Synthesis, characterization, and antimicrobial studies of new rigid linker-based bispyrazolines

Article abstract of DOI:10.1002/jhet.2021

The bispyrazolines 4a-4e were synthesized from the cyclization reaction of bischalcones 3a-3e with phenyl hydrazine by refluxing under alcoholic medium in the presence of glacial acetic acid. The bischalcones were obtained from the Claisen-Schmidt reactio

Full text of DOI:10.1002/jhet.2021

260
Synthesis, Characterization, and Antimicrobial Studies of New Rigid
Linker-Based Bispyrazolines
Vol 52
*
Mohamad Yusuf, Varsha Samdhian, and Payal Jain
Department of Chemistry, Punjabi University, Patiala-147002, Punjab, India
*
E-mail: yusuf_sah04@yahoo.co.in
Received January 4, 2013
DOI 10.1002/jhet.2021
Published online 25 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
The bispyrazolines 4a–4e were synthesized from the cyclization reaction of bischalcones 3a–3e with
phenyl hydrazine by refluxing under alcoholic medium in the presence of glacial acetic acid. The bischalcones
were obtained from the Claisen–Schmidt reaction of acetophenone with dibenzaldehydes 1a–1e and later were
obtained in good yield from the O-alkylation of 4-hydroxybenzaldehyde with suitable alkylating agents.
The structures of the prepared compounds were determined from the rigorous analysis of their spectral data
1
(UV–vis, IR, H-NMR, 13C-NMR, and ESI-MS). The elemental analysis also confirmed the purity of these
compounds. All the bischalcones 3a–3e and bispyrazolines 4a–4e were screened for their antimicrobial activity
using the serial dilution method. Seven bacterial and five fungal species were used as the antimicrobial test
strains, namely Klebsiella pneumoniae (MTCC 3384), Pseudomonas aeruginosa (MTCC 424), Escherichia
coli (MTCC 443), Staphylococcus aureus (MTCC 443), Bacillus subtilis (MTCC 441), Pseudomonas
fluorescens (MTCC 103), and Staphylococcus pyrogens (MTCC 442), and Aspergillus janus (MTCC 2751),
Penicillium glabrum (MTCC 4951), Fusarium oxysporum (MTCC 2480), Aspergillus sclerotiorum
(MTCC 1008), and Aspergillus niger (MTCC 281), respectively. The minimum inhibitory concentrations
(MIC in mg/mL) were determined by using different dilutions.
J. Heterocyclic Chem., 52, 260 (2015).
INTRODUCTION
celecobix [16], sildenefil [17], and rimonabant [18].
Bispyrazolines are the molecules that are formed by joining
two pyrazoline moieties through the carbon chains of vary-
ing lengths and structures. By keeping this aspect in view
and in continuation to our study on the bishetrocyclics [19],
present researches have been focused on the synthesis of
bispyrazolines built around five rigid linkers (trans-2-butene,
2-butyne, o-xylene, p-xylene, and 4,40-bis-methyl-diphenyl).
The chalcones are the significant class of the flavanoid
derivatives that are associated with wide spectrum of bio-
logical applications. The availability of prop-2-ene-1-one
moiety in the chalcones is responsible for their biological
activities [1–3]. The chalcones are the very important
synthones in the organic synthesis, and with proper plan-
ning and designing, these molecules can be used for the
preparation of various heterocyclic compounds [4–7]. The
cyclocondesation reaction of chalcones with hydrazine and
their derivatives lead to the formation of pyrazolines.
Pyrazolines are the important nitrogen-containing five-
membered heterocyclic compounds, and their derivatives
have been found to possess a broad spectrum of biological
activities such as tranquilizing, muscle relaxant,
psychoanaleptic, anticonvulsant and antihypertensive, and
antidepressant activities [8–13]. Antibacterial, antifungal,
and anti-inflammatory activities [14,15] of pyrazolines and
their derivatives have given much needed impetus to their
synthesis. Pyrazole moiety is also found in drugs such as
RESULTS AND DISCUSSION
The bispyrazolines 4a–4e in the present study were
synthesized from the cyclization reaction of bischalcones
3a–3e with phenyl hydrazine by refluxing under alcoholic
medium in the presence of glacial acetic acid (Scheme 1).
The bischalcones were obtained from the Claisen–Schmidt
reaction of acetophenone with dibenzaldehydes 1a–1e
and later were obtained in good yield from the O-alkylation
of 4-hydroxybenzaldehyde with suitable alkylating
agents (trans-1,4-dibromo-2-butene, 1,4-dichloro-2-butyne,
© 2014 HeteroCorporation

January 2015
Synthesis, Characterization, and Antimicrobial Studies of New Rigid Linker-Based
Bispyrazolines
261
Scheme 1
a,a0-dibromo-o-xylene, a,a0-dibromo-p-xylene and 4,
40-bis-chloromethyldiphenyl). The structures of the
prepared compounds were determined from the rigorous
analysis of their spectral data (UV–vis, IR, 1H-NMR,
13C-NMR, and ESI-MS). The elemental analysis also
confirmed the purity of these compounds.
The compounds 1a–1e were reacted with acetophenone
in the presence of NaOH/EtOH at room temperature, and
the reaction mixture was acidified using HCl furnishing
the respective solid product. Individual crude product was
subjected to crystallization in a mixture of CHCl3/MeOH
(1:1) to produce the corresponding products 3a–3e.
The structures of 3a–3e were based on their various spec-
tral analyses. Its IR spectrum exhibited major absorptions at
3057–3054 (aromatic C–H), 2926–2916, 2870–2828
(methylene C–H), 1662–1657 (CO), 1601–1597 (CC), and
1251–1215, 1035–1016 cmꢀ1 (C–O). The UV–vis spectrum
of 3a–3e exhibited two maxima at 343–328 and 292–247 nm,
which may be assigned to n! p* and p ! p* transitions,
respectively.
protons describes the trans geometry around C-2 and C-3
double bond. Regarding the remaining signals in the
aromatic region, two doublets integrating for four protons
each at d 7.78–7.60 (Jo = 8.8 Hz) and 7.06–6.96 (Jo = 8.8 Hz)
can be easily ascribed to H-200, 600, and H-300, 500, respectively.
A triplet at d 5.19–4.65 (4H, Jvic = 2.5 Hz) may be given to
OCH2 protons.
13C-NMR (100 MHz, CDCl3) spectra of 3a–3e were
very instrumental to corroborate its proposed structure.
Here, the presence of carbonyl group was confirmed by
the appearance of a downfield signal at d 190.61–189.31
(C-1). The carbon atoms belonging to the double bond
appeared at d 144.65–143.89 (C-3) and 120.09–119.30
(C-2), the downfield occurrence of the former can be as-
cribed to its b-position in the enone moiety. Other down-
field resonance present at d 160.85–160.07 could be
generated by C-400 due to its direct linkage to the electro-
negative oxygen atom. The remaining signals in the aromatic
region were found at d 138.51–137.81 (C-10), 132.30–130.62
(C-20, 60), 136.46–131.16 (C-100’), 130.28–129.21 (C-200, 600),
128.80–127.89 (C-40), 128.12–127.43 (C-30, 50), and
115.34–114.75 (C-300, 500). Toward the right-hand side of
the spectra, a signal was also placed at d 69.92–55.92, which
could be attributed to OCH2 group.
1H-NMR spectra (400 MHz, CDCl3) of 3a–3e were
quite informative, and the aromatic protons (H-20, 60, and
30, 50) produced well-defined signals at d 8.00–7.99 (4H,
dd, Jp,o = 1.2, 7.5 Hz) and 7.54–7.52 (4H, d, Jo = 7.6 Hz).
The downfield resonance of former as compared with latter
protons could be ascribed to its proximity to the CO group.
The proton H-40 resonates at d 7.60–7.52 (2H, d, Jo = 7.3
Hz), which is ortho to the H-30 and 50. In this region,
two broad doublets centered at d 7.82–7.78 (2H) and
7.51–7.42 (2H) were denoted by H-3 and H-2, respectively.
The coupling constant of 15.8–15.5 Hz between these
Alternatively, bischalcones 3a–3e were also prepared
from the O-alkylation of chalcone 2 with suitable alkylating
agents (trans-1,4-dibromo-2-butene, 1,4-dichloro-2-butyne,
a,a0-dibromo-o-xylene, a,a0-dibromo-p-xylene, and 4,
40-bis-chloromethyldiphenyl) under KOH/dry EtOH/DMF
medium. The resulting reaction mixture was decomposed
into iced HCl to give a solid compound that was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

262
M. Yusuf, V. Samdhian and P. Jain
Vol 52
recrystallized from CHCl3/MeOH (1:1) to yield pure com-
pounds 3a–3e. The chalcone 2 (68%, mp 168–170ꢁC) in turn
was obtained from the Claisen–Schmidt reaction of
acetophenone with 4-hydroxybenzaldehyde under the alka-
line medium.
The IR spectrum of 4a–4e was very helpful to interpret
its structure, which did not exhibit a strong absorption at
1662–1657 cmꢀ1 indicating the involvement of carbonyl
group during cyclization reaction of 3a–3e. Here, a signif-
icant band was observed at 1600–1596 cmꢀ1 may be due to
the CN moiety of the pyrazoline ring.
A comparison of the 1H-NMR spectra (400 MHz,
DMSO-d6) of 3a–3e and 4a–4e shows that resonances
present at d 7.82–7.78 (H-3) and 7.51–7.42 (H-2) in former
were found to be missing together in the latter thereby
pronouncing the involvement of these protons in the chemical
transformation. Here, aromatic protons H-200, 600, H-300, 500,
and H-400 were also found resonating at d 7.80–7.66
(4H, dd, Jp,o = 1.2, 8.5 Hz), 7.43–7.10 (4H, m) and 7.51–7.29
(2H, m), respectively. The phenyl ring (C-5) protons furnished
doublet of doublet at d 7.63–7.28 (4H, Jp,o = 1.3, 8.1 Hz,
H-2000, 6000) and a doublet at d 7.01–6.86 (4H, Jo = 7.7 Hz,
H-3000, 5000). The protons belonging to the N-phenyl ring
were also resonating in the aromatic region at d 7.30–
6.97 (4H, td, Jp,o = 1.0, 7.4 Hz, H-30, 50), 7.11–6.87 (4H,
m, H-20, 60), and 6.71-6.66 (2H, t, J = 7.3 Hz, H-40). The
major feature of these spectra was the signals of the
pyrazoline ring protons (H-X, M, and A), which were
centered at d 5.33–5.26 (dd, JXA = 7.1–6.6 Hz, JXM
=
12.3–12.1 Hz), 3.87–3.82 (2H, dd, JMX = 12.3–12.1 Hz,
JMA =17.5–17.3 Hz) and 3.09–3.04 (2H, dd, JXA =7.1–6.6 Hz,
JAM = 17.5–17.3 Hz), respectively. A broad singlet was also
present at d 5.08–4.53 (4H), which may be assigned to
OCH2 group protons. Its UV–vis spectrum showed two
maxima at 357–355 and 229–228 nm, which could be
ascribed to n ! p* and p ! p* transitions, respectively.
13C-NMR (100 MHz, DMSO-d6) data of 4a–4e
provided enough evidence in favor of the proposed expres-
sion. C-4000 was resonating at d 158.17–157.21 due to its
direct bonding to the oxygen atom and carbon atoms C-3
and C-10 directly connected to nitrogen atom that produced
suitable resonances at d 146.68–146.43 and 144.28–144.19,
respectively. The remaining aromatic carbon atoms were
found to be placed at the appropriate position in the
aromatic region (see Experimental section). The upfield
placement of C-3000, 5000 at d 112.90–112.81 could be
ascribed to the electron-donating effect of alkoxy (OCH2)
group at C-4000. The signals present at d 62.98–62.91 and
43.02–42.98 could be easily generated by pyrazoline rings
carbons C-5 and C-4, respectively, and downfield
resonance of former may be attributed to its benzylic nature
and its placement adjacent to nitrogen. A signal in the
upfield region was also found at d 69.00–55.30, which
could be generated by OCH2 group.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2015
Synthesis, Characterization, and Antimicrobial Studies of New Rigid Linker-Based
Bispyrazolines
263
ANTIBACTERIAL AND ANTIFUNGAL
ACTIVITIES
All the prepared bischalcones 3a–3e and bispyrazolines
4a–4e were screened for their antibacterial and antifungal
activities using the serial dilution method [20]. Seven bac-
terial and five fungal species were used as the antimicrobial
test strains, namely, Klebsiella pneumoniae (MTCC 3384),
Pseudomonas aeruginosa (MTCC 424), Escherichia coli
(MTCC 443), Staphylococcus aureus (MTCC 443), Bacillus
subtilis (MTCC 441), Pseudomonas fluorescens (MTCC
103), and Staphylococcus pyrogens (MTCC 442), and
Aspergillus janus (MTCC 2751), Penicillium glabrum
(MTCC 4951), Fusarium oxysporum (MTCC 2480),
Aspergillus sclerotiorum (MTCC 1008), and A. niger
(MTCC 281), respectively. Amoxicillin and fluconazole
were used as standard drugs against bacteria and fungi,
respectively. The minimum inhibitory concentration (MIC in
mg/mL) was determined by using different dilutions of the
concerned compound. The results were compared with posi-
tive controls, the standard drugs amoxicillin and fluconazole.
Serial dilution of the test compounds previously dissolved in
DMSO were prepared to final concentrations of 128, 64, 32,
16, 8, 4, 2 and 1 mg/mL. All the bacterial strains were grown
at 37ꢁC for 24 h in nutrient broth, and fungi were grown in malt
extract at 28ꢁC for 72 h. Each test compound was dissolved in
DMSO, and MIC thus obtained were compared with control.
The observed MIC of the aforementioned prepared compound
has been given in Tables 1 and 2, respectively.
It is evident from Table 1 that compound 3a showed
very significant activity (MIC 4 mg/mL) against bacterial
strain S. aureus, whereas compounds 3a–3e also showed
noticeable activity (MIC 8 mg/mL) against bacterial and
fungal strains, namely, K. pneumoniae, P. fluorescens, P.
aeruginosa, S. aureus, B. subtilis, A. janus, P. glabrum,
and A. sclerotiorum respectively.
Similarly, Table 2 describes that compounds 4a and 4c
displayed significant activity (MIC 4 mg/mL) against A.
sclerotiorum and A. janus, respectively, whereas compounds
4a, 4c, 4d, and 4e showed better activity against fungal
strains A. janus, F. oxysporum, A. sclerotiorum, and P.
glabrum, and bacterial strain S. pyrogens (MIC 8 mg/mL).
CONCLUSION
The present study represents a general and efficient
method for the synthesis of bispyrazolines linked through
the rigid chains. The bispyrazolines are found to be better
antimicrobial agents than the bischalcones.
EXPERIMENTAL
Melting points reported are uncorrected. IR spectra were scanned
in KBr pellets on a Perkin Elmer RXIFT (Buckinghamshire,
England) Infrared spectrophotometer. 1H-NMR spectra (Fallanden,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

264
M. Yusuf, V. Samdhian and P. Jain
Vol 52
3b. Yield (0.6 g, 65%); brown solid; mp 98–100ꢁC; IR (KBr):
max (cmꢀ1) 3057 (aromatic C–H), 2919 (methylene C–H), 1660
Switzerland) were recorded on a 400 MHz Bruker spectrometer
using TMS as the internal standard. The mass spectra have
been scanned on the Waters Micromass Q-T of Micro (ESI)
spectrometer (Vernon Hills, IL). TLC plates were coated with
silica gel suspended in MeOH–CHCl3, and iodine vapors were
used as visualizing agent. Dibenzaldehydes 1a–1e were syn-
υ
(CO), 1597 (CC), 1217, 1017 (C–O); UV-vis (MeOH): lmax (nm)
328, 247; 1H-NMR (400 MHz, DMSO-d6): d 8.02 (4H, dd, Jp,
o = 1.3, 7.6 Hz, H-20, 60), 7.80 (2H, d, Jtrans = 15.5Hz, H-3), 7.78
(4H, dt, J = 2.6, 4.7 Hz, H-200, 600), 7.60 (2H, d, Jo = 7.3 Hz, H-40),
7.51 (2H, d, Jtrans = 15.5 Hz, H-2), 7.49 (4H, d, Jo = 7.6 Hz, H-30,
50), 7.1 (4H, dt, J = 2.6, 4.5 Hz, H-300, 500), 4.89 (4H, s, OCH2);
13C-NMR (100MHz, DMSO-d6): d 190.56 (C-1), 160.55 (C-400),
143.99 (C-3), 137.96 (C-10), 132.46 (C-20, 60), 131.25 (C-100),
130.14 (C-200, 600), 128.01 (C-30, 50), 127.89 (C-40), 120.0
(C-2), 114.83 (C-300, 500), 82.00 (C-2000), 55.92 (OCH2); ESI-MS:
m/z 521 (M+ Na, 100%), 500 (M+ 2, 35%), 499 (M + 1, 57%),
473 (39%), 421 (47%), 394 (18%), 368 (22%), 355 (27%), 198
(16%), 122 (28%); Anal. Calcd for C34H26O4: Calcd C, 81.90%;
H, 5.20%; Found: C, 81.97%; H, 5.25%.
thesized according to the reported methods [21–23].
Synthesis of 3-(4-hydroxyphenyl)-1-phenylprop-2-en-1-one
2.
A solution of 4-hydroxybenzaldehyde (5 g, 0.04 mol),
acetophenone (4.8 g, 0.04 mol), and NaOH (2.5 g) in ethanol
(20.0 mL) was stirred at 0ꢁC for 8 h, and the 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 CHCl3/MeOH
(1:1, v/v) to yield pure compound 2.
2. Yield (1.5 g, 68%); yellow solid; mp 168–170ꢁC; IR (KBr):
υmax (cmꢀ1) 3217 (OH), 1651 (CO), 1599 (CC); 1H-NMR
(400 MHz, CDCl3): d 9.82 (1H, brs, OH), 8.00 (2H, dd, Jo = 8.4
Hz, H-200,600), 7.66 (1H, d, Jtrans = 15.5 Hz, H-3), 7.54 (3H, t,
J = 5.0 Hz, H-20,40, 60), 7.46 (2H, d, Jo = 7.4 Hz, H-30, 50), 7.44
(1H, d, Jtrans = 15.5 Hz, H-2), 6.83 (2H, dd, Jo = 8.4 Hz, H-300, 500);
13C-NMR (100 Hz, CDCl3): d 189.21 (C-1), 160.06 (C-400),
144.54 (C-3), 138.00 (C-10), 132.24 (C-100), 130.34 (C-200, 600),
128.26 (C-20, 60), 127.96 (C-40), 125.57 (C-30, 50), 118.14
(C-2), 115.75 (C-300, 500); ESI-MS: m/z 247 (M + Na, 100%),
225 (M + 1, 89%), 198 (67%), 122 (54%), 106 (18%); Anal.
Calcd for C15H12O2: Calcd C, 80.35%; H, 5.35%; Found: C,
The compound 3c was prepared by reacting 1c (1.0 g,
0.002 mol) with acetophenone (0.48 g, 0.004 mol) under the
similar conditions as described earlier for 3a.
3c. Yield (1.0 g, 63%); yellow solid; mp 128–130ꢁC; IR (KBr):
υ
max (cmꢀ1) 3055 (aromatic C–H), 2929, 2855 (methylene C–H),
1662 (CO), 1597 (CC), 1215, 1019 (C–O); UV-vis (MeOH): lmax
1
(nm) 340, 292; H-NMR (400 MHz, CDCl3): d 7.99 (4H, dt, Jp,
o = 1.3, 7.0 Hz, H-20, 60), 7.78 (2H, d, Jtrans = 15.7 Hz, H-3), 7.60
(4H, d, Jo = 7.8 Hz, H-200, 600), 7.52 (8H, m, H-30, 40, 50, 5000),
7.42 (2H, d, Jtrans = 15.7 Hz, H-2), 7.41 (2H, t, J = 3.8 Hz,
H-6000), 7.0 (4H, d, Jo = 8.8 Hz, H-300, 500), 5.22 (4H, s, OCH2);
13C-NMR (100 MHz, CDCl3): d 190.56 (C-1), 160.43 (C-400),
144.50 (C-3), 138.46 (C-10), 134.64 (C-100), 132.62 (C-20, 60),
130.28 (C-1000,2000), 129.21 (C-200,600’), 128.80 (C-400), 128.59
(C-3000, 6000), 128.43 (C-4000,5000), 128.12 (C-30, 50), 120.09 (C-2),
115.24 (C-300, 500), 68.19 (OCH2); ESI-MS: m/z 575 (9%), 574
(M + Na + 1, 40%), 573 (M + Na, 100%), 552 (M + 2, 20%), 551
(M + 1, 40%), 476 (14%), 475 (50%), 453 (27%), 355 (19%), 327
(40%), 275 (36%), 257 (36%), 223 (19%), 195 (20%), 177 (15%),
159 (28%), 140 (40%), 117 (23%), 116 (47%); Anal. Calcd for
C38H30O4: Calcd C, 82.90%; H, 5.45%; Found: C, 82.83%; H, 5.40%.
80.42%; H, 5.40%.
Synthesis of (2E,20E)-3,30-(4,40-(Z)-but-2-ene-1,4-diylbis(oxy)
bis(4,1-phenylene)) bis(1-phenylprop-2-en-1-one 3a. A solution
of 1a (1.0g, 0.003mol), acetophenone (0.72 g, 0.006 mol), and
NaOH (2.5 g) in ethanol (20.0 mL) was stirred for 12h at room
temperature. The progress of reaction was monitored by TLC.
After the completion of reaction, the resulting reaction mixture
was poured into iced HCl to give a yellow solid that was
filtered, thoroughly washed with water, and dried. The crude
product was crystallized from CHCl3/MeOH (1:1, v/v) to yield
pure compound 3a.
Synthesis
(methylene))bis(oxy)bis(4,1-phenylene)bis(1-phenylprop-2-en-
1-one) 3d. The compound 3d was obtained by treating 1d
of
(2E,
2E0)-3,30-(4,40-(1,4-phenylenebis
3a. Yield (1.4 g, 70%); yellow solid; mp 138–140ꢁC; IR
(KBr): υmax (cmꢀ1) 3054 (aromatic C–H), 2926, 2870 (methylene
C–H), 1660 (CO), 1601 (CC), 1251, 1035 (C–O); UV-vis
(MeOH): lmax (nm) 340, 264; 1H-NMR (400 MHz, CDCl3): d
8.00 (4H, dd, Jp,o = 1.2, 7.5 Hz, H-20, 60), 7.79 (2H, d, Jtrans = 15.6 Hz,
H-3), 7.61 (4H, d, Jo = 8.8 Hz, H-200, 600), 7.58 (2H, d, Jo =
7.3 Hz, H-40), 7.51 (4H, d, Jo = 7.6Hz, H-30, 50), 7.42 (2H,
d, Jtrans = 15.6 Hz, H-2), 6.96 (4H, d, Jo = 8.8Hz, H-300, 500),
6.12 (2H, t, Jvic =2.5Hz, CH=), 4.65 (4H, d, Jvic =2.5Hz, OCH2);
13C-NMR (100 MHz, CDCl3): d 189.31 (C-1), 160.07 (C-400),
143.89 (C-3), 137.81 (C-10), 132.30 (C-20, 60), 131.16 (C-100),
130.03 (C-200, 600), 128.23 (CH), 127.94 (C-40), 127.68 (C-
30, 50), 119.30 (C-2), 114.75 (C-300, 500), 67.18 (OCH2); ESI-MS:
m/z 524 (M +Na+ 1, 37%), 523 (M + Na, 100%), 502 (M+ 2,
16%), 501 (M + 1, 43%), 475 (37%), 453 (20%), 371 (17%), 355
(23%), 275 (13%), 257 (22%), 223 (17%), 195 (14%), 159 (20%),
140 (32%), 117 (15%), 116 (37%); Anal. Calcd for C34H28O4:
(1.0 g, 0.002 mol) with acetophenone (0.48 g, 0.004 mol) under
the same conditions as used earlier for 3a.
3d. Yield (1.2 g, 75%); light yellow solid; mp 135–137ꢁC; IR
(KBr): υmax (cmꢀ1) 3057 (aromatic C–H), 2930, 2862 (methylene
C–H), 1660 (CO), 1600 (CC), 1249, 1017 (C–O); UV-vis (MeOH):
l
max (nm) 343, 265; 1H-NMR (400MHz, CDCl3): d 8.02 (4H, dd,
Jp,o = 1.3, 7.2 Hz, H-20, 60), 7.81 (2H, d, Jtrans = 15.6Hz, H-3), 7.63
(4H, d, Jo = 8.7 Hz, H-200, 600), 7.59 (2H, d, Jo = 7.3 Hz, H-40), 7.53
(4H, d, Jo = 7.7 Hz, H-30, 50), 7.50 (4H, s, H-2000, 3000, 5000, 6000), 7.43
(2H, d, Jtrans = 15.6Hz, H-2), 7.03 (4H, d, Jo = 8.7Hz, H-300, 500),
5.15 (4H, s, OCH2); 13C-NMR (100 MHz, CDCl3): d 190.59
(C-1), 160.73 (C-400), 144.58 (C-3), 138.49 (C-10), 136.46 (C-
100), 132.60 (C-20, 60), 130.26 (C-200, 600), 128.59 (C-40),
128.43 (C-1000), 127.98 (C-30, 50), 127.80 (C-2000,6000), 120.0
(C-2), 115.3 (C-300, 500), 69.79 (OCH2); ESI-MS: m/z 574 (M +
Na + 1, 9%), 573 (M + Na, 30%), 476 (27%), 475 (100%), 393
(6%), 249 (5%), 187 (5%), 154 (4%), 135 (4%), 105 (11%);
Anal. Calcd for C38H30O4: Calcd C, 82.90%; H, 5.45%;
Found: C, 82.96%; H, 5.49%.
Calcd C, 81.60%; H, 5.60%; Found: C, 81.52%; H, 5.54%.
Synthesis of (2E, 20E)-3,30-(4,40-(but-2-yne-1,4-diylbis(oxy))
bis(4,1-phenylene)) bis(1-phenylprop-2-en-1-one) 3b.
The
Synthesis of (E)-3-(4-((40-(4-((E)-3-oxo-3-phenylprop-1-enyl)
benzyloxy)biphenyl-4yl)methoxy)phenyl)-1-phenylprop-2-en-1-
one 3e. The compound 3e was prepared by reacting 1e (1.0 g,
compound 3b was prepared by reacting 1b (1.0 g, 0.003 mol)
with acetophenone (0.72 g, 0.006 mol) under the similar
conditions as described earlier for 3a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2015
Synthesis, Characterization, and Antimicrobial Studies of New Rigid Linker-Based
Bispyrazolines
265
0.002 mol) with acetophenone (0.48 g, 0.004 mol) under the
similar conditions as described earlier for 3a.
H-3000, 5000), 6.90 (4H, m, H-20, 60), 6.71 (2H, t, Jo = 7.3 Hz,
H-40), 5.30 (2H, dd, JXA = 6.7 Hz, JXM = 12.3 Hz, H-X), 4.79
(4H, s, H-10000), 3.85 (2H, dd, JMX = 12.3 Hz, JMA = 17.3 Hz,
H-M), 3.06 (2H, dd, JXA = 6.7 Hz, JAM = 17.3 Hz, H-A);
13C-NMR (100 MHz, DMSO-d6): d 157.35 (C-400), 146.68
(C-3), 144.22 (C-10), 135.03 (C-1000), 128.89 (C-200, 600),
128.53 (C-400), 128.43 (C-100), 127.63 (C-300, 500), 126.98 (C-2000,
6000), 125.36 (C-30, 50), 118.40 (C-40), 114.99 (C-20, 60), 112.81
(C-3000, 5000), 83.00 (C-20000), 55.30 (C-10000), 62.98 (C-5), 43.02
(C-4); ESI-MS: m/z 701 (M + Na, 40%), 679 (M + 1, 100%),
648 (23%), 626 (18%), 618 (11%), 550 (19%), 474 (59%), 405
3e. Yield (1.2 g, 85%); Yellow solid; mp 126–128ꢁC; IR
(KBr): υmax (cmꢀ1) 3037 (aromatic C–H), 2916, 2828 (methylene
C–H), 1657 (CO), 1599 (CC), 1249, 1016 (C–O); UV-vis
(MeOH): lmax (nm) 340, 255; 1H-NMR (400 MHz, CDCl3): d
8.02 (4H, dd, Jp,o = 1.4, 7.0 Hz, H-20 60), 7.82 (2H, d, Jtrans = 15.8
Hz, H-3 ), 7.66 (8H, m, H-200, 600, 3000, 5000), 7.59 (2H, d,
J = 7.3 Hz, H-40), 7.54 (8H, m, H-30, 50, 2000, 6000), 7.45 (2H, Jtrans
=
15.8 Hz, H-2), 7.06 (4H, d, Jo = 8.8 Hz, H-300, 500), 5.19 (4H, s,
OCH2); 13C-NMR (100 MHz, CDCl3): d 190.61 (C-1), 160.85
(C-400), 144.65 (C-3), 139.9 (C-1000), 138.51 (C-10), 137.90 (C-4000),
135.36 (C-100), 132.6 (C-20, 60), 130.28 (C-200, 600), 128.59 (C-40),
128.21 (C-3000, 5000), 128.01 (C-2000, 6000), 127.43 (C-30, 50), 119.96
(C-2), 115.34 (C-300, 500), 69.9 (OCH2); ESI-MS: m/z 648 (M + Na,
73%), 626 (M + 1, 100%), 627 (M + 2, 32%), 599 (58%), 493 (21%),
467 (25%), 437 (19%), 361 (38%), 285 (7%); Anal. Calcd for
C44H34O4: Calcd C, 84.34%; H, 5.43%; Found: C, 84.40%; H, 5.47%.
Synthesis of (Z)-1-(4-((S)-1,3-diphenyl-4,5-dihydro-1H-
pyrazol-5-yl)phenoxy)-4-(4-(1,3-diphenyl-4,5-dihydro-1H-pyrazol-
5-yl)phenoxy)but-2-ene 4a. A mixture of 3a (0.5 g, 0.001 mol),
phenyl hydrazine (0.22 g, 0.002 mol), and glacial acetic acid
(5.0 mL) in dry EtOH (25.0 mL) was refluxed for 8 h. The
progress of reaction was monitored by TLC. After the completion
of reaction, the resulting reaction mixture was concentrated under
vacuum, which upon cooling in an ice bath, yielded a yellow
solid. The crude product thus obtained was crystallized from
MeOH to provide pure compound 4a.
(38%), 205 (43%), 184 (28%), 94 (12%); Anal. Calcd for
C46H38N4O2: Calcd C, 81.41%; H, 5.60%; N, 8.25%; Found:
C, 81.45%; H, 567%; N, 8.28%.
Synthesis of 1,2-bis [(4-(1,3-diphenyl-4,5-dihydro-1H-
pyrazol-5-yl)phenoxy methyl)benzene] 4c. The compound 4c
was obtained by reacting 3c (0.5 g, 0.0009 mol) with phenyl
hydrazine (0.19 g, 0.0018 mol) under the similar conditions as
used earlier for 4a.
4c. Yield (0.4 g, 66%); yellow solid; mp 78–80ꢁC; IR (KBr):
υmax (cmꢀ1) 3026 (aromatic C–H), 2917 (methylene C–H),
1596 (CN), 1172, 1012 (C–O); UV-vis (MeOH): lmax (nm)
356, 228; 1H-NMR (400 MHz, DMSO-d6): d 7.66 (4H, d, Jo = 7.4
Hz, H-200, 600), 7.43 (4H, dd, J = 3.6, 5.5 Hz, H-300, 500), 7.42
(2H, dd, J = 3.6, 5.9 Hz, H-400), 7.33 (2H, d, Jo = 7.2 Hz, H-40000
5
,
0000), 7.28 (4H, m, H-2000, 6000), 7.13 (2H, dd, Jm,o = 2.2, 8.6 Hz,
H-30000, 60000), 7.08 (8H, m, H-20, 30, 50, 60), 6.86 (4H, d, Jo = 7.6
Hz, H-3000, 5000), 6.67 (2H, t, Jo = 6.8 Hz, H-40), 5.26 (2H, dd,
JXA = 6.7 Hz, JXM = 12.2 Hz, H-X), 5.08 (4H, s, OCH2), 3.82
(2H, dd, JMX = 12.2 Hz, JMA = 17.5 Hz, H-M), 3.04 (2H,
dd, JAX = 6.3 Hz, JAM = 16.9 Hz, H-A); 13C-NMR (100 MHz,
DMSO-d6): d 157.44 (C-4000), 146.43 (C-3), 144.19 (C-10), 134.75
(C-1000), 134.49 (C-100), 132.22 (C-10000), 128.50 (C-200, 600), 128.45
(C-400), 128.20 (C-50000), 127.8 (C-60000), 127.38 (C-300, 500), 126.73
(C-2000, 6000), 125.30 (C-30, 50), 118.42 (C-40), 114.91 (C-20,
60), 112.8 (C-3000, 5000), 67.27 (OCH2), 62.97 (C-5), 42.98 (C-4);
ESI-MS: m/z 732 (M + 2, 16%), 731 (M+ 1, 30%), 729 (37%),
701 (30%), 679 (24%), 491 (13%), 476 (23%), 475 (70%), 453
(40%), 380 (23%), 355 (49%), 299 (23%), 275 (50%), 257 (90%),
223 (47%), 195 (47%), 177 (35%), 159 (66%), 140 (94%),
116 (100%); Anal. Calcd for C50H42N4O2: Calcd C, 82.19%;
4a. Yield (0.5 g, 71%); light yellow solid; mp 98–100ꢁC; IR
(KBr): υmax (cmꢀ1) 3025 (aromatic C-H), 2910, 2858 (methylene
C–H), 1599 (CN), 1172, 1010 (C–O); UV-vis (MeOH): lmax
1
(nm) 355, 228; H-NMR (400MHz, DMSO-d6): d 7.72 (4H, dd,
Jp,o = 1.2, 8.5Hz, H-200, 600), 7.42 (2H, m, H-400), 7.34 (4H, dd, Jp,
o = 1.3, 8.1Hz, H-2000, 6000), 7.19 (4H, m, H-300, 500), 7.11 (4H, td,
Jp,o = 1.0, 7.4 Hz, H-30, 50), 7.01 (4H, d, Jo = 7.7 Hz, H-3000, 5000),
6.87 (4H, m, H-20, 60), 6.70 (2H, t, J = 7.3 Hz, H-40), 6.00
(2H, brs, CH), 5.33 (2H, dd, JXA = 6.7 Hz, JXM = 12.3 Hz, H-X),
4.53 (4H, brs, OCH2), 3.87 (2H, dd, JMX = 12.3 Hz, JMA = 17.3Hz,
H-M), 3.09 (2H, dd, JAX = 6.7 Hz, JAM = 17.3 Hz, H-A); 13C-NMR
(100 MHz, DMSO-d6): d 157.21 (C-4000), 146.55 (C-3), 144.2
(C-10), 134.36 (C-1000), 128.78 (C-2000, 6000), 128.76 (C-200, 600),
128.58 (CH), 128.50 (C-400), 128.27 (C-100), 127.96 (C-300, 500),
125.37 (C-30, 50), 118.42 (C-40), 114.85 (C-20, 60), 112.90
(C-3000, 5000), 67.09 (OCH2), 62.91 (C-5), 43.00 (C-4); ESI-MS:
m/z 682 (M + 2, 47%), 681 (M + 1, 100%), 679 (47%), 588
(23%), 476 (85%), 475 (85%), 453 (50%), 435 (18%), 380
(18%), 313 (17%), 282 (18%), 275 (41%), 257 (73%), 233
(62%), 223 (30%), 195 (42%), 163 (28%), 159 (57%), 140
(89%), 116 (90%); Anal. Calcd for C46H40N4O2: Calcd C, 81.17%;
H, 5.88%, N, 8.23%; Found: C, 81.24%; H, 5.93%; N, 8.27%.
Synthesis of 1-(4-((S)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-
5-yl)phenoxy)-4-(4-(1,3-diphenyl-4,5-dihydro-1H-pyrazol-5-yl)
H, 5.75%, N, 7.67%; Found: C, 82.13%; H, 5.71%; N, 7.71%.
Synthesis of 1,4bis[(4-(1,3-diphenyl-4,5-dihydro-1H-pyrazol-
5yl)phenoxy) methyl)benzene] 4d.
The compound 4d was
prepared by treating 3d (0.5 g, 0.0009 mol) with phenyl
hydrazine (0.19 g, 0.0018 mol) under the same conditions as
used earlier for 4a.
4d. Yield (0.4 g, 68%); yellow solid; mp 156–158ꢁC; IR
(KBr): υmax (cmꢀ1) 3027 (aromatic C–H), 2910, 2865 (methylene
C–H), 1599 (CN), 1168, 1011 (C–O); UV-vis (MeOH): lmax
1
(nm) 355, 228; H-NMR (400 MHz, DMSO-d6): d 7.67 (4H, d,
Jo = 7.4 Hz, H-200, 600), 7.51 (4H, d, Jo = 8.6 Hz, H-2000, 6000), 7.43
(4H, s, H-20000, 30000, 50000, 60000), 7.29 (2H, d, Jo = 8.6 Hz, H-400), 7.10
(4H, m, H-300, 500), 7.00 (4H, d, Jo = 8.3 Hz, H-3000, 5000), 6.97 (8H,
m, H-20, 30, 50, 60), 6.66 (2H, t, Jo = 7.2 Hz, H-40), 5.27 (2H,
dd, JXA = 6.7 Hz, JXM = 12.2 Hz, H-X), 5.08 (4H, s, OCH2), 3.85
phenoxy)but-2-yne 4b.
The compound 4b was prepared by
reacting 3b (0.5 g, 0.001 mol) with phenyl hydrazine (0.22 g,
0.002mol) under the similar conditions as described earlier for 4a.
4b. Yield (0.4 g, 62%); brown solid; mp 148–150ꢁC; IR (KBr):
υ
max (cmꢀ1) 3023 (aromatic C–H), 2912, 2858 (methylene C–H),
(2H, dd, JMX = 12.2Hz, JMA = 17.5 Hz, H-M), 3.06 (2H, dd, JXA
=
6.6 Hz, JAM = 17.5 Hz, H-A); 13C-NMR (100MHz, DMSO-d6): d
158.1 (C-4000), 146.4 (C-3), 144.21 (C-10), 136.32 (C-1000), 136.15
(C-10000), 128.68 (C-200, 600), 128.47 (C-400), 128.23 (C-100), 127.40
(C-300, 500), 126.75 (C-2000, 6000), 125.33 (C-30, 50), 118.43 (C-40),
118.17 (C-20000, 60000), 114.93 (C-20, 60), 112.89 (C-3000, 5000), 69.0
1600 (CN), 1177, 1015 (C–O); UV-vis (MeOH): lmax (nm)
357, 228; 1H-NMR (400 MHz, DMSO-d6): d 7.80 (4H, dd,
Jp,o = 1.2, 8.5 Hz, H-200, 600), 7.51 (2H, m, H-400), 7.40 (4H,
dd, Jp,o = 1.2, 8.1, H-2000, 6000), 7.22 (4H, m, H-300, 500), 7.20
(4H, td, Jp,o = 1.0, 7.4 Hz, H-30, 50), 6.98 (4H, d, Jo = 7.7 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

266
M. Yusuf, V. Samdhian and P. Jain
Vol 52
[3] Mulder, R.; Wellinga, K.; Daalen J. J. V. Naturwissenschaften
1975, 62, 531.
[4] Patel, B. N.; Patel, P. S.; Patel Der, V. G. Pharma Chemica
2010, 2, 295.
[5] Mokle, S. S.; Vibhute, A. Y.; Khansole, S. V.; Zangade, S. B.;
Vibhute, Y. B. Res J Pharma Bio Chem Sci 2010, 1, 631.
[6] Das, B. C.; Bhowmik, D., Chiranjit, B.; Mariappan, G. J
Pharmacy Res. 2010, 3(6), 1345.
(OCH2), 62.96 (C-5), 43.0 (C-4); ESI-MS: m/z 731 (M+ 1, 30%),
729 (45%), 701 (53%), 679 (37%), 476 (27%), 475 (100%), 453
(63%), 380 (24%), 282 (21%), 275 (42%), 257 (69%), 223 (30%),
195 (37%), 163 (26%), 159 (54%), 140 (77%), 116 (78%); Anal.
Calcd for C50H42N4O2: Calcd C, 82.19%; H, 5.75%; N, 7.67%;
Found: C, 82.24%; H, 5.80%; N, 7.72%.
Synthesis of bis[4-(4-(S)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-
5-yl)phenoxy) methyl] 4e.
The compound 4e was obtained by
[7] Nassar, E. J Am Sci 2010, 6, 463.
[8] Polevoi, L. G. Chem Abstr 1996, 65, 9147d.
[9] Batulin Farmakol Toksikol, Y. M. 1968, 31, 533. Chem Abstr
1969, 70, 2236a.
[10] Parmar, S. S.; Pandey, D. R.; Dwivedi, C.; Harbinson, R. D. J
Pharm Sci 1974, 63, 1152.
[11] Soni, N.; Pande, K.; Kalsi, R.; Gupta, T. K.; Parmar, S. S.;
Barthwal, J. P. Res Commun Chem Pathol Pharmacol 1987, 56, 129.
[12] Turan-Zitouni, G.; Chevallet, P.; Kilic, F. S.; Erol, K. Eur J
Med Chem 2000, 35, 635.
[13] Prasad, R.; Rao, A. L.; Prasoona, K.; Murali, K.; Kumar, R.
Bioorg Med Chem Lett 2005, 15, 5030.
treating 3e (0.5 g, 0.0007 mol) with phenyl hydrazine (0.15 g,
0.0014 mol) under the similar conditions as used earlier for 4a.
4e. Yield (0.4 g, 65%); yellow solid; mp 208–210ꢁC; IR (KBr):
υ
max (cmꢀ1) 3036 (aromatic C–H), 2916, 2859 (methylene C–H),
1598 (CN), 1174, 1015 (C–O); UV-vis (MeOH): lmax (nm)
1
356, 229; H-NMR (400 MHz, DMSO-d6): d 7.72 (4H, dd, Jo = 8.1
Hz, H-200, 600), 7.63 (4H, d, Jo = H-2000, 6000), 7.50 (6H, m, H-400, 30000
,
5
0000), 7.30 (8H, m, H-30, 50, 300, 500), 7.11 (4H, m, H-20, 60), 6.98 (4H,
d, Jo = 7.4Hz, H-20000, 60000), 6.92 (4H, d, Jo = 8.0 Hz, H-3000, 5000), 6.67
(2H, t, Jo = 7.2 Hz, H-40), 5.32 (2H, dd, JXA = 7.1 Hz, JXM = 12.4
[14] Zitouni, G. T.; Ozdemir, A.; Guven, K. Arch Pharm
(Weinheim) 2005, 338, 96.
Hz, H-X), 5.05 (4H, s, OCH2), 3.84 (2H, dd, JMX = 12.1 Hz, JMA
=
17.3Hz, H-M), 3.05 (2H, dd, JAX = 7.1 Hz, JAM = 17.0Hz, H-A);
13C-NMR (100 MHz, DMSO-d6): d 157.81 (C-4000), 146.45
(C-3), 144.28 (C-10), 137.95 (C-40000), 135.42 (C-1000), 130.01
(C-10000), 128.65 000(C-200, 600), 128.58 (C-400), 128.35(C-100),
127.94 (C-2000, 6 ), 127.55 (C-300, 500), 126.98 (C-20000, 60000),
126.87 (C-30000, 50000), 125.35 (C-30, 50), 118.43 (C-40), 114.89
(C-20, 60), 112.87 (C-3000, 5000), 63.00 (OCH2), 62.95 (C-5), 43.00
(C-4); ESI-MS: m/z 829 (M + Na, 100%), 807 (M + 1, 57%), 652
(47%), 585 (33), 555 (39%), 479 (11%), 478 (18%), 403 (26%),
401 (20%), 371 (13%), 297 (22%), 230 (56%), 153 (43%); Anal.
Cal. for C56H46N4O2: Calcd C, 83.37%; H, 5.70%; N, 6.94%;
Found: C, 83.44%; H, 5.74%; N, 6.99%.
[15] Fathalla, O. A.; Zaki, M. E.; Swelam, S. A.; Nofal, S. M.;
El-Eraky, W. I. Acta Pol Pharm 2003, 60, 51.
[16] Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J., Yu, S. S.; Anderson, G.
D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson,
P. C. J Med Chem 1997, 40, 1347.
[17] Terrett, N. K.; Bell, A. S.; Brown, D.; Ellis, P. Bioorg Med
Chem Lett 1996, 6, 1819.
[18] Seltzmann, H. H.; Caroll, F. I.; Burgess, J. P.; Wyrick, C. D.;
Burch, D. F. J. Chem Soc Chem Commun 1995, 15, 1549.
[19] (a) Yusuf, M.; Jain, P. Spectrochim Acta A Mol Biomol
Spectrosc 2012, 96, 295; (b) Yusuf, M.; Jain, P. J Het Chem 2012,
doi:10.1002/jhet.1805; (c) Yusuf, M.; Kaur, M.; Jain, P.; Solanki, I.
Spectrochim Acta A Mol Biomol Spectrosc 2012, 97, 470.
[20] Pandey, K. S.; Khan, N. Arch Pharm Chem Life Sci 2008, 341,
418.
[21] Abdelhamid, A. O.; El-Shaity, F. H. H. Phosphorus, Sulfur
Silicon 1988, 39, 45.
[22] Ibrahim, Y. A.; Elwahy, A. H. M.; Elkareish, G. M. M. J Chem
Res (S) 1994, 11, 2321.
Acknowledgment. The authors are highly thankful to DST
(SERB, Fast Track Scheme no. SR/FT/CS-041/2010), New
Delhi, for providing the financial support for this research work.
REFERENCES AND NOTES
[1] Cole, W.; Julian, P. L. J Org Chem 1954, 19, 131.
[2] Main, L.; Old, K. B. Tetrahedron Lett 1977, 2809.
[23] Yusuf, M.; Solanki, I.; Jain, P. J Chem Sciences 2012,
124, 703.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet