropyrazole) Derivatives
binding energies over the conformational search space
using Lamarckian genetic algorithm. Default docking
parameters were used with some exceptions. In the
output log file, we have considered the minimum energy
conformation state of each ligand showing binding
affinity in kcal/mol.
Hydrogen-bonding and hydrophobic interactions
between docked molecules and receptor were analyzed
using Auto Dock tools (ADT 4.0). The polar contacts
between ligand and receptor were noted down by
PyMOL. The best docking result can be considered to be
the conformation with the highest negative binding
affinity.
To analyze the antimicrobial behavior of prepared
compounds on structural basis, we docked compounds
2(a–g) and 3(a–g) and standard drugs at Peptide
deformylase (IDFF), Malate synthase (2JQX) and
methionine aminopeptidase (2MAT) of E. coli.
Amoxicillin shows binding affinity of ꢀ7.0, ꢀ8.5, and
ꢀ7.4 kcal/mol with peptide deformylase, malate synthase,
and methinine aminopeptidase, respectively, as shown in
Tables 3 and 4.
Docking simulation of amoxicillin (Fig. 1) at the active
site of malate synthase of E. coli shows five hydrogen-
bonding interactions with Arg382 (3.16 Ao), Glu108
(3.18 Ao), Ala113 (3.20 Ao), Gln112 (2.79 Ao), and
lys232 (3.04 Ao) with auto dock binding affinity of
ꢀ8.5 kcal/mol (Table 3). Ten amino acid residues of the
active site, namely, lle265, His330, Arg134, Leu334,
Glu384, Thr383, Asp106, Asn380, Ser107, and Leu236
are involved in hydrophobic interactions with the
Amoxicillin. Ligand 2c showed maximum autodock
negative binding affinity of ꢀ9.0 (kcal/mol) when
docked at the active site of the malate synthase of E. coli.
Docking conformation (Fig. 1) of 2c showed two
hydrogen-bonding interactions with His123 (2.95 Ao)
and lys301 (3.14 Ao) residues of active site of malate
synthase. Thirteen amino acid residues, namely,
Val611, Lys720, Arg716, Asn123, Arg307, Trp160,
Met122, Gly614, Arg288, Lys301, Lle284, leu285,
and Gln299 exhibited hydrophobic interactions with
ligand 2c. It may be suggested that the binding
affinities of 2(a–g) to the active sites of E. coli may
be majorly contributed to their hydrogen-bonding and
hydrophobic interactions with the appropriate part of
active sites.
Bispyrazolines 3(a–g) showed better autodock negative
binding affinity results (Table 4) in comparison with their
bischalcones, as in accordance with the antimicrobial data
(Tables 1 and 2). Molecular docking (Fig. 2) of 3a and
3b with malate synthase have demonstrated autodock
binding affinity of ꢀ9.0 and ꢀ9.3 kcal/mol,
respectively. Analysis of docking simulation shows zero
hydrogen-bonding interaction of the active site with the
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M. Yusuf, A. Kaur, and M. Abid
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ligand 3a and 3b, but 3a shows 16 hydrophobic
interactions with Ile623, Asn599, Met511, Trp500,
Lys477, Met476, Glu591, Gln594, The634, Pro512,
Ser638, Leu635, Gly602, Glu630, Ile603, and similar 16
hydrophobic interactions were observed in the docking
conformation of 3b with the active site of malate
synthase of E. coli. Similarly, docking of 3b and 3c
(Fig. 2) with methionine aminopeptidase exhibit binding
affinity of ꢀ9.2 and ꢀ9.0 kcal/mol, which is more than
the standard drug. Ligand 3b is involved in hydrogen-
bonding interactions with His63 (2.71 Ao and 2.73 Ao)
and His178 (1.66 Ao and 2.78 Ao) while hydrophobic
interactions with Tyr65, Trp221, Tyr62, Phe177, Cys59,
Tyr168, His79, Gln182, Gly170, Cys169, met206,
Glu204, and Asp97, respectively. Elucidation of docking
conformation of 3c (Fig. 2) with the active site of
2MAT shows one hydrogen-bonding interaction with
Tyr62 (2.98 Ao), amino acid residue showing
hydrophobic interactions are similar as observed in the
case of ligand 3b. The docking studies with E. coli
active sites are found in concurrence with antimicrobial
results, and maximum compounds were found to
possessing more negative value of autodock binding
affinity relative to the standard drug. Binding affinities
of 3(a–g) to the active sites of E. coli are majorly
contributed by their hydrophobic interactions with the
appropriate part of active sites. The results of autodock
binding affinities showed that prepared compounds
could be considered as effective deformylase, malate
Figure 1. 2D conformations showing docking simulation of Amoxicillin
and most active ligand 2c with active site of malate synthase. Hydrogen
bonds are shown in green dashed lines, and hydrophobic interactions are
represented with red arcs radiating lines. Carbon atoms are presented with
black color while different colors are used to distinguish between
heteroatoms. [Color figure can be viewed at wileyonlinelibrary.com]
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Synthesis of New bis(4,5-dihydropyrazole) Derivatives
Figure 2. Showing 2D docking conformation of ligands 3a and 3b at the active site of malate synthase (2JQX), ligands 3b and 3c at the active site of
Methionine amino peptidase (2MAT) of E. coli. Green dashed lines show hydrogen-bonding interactions while red arc represents the hydrophobic inter-
actions with the active site. Carbon atoms are represented in black color while different colors are used to distinguish between the heteroatoms. [Color
figure can be viewed at wileyonlinelibrary.com]
synthase, and methionine aminopeptidase activity
inhibitors.
study would help in synthesis of new heterocyclics that
causes malfunctioning of active sites of E. coli.
CONCLUSION
EXPERIMENTAL
In this communication, we report the synthesis of
bispyrazoline linked through alkyl chains of varying
lengths. These compounds exhibit very significant
antibacterial and antifungal activities. The docking
simulations of prepared compounds at the active sites of
E. coli for elucidating nature of bonding and type of
interactions involved between the compounds and active
sites were carried out. Examination of autodock binding
affinity results showed that prepared compounds could be
considered as enhanced E. coli growth inhibitors, resulting
in bacterial death. We anticipated that the findings of this
Melting points reported are uncorrected. IR spectra were
scanned in a KBr pellets on perkin Elmer RXIFT IR
spectrophotometer. H-NMR spectra were scanned on a
1
400 MHz Bruker spectrometer using TMS as an internal
standard and CDCl3/DMSO-d6 as solvents. Mass spectra
have been recorded on Waters Micromass Q-T of Micro
(ESI) spectrometer. UV–vis spectra were recorded in
MeOH with Shimadzu UV-1800 Spectrophotometer.
Silica gel suspended in MeOH-CHCl3 was used for
coating TLC plates, and iodine vapors were used as
visualizing agent.
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Synthesis of (E)-3-(3-hydroxyphenyl)-1-(thiophen-2-yl)
prop-2-en-1-one (1).
Jvic = 6.1 Hz, OCH2CH2); 13C-NMR (100 MHz,
DMSO-d6): δ 181.44 (C = O), 158.85 (C-3″), 145.40
(C-20), 142.97 (C-3), 135.84 (C-50), 134.96 (C-1″),
133.27 (C-30), 129.74 (C-6″), 128.48 (C-5″), 122.04
(C-40), 121.66 (C-2), 116.91 (C-2″), 113.81 (C-4″),
64.26 (OCH2), 28.72 (OCH2CH2); ESI-MS: m/z 523
(M + Na, 100%), 501 (M + 1, 77%); Anal. Calcd for
C29H24S2O4: Calcd C, 69.60%; H, 4.80%; S, 12.80%;
A
solution
of
3-hydroxybenzaldehyde (4.8 g, 0.03963 mol), 2-
acetylthiophene (4.98 g, 0.03963 mol), and NaOH (5.0 g,
0.024 mol) in EtOH (20 ml) was stirred at 0°C for 8 h,
and resulting reddish mass was kept in refrigerator
overnight. The reaction mixture was poured into iced-
HCl to yield a yellow solid that was filtered thoroughly,
washed with water, and dried. The crude product thus
obtained was crystallized from MeOH to yield a pure
chalcone 1.
found: C, 69.54%; H, 4.79%; S, 12.82%.
Synthesis of (2E,20E)-3,30-(3,30-(butane-1,4-diylbis(oxy))bis(3,1-
phenylene))bis(1-(thiophen-2-yl)prop-2-en-1-one) (2b).
The
compound 2b was obtained by treating chalcone 1a
(2.24 g, 0.01 mol) with 1,4-dibromobutane (1.08 g,
0.005 mol) under the same conditions as used earlier for
2a.
1: Yield (7.0 g, 77%); yellow needles; m.p.: 139–141°C;
IR (KBr): ʋmax (cmꢀ1): 3340 (OH), 3084 (aromatic C-H),
1649 (C = O), 1583 (C = C) and 1244, 1070 (C-O); UV–
vis (MeOH): λmax(nm) 316, 260; 1H-NMR (400 MHz,
2b: Yield (3.8 g, 74%); light yellow solid; m.p.:
138–140°C; IR (KBr): ʋmax (cmꢀ1) 3077 (aromatic C-H),
2926, 2944 (methylene C-H), 1649 (C = O), 1595
DMSO-d6):
δ 9.58 (1H, s, OH), 8.23 (1H, dd,
J3 ,5 = 0.9 Hz, J3 ,4 = 3.9 Hz, H-30), 7.94 (1H, dd,
0
0
0
0
J5 ,3 = 0.9 Hz, J5 ,4 = 4.8 Hz, H-50), 7.73 (1H, d,
Jtrans = 15.6 Hz, H-3), 7.67 (1H, d, Jtrans = 15.6 Hz, H-2),
7.27 (1H, d, Jp = 1.2 Hz, H-6″), 7.23 (2H, m, H-5″,4″),
0
0
0
0
(C = C), and 1259, 1060 (C-O); UV–vis (MeOH):
1
λ
max(nm) 318, 255; H-NMR (400 MHz, DMSO-d6): δ
8.22 (2H, d, J3 ,4 = 3.9 Hz, H-30), 7.90 (2H, dd,
0
0
0
0
7.21 (1H, s, H-2″), 6.90 (1H, dt, J4 ,3 = 3.9 Hz,
J5 ,3 = 0.6 Hz, J5 ,4 = 4.8 Hz, H-50), 7.75 (2H, d,
Jtrans = 15.6 Hz, H-3), 7.68 (2H, d, Jtrans = 15.6 Hz, H-2),
7.39 (2H, d, Jp = 0.9 Hz, H-2″), 7.34 (2H, s, H-6″), 7.33
J4 ,5 = 4.8 Hz, H-40); 13C-NMR (100 MHz, DMSO-d6): δ
181.46 (C = O), 157.70 (C-3″), 145.40 (C-20), 143.37
(C-3), 135.66 (C-50), 134.95 (C-1″), 133.16 (C-30),
129.67 (C-6″), 128.60 (C-5″), 121.59 (C-40), 119.74
(C-2), 117.79 (C-2″), 115.13 (C-4″); Anal. Calcd for
C13H10SO2: Calcd C, 67.80%; H, 4.34%; S, 13.90%;
found: C, 67.60%; H, 4.33%; S, 13.92%.
0
0
0
0
0
0
0
0
(2H, s, H-5″), 7.24 (2H, dd, J4 ,3
= 3.9 Hz,
J4 ,5 = 4.8 Hz, H-40) 7.00 (2H, td, Jm,o = 2.6, 8.1 Hz,
H-4″), 4.14 (4H, brs, OCH2), 1.99 (4H, brs, OCH2CH2);
13C-NMR (100 MHz, DMSO-d6): δ 181.37 (C = O),
158.94 (C-3″), 145.36 (C-20), 143.03 (C-3), 135.71
(C-50), 134.70 (C-1″), 133.00 (C-30), 129.64 (C-6″),
128.36 (C-5″), 121.85 (C-40), 121.39 (C-2), 116.75
(C-2″), 113.73 (C-4″), 67.12 (OCH2),25.45 (OCH2CH2);
ESI-MS: m/z 537 (M + Na, 30%), 515 (M + 1, 10%);
Anal. Calcd for C30H26S2O4: C, 70.03%; H, 5.05%; S,
12.44%; found: C, 69.78%; H, 5.03%; S, 12.45%.
0
0
Synthesis of (2E,20E)-3,30-(3,30-(alkane-1,n-diylbis(oxy))bis(3,1-
phenylene))bis(1-(thiophen-2-yl)prop-2-en-1-one) (2a).
A
suspension of chalcone 1 (2.24 g, 0.01 mol), K2CO3
(2.0 g), 1,3-dibromopropane (0.005 mol) and tetrabutyl
ammonium iodide (1.0 g) in dry acetone (25 mL) was
refluxed for 6 h with continuous stirring. The progress of
reaction was monitored by TLC. After the completion of
reaction, the reaction mixture turned into a colorless
mass, which was poured over iced-HCl to provide a
crude solid, which was recrystallized from CH3OH:
Synthesis of (2E,20E)-3,30-(3,30-(pentane-1,5-diylbis(oxy))bis(3,1-
phenylene))bis(1-(thiophen-2-yl)prop-2-en-1-one) (2c).
The
compound 2c was obtained from the reaction of chalcone
1a (2.24 g, 0.01 mol) with 1,5-dibromopentane (1.14 g,
0.005 mol) under the same conditions as described
previously for 2a
CHCl3 (3:1) to yield a pure compound 2a.
Synthesis of (2E,20E)-3,30-(3,30-(propane-1,3-diylbis(oxy))bis(3,1-
phenylene))bis(1-(thiophen-2-yl)prop-2-en-1-one) (2a).
2a:
2c: Yield (3.8 g, 73%); yellow solid; m.p.: 118–120°C;
IR (KBr): ʋmax (cmꢀ1) 3078 (aromatic C-H), 2922, 2854
(methylene C-H), 1653 (C = O), 1587(C = C), and 1261,
Yield (3.7 g, 73%); yellow solid; m.p.: 155-156°C; IR
(KBr): ʋmax (cmꢀ1) 3077 (aromatic C-H), 2944, 2868,
(methylene C-H), 1649 (C = O), 1595 (C = C), and
1259, 1060 (C-O); UV–vis (MeOH): λmax(nm) 319,
1
1072 (C-O); UV–vis (MeOH): λmax(nm) 319, 253; H-
1
0
0
NMR (400 MHz, CDCl3): δ 7.86 (2H, dd, J3 ,5 = 1.1 Hz,
265; H-NMR (400 MHz, DMSO-d6): δ 8.19 (2H, dd,
J3 ,4 = 3.8 Hz, H-30), 7.80 (2H, d, Jtrans = 15.6 Hz, H-3),
J3 ,5 = 0.8 Hz, J3 ,4 = 3.9 Hz, H-30), 7.88 (2H, dd,
0
0
0
0
0
0
7.68 (2H, dd, J5 ,3 = 1.1 Hz, J5 ,4 = 5.0 Hz, H-50), 7.39
(2H, d, Jtrans = 15.6 Hz, H-2), 7.33 (2H, t, Jo = 7.9 Hz,
H-6″), 7.24 (2H, t, Jo = 6.5 Hz, H-5″), 7.18 (2H, dd,
J5 ,3 = 0.8 Hz, J5 ,4 = 4.8 Hz, H-50), 7.73 (2H, d,
Jtrans = 15.6 Hz, H-3), 7.68 (2H, d, Jtrans = 15.6 Hz,
H-2), 7.40 (2H, d, Jp = 1.2 Hz, H-2″), 7.36 (2H, d,
Jo = 7.6 Hz, H-6″), 7.32 (2H, dd, J = 1.1, 4.7 Hz,
0
0
0
0
0
0
0
0
J4 ,3 = 3.8 Hz, J4 ,5 = 5.0 Hz, H-40), 7.15 (2H, t,
Jm = 2.1 Hz, H-2″), 6.96 (2H, td, Jm,o = 1.8, 7.5 Hz, H-
4″), 4.05 (4H, t, Jvic = 6.3 Hz, OCH2), 1.93 (4H, quintet,
Jvic = 6.7 Hz, OCH2CH2 ), 1.72 (2H, m, OCH2CH2CH2);
0
0
0
0
0
0
0
0
H-5″), 7.24 (2H, dd, J4 ,3 = 3.9 Hz, J4 ,5 = 4.8 Hz,
H-40), 7.02 (2H, td, Jm,o = 2.6, 6.2 Hz, H-4″), 4.27
(4H, t, Jvic = 6.1 Hz, OCH2), 2.30 (2H, quintet,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of New bis(4,5-dihydropyrazole) Derivatives
13C-NMR (100 MHz, CDCl3): δ 181.33 (C = O), 159.01
(C-3″), 145.31 (C-20), 143.01 (C-3), 135.58 (C-50),
134.31 (C-1″), 133.00 (C-30), 129.51 (C-6″), 128.53
(C-5″), 121.60 (C-40), 121.13 (C-2), 116.87 (C-2″),
113.20 (C-4″), 67.39 (OCH2), 28.64 (OCH2CH2), 25.21
(OCH2CH2CH2); ESI-MS: m/z 551 (M + Na, 40%), 529
(M + 1, 70%); Anal. Calcd for C31H28S2O4: Calcd C,
70.45%; H, 5.30%; S, 12.12%; found: C, 70.30%; H,
5.28%; S, 12.13%.
7.17 (2H, t, Jm = 1.6, Hz, H-2″), 6.98 (2H, dd, Jm,o = 2.0,
8.0 Hz, H-4″), 4.03 (4H, t, Jvic = 6.5 Hz, OCH2), 1.86
(4H, quintet, Jvic = 6.5 Hz, OCH2CH2), 1.46 (4H, quintet,
Jvic
=
3.3 Hz, OCH2CH2CH2), 1.35 (4H, m,
OCH2CH2CH2CH2); 13C-NMR (100 MHz, DMSO-d6): δ
180.34 (C = O), 158.00 (C-3″), 145.21 (C-20), 144.09
(C-3), 134.59 (C-50), 135.18 (C-1″), 133.54 (C-30), 128.57
(C-6″), 128.21 (C-5″), 121.58 (C-40), 120.11 (C-2), 115.58
(C-2″), 113.76 (C-4″), 67.03 (OCH2), 27.57 (OCH2CH2),
24.24 (OCH2CH2CH2), 17.10 (OCH2CH2CH2CH2);
ESI-MS: m/z 593 (M + Na, 18%), 571 (M + 1, 21%);
Anal. Calcd for C34H34S2O4: Calcd C, 71.57%; H, 5.96%;
S, 11.22%; found: C, 71.43%; H, 5.97%; S, 11.20%.
Synthesis of (2E,20E)-3,30-(3,30-(hexane-1,6-diylbis(oxy))bis(3,1-
phenylene))bis(1-(thiophen-2-yl)prop-2-en-1-one) (2d).
The
compound 2d was synthesized by reacting chalcone 1a
(2.24 g, 0.01 mol) with 1,6-dibromohexane (1.22 g,
0.005 mol) under the same conditions as given
previously for 2a.
Synthesis of (2E,20E)-3,30-(3,30-(decane-1,10-diylbis(oxy))bis(3,1-
phenylene))bis(1-(thiophen-2-yl)prop-2-en-1-one) (2f).
The
2d: Yield (4.0 g, 70%); yellow solid; m.p.: 116-118°C;
IR (KBr): ʋmax (cmꢀ1) 3078 (aromatic C-H), 2926, 2848
(methylene C-H), 1650 (C = O), 1576 (C = C), and 1261,
1061 (C-O); UV–vis (MeOH): λmax(nm) 318, 255;
1H-NMR (400 MHz, DMSO-d6): δ 8.14 (2H, dd,
compound 2f was prepared from the reaction of
chalcone 1a (2.24 g, 0.01 mol) with 1,10-
dibromodecane (1.5 g, 0.005 mol) under the same
conditions as given earlier for 2a.
2f: Yield (4.1 g, 71%); white solid; m.p.: 122–124°C; IR
(KBr): ʋmax (cmꢀ1) 3078 (aromatic C-H), 2922, 2854
(methylene C-H), 1653 (C = O), 1587(C = C), and 1261,
J3 ,5 = 0.8 Hz, J3 ,4 = 3.8 Hz, H-30), 7.85 (2H, dd,
0
0
0
0
J5 ,3 = 0.8 Hz, J5 ,4 = 4.8 Hz, H-50), 7.67 (2H, d,
Jtrans = 15.8 Hz, H-3), 7.40 (2H, d, Jtrans = 15.8 Hz,
H-2), 7.34 (2H, d, Jo = 7.6 Hz, H-6″), 7.31 (2H, d,
Jm = 2.6 Hz, H-5″), 7.29 (2H, m, H-2″), 7.23 (2H, dd,
0
0
0
0
1
1072 (C-O); UV–vis (MeOH): λmax(nm) 318, 258; H-
0
0
NMR (400 MHz, CDCl3): δ 7.84 (2H, dd, J3 ,5 = 1.1 Hz,
J3 ,4 = 3.8 Hz, H-30), 7.82 (2H, d, Jtrans = 15.6 Hz, H-3),
0
0
J4 ,3 = 3.8 Hz, J4 ,5 = 4.8 Hz, H-40), 6.96 (2H, dd, Jm,
0
0
0
0
7.63 (2H, dd, J5 ,3 = 1.1 Hz, J5 ,4 = 5.0 Hz, H-50), 7.42
(2H, d, Jtrans = 15.6 Hz, H-2), 7.33 (2H, t, J = 7.8 Hz, H-
6″), 7.25 (2H, t, J = 6.5 Hz, H-5″), 7.19 (2H, dd,
0
0
0
0
= 2.0, 7.6 Hz, H-4″), 4.06 (4H, t, Jvic = 6.8 Hz,
o
OCH2), 1.84 (4H, t, Jvic = 6.2 Hz, OCH2CH2), 1.60
(4H, quintet, Jvic = 7.1 H z, OCH2CH2CH2); 13C-NMR
(100 MHz, DMSO-d6): δ 181.34 (C = O), 159.00
(C-3″), 145.26 (C-20), 143.09 (C-3), 135.59 (C-50),
134.38 (C-1″), 132.64 (C-30), 129.57 (C-6″), 128.23
(C-5″), 121.68 (C-40), 121.11 (C-2), 116.60 (C-2″),
113.66 (C-4″), 67.40 (OCH2), 28.67 (OCH2CH2), 25.34
(OCH2CH2CH2); ESI-MS: m/z 565 (M + Na, 100%),
543 (M + 1, 55%); Anal. Calcd For C32H30S2O4: Calcd
C, 70.84%; H, 5.53%; S, 11.80%; found: C, 70.70%;
H, 5.54%; S, 11.79%.
J4 ,3 = 3.8 Hz, J4 ,5 = 5.0 Hz, H-40), 7.17 (2H, t,
Jm, = 2.0, Hz, H-2″), 6.90 (2H, td, J = 1.8, 7.5 Hz, H-4″),
4.1 (4H, t, Jvic = 6.3 Hz, OCH2), 1.86 (4H, quintet,
0
0
0
0
Jvic
Jvic
=
=
6.6 Hz, OCH2CH2 ), 1.46 (4H, quintet,
3.3 Hz, OCH2CH2CH2), 1.28 (4H, m,
OCH2CH2CH2CH2), 1.22 (4H, m, OCH2CH2CH2CH2CH2);
13C-NMR (100 MHz, CDCl3): δ 180.34 (C = O), 158.11
(C-3″), 146.00 (C-20), 141.09 (C-3), 135.59 (C-50), 134.01
(C-1″), 132.64 (C-30), 128.57 (C-6″), 128.21 (C-5″), 120.68
(C-40), 121.11 (C-2), 115.60 (C-2″), 113.60 (C-4″), 67.40
(OCH2), 28.61 (OCH2CH2), 25.31 (OCH2CH2CH2), 22.10
(OCH2CH2CH2CH2), 19.11 (OCH2sCH2CH2CH2CH2);
ESI-MS: m/z 621 (M + Na, 55%), 599 (M + 1, 45%);
Anal. Calcd for C36H38S2O4: Calcd C, 72.24%; H, 6.35%;
S, 10.70%; found: C, 72.11%; H, 6.34%; S, 10.72%.
Synthesis of (2E,20E)-3,30-(3,30-(octane-1,8-diylbis(oxy))bis(3,1-
phenylene))bis(1-(thiophen-2-yl)prop-2-en-1-one (2e).
The
compound 2e was obtained by reacting chalcone 1a
(2.24 g, 0.01 mol) with 1,8-dibromooctane (1.36 g,
0.005 mol) under the similar conditions as described
previously for 2a.
Synthesis
diylbis(oxy))bis(3,1-phenylene))bis(1-(thiophen-2-yl)prop-2-
en-1-one) (2g).
of
(2E,20E)-3,30-(3,30-(dodecane-1,12-
2e: Yield (4.0 g, 70%); yellow solid; m.p.: 132–134°C;
IR (KBr): ʋmax (cmꢀ1) 3077 (aromatic C-H), 2926, 2944,
(methylene C-H), 1650 (C = O), 1596 (C = C), and 1250,
1060 (C-O); UV–vis (MeOH): λmax(nm) 317, 258;
1H-NMR (400 MHz, DMSO-d6): δ 7.89 (2H, dd,
The compound 2g was obtained by
treating chalcone 1a (2.24 g, 0.01 mol) with 1,12-
dibromododecane (1.64 g, 0.005 mol) under the similar
conditions as described previously for 2a.
J3 ,5 = 1.0 Hz, J3 ,4 = 3.8 Hz, H-30), 7.83 (2H, d,
0
0
0
0
2 g: Yield (4.5 g, 72%); brown solid; m.p.: 122–124°C;
IR (KBr): ʋmax (cmꢀ1) 3079 (aromatic C-H), 2927, 2939
(methylene C-H), 1651 (C = O), 1580(C = C), and 1260,
0
0
Jtrans = 15.8 Hz, H-3), 7.71 (2H, dd, J5 ,3 = 1.0 Hz,
J5 ,4 = 5.0 Hz, H-50), 7.41 (2H, d, Jtrans = 15.8 Hz, H-2),
7.34 (2H, t, Jo = 8.0 Hz, H-6″), 7.24 (2H, d, Jo = 7.7 Hz,
0
0
1
1061 (C-O); UV–vis (MeOH): λmax(nm) 317, 218; H-
H-5″), 7.20 (2H, dd, J4 ,3 = 3.8 Hz, J4 ,5 = 5.0 Hz, H-40),
0
0
0
0
0
0
NMR (400 MHz, CDCl3): δ 8.16 (2H, dd, J3 ,5 = 0.8 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Yusuf, A. Kaur, and M. Abid
Vol 000
J3 ,4 = 3.8 Hz, H-30), 7.80 (2H, dd, J5 ,3 = 0.8 Hz,
(C-1‴), 128.74 (C-6‴), 128.52 (C-30,50), 127.25 (C-3″),
126.58 (C-5‴), 126.37 (C-4″), 118.59 (C-2‴), 117.57
(C-40), 112.87 (C-20,60), 111.73 (C-4‴), 66.88 (OCH2),
63.61 (C-5), 44.72 (C-4), 25.36 (OCH2CH2) ESI-MS:
m/z 703 (M + Na, 10%), 682 (M + 2, 5%), (M + 1,
10%); Anal. Calc for C41H36S2N4O2: Calcd C, 72.35%;
H, 5.29%; S, 9.41%; N, 8.23%; found: C, 72.20%; H,
5.28%; S, 9.39%; N, 8.25%.
0
0
0
0
J5 ,4 = 4.8 Hz, H-50), 7.65 (2H, d, Jtrans = 15.8 Hz, H-3),
7.48 (2H, d, Jtrans = 15.8 Hz, H-2), 7.32 (2H, d,
Jo = 7.6 Hz, H-6″), 7.28 (2H, d, Jm = 2.6 Hz, H-5″), 7.25
0
0
0
0
(2H, m, H-2″), 7.18 (2H, dd, J4 ,3
0
= 3.8 Hz,
J4 ,5 = 4.8 Hz, H-40), 6.87 (2H, dd, Jm,o = 2.0, 7.6 Hz, H-
4″), 4.27 (4H, t, Jvic = 6.7 Hz, OCH2), 2.30 (4H, quintet,
Jvic = 6.1 Hz, OCH2CH2), 1.86 (4H, q, Jvic = 3.3 Hz,
OCH2CH2CH2), 1.46 (4H, m, OCH2CH2CH2CH2), 1.35
(4H, m, OCH2CH2CH2CH2CH2), 1.01 (4H, m,
OCH2CH2CH2CH2CH2CH2); 13C-NMR (100 MHz,
CDCl3): δ 181.30 (C = O), 158.94 (C-3″), 145.38 (C-20),
143.03 (C-3), 136.71 (C-50), 134.71 (C-1″), 133.13 (C-
30), 129.60 (C-6″), 127.91 (C-5″), 121.85 (C-40), 120.39
(C-2), 116.70 (C-2″), 113.73 (C-4″), 68.12 (OCH2),
25.45 (OCH2CH2), 25.34 (OCH2CH2CH2), 23.21
(OCH2CH2CH2CH2), 19.11 (OCH2CH2CH2CH2CH2),
15.01 (OCH2CH2CH2CH2CH2CH2); ESI-MS: m/z 649
(M + Na, 40%), 627 (M + 1, 100%); Anal. Calcd for
C38H42S2O4: Calcd C, 72.84%; H, 6.70%; S, 10.22%;
found: C, 72.71%; H, 6.69%; S, 10.24%.
0
Synthesis of 1-(3-((R)-1-phenyl-3-(thiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl)phenoxy)-4-(3-((S)-1-phenyl-3-(thiophen-2-yl)-4,5-
dihydro-1H-pyrazol-5-yl)phenoxy)butane (3b).
3b: Yield
(0.47 g, 70%); yellow solid; m.p.: 84–86°C; IR (KBr):
ʋmax (cmꢀ1
3049 (aromatic C-H), 2922, 2864
(methylene C-H), 1593 (C = N), and 1244, 1053 (C-O);
UV–vis (MeOH):
max(nm) 365, 265; 1H-NMR
)
λ
(400 MHz, DMSO-d6): δ 7.41 (2H, d, J5″,3″ = 0.6 Hz,
J5″,4″ = 4.8 Hz, H-5″), 7.33 (2H, t, Jo = 7.9 Hz, H-6‴),
7.21 (4H, t, Jo = 7.7 Hz, H-50,30), 7.13 (2H, d,
J3″,4″ = 3.8 Hz, H-3″), 7.09 (2H, d, Jo = 8.4 Hz, H-40),
7.02 (2H, dd, J4″,3″ = 3.8 Hz, J4″,5″ = 4.8 Hz, H-4″), 6.96
(2H, d, Jo = 7.9 Hz, H-4‴), 6.83 (2H, t, Jo = 6.7 Hz,
H-5‴), 6.76 (2H, d, Jo = 8.2 Hz, 2‴), 6.70 (4H, t,
Jo = 7.2 Hz, H-20,60), 5.28 (2H, dd, JXA = 6.9 Hz,
JXM = 12.1 Hz, H-X), 3.95 (4H, t, Jvic = 6.8 Hz, OCH2),
3.87 (2H, dd, JMX = 12.1 Hz, JMA = 17.1 Hz, H-M), 3.09
(2H, dd, JAX = 6.9 Hz, JAM = 17.1 Hz, H-A), 1.87 (4H, m,
OCH2CH2); 13C-NMR (100 MHz, DMSO-d6): δ 159.57
(C-3‴), 144.83 (C-3), 144.11 (C-2″), 142.98 (C-10), 136.61
(C-5″), 130.29 (C-1‴), 128.89 (C-30,50), 127.33 (C-6‴),
126.54 (C-3″), 125.92 (C-5‴), 119.27 (C-4″), 118.19
(C-2‴), 113.54 (C-20, 60), 113.50 (C-40), 111.99 (C-4‴),
64.76 (OCH2), 64.38 (C-5), 44.35 (C-4), 29.24
(OCH2CH2); ESI-MS: m/z 717 (M + Na, 15%), 696
(M + 2, 15%), 695 (M + 1, 20%); Anal. Calcd for
C42H38S2N4O2: Calcd C, 72.62%; H, 5.47%; S, 9.22%; N,
8.06%; found: C, 72.50%; H, 5.46%; S, 9.23%; N, 8.05%.
Synthesis of 1-(3-((R)-1-phenyl-3-(thiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl)phenoxy)-n-(3-((S)-1-phenyl-3-(thiophxen-2-yl)-
4,5-dihydro-1H-pyrazol-5-yl)phenoxy)alkane
3(a–g).
A
mixture of compound 2(a–g) (0.001 mol), phenyl
hydrazine (0.002 mol), and NaOH (0.5 g, 0.013 mol) in
dry EtOH (25 ml) was refluxed for 4 h. The progress of
reaction was monitored by TLC. After the completion of
reaction, the reaction mixture was concentrated under
vacuum, and resulting mass was poured into iced-HCl to
yield a solid substance. The crude product thus obtained
was crystallized from MeOH to yield a pure compound
3(a–g).
Synthesis of 1-(3-((R)-1-phenyl-3-(thiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl)phenoxy)-3-(3-((S)-1-phenyl-3-(thiophen-2-yl)-4,5-
dihydro-1H-pyrazol-5-yl)phenoxy)propane (3a).
3a: Yield
(0.6 g, 88%); orange solid; m.p.: 78–80°C; IR (KBr):
ʋmax (cmꢀ1
3067 (aromatic C-H), 2924, 2858
Synthesis of 1-(3-((R)-1-phenyl-3-(thiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5- yl)phenoxy)-5-(3-((S)-1-phenyl-3-(thiophen-2-yl)-4,5-
)
(methylene C-H), 1593 (C = N), and 1261, 1067
(C-O); UV–vis (MeOH): λmax(nm) 361, 260; 1H-NMR
(400 MHz, CDCl3): δ 7.30 (2H, d, J5″,4″ = 4.7 Hz,
H-5″), 7.25 (2H, t, Jo = 6.3 Hz, H-6‴), 7.15 (4H, t,
Jo = 8.3, H-30,50), 7.14 (2H, d, J3″,4″ = 3.6 Hz, H-3″),
7.02 (2H, d, Jo = 5.4 Hz, H-40), 7.00 (2H, d,
Jo = 2.3 Hz, H-4‴), 6.97 (2H, d, J4″,5″ = 4.7 Hz,
H-4″), 6.89 (2H, d, Jo = 7.8 Hz, H-5‴), 6.84 (2H, d,
Jm = 2.1 Hz, H-2‴), 6.77 (4H, td, Jm,o = 2.7, 8.1 Hz,
H-20,60), 5.17 (2H, dd, JXA = 7.5 Hz, JXM = 12.3 Hz,
H-X), 4.07 (4H, t, Jvic = 5.6 Hz, OCH2), 3.79 (2H, dd,
JMX = 12.3 Hz, JMA = 16.9 Hz, H-M), 3.11 (2H, dd,
JAX = 7.5 Hz, JAM = 16.9 Hz, H-A), 2.16 (2H,
dihydro-1H-pyrazol-5-yl)phenoxy)pentane (3c).
3c: Yield
(0.55 g, 82%); mustard solid; m.p.: 90–92°C; IR
(KBr): ʋmax (cmꢀ1) 3049 (aromatic C-H), 2933, 2885
(methylene C-H), 1593 (C = N), and 1257, 1049
(C-O); UV–vis (MeOH): λmax(nm) 380, 258; 1H-NMR
(400 MHz, CDCl3): δ 7.23 (2H, dd, J5″,3″ = 1.1 Hz,
J5″,4″ = 4.8 Hz, H-5″), 7.21 (2H, t, Jo = 8.0 Hz, H-
6‴), 7.18 (2H, d, J3″,4″ = 3.6 Hz, H-3″), 7.14 (4H, dd,
Jo = 7.7, 8.9 Hz, H-30,50), 7.02 (2H, d, Jo = 7.8 Hz,
H-40), 6.99 (2H, dd, J = 2.3, 3.4 Hz, H-4‴), 6.97 (2H,
dd, J4″,3″ = 3.6 Hz, J4″,5″ = 4.8 Hz, H-4″), 6.87 (2H,
d, Jo = 7.7 Hz, H-5‴), 6.83 (2H, d, Jm = 2.1 Hz,
H-2‴), 6.75 (4H, td, Jm,o = 2.7, 5.6 Hz, H-20,60), 5.13
(2H, dd, JXA = 7.5 Hz, JXM = 12.4 Hz, H-X), 3.86
quintet, Jvic
=
5.9 Hz, OCH2CH2); 13C-NMR
(100 MHz, CDCl3): δ 159.03 (C-3‴), 144.11 (C-3),
(4H, t, Jvic
= 6.6 Hz, OCH2), 3.75 (2H, dd,
143.59 (C-2″), 143.01 (C-10), 135.74 (C-5″), 129.90
JMX = 12.4 Hz, JMA = 16.9 Hz, H-M), 3.09 (2H, dd,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of New bis(4,5-dihydropyrazole) Derivatives
JAX = 7.5 Hz, JAM = 16.9 Hz, H-A), 1.77 (4H, quintet,
Jvic 7.1 Hz, OCH2CH2), 1.56 (2H, quintet,
8.2 Hz, H-4‴), 6.70 (2H, t, Jo = 7.2 Hz, H-40), 5.38 (2H,
dd, JXA = 6.8 Hz, JXM = 12.4 Hz, H-X), 3.89 (6H, m,
=
Jvic = 5.2 Hz, OCH2CH2CH2); 13C-NMR (100 MHz,
CDCl3): δ 159.79 (C-3‴), 144.85 (C-3), 144.10 (C-2″),
143.05 (C-10), 136.62 (C-5″), 130.29 (C-1‴), 129.32
(C-30,50), 127.39 (C-6‴), 126.58 (C-3″), 126.00 (C-5‴),
119.28 (C-4″), 118.05 (C-2‴), 113.51 (C-20,60), 112.80
(C-40), 111.96 (C-4‴), 67.72 (OCH2), 64.77 (C-5),
44.36 (C-4), 29.01 (OCH2CH2), 22.72 (OCH2CH2CH2);
ESI-MS: m/z 731 (M + Na, 20%), 709 (M + 1, 70%);
Anal. Calcd for C43H40S2N4O2: Calcd C, 72.88%; H,
5.64%; S, 9.03%; N, 7.90%; found: C, 72.70%; H,
5.66%; S, 9.02%; N, 7.91%.
H-M, OCH2), 3.09 (2H, dd, JAX
=
6.8 Hz,
JAM = 17.3 Hz, H-A), 1.66 (4H, quintet, Jvic = 6.7 Hz,
OCH2CH2), 1.40 (4H, m, OCH2CH2CH2), 1.30 (4H, m,
OCH2CH2CH2CH2), 13C-NMR(100 MHz, DMSO-d6): δ
159.08 (C-3‴), 144.08 (C-3), 143.76 (C-2″), 143.43
(C-10), 135.66 (C-5″), 130.05 (C-1‴), 128.70 (C-30,50),
128.55 (C-6‴), 127.11 (C-3″), 127.03 (C-5‴), 128.58
(C-4″), 117.57 (C-2‴), 112.97 (C-40), 112.87 (C-20,60),
111.90 (C-4‴), 67.26 (OCH2), 63.31 (C-5), 43.69 (C-4),
28.69 (OCH2CH2), 28.58 (OCH2CH2CH2), 25.42
(OCH2CH2CH2CH2); ESI-MS: m/z 773 (M + Na, 15%),
751 (M + 1, 20%); Anal. Calcd for C46H46S2N4O2: Calcd
C, 73.60%; H, 5.60%; S, 8.53%; N, 7.46%; found: C,
Synthesis of 1-(3-((R)-1-phenyl-3-(thiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl)phenoxy)-6-(3-((S)-1-phenyl-3-(thiophen-2-yl)-4,5-
73.45%; H, 5.58%; S, 8.54%; N, 7.48%.
Synthesis of 1-(3-((R)-1-phenyl-3-(thiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl)phenoxy)-10-(3-((S)-1-phenyl-3-(thiophen-2-yl)-4,
dihydro-1H-pyrazol-5-yl)phenoxy)hexane (3d).
3d: Yield
(0.6 g, 88%); mustard solid; m.p.: 70–72°C; IR (KBr):
max (cmꢀ1) 3049 (aromatic C-H), 2941, 2894 (methylene
ʋ
5-dihydro-1H-pyrazol-5-yl)phenoxy)decane (3f).
3f: Yield
(0.49 g, 75%); brown solid; m.p.: 72–74°C; IR (KBr):
ʋmax (cmꢀ1
3049 (aromatic C-H), 2927, 2862
C-H), 1590 (C = N), and 1258, 1053 (C-O); UV–vis
(MeOH): λmax(nm) 371, 253; 1H-NMR (400 MHz,
CDCl3): δ 7.28 (2H, dd, J5″,3″ = 1.1 Hz, J5″,4″ = 4.8 Hz,
H-5″), 7.23 (2H, t, Jo = 8.0 Hz, H-6‴), 7.19 (2H, d,
J3″,4″ = 3.6 Hz, H-3″), 7.11 (4H, dd, Jo = 7.7, 8.9 Hz,
H-50,30), 7.02 (2H, d, Jo = 7.8 Hz, H-40), 6.89 (2H, dd,
J = 2.3, 3.4 Hz, H-4‴), 6.81 (2H, dd, J4″,3″ = 3.6 Hz,
J4″,5″ = 4.8 Hz, H-4″), 6.77 (2H, d, Jo = 7.7 Hz, H-5‴),
6.66 (2H, d, Jm = 2.1 Hz, H-2‴), 6.61 (4H, td, Jm,o = 2.7,
)
(methylene C-H), 1591 (C = N), and 1255, 1049
(C-O); UV–vis (MeOH): λmax(nm) 380, 255; 1H-NMR
(400 MHz, CDCl3): δ 7.58 (2H, d, J5″,4″ = 4.7 Hz,
H-5″), 7.28 (2H, d, J3″,4″ = 3.7 Hz, H-3″), 7.23 (2H, t,
Jo = 7.7 Hz, H-6‴), 7.15 (4H, t, Jo = 7.6 Hz, H-30,50),
7.04 (2H, d, Jo = 8.0 Hz, H-5‴), 7.01 (2H, d,
Jo = 8.5 Hz, H-40), 6.97 (2H, dd, J4″,3″ = 3.7 Hz,
J4″,5″ = 4.7 Hz, H-4″), 6.87 (2H, d, Jo = 7.6 Hz,
H-4‴), 6.84 (2H, s, H-2‴), 6.76 (4H, t, Jo = 7.5 Hz,
H-20,60), 5.15 (2H, dd, JXA = 7.6 Hz, JXM = 12.4 Hz,
H-X), 3.87 (4H, t, J = 6.4 Hz, OCH2), 3.78 (2H, dd,
JMX = 12.4 Hz, JMA = 16.9 Hz, H-M), 3.10 (2H, dd,
JAX = 7.6 Hz, JAM = 16.9 Hz, H-A), 1.70 (4H,
quintet, Jvic = 6.4 Hz, OCH2CH2), 1.4 (4H, m,
OCH2CH2CH2), 1.28 (4H, m, OCH2CH2CH2CH2), 1.22
(4H, brs, OCH2CH2CH2CH2CH2); 13C-NMR (100 MHz,
CDCl3): δ 159.88 (C-3‴), 144.87 (C-3), 144.08 (C-2″),
143.00 (C-10), 136.64 (C-5″), 130.25 (C-1‴), 128.91
(C-30,50), 127.36 (C-6‴), 126.55 (C-3″), 125.95 (C-5‴),
119.27 (C-4″), 117.95 (C-2‴), 113.51 (C-20,60), 111.95
(C-40), 111.73 (C-4‴), 67.99 (OCH2), 64.82 (C-5), 44.37
(C-4), 29.49 (OCH2CH2), 29.41 (OCH2CH2CH2), 29.28
(OCH2CH2CH2CH2), 26.06 (OCH2CH2CH2CH2CH2);
ESI-MS: m/z 801 (M + Na, 10%), 779 (M + 1, 100%);
Anal. Calcd for C48H50S2N4O2: Calcd C, 74.03%; H,
6.42%; S, 8.22%; N, 7.19%; found: C, 73.95%; H,
6.43%; S, 8.24%; N, 7.17%.
5.6 Hz, H-20,60), 5.38 (2H, dd, JXA
= 6.5 Hz,
JXM = 12.4 Hz, H-X), 3.89 (6H, m, H-M, OCH2), 3.09
(2H, dd, JAX = 6.5 Hz, JAM = 17.3 Hz, H-A), 1.66 (4H,
quintet, Jvic = 6.7 Hz, OCH2CH2), 1.40 (4H, m,
OCH2CH2CH2), 13C-NMR (100 MHz, CDCl3): δ 159.57
(C-3‴), 144.82 (C-3), 144.12 (C-2″), 143.02 (C-10),
136.59 (C-5″), 130.32 (C-1‴), 129.32 (C-30,50), 127.36
(C-6‴), 126.57 (C-3″), 125.98 (C-5‴), 119.28 (C-4″),
118.19 (C-2‴), 113.49 (C-20,60), 112.80 (C-40), 111.98
(C-4‴), 64.72 (OCH2), 64.37 (C-5), 44.35 (C-4), 29.24
(OCH2CH2), 23.01 (OCH2CH2CH2); ESI-MS: m/z 745
(M + Na, 15%), 723 (M + 1, 20%); Anal. Calcd for
C44H42S2N4O2: Calcd C, 73.13%; H, 5.81%; S, 8.86%; N,
7.75%; found: C, 72.95%; H, 5.80%; S, 8.87%; N, 7.73%.
Synthesis of 1-(3-((R)-1-phenyl-3-(thiophen-2-yl)-4,5-dihydro-
1H-pyrazol-5-yl)phenoxy)-8-(3-((S)-1-phenyl-3-(thiophen-2-yl)-4,5-
dihydro-1H-pyrazol-5-yl)phenoxy)octane (3e).
3e: Yield
(0.5 g, 77%); yellow solid; m.p.: 95–97°C; IR (KBr):
ʋmax (cmꢀ1
3049 (aromatic C-H), 2941, 2893
(methylene C-H), 1591 (C = N), and 1255, 1055 (C-O);
UV–vis (MeOH):
max(nm) 375, 255; 1H-NMR
)
λ
Synthesis
dihydro-1H-pyrazol-5-
of
1-(3-((R)-1-phenyl-3-(thiophen-2-yl)-4,5-
yl)phenoxy)-12-(3-((S)-1-phenyl-3-
(400 MHz, DMSO-d6): δ 7.52 (2H, d, J5″,4″ = 5.0 Hz,
H-5″), 7.22 (2H, t, Jo = 7.8 Hz, H-6‴), 7.18 (2H, d,
J3″,4″ = 3.5 Hz, H-3″), 7.12 (4H, t, Jo = 7.4 Hz, H-30,50),
7.06 (2H, dd, J4″,3″ = 3.7 Hz, J4″,5″ = 5.0 Hz, H-4″),
6.94 (4H, d, Jo = 7.8 Hz, H-20,60), 6.84 (2H, brs, H-2‴),
6.81 (2H, d, Jm = 2.5 Hz, H-5‴), 6.78 (2H, dd, Jm,o = 1.9,
(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl)phenoxy)dodecane
(3g). 3 g: Yield (0.58 g, 90%); brown solid; m.p.: 60–62°C;
IR (KBr): ʋmax (cmꢀ1): 3048 (aromatic C-H), 2943, 2891
(methylene C-H), 1598 (C = N), and 1256, 1049 (C-O);
1
UV–vis (MeOH): λmax(nm) 376, 254; H-NMR (400 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Yusuf, A. Kaur, and M. Abid
Vol 000
[3] MacManus, M. C. Am J Health Syst Pharm 1997, 54, 1420.
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CDCl3): δ 7.59 (2H, d, J5″,4″ = 4.9 Hz, H-5″), 7.28 (2H, d,
J3″,4″ = 3.7 Hz, H-3″), 7.23 (2H, t, Jo = 7.7 Hz, H-6‴), 7.14
(4H, t, Jo = 8.2 Hz, H-30,50), 7.08 (2H, dd, J4″,3″ = 3.7 Hz,
J4″,5″ = 4.9 Hz, H-4″), 6.93 (4H, d, Jo = 8.4, H-20,60), 6.81
(6H, m, H-2‴, 4‴, 5‴), 6.71 (2H, t, Jo = 7.3 Hz ,H-40), 5.42
(2H, dd, JXA = 6.3 Hz, JXM = 12.4 Hz, H-X), 3.89 (6H, m,
H-M, OCH2), 3.10 (2H, dd, JAX = 6.3 Hz, JAM = 17.3 Hz,
H-A), 1.63 (4H, quintet, Jvic = 6.8 Hz, OCH2CH2), 1.28
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J Med Chem 2010, 45, 114.
(16H,
m,
OCH2CH2CH2,
OCH2CH2CH2CH2,
OCH2CH2CH2CH2CH2,
OCH2CH2CH2CH2CH2CH2);
13C-NMR (100 MHz, CDCl3): δ 159.08 (C-3‴), 144.80
(C-3), 144.01 (C-2″), 143.12 (C-10), 137.64 (C-5″), 131.25
(C-1‴), 128.90 (C-30,50), 127.30 (C-6‴), 126.50 (C-3″),
125.91 (C-5‴), 118.09 (C-4″), 117.90 (C-2‴), 113.50
(C-20,60), 112.01 (C-40), 111.70 (C-4‴), 67.89 (OCH2),
64.70 (C-5), 44.35 (C-4), 29.12 (OCH2CH2), 28.38
(OCH2CH2CH2), 28.30 (OCH2CH2CH2CH2), 26.05
(OCH2CH2CH2CH2CH2), 24.01 (OCH2CH2CH2CH2CH2CH2);
ESI-MS: m/z 829 (M + Na, 50%), 807 (M + 1, 45%);
Anal. Calcd for C50H54S2N4O2: Calcd C, 74.44%; H,
6.69%; S, 7.94%; N, 6.94%; found: C, 74.30%; H, 6.67%;
S, 7.92%; N, 6.96%.
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Acknowledgment. We are very thankful to the Head, Department
of Chemistry, Punjabi University Patiala for providing the
required facilities for this research work.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet