Synthesis and antibacterial activity of 4,4′-(aryl or alkyl methylene)-bis(1H-pyrazol-5-ol) derivatives

Article abstract of DOI:10.1007/s00044-013-0623-3

A rapid, improved, and environmentally benign synthesis of 4,4′-aryl or alkyl methylene-bis(1H-pyrazol-5-ols) has been accomplished by tandem Knoevenagel-Michael reaction of 1-aryl-3-alkyl-1H-pyrazol-5-ol with various aldehydes catalyzed by ammonium aceta

Full text of DOI:10.1007/s00044-013-0623-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0623-3
ORIGINAL RESEARCH
Synthesis and antibacterial activity of 4,40-(aryl or alkyl
methylene)-bis(1H-pyrazol-5-ol) derivatives
•
S. Bhavanarushi V. Kanakaiah Gandu Bharath
•
•
•
A. Gangagnirao J. Vatsala Rani
Received: 31 January 2013 / Accepted: 6 May 2013
Ó Springer Science+Business Media New York 2013
Abstract A rapid, improved, and environmentally benign
synthesis of 4,40-aryl or alkyl methylene-bis(1H-pyrazol-5-
ols) has been accomplished by tandem Knoevenagel–
Michael reaction of 1-aryl-3-alkyl-1H-pyrazol-5-ol with
various aldehydes catalyzed by ammonium acetate. All the
synthesized compounds 3a–v were evaluated in vitro for
their antibacterial activity against Pseudomonas aerugin-
osa, Xanthomonas protophormiae, Bacillus licheniformis,
and Staphylococcus aureus. Among the tested compounds,
compounds with trifluromethyl group show excellent
antibacterial activity.
molecular properties. Some of the most recognized fluo-
rine-containing drugs with antibacterial activity are the
fluoroquinolones. The isosteric replacement of hydrogen
by fluorine in organofluorine compounds enhances the
lipophilicity and thus increases the rate of diffusion of the
molecule in the cell, which is a very essential feature in
drug delivery, both referring to prokaryotic, gram-negative
bacteria as well as eukaryotic cells. The superior polariz-
ability due to the C–F bond may give rise to new potential
for binding to the receptor. Fluorine substitution can also
control pharmacokinetic and pharmacodynamic properties
of the molecule (Saeed et al., 2009). Today, many tri-
fluoromethyl group-containing molecules have been
developed as well-known drugs such as bicalutamide
(anticancer agent), fluoxetin (antidepressant), fluconazole
(anti-fungal agent), and desflurane (inhalation anaesthetic)
(Abid and Torok, 2005). Therefore, the development of
synthetic methods for trifluoromethylated compounds is
very important in synthetic organic chemistry and or-
ganofluorine chemistry.
Keywords 1-Aryl-3-alkyl-1H-pyrazol-5-ol ꢀ
4,40-Aryl or alkyl methylene-bis(1H-pyrazol-5-ol) ꢀ
Ammonium acetate ꢀ Antibacterial activity
Introduction
Trifluoromethyl group-containing organic compounds can
bring about significant changes in the physical, chemical,
and biological properties (Filler and Saha, 2009; Pursor
et al., 2008). Fluoro and trifluoromethylated compounds
are of great interest, the strong electron-withdrawing effect
of F and CF3 groups adds to a number of biologically vital
Presently, pyrazolone derivatives are paid much atten-
tion for their various biological activities, such as selective
COX-2 inhibitory (EI-Sayed et al., 2012), antitumor (Balbi
et al., 2011), besides they can be used as human MAO
inhibitors (Jagrat et al., 2011), tyrosine kinase-3 (FLT3)
inhibitors (Lin et al., 2011). 2,4-Dihydro-3H-pyrazol-3-one
derivatives including 4,40-(arylmethylene)-bis(3-methyl-1-
phenyl-1H-pyrazol-5-ols) have broad spectrum of approved
biological activity; they are being used as antiviral (Sujatha
et al., 2009), anti-inflammatory (Lingaiah et al., 2011),
antidepressant (Secci et al., 2011), and antibacterial
activity (Rahimizadeh et al., 2010). Thus, in view of the
diverse therapeutic activity of 4,40(arylmethylene)-bis(1H-
pyrazol-5-ols) and in continuation of our work in the bio-
logical activities of pyrazole moiety, we herein report for
S. Bhavanarushi ꢀ V. Kanakaiah ꢀ J. Vatsala Rani (&)
Fluoro Organic Division, Indian Institute of Chemical
Technology, Hyderabad 500 0607, India
e-mail: j21_vat@rediffmail.com; vatsala@iict.res.in
G. Bharath ꢀ A. Gangagnirao
Bioengineering and Environmental Engineering Centre (BEEC),
Indian Institute of Chemical Technology, Hyderabad 500 0607,
India
123

Med Chem Res
the first time in vitro antibacterial activity of 4,40(aryl or
alkyl methylene)-bis(1H-pyrazol-5-ols) against P. aerugi-
nos, X. protophormiae, B. licheniformis, and S. aureus.
Bacillus licheniformis causes several human infections
in immune suppressed individuals. It causes septicemia,
peritonitis, ophthalmitis, and food poisoning in humans, as
well as with bovine toxemia and abortions in cows. It is an
opportunistic pathogen in compromised hosts (Turnbull P
C et al., 1995). Xanthomonas protophormiae causes plant
diseases in citrus, beans, grapes, cotton, and rice (Gent and
Schwartz, 2005). Staphylococcus aureus, the most virulent
of the many staphylococcal species, has demonstrated its
versatility by remaining a major cause of morbidity and
mortality despite the availability of numerous effective
antistaphylococcal antibiotics. Staphylococcus aureus is a
pluripotent pathogen, causing disease through both toxin-
mediated and non-toxin-mediated mechanisms. This
organism is responsible for both nosocomial and commu-
nity-based infections that range from relatively minor skin
and soft tissue infections to life threatening systemic
infections (Grundmann et al., 2006). Pseudomonas aeru-
ginosa is an opportunistic pathogen and individuals with
suppressed immune systems, especially those with neu-
tropenia (low white blood cell count), are most susceptible
(Trautmann et al., 2008).
(SBSSA) as a catalyst. Finally, Kiran et al. (2012)
reported its synthesis in ethanol using phosphomolybdic
acid as recyclable solid acid catalyst. Further, Sobhani
et al., 2012 reported its synthesis in acetonitrile using
3-aminopropylated silica gel as reusable heterogeneous
catalyst. However, most of the methods suffer from at
least one limitation that may include moderate yields, long
reaction times, harsh reaction conditions, or tedious
workup procedures.
More recently, ammonium acetate has been used widely
as a base catalyst in Biginelli reactions (Yadav et al., 2004;
Mabry and Ganem, 2006), Hantsch reactions (Lee, 2005),
and other reactions (Mitsumori et al., 2006; Sakamoto
et al., 2005), and also grinding method has increasingly
been used in organic synthesis in recent years. Compared
with traditional methods, this method is more efficient and
selective. A large number of organic reactions can be
carried out in high yields with mild conditions, simplicity
in process and by the grinding method (Tong-Shou et al.,
2004; Jin et al., 2005; Wang et al., 2004). All of these
reasons spur us to study the possibility of synthesis of 4, 40-
aryl or alkyl methylene-bis(3-alkyl-1-aryl-1H-pyrazol-5-
ols) derivatives under solvent-free conditions. In this
manuscript, we here describe a simple and efficient pro-
cedure for the synthesis of 4, 40-aryl or alkyl methylene-
bis(3-alkyl-1-aryl-1H-pyrazol-5-ols) catalyzed by ammo-
nium acetate by grinding method at room temperature.
The conventional synthetic method for the synthesis of
4,40-(arylmethylene)-bis(3-methyl-1-phenyl-pyrazol-5-ols)
involves the successive Knoevenagel synthesis of the
corresponding arylidenepyrazolones and its base-promoted
Michael reaction and also one-pot tandem Knoevenagel–
Michael reaction of aromatic aldehydes with two equiva-
lents of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
performed under a variety of reaction conditions (Ham-
ama, 2001; Li et al., 1998). The first set of procedures
utilizes the catalysis of the components with piperidine in
ethanolic solution (Singh and Singh, 1984; Mitra and
Rout, 1961). The second set of methods involve the non-
catalyzed tandem Knoevenagel–Michael reaction under
neutral conditions in either ethanol (Pavlov et al., 1998) or
benzene (Buzykin and Lonshchakova, 1971) solutions.
Although it affords the corresponding 4,40-(arylmethyl-
ene)-bis(1H-pyrazol-5-ols) in reliable 70–90 % yields, the
reaction requires 3–12 h of initial reflux with further 24 h
under ambient temperature to go to completion. Wang
et al. (2005) reported its synthesis in water using sodium
dodecyl sulfate as the surfactant catalyst over 1-h period,
Results and discussion
Chemistry
All the substituted pyrazoles were prepared by the known
method (Liu et al., 2006) which involves reaction of the
corresponding ethyltrifluoroaceto-acetate with aryl hydra-
zine in the presence of aqHCl catalyst using EtOH as the
solvent. The novel 4,40-aryl or alkyl methylene-bis(3-alkyl-
1-aryl-1H-pyrazol-5-ol) derivatives (3a–v) were synthe-
sized by mechanical grinding of the aldehydes with 2
equivalents of 1-aryl-3-alkyl-1H-pyrazol-5ol by using
ammonium acetate as a catalyst at room temperature. The
reactions lead to completion in 5–10 min with good yields
(Table 1) and easy work up. The synthetic protocol is
shown as following in scheme 1.
A plausible mechanism for the formation of 4,40-aryl or
alkyl methylene-bis(3-alkyl-1-aryl-1H-pyrazol-5-ol) is
outlined in scheme 2. The reaction is initiated via Knoe-
venagel-type condensation of aldehyde (2) with 1-aryl-3-
alkyl-1H-pyrazol-5ol (1) in the presence of NH4OAc to
offer (3) followed by Michael addition of 1-aryl-3-alkyl-
1H-pyrazol-5ol (1) to give bis (pyrazolyl) methanes (4).
o
but the process needs a temperature of 100 C. Elinson
et al. (2008) utilized electrocatalytic procedure for its
synthesis. Perumal and co-workers reported the synthesis
and antiviral activity of 4,40-(arylmethylene)bis(3-methyl-
1-phenyl-1H-pyrazol-5-ols) using CAN as a catalyst (Su-
jatha et al., 2009). Niknam et al., 2010 reported its syn-
thesis in ethanol using silica-bonded S-sulfonic acid
123

Med Chem Res
Table 1 Synthesis of 4,40-(aryl or alkyl methylene)-bis(3-alkyl-1-aryl-1H-pyrazol-5-ols) along with yields 3a–v
S.No.
R
R1
R2
Product
Time (min)
Yielda (%)
1
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CH3
CH3
CH3
C6H5
4-NO2C6H4
4-OCH3C6H4
2-thionyl
3a
3b
3c
3d
3e
3f
5
93.2
87.8
83.6
95.7
88.2
93.0
93.9
82.6
80.2
92.3
93.7
87.4
95.1
93.7
87.2
94.2
87.8
89.3
92.1
91.6
89.7
86.5
2
C6H5
5
3
C6H5
10
5
4
C6H5
4-FC6H4
5
C6H5
C6H5
5
6
C6H5
4-ClC6H4
4-isopropyl-C6H4
Cyclohexyl
CH3(CH2)3–
C6H5
5
7
C6H5
3g
3h
3i
5
8
C6H5
10
10
5
9
C6H5
10
11
12
13
14
15
16
17
18
19
20
21
22
a
3-ClC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
C6H5
3j
C6H5
3k
3l
5
4-OCH3C6H4
4-NO2C6H4
C6H5
5
3m
3n
3o
3p
3q
3r
3s
5
5
4-OCH3C6H4
4-NO2C6H4
C6H5
5
5
5
4-OCH3C6H4
4-NO2C6H4
4-NO2C6H4
4-OCH3C6H4
C6H5
5
5
3t
5
C6H5
3u
3v
5
C6H5
5
Isolated yield
Scheme1 Synthesis of 4,40-
(aryl or alkyl methylene)-bis(3-
alkyl-1-aryl-1H-pyrazol-5-ols)
3a–v
R2
R
R
R
O
NH4OAc
N
N
N
grinding, rt, 5-10 min
OH
R2
H
N
R1
N
N
OH
HO
R1
R1
1
2
3(a-v), 80-96%
Antimicrobial evaluation
compounds (Shamroukh et al., 2007; Patel et al., 2012).
The inhibition zone diameter values and MIC (lg/mL)
values are presented in Table 2 and 3, respectively. From
antibacterial activity data, it is confirmed that compounds
containing strong electron-withdrawing group (CF3 group)
i.e., 3a–s exhibited excellent activity against all microbial
strains, while compounds containing CH3 group i.e., 3t–v
did not show any activity against all species of gram-
positive and -negative bacteria used in the study. The
compounds 3k–m which have CF3 group on third position
of pyrazole ring and F on para position of phenyl group
present maximum activity. The presence of strong electron-
withdrawing groups CF3 and F in the molecule may lead to
All the synthesized compounds, 3a–v were evaluated for
their antibacterial activity against two gram-negative bac-
terial strains, P. aeruginosa and X. protophormiae and two
gram-positive bacteria B. licheniformis and S. aureus.
Agar-diffusion method was used for the determination of
the preliminary antibacterial activity. Ciprofloxacin was
used as reference drug. The results were recorded for each
tested compound, diameter of inhibition zone of bacte-
rial growth around the disks was measured in mm. The
minimum inhibitory concentration (MIC) measurement
was also determined for significant growth inhibition
123

Med Chem Res
Scheme 2 Proposed
R
R
mechanism for the formation of
4,40-(aryl or alkyl methylene)-
bis(3-alkyl-1-aryl-1H-pyrazol-
5-ols) 3a–v by using ammonium
acetate catalyst
O
NH4OAc
- H2O
N
N
O
OH
R2
H
N
N
2
R1
R1
1
R2
R
R2
R
R
R
H
N
N
N
N
O
O
N
N
R1
1
HO
OH
N
N
H
R1
R1
R1
4
3
higher polarizability of the molecule and give rise to new
potential for binding the molecule to the receptor which
finally enhances the lipophilicity of the molecule and in
turn its diffusion rate in the cell on the whole. This effect
was pronounced when in addition to CF3, F was present on
para position of phenyl group. The nil activity of the
molecule with CH3 may be due to very less lipophilicity or
nil binding potential of the molecule to the receptor, since
CH3 group is electron donating and does not polarize the
molecule.
values of compounds 3a, 3d–e 3h, 3k–l, and 3m showed
good inhibitory activity (100–12.5 lg/mL) against gram-
positive bacterial strains and compounds 3h, 3k, 3l, and 3m
showed moderate to good activity (50–25 lg/mL) against
gram-negative strains, with respect to reference drug.
Conclusion
In summary, we have developed an efficient, economical,
and environmentally benign method to synthesize the 4,40-
aryl or alkyl methylene-bis(3-alkyl-1-aryl-1H-pyrazol-5-
ols). These compounds were tested in vitro antibacterial
activity against P. aeruginosa, X. protophormiae, B. li-
cheniformis, and S. aureus. Among the tested compounds
3a–v indicated that CF3 group-containing compounds
exhibit excellent antibacterial activity and CH3 group-
containing compounds were not active.
In particular, the positions of fluorine and trifluoro-
methyl substituents on phenyl ring appreciably influenced
the antibacterial activity. Placement of fluorine in a stra-
tegic position of a molecule has materialized as a very
influential and flexible tool for the development of the
compounds capable with biological activities. The presence
of fluorine frequently leads to enhanced lipid solubility,
thereby escalating the rate of in vivo absorption and
transport of drugs (Smart, 2001).
Compounds 3a–s showed zone of inhibition ranging
between 8 and 26 mm. On the basis of zone of the inhi-
bition produced against the test bacteria, compounds 3a,
3d, 3f, 3h, 3k–l, and 3m were found to be most effective
against both gram-positive and -negative showing maxi-
mum zone of inhibition ranging between 21 and 26 mm,
respectively, when compared with commercial antibiotic
ciprofloxacin, which showed maximum zone of inhibition
of 38 and 35 mm against gram-negative bacteria, P.
aeruginosa and X. protophormiae, respectively. Com-
pounds 3b–c, 3e, 3g, 3i–j, and 3n–s showed moderate
effect against both gram-positive and -negative. The MIC
Experimental
All chemicals were of analytical grade; ethyltrifluoroaceto-
acetate (ETFAA) was purchased from SigmaAldrich (St.
Louise, USA); melting points of all the compounds were
recorded on Casiae-Siamia (VMP-AM) melting point
apparatus and are uncorrected. IR spectra were recorded on
a Perkine-Elmer FT-IR 240-C spectrophotometer using
1
KBr optics. H NMR, 13C NMR spectra were recorded on
Bruker AV 300 MHz in DMSO using TMS as internal
123

Med Chem Res
Table 2 Antibacterial activity
of 4,40-(aryl or alkyl
Compound
Zone of inhibition (mm)
methylene)-bis(3-alkyl-1-aryl-
1H-pyrazol-5-ols) 3a–v
Gram-negative (-ve) bacteria
Gram-positive (?ve) bacteria
Pseudomonas
aeruginosa
Xanthomonas
protophormiae
Bacillus
licheniformis
Staphylococcus
aureus
3a
25
18
13
20
20
20
15
25
15
16
25
24
21
17
16
15
18
14
14
–
20
17
8
25
23
20
24
20
25
23
22
17
15
23
25
21
15
12
13
14
13
16
–
20
18
14
21
19
20
17
23
13
15
24
23
20
16
13
14
18
16
20
–
3b
3c
3d
9
3e
18
20
19
25
19
15
23
26
20
15
16
12
19
12
13
–
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
–
–
–
–
3v
–
–
–
–
Ciprofloxacin
Control (1 % DMSO)
38
–
35
–
33
–
30
–
‘‘–’’ denotes no activity
Table 3 MICs of 3a, 3d, 3e,
3h, 3k, 3l, and 3m compounds
Organic compound
MIC (lg/mL)
Gram-negative (-ve) bacteria
Gram-positive (?ve) bacteria
Pseudomonas
aeruginosa
Xanthomonas
protophormiae
Bacillus
licheniformis
Staphylococcus
aureus
3a
200
200
200
50
200
100
200
50
50
25
3d
50
25
3e
50
100
25
3h
50
3k
50
50
25
50
3l
25
25
25
50
3m
25
25
12.5
12.5
–
12.5
12.5
–
Ciprofloxacin
Control (1 % DMSO)
12.5
–
12.5
–
‘‘–’’ denotes no activity
standard. Electron Spray Ionization (ESI) and high-reso-
lution spectra were recorded on QSTARXL hybrid MS/MS
system (Applied Biosystems, USA) under electrospray
ionization. All the reactions were monitored by thin layer
chromatography (TLC) on precoated silica gel 60 F254
(mesh); spots were visualized with UV light.
123

Med Chem Res
General procedure for the synthesis of 4,40-(aryl
or alkyl methylene)-bis(3-alkyl-1-aryl-1H-pyrazol-5-
ols) 3a–v
123.68, 124.03, 125.41, 126.41, 128.55, 139.21, 148.56,
157.92; HRMS m/z Calcd. for C25H17O2N4F6S ([M?H]?):
551.0970 Found: 551.0972.
A
mixture of 3-alkyl-1-aryl-1H-pyrazol-5-ol (1)
3-(Trifluoromethyl)-4-((3-(trifluoromethyl)-5-hydroxy-1-
phenyl-1H-pyrazol-4-yl)(4-fluorophenyl)methyl)-1-phenyl-
1H-pyrazol-5-ol (3d)
(2.0 mmol), aldehyde (2) (1.0 mmol), and NH4OAc (1.0
mmol) is ground at room temperature with the mortar and
pestle. The reaction is monitored by TLC. The mixture is
transferred to cold water and then is filtered off. The crude
product is recrystallized by ethanol.
Yield = 0.54 g (95.7 %), m.p. 199–201 °C; FTIR (KBr
pallet, cm-1): 3425, 3064, 1697, 1593, 1496, 1226, 1132,
1000; 1H NMR (300 MHz, DMSO-d6) d ppm : 5.28 (s, 1H,
CH), 7.16–7.26 (m, 4H, Ar–H), 7.34–7.42 (m, 6H, Ar–H),
8.00 (d, J = 7.91 Hz, 4H, Ar–H); 13C NMR (75 MHz,
DMSO-d6) d ppm : 33.30, 96.83, 101.79, 115.40, 115.69,
121.51, 122.70, 125.09, 127.05, 129.66, 139.05, 139.89,
140.29, 158.62, 160.11; HRMS m/z Calcd. for
C27H18F7N4O2([M?H]?): 563.1273 Found: 563.1247.
3-(Trifluoromethyl)-4-((3-(trifluoromethyl)-5-hydroxy-1-
phenyl-1H-pyrazol-4-yl)(4-nitrophenyl)methyl)-1-phenyl-
1H-pyrazol-5-ol (3a)
Yield = 0.55 g (93.2 %), m.p. 150–152 °C; FTIR (KBr
pallet, cm-1): 3389, 1641, 1600, 1513, 1479, 1353, 1270,
1
1227, 1134, 998; H NMR (300 MHz, DMSO-d6) d ppm :
5.33 (s, 1H, CH), 7.15 (t, J = 7.37 Hz, 2H, Ar–H), 7.34 (t,
J = 8.12 Hz, 4H, Ar–H), 7.55 (d, J = 8.50 Hz, 2H, Ar–
H), 7.94 (d, J = 7.74 Hz, 4H, Ar–H), 8.06 (d,
J = 8.69 Hz, 2H, Ar–H); 13C NMR (75 MHz, DMSO-d6)
d ppm: 32.97, 99.24, 120.87, 123.36, 125.57, 128.19,
128.58, 139.09, 145.77, 151.20, 157.96; HRMS m/z Calcd.
for C27H18F6N5O4 ([M?H]?): 590.1218 Found: 590.1221.
3-(Trifluoromethyl)-4-((3-(trifluoromethyl)-5-hydroxy-1-
phenyl-1H-pyrazol-4-yl)(phenyl)methyl)-1-phenyl-1H-
pyrazol-5-ol (3e)
Yield = 0.48 g (88.2 %), m.p. 202–204 °C; FTIR (KBr
pallet, cm-1): 3394, 3064, 2923, 2853, 1698, 1593, 1490,
1
1364, 1265, 1128, 999; H NMR (300 MHz, DMSO-d6) d
ppm : 5.22 (s, 1H, CH), 7.12 (t, J = 6.60 Hz, 1H, Ar–H),
7.23–7.29 (m, 6H, Ar–H), 7.40 (t, J = 8.00 Hz, 4H, Ar–
H), 7.87 (d, J = 7.60 Hz, 4H, Ar–H); 13C NMR (75 MHz,
DMSO-d6) d ppm : 32.87, 95.77, 100.60, 120.82, 124.82,
125.19, 127.30, 127.57, 128.12, 139.75, 143.94, 158.12;
HRMS m/z Calcd. for C27H19F6N4O2([M?H]?): 545.1367
Found: 545.1343.
3-(Trifluoromethyl)-4-((3-(trifluoromethyl)-5-hydroxy-1-
phenyl-1H-pyrazol-4-yl)(4-methoxy phenyl)methyl)-1-
phenyl-1H-pyrazol-5-ol (3b)
Yield = 0.50 g (87.8 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3426, 2930, 1602, 1484, 1373, 1273, 1133, 998;
1H NMR (300 MHz, DMSO-d6) d ppm : 3.71 (s, 3H,
OCH3), 5.19 (s, 1H, CH), 6.70 (d, J = 8.50 Hz, 2H, Ar–
H), 7.13 (t, J = 7.37 Hz, 2H), 7.23 (d, J = 8.50 Hz, 2H,
Ar–H), 7.33 (t, J = 7.93 Hz, 4H, Ar–H), 7.94 (d,
J = 7.93 Hz, 4H, Ar–H); 13C NMR (75 MHz, DMSO-d6)
d ppm : 31.81, 54.51, 95.54, 100.63, 112.77, 120.77,
120.58, 124.58, 127.91, 127.97, 135.79, 139.53, 156.94,
157.85; HRMS m/z Calcd. for C28H21F6N4O3 ([M?H]?):
575.1473 Found: 575.1458.
4-((4-Chlorophenyl)(3-(trifluoromethyl)-5-hydroxy-1-
phenyl-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1-
phenyl-1H-pyrazol-5-ol (3f)
Yield = 0.54 g (93.0 %), m.p. 146–148 °C; FTIR (KBr
pallet, cm-1): 3408, 2929, 1700, 1600, 1489, 1375, 1259,
1
1136, 998; H NMR (300 MHz, DMSO-d6) d ppm : 5.23
(s, 1H, CH), 7.12–7.17 (m, 4H, Ar–H), 7.27–7.36 (m, 6H,
Ar–H), 7.94 (d, J = 8.56 Hz, 4H, Ar–H); 13C NMR
(75 MHz, DMSO-d6) d ppm : 32.17, 95.50, 99.93, 120.67,
124.97, 127.51, 128.15, 128.76, 130.27, 139.33, 142.40,
157.84; HRMS m/z Calcd. for C27H18O2N4ClF6
([M?H]?): 579.1017 Found: 579.1006.
3-(Trifluoromethyl)-4-((3-(trifluoromethyl)-5-hydroxy-1-
phenyl-1H-pyrazol-4-yl)(thiophen-2-yl)methyl)-1-phenyl-
1H-pyrazol-5-ol (3c)
Yield = 0.46 g (83.6 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3426, 2927, 1696, 1594, 1482, 1413, 1369,
3-(Trifluoromethyl)-4-((3-(trifluoromethyl)-5-hydroxy-1-
phenyl-1H-pyrazol-4-yl)(4-isopropylphenyl)methyl)-1-
phenyl-1H-pyrazol-5-ol (3g)
1
1295, 1241, 1130, 999; H NMR (300 MHz, DMSO-d6) d
ppm: 5.40 (s, 1H, CH), 6.76–6.83 (m, 2H), 7.03 (d,
J = 4.53 Hz, 1H), 7.14 (t, J = 7.37 Hz, 2H), 7.34 (t,
J = 7.55 Hz, 4H), 7.95 (d, J = 7.74 Hz, 4H); 13C NMR
(75 MHz, DMSO-d6) d ppm : 28.89, 95.36, 100.40, 120.77,
Yield = 0.55 g (93.9 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3409, 2967, 1698, 1594, 1481, 1374, 1265,
123

Med Chem Res
1
1137, 996; H NMR (300 MHz, DMSO-d6) d ppm : 1.23
m/z Calcd. for C27H17O2N4Cl2F6 ([M?H]?): 613.0627
Found: 613.0622.
(d, J = 6.92 Hz, 6H), 2.81–2.89 (m, 1H), 5.23 (s, 1H, CH),
7.05 (d, J = 8.90 Hz, 2H), 7.16 (t, J = 6.92 Hz, 2H), 7.27
(d, J = 7.91 Hz, 2H), 7.36 (t, J = 6.92 Hz, 4H), 7.99 (d,
J = 7.91 Hz, 4H); 13C NMR (75 MHz, DMSO-d6) d ppm :
23.83, 32.38, 32.93, 95.48, 100.52, 120.72, 125.10, 125.66,
126.95, 128.32, 139.43, 141.09, 145.26, 157.91; HRMS
m/z Calcd. for C30H25F6N4O2([M?H]?): 587.1837 Found:
587.1809.
3-(Trifluoromethyl)-4-((3-(trifluoromethyl)-1-(4-
fluorophenyl)-5-hydroxy-1H-pyrazol-4-yl)(phenyl)methyl)-
1-(4-fluorophenyl)-1H-pyrazol-5-ol (3k)
Yield = 0.54 g (93.7 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3292, 2819, 1580, 1494, 1463, 1405, 1263,
1
1133, 1001; H NMR (300 MHz, DMSO-d6) d ppm : 5.36
(s, 1H, CH), 7.00–7.14 (m, 5H), 7.22 (t, J = 7.14 Hz, 2H),
7.39 (d, J = 7.55 Hz, 2H), 7.84–7.94 (m, 4H); 13C NMR
(75 MHz, DMSO-d6) d ppm : 32.49, 100.65, 114.45,
114.75, 122.93, 125.16, 126.94, 127.43, 135.15, 143.01,
157.23, 158.07, 161.30; HRMS m/z Calcd. for
C27H17O2N4F8 ([M?H]?): 581.1218 Found: 581.1212.
4-(Cyclohexyl(3-(trifluoromethyl)-5-hydroxy-1-phenyl-1H-
pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1-phenyl-1H-
pyrazol-5-ol (3h)
Yield = 0.45 g (82.6 %), m.p. 101–103 °C; FTIR (KBr
pallet, cm-1): 3434, 2929, 2855, 1602, 1479, 1378, 1305,
1
1247, 1128, 998; H NMR (300 MHz, DMSO-d6) d ppm :
3-(Trifluoromethyl)-4-((3-trifluoromethyl)-1-(4-fluorophenyl)-
5-hydroxy-1H-pyrazol-4-yl)(4-methoxyphenyl)methyl)-1-
(4-fluorophenyl)-1H-pyrazol-5ol (3l)
0.71–0.90 (m, 2H), 1.07–1.32 (m, 4H), 1.58–1.72 (m, 4H),
3.41–3.51 (m, 1H), 4.05 (d, J = 6.99 Hz, 1H), 7.14–7.22
(t, J = 6.61 Hz, 2H), 7.32–740 (m, 4H), 7.92 (d,
J = 8.31 Hz, 4H); 13C NMR (75 MHz, DMSO-d6) d ppm :
26.03, 28.93, 31.67, 34.64, 36.50, 95.44, 100.86, 120.65,
124.70, 127.96, 139.20, 157.01; HRMS m/z Calcd. for
C27H25F6N4O2 ([M?H]?): 551.1837 Found: 551.1796.
Yield = 0.53 g (87.4 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3413, 2925, 2854, 1722, 1600, 1485, 1239,
1
1129, 1005; H NMR (300 MHz, DMSO-d6) d ppm : 3.74
(s, 3H, OCH3), 5.23 (s, 1H, CH), 6.75 (d, J = 8.12 Hz,
2H), 7.03–7.13 (m, 4H), 7.26 (d, J = 8.12 Hz, 2H),
7.89–7.97 (m, 4H); 13C NMR (75 MHz, DMSO-d6) d ppm
: 31.86, 54.64, 100.76, 112.88, 114.52, 114.82, 122.66,
122.76, 123.82, 128.01, 135.60, 157.59; HRMS m/z Calcd.
for C28H19F8N4O3 ([M?H]?): 611.1285 Found: 611.1221.
3-(Trifluoromethyl)-4-(1-(3-(trifluoromethyl)-5-hydroxy-1-
phenyl-1H-pyrazol-4-yl)pentyl)-1-phenyl-1H-pyrazol-5-ol
(3i)
Yield = 0.49 g (94.2 %), m.p. 94–96 °C; FTIR (KBr pal-
let, cm-1): 1418, 3065, 2931, 1603, 1507, 1373, 1272,
1133, 997; 1H NMR (300 MHz, DMSO-d6) d ppm : 0.86 (t,
J = 6.80 Hz, 3H), 1.11–1.20 (m, 2H), 1.23–1.34 (m, 2H),
1.95–2.06 (m, 2H), 3.80 (t, J = 7.74 Hz, 1H), 7.14 (t,
J = 6.99 Hz, 2H), 7.34 (t, J = 7.74 Hz, 4H), 7.95 (d,
J = 7.93 Hz, 4H); 13C NMR (75 MHz, DMSO-d6) d ppm :
13.76, 21.87, 27.89, 29.78, 32.08, 95.44, 101.38, 120.49,
124.53, 127.90, 139.49, 157.50; HRMS m/z Calcd. for
C25H23O2N4F6 ([M?H]?): 525.1719 Found: 525.1719.
3-(Trifluoromethyl)-4-((3-trifluoromethyl)-1-(4-fluorophenyl)-
5-hydroxy-1H-pyrazol-4-yl(4-nitrophenyl)methyl)-1-(4-
fluorophenyl)-1H-pyrazol-5ol (3m)
Yield = 0.59 g (95.1 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3465, 2927, 1602, 1594, 1514, 1376, 1244,
1
1125, 1000; H NMR (300 MHz, DMSO-d6) d ppm : 5.41
(s, 1H, CH), 7.05 (t, J = 8.69 Hz, 4H), 7.58 (d,
J = 8.31 Hz, 2H), 7.92 (q, J = 4.91&3.97 Hz, 4H), 8.07
(d, J = 8.50 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) d
ppm : 27.67, 98.31, 105.51, 110.12, 120.76, 125.36,
128.51, 139.16, 154.91, 157.97; HRMS m/z Calcd. for
C27H16F8N5O4 ([M?H]?): 626.1030 Found: 626.0965.
1-(3-Chlorophenyl)-4-((1-(3-chlorophenyl)-3-
(trifluoromethyl)-5-hydroxy-1H-pyrazol-4-
yl)(phenyl)methyl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (3j)
Yield = 0.57 g (92.3 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3291, 2827, 1595, 1470, 1401, 1262, 1129,
1013; 1H NMR (300 MHz, DMSO-d6) d ppm : 5.27 (s, 1H,
CH), 7.08–7.25 (m, 5H, Ar–H), 7.30–7.36 (m, 4H), 7.94 (d,
J = 8.31 Hz, 2H), 8.03–8.05 (m, 2H); 13C NMR (75 MHz,
DMSO-d6) d ppm : 36.61, 58.42, 95.43, 99.05, 118.94,
119.12, 120.67, 121.83, 122.25, 127.12, 128.08, 130.59,
133.46, 134.14, 137.52, 142.95, 158.43, 164.91; HRMS
1-(4-Chlorophenyl)-4-((1-(4-chlorophenyl)-3-(trifluorome-
thyl)-5-hydroxy-1H-pyrazol-4-yl)(phenyl)methyl)-3-
(trifluoromethyl)-1H-pyrazol-5-ol (3n)
Yield = 0.57 g (93.7 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3418, 3029, 2929, 1659, 1596, 1488, 1407,
1
1264, 1132, 998; H NMR (300 MHz, DMSO-d6) d ppm :
5.30 (s, 1H, CH), 7.08–7.16 (m, 1H), 7.18–7.26 (m, 2H),
123

Med Chem Res
7.28–7.41 (m, 6H), 7.90–8.00 (m, 4H); 13C NMR (75 MHz,
DMSO-d6) d ppm : 32.62, 100.71, 122.16, 125.44, 127.05,
127.70, 128.24, 129.81, 137.96, 143.14, 157.78; HRMS m/z
Calcd. for C27H17Cl2F6N4O2 ([M?H]?): 613.0702 Found:
613.0684.
3-(Trifluoromethyl)-4-((3-(trifluoromethyl)-5-hydroxy-1-
(4-methoxyphenyl)-1H-pyrazol-4-yl)(4-methoxyphenyl)
methyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-ol (3r)
Yield = 0.57 g (89.3 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3388, 2929, 2516, 1661, 1599, 1477, 1383,
1257, 1125, 1015; 1H NMR (300 MHz, DMSO-d6) d ppm :
3.73 (s, 3H, OCH3), 3.81 (s, 6H, OCH3), 5.35 (s, 1H, CH),
6.76 (d, J = 8.69 Hz, 2H), 6.89 (d, J = 9.07 Hz, 4H), 7.25
(d, J = 8.50 Hz, 2H), 7.71 (d, J = 8.88 Hz, 4H); 13C NMR
(75 MHz, DMSO-d6) d ppm : 31.62, 54.57, 54.91, 102.08,
112.93, 113.25, 123.42, 127.86, 130.98, 133.86, 156.20,
157.20, 157.45; HRMS m/z Calcd. for C30H25F6N4O5
([M?H]?): 635.1684 Found: 635.1627.
1-(4-Chlorophenyl)-4-((1-(4-chlorophenyl)-3-
(trifluoromethyl)-5-hydroxy-1H-pyrazol-4-yl)(4-
methoxyphenyl)methyl)-3-(trifluoromethyl)-1H-pyrazol-5-
ol (3o)
Yield = 0.56 g (87.2 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3621, 3381, 2957, 1679, 1598, 1508, 1478,
1364, 1269, 1223, 1125, 997; 1H NMR (300 MHz, DMSO-
d6) d ppm : 3.72 (s, 3H, OCH3), 5.27 (s, 1H, CH), 6.75 (d,
J = 8.69 Hz, 2H), 7.30 (t, J = 8.88 Hz, 6H), 7.96 (d,
J = 8.69 Hz, 4H); 13C NMR (75 MHz, DMSO-d6) d ppm :
30.24, 54.68, 100.97, 112.88, 122.15, 127.99, 129.76,
138.08, 157.05, 157.90; HRMS m/z Calcd. for C28H19Cl2
F6N4O3 ([M?H]?): 643.1305 Found: 643.1326.
3-(Trifluoromethyl)-4-((3-(trifluoromethyl)-5-hydroxy-1-
(4-methoxyphenyl)-1H-pyrazol-4-yl)(4-nitrophenyl)
methyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-ol (3s)
Yield = 0.60 g (92.1 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3412, 2925, 1667, 1595, 1485, 1350, 1239,
1
1129, 1005; H NMR (300 MHz, DMSO-d6) d ppm : 3.80
(s, 6H, OCH3), 5.42 (s, 1H, CH), 6.87 (d, J = 8.88 Hz,
4H), 7.59 (d, J = 8.50 Hz, 2H), 7.78 (d, J = 8.88 Hz, 4H),
8.06 (d, J = 8.69 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
d ppm : 33.04, 54.95, 99.27, 113.17, 122.66, 122.91,
128.11, 132.38, 151.68, 156.93, 157.29; HRMS m/z Calcd.
for C29H22F6N5O6 ([M?H]?): 650.1430 Found: 650.1463.
1-(4-Chlorophenyl)-4-((1-(4-chlorophenyl)-3-
(trifluoromethyl)-5-hydroxy-1H-pyrazol-4-yl)(4-
nitrophenyl)methyl)-3-(trifluoromethyl)-1H-pyrazol-5-ol
(3p)
Yield = 0.62 g (94.2 %), m.p. [ 250 °C; FTIR (KBr
pallet, cm-1): 3418, 2929, 1662, 1597, 1480, 1349,
1
1223, 1129, 998; H NMR (300 MHz, DMSO-d6) d ppm :
4-((5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(4-
nitophenyl)methyl)-3-methyl-1-phenyl-1H-pyrazol-5-ol (3t)
5.42 (s, 1H, CH), 7.31 (d, J = 8.50 Hz, 4H), 7.57 (d,
J = 8.31 Hz, 2H), 7.96 (d, J = 8.50 Hz, 4H), 8.07 (d,
J = 8.69 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) d ppm :
32.73, 99.20, 121.83, 122.80, 127.97, 128.06, 129.56,
137.83, 145.53, 150.96, 157.88, 160.64; HRMS m/z Calcd.
for C27H16Cl2F6N5O4 ([M?H]?): 658.0716 Found: 658.0692.
Yield = 0.44 g (92.5 %), m.p. 230–232 °C; FTIR (KBr
pallet, cm-1): 3065, 2923, 1600, 1499, 1415, 1345, 1109,
1025; 1H NMR (300 MHz, DMSO-d6) d ppm : 1.22 (s, 6H,
CH3), 3.91 (s, 1H, CH), 6.17–6.27 (m, 2H, Ar–H),
6.30–6.46 (m, 6H, Ar–H), 6.59–6.70 (m, 4H, Ar–H),
7.11–7.24 (m, 2H, Ar–H); 13C NMR (75 MHz, DMSO-d6)
d ppm : 11.43, 33.65, 104.7, 121.37, 123.46, 128.15, 128.9,
136.61, 146.15, 148.57, 157.41; HRMS m/z Calcd. for
C27H24O4N5 ([M?H]?): 482.1822 Found: 482.1801.
3-(Trifluoromethyl)-4-((3-(trifluoromethyl)-5-hydroxy-1-
(4-methoxyphenyl)-1H-pyrazol-4-yl)(phenyl)methyl)-1-(4-
methoxyphenyl)-1H-pyrazol-5-ol (3q)
Yield = 0.53 g (87.8 %), m.p. [ 250 °C; FTIR (KBr pal-
let, cm-1): 3227, 2965, 2851, 1657, 1581, 1495, 1287,
4-((5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-
yl)(phenyl)methyl)-3-methyl-1-phenyl-1H-pyrazol-5-ol
(3u)
1
1135, 1049, 991; H NMR (300 MHz, DMSO-d6) d ppm :
3.78 (s, 6H, OCH3), 5.36 (s, 1H, CH), 6.86 (d,
J = 8.88 Hz, 4H), 7.09 (t, J = 7.18 Hz, 1H), 7.20 (t,
J = 7.74 Hz, 2H), 7.41 (d, J = 7.55 Hz, 2H), 7.77 (d,
J = 8.88 Hz, 4H); 13C NMR (75 MHz, DMSO-d6) d ppm :
32.64, 54.86, 100.15, 113.07, 122.47, 124.95, 127.02,
127.33, 132.63, 143.81, 156.65, 157.31; HRMS m/z Calcd.
for C29H23F6N4O4 ([M?H]?): 605.1579 Found: 605.1545.
Yield = 0.42 g (89.7 %), m.p. 172–174 °C; FTIR (KBr
pallet, cm-1): 3423, 3060, 2922, 1599, 1497, 1413, 1368,
1
1284, 1027; H NMR (300 MHz, DMSO-d6) d ppm : 2.05
(s, 6H, CH3), 4.73 (s, 1H, CH), 7.05–7.12 (m, 2H, Ar–H),
7.14–7.28 (m, 9H, Ar–H), 7.54 (d, J = 7.55 Hz, 4H, Ar–
123

Med Chem Res
H); 13C NMR (75 MHz, DMSO-d6) d ppm : 11.42, 33.50,
105.63, 121.22, 126.11, 127.07, 128.23, 128.78, 136.84,
140.71, 146.36, 157.52; HRMS m/z Calcd. for C27H25O2N4
([M?H]?): 437.1972 Found: 437.1955.
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Yield = 0.39 g (90.5 %), m.p. 175–177 °C; FTIR (KBr
pallet, cm-1): 3421, 3063, 2924, 2854, 1601, 1504, 1412,
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