Facile synthesis of novel fluorine containing pyrazole based thiazole derivatives and evaluation of antimicrobial activity

Article abstract of DOI:10.1016/j.jfluchem.2012.06.021

A series of compounds 2-(5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3- (aryl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-ones (4a-q) were synthesized and structures of these compounds were elucidated by spectral (IR, ¹H NMR, ¹³C

Full text of DOI:10.1016/j.jfluchem.2012.06.021

Journal of Fluorine Chemistry 142 (2012) 67–78
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Facile synthesis of novel fluorine containing pyrazole based thiazole derivatives
and evaluation of antimicrobial activity
*
N.C. Desai , V.V. Joshi, K.M. Rajpara, H.V. Vaghani, H.M. Satodiya
Division of Medicinal Chemistry, Department of Chemistry, Mahatma Gandhi Campus, Maharaja Krishnakumarsinji Bhavnagar University, Bhavnagar 364 002, Gujarat, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of compounds 2-(5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(aryl)-4,5-dihydro-1H-
pyrazol-1-yl)thiazol-4(5H)-ones (4a–q) were synthesized and structures of these compounds were
elucidated by spectral (IR, 1H NMR, 13C NMR, mass spectra) analysis. Synthesized compounds were
screened for in vitro antibacterial activity against the representative panel of Gram-positive
(Staphylococcus aureus, Streptococcus pyogenes) and Gram-negative (Escherichia coli, Pseudomonas
aeruginosa) bacteria. These compounds were also tested for their inhibitory action against strains of fungi
(Candida albicans, Aspergillus niger, Aspergillus clavatus). The synthesized compounds showed potent
inhibitory action against the test organisms.
Received 3 February 2012
Received in revised form 13 June 2012
Accepted 19 June 2012
Available online 2 July 2012
Keywords:
Pyrazole
Pyrazoline
ß 2012 Elsevier B.V. All rights reserved.
Thiazole
Antibacterial activity
Antifungal activity
MIC
1. Introduction
demonstrated a broad spectrum of antimicrobial activity [14,15].
In addition, 1-unsubstituted-3,5-diaryl-2-pyrazolines are reported
The chemistry of fluorine-containing compounds has been
tremendously developed. Intrinsic properties of the fluorine atom,
such as high electronegativity, small atomic radius, and low
polarisability of the C–F bond, impart significant improvement on
the biological activity of fluorinated molecules [1]. Fluorinated
compounds have proved invaluable as antibacterial and antifungal
agents, and have been used for the treatment of obesity and
various diseases associated with the cardiovascular and central
nervous systems [2–5]. Thus, fluorine substitution remains an
attractive means in the development of more active and selective
pharmaceutical drug molecules.
Pyrazoles and several N-substituted pyrazoles are known to
possess numerous chemical, biological and medicinal, applications
because of their versatile biological activities such as antimicrobial
[6], antitumor [7], antileukemia [8], antidepressant [9], anticonvul-
sant [10], antifungal [11] and antitubercular [12]. It is considered a
typical model of pyrazole containing, diaryl-heterocyclic template
that is known to selectively inhibit (cyclooxygenase enzyme) COX-2
[13]. Celecoxib(Fig. 1)isshowntobepotentandgastrointestinal(GI)
safe anti-inflammatory and analgesic agent. Much attention is given
to pyrazoles as antimicrobial agents after the discovery of
the natural pyrazole C-glycoside, pyrazofurin (Fig. 1) which
to exhibit human Acyl CoA cholesterol acyltransferase activity [16]
as well as activity of low-density lipoprotein oxidation inhibitors
[17]. Thiazoles and their derivatives have found applications in drug
development for the treatment of allergies [18], hypertension [19],
inflammation [20], schizophrenia [21], bacterial infections [22], HIV
infections [23], hypnotics [24] and more recently for the treatment
of pain [25], as fibrinogen receptor antagonists with antithrombotic
activity [26] and as new inhibitors of bacterial DNA gyrase B [27].
Thiazolenucleusisalsoanintegral partofall the available penicillins
which have revolutionized the therapy of bacterial diseases [28].
Several thiazole containing drugs are available such as; nizatidine is
a histamine H2-receptor antagonist that inhibits stomach acid
production, and commonly used in the treatment of peptic ulcer
disease (PUD) and gastroesophageal reflux disease (GERD), nirida-
zole as schistosomicidal, sulfathiazole as antibiotic, fanetizole as
anti-inflammatory, combendazole as fungicidal. Structures of
commercially available drugs containing pyrazole, pyrazoline and
thiazole nucleus are shown in Fig. 1.
As a result of remarkable pharmacological efficiency of pyrazole
and thiazole, derivatives, our studies have been focused toward the
synthesis and bio-evaluation of these derivatives by hybrid
approach as possible bioactive molecules. Earlier our research
group has synthesized different heterocyclic derivatives as
potential antimicrobial agents [29–33]. In continuation to this,
we synthesized 2-(5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-
yl)-3-(aryl)-4-5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-ones
* Corresponding author. Tel.: +91 278 2439852; fax: +91 278 2439852.
E-mail address: dnisheeth@rediffmail.com (N.C. Desai).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.06.021

68
N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
Fig. 1. Commercially available drug candidates containing pyrazole, pyrazoline and thiazole nucleus.
(4a–q) derivatives and screened then for their antimicrobial
activity. The synthesized compounds (4a–q) were characterized by
IR, NMR and mass spectra.
the corresponding 4-carboxaldehyde functionalized pyrazole ring.
It was furnished in mild operating conditions to obtain the 3-(4-
fluorophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (1) in good
yield. The key chalcone intermediates (2a–q) were synthesized
through the Claisen–Schmidt condensation of equimolar amounts
of acetophenone derivatives and (1) through stirring the reactants
in aqueous alcoholic solution containing 20% sodium hydroxide at
room temperature for 24 h in accordance with the method
described in the literature [34]. The newly synthesized compounds
5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(aryl)-4,5-
dihydro-1H-pyrazole-1-carbothioamides (3a–q) were obtained by
heating at reflux equimolar amounts of thiosemicarbazide and the
2. Results and discussion
2.1. Chemistry
Synthesis of intermediates and target compounds were
accomplished according to the steps illustrated in Schemes 1
and 2. One of the most important feature of this synthetic route is
the use of 3-(4-fluorophenyl)-1-phenyl-1H-pyrazole-4-carbalde-
hyde (1) as a key starting material for further transformations.
Compound (1) was prepared in two steps. In the first step, reaction
took place between 1-(4-fluorophenyl)ethanone and phenyl
hydrazine. Then the resulted product hydrazone derivative was
treated with the Vilsmeier–Haack reagent (DMF–POCl3) leading to
corresponding
a,b-unsaturated ketones (2a–q) in hot ethanolic
sodium hydroxide solution for 8 h (Scheme 1). This 1-thiocarba-
moyl pyrazole derivative (3a) was characterized using IR and NMR
spectra. IR spectra showed strong absorption bands at 3370 and
3442 cmÀ1 due to primary amine group. The characteristic signals
Scheme 1. Synthetic route for the preparation of compound 1.

N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
69
in 1H NMR of 1-thiocarbamoyl pyrazole derivative (3a) was of
Compound 4b (2-Cl) showed excellent activity at MIC = 25
m
g/mL,
three pyrazoline protons which displayed doublet of doublet.
while compound 4h (2-NO2) exhibited highest inhibition against E.
coli at MIC = 12.5 g/mL as compared to standard ampicillin
(MIC = 100 g/mL). Compounds 4c (3-Cl), 4g (4-F) and 4h (2-NO2)
displayed very good activity at MIC = 50 g/mL, whereas com-
pounds 4e (2-F) and 4j (4-NO2) displayed excellent inhibitory
activity against P. aeruginosa at MIC = 25 g/mL as compared to
ampicillin (MIC = 100 g/mL). Compounds 4b (2-Cl), 4d (4-Cl) and
4g (4-F) were found to exhibit activity at MIC = 100 g/mL, while
compound 4h (2-NO2) showed highest inhibition at MIC = 50 g/
mL against S. aureus as compared to standard ampicillin
(MIC = 250 g/mL). Compounds 4b (2-Cl), 4e (2-F) and 4j (4-
NO2) showed very good activity (MIC = 50 g/mL), while com-
Methine proton of pyrazolines displayed signal at
d
= 6.11 ppm as a
m
doublet of doublet with coupling constants of nearly 11.04 Hz and
3.01 Hz. The two methylene protons displayed two signals; a
m
m
doublet of doublet at
d = 3.86 ppm with coupling constants of
nearly 17.35 Hz and 11.04 Hz and a doublet of doublet at
m
d
= 3.09 ppm with coupling constants of nearly 17.34 Hz and
m
3.01 Hz. Furthermore, 13C NMR spectra displayed a signal at
m
176.3 ppm assignable to thiocarbamoyl carbon (C55S). Carbon of
m
methine showed a chemical shift at
methylene displayed a chemical shift at
d
= 63.1 ppm. Carbon of
= 43.2 ppm. The mass
d
m
spectrum of (3a) showed a molecular ion peak at m/z = 441 (M+)
corresponding to a molecular formula C25H20FN5S. Moreover, the
aforementioned 1-thiocarbamoyl pyrazole derivatives (3a–q)
were cyclized (4a–q) through their reaction with ethyl bromoa-
cetate in hot ethanol for 1 h. Compound (4a) showed strong
absorption band at 1694 cmÀ1 due to carbonyl group in IR spectra.
In addition to this, 1H NMR spectra revealed the appearance of
m
pounds 4d (4-Cl), 4f (3-F) and 4h (2-NO2) have shown excellent
activity against S. pyogenes as compared to ampicillin
(MIC = 100
Antifungal activity showed that compounds 4c (3-Cl), and 4j (4-
NO2) were found to have very good activity at MIC = 250 g/mL,
mg/mL).
m
while compounds 4b (2-Cl), 4e (2-F), 4g (4-F) and 4h (2-NO2)
singlet peak at
thiazolone ring. 13C NMR confirmed the proposed structure due
to the appearance of signal at = 187.5 ppm due to carbonyl
carbon as well as the appearance of signal around = 39.4 ppm
assignable to methylene group of the thiazolone ring. Moreover,
the mass spectrum of (4a) showed a molecular ion peak at m/
z = 481 (M+) corresponding to a molecular formula C27H20FN5OS.
d
= 4.11 ppm integrating two protons of the
showed enhanced activity and displayed excellent activity against
C. albicans at MIC = 100
(MIC = 500 g/mL). Compounds 4b (2-Cl), 4c (3-Cl) and 4h (2-
NO2) exhibited very good activity against A. niger at MIC = 50 g/
mL, whereas compounds 4e, 4g and 4j bearing 2-F, 4-F and 4-NO2
groups showed excellent activity against A. niger at MIC = 25 g/
mL as compared to griseofulvin (MIC = 100 g/mL). Compounds
4b (2-Cl) and 4j (4-NO2) displayed very good activity at
MIC = 50 g/mL, and compounds 4d (4-Cl), 4g (4-F) were found
to have activity at MIC = 25 g/mL whereas compound 4h (2-NO2)
mg/mL as compared to griseofulvin
d
m
d
m
m
m
2.2. Antimicrobial activity
m
m
Compounds 4a–q were evaluated against Gram-positive, Gram-
was found to exhibit highest activity at MIC = 12.5
m
g/mL against
negative bacterial and fungal strains. The individual minimum
A. clavatus as compared to griseofulvin (MIC = 100 mg/mL).
inhibitory concentration (MIC,
mg/mL) obtained for compounds
4a–q are presented in (Table 1). It was observed that compounds
4b (2-Cl), 4d (4-Cl), 4e (2-F), 4f (3-F), 4g (4-F), 4h (2-NO2) and 4j (4-
NO2) were most active compounds. On the basis of antibacterial
screening, compounds 4d (4-Cl), 4e (2-F) and 4j (4-NO2) were
2.3. Structure–activity relationship
The structure–activity relationship (SAR) of compounds 4a–q
was determined using the data presented in Table 1. SAR studies
revealed that the presence of an electron-withdrawing group on
found to show very good activity against E. coli at MIC = 50
mg/mL.
Table 1
Results of antibacterial and antifungal screening of compounds (4a–q).
Entry
-R
Minimum inhibitory concentration for bacteria (
mg/mL) Æ SD
Minimum inhibitory concentration for fungi (mg/
mL)Æ SD
Gram-negative
Gram-positive
E. coli
P. aeruginosa
S. aureus
S. pyogenes
C. albicans
A. niger
A. clavatus
MTCC 443
MTCC 1688
MTCC 96
MTCC 442
MTCC 227
MTCC 282
MTCC 1323
4a
4b
4c
4d
4e
4f
-H
250 Æ 3.05
25 Æ 2.64*
100 Æ 3.21
50 Æ 1.60**
50 Æ 3.61*
100 Æ 3.60
250 Æ 1.20**
12.5 Æ 1.78*
100 Æ 3.78*
50 Æ 2.44*
500 Æ 4.40
100 Æ 2.19*
250 Æ 1.60***
500 Æ 3.78*
50 Æ 2.21**
250 Æ 1.52*
500 Æ 3.60
100 Æ 2.05
–
250 Æ 1.00*
100 Æ 1.00**
50 Æ 2.88
250 Æ 4.04*
100 Æ 3.21**
250 Æ 2.05**
100 Æ 3.05*
250 Æ 1.16*
250 Æ 1.05***
100 Æ 2.04*
50 Æ 1.16***
250 Æ 2.04*
100 Æ 4.16***
500 Æ 3.78**
500 Æ 4.60*
500 Æ 2.64*
500 Æ 4.04
500 Æ 3.60*
500 Æ 4.04*
500 Æ 2.50*
250 Æ 1.52
–
100 Æ 3.46*
50 Æ 3.60**
250 Æ 2.05*
25 Æ 3.21*
50 Æ 3.21*
25 Æ 4.16*
100 Æ 1.92*
12.5 Æ 3.78**
250 Æ 3.46
50 Æ 1.78
500 Æ 4.04***
100 Æ 2.88*
250 Æ 3.60
500 Æ 4.35***
100 Æ 2.72*
500 Æ 2.18**
100 Æ 4.60***
100 Æ 1.16**
500 Æ 1.52*
250 Æ 2.05**
1000 Æ 4.72
500 Æ 2.56*
1000 Æ 2.88*
500 Æ 2.05
500 Æ 3.21*
1000 Æ 4.61**
500 Æ 4.04
–
250 Æ 3.70*
50 Æ 4.04*
50 Æ 1.20***
250 Æ 4.16*
25 Æ 2.58***
100 Æ 4.04*
25 Æ 1.60**
50 Æ 1.18*
500 Æ 1.60*
25 Æ 3.78
100 Æ 1.00
50 Æ 4.16
-2-Cl
-3-Cl
100 Æ 4.50**
25 Æ 3.46
-4-Cl
100 Æ 2.04**
25 Æ 4.04
-2-F
100 Æ 1.50**
100 Æ 4.04
25 Æ 2.05**
12.5 Æ 3.78*
100 Æ 3.52*
50 Æ 3.78
-3-F
100 Æ 1.60**
50 Æ 3.60*
50 Æ 2.21**
100 Æ 3.78
25 Æ 1.21*
500 Æ 3.26
100 Æ 1.04***
500 Æ 3.78*
500 Æ 3.60*
500 Æ 3.78**
250 Æ 2.04**
500 Æ 1.16*
100 Æ 1.0
4g
4h
4i
-4-F
-2-NO2
-3-NO2
-4-NO2
-2-OH
-3-OH
-4-OH
-2-CH3
-4-CH3
-2-OCH3
-4-OCH3
Ampicillin
Griseofulvin
4j
4k
4l
500 Æ 4.61*
250 Æ 3.78*
500 Æ 2.64**
500 Æ 4.04
250 Æ 2.06
500 Æ 2.05***
250 Æ 3.60*
100 Æ 2.06
–
250 Æ 1.60*
500 Æ 4.16**
500 Æ 2.64*
250 Æ 2.05
250 Æ 3.21*
500 Æ 4.16
250 Æ 4.16*
–
500 Æ 3.60*
500 Æ 4.72**
1000 Æ 1.00**
250 Æ 2.05
250 Æ 3.21*
1000 Æ 3.21*
1000 Æ 1.86**
–
4m
4n
4o
4p
4q
–
500 Æ 0.52
100 Æ 1.0
100 Æ 1.18
ÆSD, standard deviation. All values are presented as mean of 6 experiments (n = 6). All significant differences are considered from control value 0.00.
*
P < 0.05 significant.
**
P < 0.01 moderately significant.
***
P < 0.001 extremely significant.

70
N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
Scheme 2. Synthetic route for the preparation of title compounds 4a–q.
the benzene ring increased the antimicrobial activity, and activity
decreased in the presence of electron-releasing atoms or groups.
Specifically, compounds with a nitro group in either position 2 or
position 4 of the benzene ring significantly increased potency
against different panel of microbial strains. The dependence of
compounds efficacy (biological activity) on the position of the nitro
group did not appear to be important. In this case, the use of
electron withdrawing group on the benzene ring in basic
structures was worthy. Compounds bearing 2-Cl, 4-Cl, 2-F, 3-F,
4-F, 2-NO2 and 4-NO2 exhibited more pronounced activity.
4. Materials and methods
4.1. General
All reactions except those in aqueous media were carried out
by standard techniques for the exclusion of moisture. Melting
points were determined on an electro thermal melting point
apparatus and were reported uncorrected. TLC on silica gel plates
(Merck, 60, F254) was used for purity checking and reaction
monitoring. Column chromatography on silica gel (Merck,
70–230 mesh and 230–400 mesh ASTH for flash chromatography)
was applied when necessary to isolate and purify the reaction
products. Elemental analysis (%C, H, N) was carried out by a
Perkin-Elmer 2400 CHN analyzer. IR spectra of all compounds
were recorded on a Perkin-Elmer FT-IR spectrophotometer in KBr.
3. Conclusion
The new compounds (4a–q) presented here clearly differ in
their corresponding antimicrobial activity depending on the type
of substituent. In course of this study, particular derivatives
possessing electron withdrawing groups such as halogen and
nitro are identified as exhibiting potent antimicrobial activity
against microbial strains. These results, combined with potential
benefits or at least differences in pharmacokinetics make the
titled pyrazole congeners not only interesting simplified leads for
further chemical optimization of this class but also potentially
interesting for future scope to study their mechanism of action
and would be worthy of additional structure–activity relationship
investigation.
1H NMR spectra were recorded on Varian Gemini 300 MHz and 13
C
NMR spectra on Varian Mercury-400 100 MHz in DMSO-d6 as a
solvent and tetramethylsilane (TMS) as an internal standard. All
chemical shifts were expressed in ppm, coupling constants (J)
were given in Hz. 19F NMR spectra were obtained on Bruker AM
300 (282 MHz) spectrometer in CDCl3 with CFCl3 as external
standard, downfield shifts being designated as negative. Mass
spectra were scanned on a Shimadzu LCMS 2010 spectrometer.
Anhydrous reactions were carried out in oven-dried glassware in
nitrogen atmosphere.

N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
71
4.2. Antibacterial assay
5. Experimental
The newly synthesized compounds (4a–q) were screened for
their antibacterial activity against Gram-positive bacteria (Staph-
ylococcus aureus (MTCC-96), Streptococcus pyogenes (MTCC-442))
and Gram-negative bacteria (Escherichia coli (MTCC-443), Pseudo-
monas aeruginosa (MTCC-1688)). All MTCC cultures were collected
from Institute of Microbial Technology, Chandigarh. The activity of
compounds was determined as per National Committee for Clinical
Laboratory Standards (NCCLS) protocol using Mueller Hinton Broth
(Becton Dickinson, USA) [35,36]. Compounds were screened for
their antibacterial activity as primary screening in six sets against
E. coli, S. aureus, P. aeruginosa and S. pyogenes at different
5.1. Synthesis of 1-(1-(4-fluorophenyl)ethylidene)-2-
phenylhydrazine
Glacial acetic acid (1 mL) and phenylhydrazine (0.01 mol) were
added to a solution of 1-(4-fluorophenyl)ethanone (0.01 mol) in
30 mL of ethanol. Then, the reaction mixture was refluxed for 1 h at
room temperature. The precipitate was filtered and washed with
ethanol (95%). Then it was dried in vacuum over P2O5. Light yellow
crystal, yield: 82%; m.p.: 134–136 8C; IR (KBr, cmÀ1): 3354 (N–H
stretching, secondary amine), 3024 (C–H stretching, CH55N
linkage), 3063, 3045 (C–H stretching, aromatic ring), 2935 (C–H
stretching, –CH3), 1611, 1582, 1518 (C55N, C55C stretching,
aromatic ring), 1383 (C–H bending, –CH3), 1431 (C–H bending,
concentrations of 1000, 500, 250
to be active in primary screening were similarly diluted to obtain
200, 125, 100, 62.5, 50, 25 and 12.5 g/mL concentrations for
mg/mL. The compounds found
m
–CH55N linkage), 1152 (C–F); 1H NMR (300 MHz, DMSO-d6,
ppm): 2.28 (s, 3H), 7.37 (s, 1H, NH), 6.76–7.83 (m, 9H, Ar–H); 13
NMR (100 MHz, DMSO-d6,
163.1 (C–F), 167.3 (–C55N); 19F NMR (282 MHz, DMSO-d6,
d
C
,
secondary screening to test in a second set of dilution against all
microorganisms. Inoculum size for test strain was adjusted to
108 CFU/mL (Colony Forming Unit per milliliter) by comparing the
turbidity (turbidimetric method). Mueller Hinton Broth was used
as nutrient medium to grow and dilute the compound suspension
for test bacteria. 2% DMSO was used as a diluent/vehicle to obtain
the desired concentration of synthesized compounds and standard
drugs to test upon standard microbial strains. Synthesized
d
, ppm): 17.8 (CH3), 113.7–145.3 (Ar–C),
, ppm):
d
À118.37 (s, 1F, 4-F); LCMS (m/z): 228 (M+); Anal. Calcd.
For C14H13FN2: C-73.66, H-5.74, N-12.27; Found: C-73.60,
H-5.79, N-12.36%.
5.2. Synthesis of 3-(4-fluorophenyl)-1-phenyl-1H-pyrazole-4-
compounds were diluted to 1000
m
g/mL concentration, as a stock
carbaldehyde (1)
solution. The control tube containing no antibiotic was immedi-
ately subcultured [before inoculation] by spreading a loopful
evenly over a quarter of plate of medium suitable for the growth of
test organisms. The tubes were then put for incubation at 37 8C for
Dimethylformamide and phosphorus oxychloride were sepa-
rately cooled at 0 8C before being stirred at same temperature. A
solution of 1-(1-(4-fluorophenyl)ethylidene)-2-phenylhydrazine
(0.01 mol) in dimethylformamide was added dropwise to the
reaction mixture which was then warmed at room temperature and
heated at 70–80 8C for 5 h. After cooling at room temperature, the
mixture was basified with a cool saturated K2CO3 solution. The
precipitatewasfiltered, stronglywashedwithwaterandcrystallized
from ethanol (95%). Light yellow crystal; yield: 68%; m.p.: 173–
175 8C; IR (KBr, cmÀ1): 3072, 3054 (C–H stretching, aromatic ring),
1711(C55O stretching,carbonylgroup), 1613, 1581, 1510(C55N, C55C
stretching, aromaticring), 1145 (C–F); 1H NMR (300 MHz, DMSO-d6,
24 h for bacteria. 10
mg/mL suspensions were further inoculated
on an appropriate media and growth was noted after 24 h and 48 h.
The highest dilution (lowest concentration) preventing appearance
of turbidity was considered as minimum inhibitory concentration
(MIC,
mg/mL) i.e. the amount of growth from the control tube
before incubation (which represents the original inoculum) was
compared. A set of tubes containing only seeded broth and solvent
controls were maintained under identical conditions so as to make
sure that the solvent had no influence on strain growth. The result
of this is greatly affected by the size of inoculum. The test mixture
should contain 108 CFU/mL organisms. Standard drug used in the
present study was ‘ampicillin’ for evaluating antibacterial activity
d
, ppm): 7.28 (m, 10H, Ar–H), 10.11 (s, 1H, HC55O); 13C NMR
(400 MHz, DMSO-d6, , ppm): 113.6–150.3 (Ar–C), 162.4 (C–F),
d
183.7 (C55O); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.32 (s, 1F,
which showed 100, 100, 250 and 100
m
g/mL MIC against E. coli, P.
4-F); LCMS (m/z): 266 (M+). Anal. Calcd. For C16H11FN2O: C-72.17,
aeruginosa, S. aureus and S. pyogenes respectively.
H-4.16, N-10.52; Found: C-72.22, H-4.11, N-10.48%.
4.3. Antifungal assay
5.3. General procedure for the preparation of 3-(3-(4-fluorophenyl)-
1-phenyl-1H-pyrazol-4-yl)-1-(aryl)prop-2-en-1-ones (2a–q)
The same compounds (4a–q) were tested for antifungal
activity as primary screening in six sets against Candida albicans,
Aspergillus niger and Aspergillus clavatus at various concentrations
Compounds were prepared according to literature method [34].
A mixture of 3-(4-fluorophenyl)-1-phenyl-1H-pyrazole-4-carbal-
dehyde (1) (0.01 mol) and acetophenone (0.01 mol) was stirred in
methanolic sodium hydroxide for 24 h at room temperature. The
yellow crystals formed were filtered off, washed with water and
crystallized from ethanol (95%).
of 1000, 500, 250
mg/mL. The compounds found to be active in
primary screening were similarly diluted to obtain 200, 125, 100,
62.5, 50, 25 and 12.5
screening to test in
m
g/mL concentrations for secondary
a
second set of dilution against all
microorganisms. Griseofulvin was used as a standard drug for
antifungal activity, which showed 500, 100 and 100 g/mL MIC
m
5.3.1. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-
against C. albicans, A. niger and A. clavatus. For fungal growth, in the
present protocol, we have used Sabourauds dextrose broth at
22 8C in aerobic condition for 72 h.
phenylprop-2-en-1-one (2a)
Yield: 72%; m.p.: 194–196 8C; IR (KBr)
aromatic), 3011 (C–H stretching), 1587 (C55N), 1521 (C55C), 1148
(C–F), 961 (C–H bending); 1H NMR (300 MHz, DMSO-d6,
, ppm):
7.21–8.23 (m, 15H, Ar–H), 7.63 (d, 1H, J = 14.1, H- ), 8. 08 (d, 1H,
J = 14.1, H- , ppm): 114.4–150.5
); 13C NMR (100 MHz, DMSO-d6,
n
max/cmÀ1: 3068 (C–H,
d
4.4. Statistical analysis
a
b
d
Standard deviation value was expressed in terms of ÆSD. On the
basis of calculated value by using one-way ANOVA method followed
by independent two sample t-test, it has been observed that
differences below 0.001 level were considered as statistically
significant.
(Ar–C), 127.4 (CH of alkene attched to carbonyl carbon), 148.3 (CH
of alkene attched to pyrazole), 162.7 (C–F of fluorophenyl ring),
183.6 (C55O); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.24
(s, 1F, 4-F); LCMS (m/z): 368 (M+); Anal. Calcd. For C24H17FN2O:
C-78.24, H-4.65, N-7.60; Found: C-78.30, H-4.61, N-7.66%.

72
N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
5.3.2. 1-(2-Chlorophenyl)-3-(3-(4-fluorophenyl)-1-phenyl-1H-
(282 MHz, DMSO-d6,
d
, ppm): À118.17 (s, 1F, 4-F); LCMS (m/z):
pyrazol-4-yl)prop-2-en-1-one (2b)
386 (M+); Anal. calcd. for C24H16F2N2O: C-74.60, H-4.17, N-7.25;
Found: C-74.66, H-4.12, N-7.20%.
Yield: 76%; m.p.: 194–196 8C; IR (KBr) n
max/cmÀ1: 3061 (C–H,
aromatic), 3006 (C–H stretching), 1580 (C55N), 1517 (C55C), 1155
(C–F), 977 (C–H bending), 756 (C–Cl stretching); 1H NMR
5.3.7. 1-(4-Fluorophenyl)-3-(3-(4-fluorophenyl)-1-phenyl-1H-
(300 MHz, DMSO-d6,
1H, J = 14.3, H- ), 8. 05 (d, 1H, J = 14.3, H-
DMSO-d6, , ppm): 114.3–150.7 (Ar–C), 127.1 (CH of alkene
attched to carbonyl carbon), 148.3 (CH of alkene attched to
pyrazole), 162.3 (C–F of fluorophenyl ring), 183.2 (C55O); 19F NMR
d
, ppm): 7.18–8.19 (m, 14H, Ar–H), 7.67 (d,
pyrazol-4-yl)prop-2-en-1-one (2g)
a
b
); 13C NMR (100 MHz,
Yield: 79%; m.p.: 204–206 8C; IR (KBr) n
max/cmÀ1: 3054 (C–H,
d
aromatic), 3007 (C–H stretching), 1585 (C55N), 1511 (C55C), 1147
(C–F), 983 (C–H bending), 746 (C–Cl Stretching); 1H NMR
(300 MHz, DMSO-d6,
1H, J = 14.3, H- ), 8. 05 (d, 1H, J = 14.3, H-
DMSO-d6, , ppm): 114.5–150.9 (Ar–C), 127.7 (CH of alkene
d
, ppm): 7.22–8.43 (m, 14H, Ar–H), 7.69 (d,
(282 MHz, DMSO-d6,
d
, ppm): À118.31 (s, 1F, 4-F); LCMS (m/z): 402
a
b
); 13C NMR (100 MHz,
(M+); Anal. Calcd. For C24H16ClFN2O: C-71.55, H-4.00, N-6.95;
Found: C-71.63, H-4.07, N-6.89%.
d
attched to carbonyl carbon), 148.5 (CH of alkene attched to
pyrazole), 162.4 (C–F of fluorophenyl ring), 168.1 (C–F of 4-
5.3.3. 1-(3-Chlorophenyl)-3-(3-(4-fluorophenyl)-1-phenyl-1H-
fluorophenyl ring), 183.8 (C55O); 19F NMR (282 MHz, DMSO-d6,
d,
pyrazol-4-yl)prop-2-en-1-one (2c)
ppm): À118.30 (s, 1F, 4-F); LCMS (m/z): 386 (M+); Anal. calcd. for
C24H16F2N2O: C-74.60, H-4.17, N-7.25; Found: C-74.54, H-4.24, N-
7.30%.
Yield: 74%; m.p.: 217–219 8C; IR (KBr) n
max/cmÀ1: 3077 (C–H,
aromatic), 3014 (C–H stretching), 1580 (C55N), 1524 (C55C), 1144
(C–F), 967 (C–H bending), 752 (C–Cl stretching); 1H NMR
(300 MHz, DMSO-d6,
1H, J = 14.0, H- ), 8.11 (d, 1H, J = 14.0, H-
DMSO-d6, , ppm): 114.7–150.8 (Ar–C), 127.6 (CH of alkene
d
, ppm): 7.21–8.24 (m, 14H, Ar–H), 7.61 (d,
5.3.8. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-
a
b
); 13C NMR (100 MHz,
nitrophenyl)prop-2-en-1-one (2h)
d
Yield: 79%; m.p.: 196–198 8C; IR (KBr) n
max/cmÀ1: 3074 (C–H,
attched to carbonyl carbon), 148.2 (CH of alkene attched to
pyrazole), 162.6 (C–F of fluorophenyl ring), 183.7 (C55O); 19F NMR
aromatic), 3015 (C–H stretching), 1584 (C55N), 1519 (C55C), 1482,
1356 (NO2), 1157 (C–F), 985 (C–H bending); 1H NMR (300 MHz,
(282 MHz, DMSO-d6,
d
, ppm): À118.27 (s, 1F, 4-F); LCMS (m/z): 402
DMSO-d6,
d
, ppm): 7.26–8.45 (m, 14H, Ar–H), 7.63 (d, 1H, J = 14.5,
); 13C NMR (100 MHz, DMSO-d6,
(M+); Anal. calcd. for C24H16ClFN2O: C-71.55, H-4.00, N-6.95;
Found: C-71.62, H-3.95, N-6.88%.
H- ), 8. 08 (d, 1H, J = 14.5, H-
a
b
d,
ppm): 113.8–150.8 (Ar–C), 127.7 (CH of alkene attched to carbonyl
carbon), 148.7 (CH of alkene attched to pyrazole), 160.4 (C–F of 2-
fluorophenyl ring), 162.7 (C–F of fluorophenyl ring), 183.8 (C55O);
5.3.4. 1-(4-Chlorophenyl)-3-(3-(4-fluorophenyl)-1-phenyl-1H-
pyrazol-4-yl)prop-2-en-1-one (2d)
19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.31 (s, 1F, 4-F); LCMS
Yield: 76%; m.p.: 187–189 8C; IR (KBr)
n
max/cmÀ1: 3064 (C–H,
(m/z): 413 (M+); Anal. calcd. for C24H16FN3O3: C-69.73, H-3.90, N-
aromatic), 3007 (C–H stretching), 1584 (C55N), 1517 (C55C), 1153
(C–F), 985 (C–H bending), 746 (C–Cl Stretching); 1H NMR
10.16; Found: C-69.77, H-3.96, N-10.23%.
(300 MHz, DMSO-d6,
1H, J = 14.6, H- ), 8. 11 (d, 1H, J = 14.6, H-
DMSO-d6, , ppm): 114.7–150.4 (Ar–C), 127.8 (CH of alkene
d
, ppm): 7.20–8.29 (m, 14H, Ar–H), 7.64 (d,
5.3.9. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(3-
a
b
); 13C NMR (100 MHz,
nitrophenyl)prop-2-en-1-one (2i)
d
Yield: 76%; m.p.: 218–220 8C; IR (KBr) n
max/cmÀ1: 3058 (C–H,
attched to carbonyl carbon), 148.5 (CH of alkene attched to
pyrazole), 162.4 (C–F of fluorophenyl ring), 183.2 (C55O); 19F NMR
aromatic), 3011 (C–H stretching), 1578 (C55N), 1528 (C55C), 1477,
1352 (NO2), 1151 (C–F), 974 (C–H bending); 1H NMR (300 MHz,
(282 MHz, DMSO-d6,
d
, ppm): À118.33 (s, 1F, 4-F); LCMS (m/z): 402
DMSO-d6,
d
, ppm): 7.26–8.52 (m, 14H, Ar–H), 7.61 (d, 1H, J = 14.1,
); 13C NMR (100 MHz, DMSO-d6,
(M+); Anal. calcd. for C24H16ClFN2O: C-71.55, H-4.00, N-6.95;
Found: C-71.49, H-3.94, N-7.02%.
H- ), 8. 09 (d, 1H, J = 14.1, H-
a
b
d,
ppm): 114.1–150.1 (Ar–C), 127.2 (CH of alkene attched to carbonyl
carbon), 148.1 (C–NO2), 148.4 (CH of alkene attched to pyrazole),
162.7 (C–F of fluorophenyl ring), 183.8 (C55O); 19F NMR (282 MHz,
5.3.5. 1-(2-Fluorophenyl)-3-(3-(4-fluorophenyl)-1-phenyl-1H-
pyrazol-4-yl)prop-2-en-1-one (2e)
DMSO-d6,
d
, ppm): À118.27 (s, 1F, 4-F); LCMS (m/z): 413 (M+);
Yield: 71%; m.p.: 197–199 8C; IR (KBr)
aromatic), 3010 (C–H stretching), 1581 (C55N), 1515 (C55C), 1152
(C–F), 981 (C–H bending); 1H NMR (300 MHz, DMSO-d6,
, ppm):
7.26–8.45 (m, 14H, Ar–H), 7.63 (d, 1H, J = 14.5, H- ), 8. 08 (d, 1H,
J = 14.5, H- , ppm): 113.8–150.8
); 13C NMR (100 MHz, DMSO-d6,
n
max/cmÀ1: 3055 (C–H,
Anal. calcd. for C24H16FN3O: C-69.73, H-3.90, N-10.16; Found:
C-69.67, H-4.00, N-10.20%.
d
a
5.3.10. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(4-
b
d
nitrophenyl)prop-2-en-1-one (2j)
(Ar–C), 127.7 (CH of alkene attched to carbonyl carbon), 148.7 (CH
of alkene attched to pyrazole), 160.4 (C–F of 2-fluorophenyl ring),
162.7 (C–F of fluorophenyl ring), 183.8 (C55O); 19F NMR (282 MHz,
Yield: 74%; m.p.: 188–190 8C; IR (KBr) n
max/cmÀ1: 3068 (C–H,
aromatic), 3008 (C–H stretching), 1588 (C55N), 1517 (C55C), 1481,
1358 (NO2), 1147 (C–F), 983 (C–H bending); 1H NMR (300 MHz,
DMSO-d6,
DMSO-d6,
d
, ppm): À118.31 (s, 1F, 4-F); LCMS (m/z): 386 (M+);
d
, ppm): 7.25–8.48 (m, 14H, Ar–H), 7.65 (d, 1H, J = 14.0,
); 13C NMR (100 MHz, DMSO-d6,
Anal. calcd. for C24H16F2N2O: C-74.60, H-4.17, N-7.25; Found: C-
74.52, H-4.08, N-7.29%.
H- ), 8. 11 (d, 1H, J = 14.0, H-
a
b
d,
ppm): 114.7–150.4 (Ar–C), 127.3 (CH of alkene attched to carbonyl
carbon), 148.7 (CH of alkene attched to pyrazole), 162.8 (C–F of
fluorophenyl ring), 153.7 (C–NO2), 183.6 (C55O); 19F NMR
5.3.6. 1-(3-Fluorophenyl)-3-(3-(4-fluorophenyl)-1-phenyl-1H-
pyrazol-4-yl)prop-2-en-1-one (2f)
(282 MHz, DMSO-d6,
d
, ppm): À118.30 (s, 1F, 4-F); LCMS (m/z):
Yield: 74%; m.p.: 185–187 8C; IR (KBr)
aromatic), 3010 (C–H stretching), 1582 (C55N), 1522 (C55C), 1157
(C–F), 974 (C–H bending); 1H NMR (300 MHz, DMSO-d6,
, ppm):
7.26–8.47 (m, 14H, Ar–H), 7.64 (d, 1H, J = 14.1, H- ), 8. 06 (d, 1H,
J = 14.1, H- , ppm): 113.8–150.8
); 13C NMR (100 MHz, DMSO-d6,
n
max/cmÀ1: 3058 (C–H,
413 (M+); Anal. calcd. for C24H16FN3O: C-69.73, H-3.90, N-10.16;
Found: C-69.78, H-4.00, N-10.20%.
d
a
5.3.11. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-
b
d
hydroxyphenyl)prop-2-en-1-one (2k)
(Ar–C), 127.7 (CH of alkene attched to carbonyl carbon), 148.8 (CH
of alkene attched to pyrazole), 162.3 (C–F of fluorophenyl ring),
163.1 (C–F of 3-fluorophenyl ring), 183.6 (C55O); 19F NMR
Yield: 76%; m.p.: 221–223 8C; IR (KBr) n
max/cmÀ1: 3416 (O–H
stretching), 3062 (C–H, aromatic), 3009 (C–H stretching), 1578
(C55N), 1523 (C55C), 1480, 1351 (NO2), 1154 (C–F), 980 (C–H

N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
73
bending); 1H NMR (300 MHz, DMSO-d6,
14H, Ar–H), 7.67 (d, 1H, J = 14.2, H- ), 8. 04 (d, 1H, J = 14.2, H-
9.13 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6,
, ppm): 113.4–
d
, ppm): 6.92–8.14 (m,
),
C25H19FN2O: C-78.52, H-5.01, N-7.33; Found: C-78.46, H-4.94,
N-7.27%.
a
b
d
150.7 (Ar–C), 127.9 (CH of alkene attched to carbonyl carbon),
148.4 (CH of alkene attched to pyrazole), 162.7 (C–F of
fluorophenyl ring), 163.4 (C–OH), 183.3 (C55O); 19F NMR
5.3.16. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-
methoxyphenyl)prop-2-en-1-one (2p)
Yield: 78%; m.p.: 176–178 8C; IR (KBr) n
max/cmÀ1: 3070 (C–H,
(282 MHz, DMSO-d6,
d
, ppm): À118.27 (s, 1F, 4-F); LCMS (m/z):
aromatic), 3008 (C–H stretching), 2937 (C–H stretching), 1580
(C55N), 1514 (C55C), 1383 (C–H bending), 1159 (C–F), 986 (C–H
384 (M+); Anal. calcd. for C24H17FN2O2: C-74.99, H-4.46, N-7.29;
Found: C-74.92, H-4.40, N-7.37%.
bending); 1H NMR (300 MHz, DMSO-d6,
d
, ppm): 3.52 (s, 3H, –
OCH3), 7.13–8.44 (m, 14H, Ar–H), 7.64 (d, 1H, J = 14.2, H- ), 8.13
(d, 1H, J = 14.2, H- , ppm): 54.7
); 13C NMR (100 MHz, DMSO-d6,
a
5.3.12. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(3-
b
d
hydroxyphenyl)prop-2-en-1-one (2l)
(OCH3), 111.7–150.4 (Ar–C), 127.4 (CH of alkene attched to
carbonyl carbon), 148.8 (CH of alkene attched to pyrazole), 157.3
(OCH3), 162.8 (C–F of fluorophenyl ring), 184.3 (C55O); 19F NMR
Yield: 76%; m.p.: 202–204 8C; IR (KBr) n
max/cmÀ1: 3410 (O–H
stretching), 3056 (C–H, aromatic), 3012 (C–H stretching), 1584
(C55N), 1534 (C55C), 1483, 1357 (NO2), 1157 (C–F), 984 (C–H
(282 MHz, DMSO-d6,
d
, ppm): À118.25 (s, 1F, 4-F); LCMS (m/z): 398
bending); 1H NMR (300 MHz, DMSO-d6,
d
, ppm): 7.19–8.43 (m,
), 8. 03 (d, 1H, J = 14.4, H- ),
9.17 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6,
, ppm): 113.8–
(M+); Anal. calcd. for C25H19FN2O2: C-75.36, H-4.81, N-7.03;
Found: C-75.30, H-4.87, N-7.09%.
14H, Ar–H), 7.65 (d, 1H, J = 14.4, H-
a
b
d
150.6 (Ar–C), 127.4 (CH of alkene attched to carbonyl carbon),
148.4 (CH of alkene attched to pyrazole), 162.4 (C–F of
fluorophenyl ring), 164.2 (C–OH), 183.7 (C55O); 19F NMR
5.3.17. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(4-
methoxyphenyl)prop-2-en-1-one (2q)
Yield: 75%; m.p.: 165–167 8C; IR (KBr) n
max/cmÀ1: 3087 (C–H,
(282 MHz, DMSO-d6,
d
, ppm): À118.32 (s, 1F, 4-F); LCMS (m/z):
aromatic), 3014 (C–H stretching), 2920 (C–H stretching), 1585
(C55N), 1520 (C55C), 1386 (C–H bending), 1150 (C–F), 961 (C–H
384 (M+); Anal. calcd. for C24H17FN2O2: C-74.99, H-4.46, N-7.29;
Found: C-75.05, H-4.53, N-7.22%.
bending); 1H NMR (300 MHz, DMSO-d6,
d
, ppm): 3.57 (s, 3H, –
OCH3), 7.18–8.48 (m, 14H, Ar–3H), 7.67 (d, 1H, J = 14.5, H- ), 8. 10
(d, 1H, J = 14.5, H- , ppm): 54.3
); 13C NMR (100 MHz, DMSO-d6,
a
5.3.13. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(4-
b
d
hydroxyphenyl)prop-2-en-1-one (2m)
(OCH3), 113.8–150.6 (Ar–C), 127.8 (CH of alkene attched to
carbonyl carbon), 148.6 (CH of alkene attched to pyrazole), 162.8
(C–F of fluorophenyl ring), 166.2 (C–OCH3), 184.6 (C55O); 19F NMR
Yield: 79%; m.p.: 180–182 8C; IR (KBr) n
max/cmÀ1: 3419 (O–H),
3070 (C–H, aromatic), 3011 (C–H stretching), 1587 (C55N), 1526
(C55C), 1482, 1353 (NO2), 1150 (C–F), 987 (C–H bending); 1H NMR
(282 MHz, DMSO-d6,
d
, ppm): À118.34 (s, 1F, 4-F); LCMS (m/z): 398
(300 MHz, DMSO-d6,
1H, J = 14.7, H- ), 8. 07 (d, 1H, J = 14.7, H-
NMR (100 MHz, DMSO-d6, , ppm): 113.8–150.8 (Ar–C), 127.4 (CH
d
, ppm): 6.87–8.44 (m, 14H, Ar–H), 7.61 (d,
(M+); Anal. Calcd. for C25H19FN2O2: C-75.36, H-4.81, N-7.03;
Found: C-75.42, H-4.74, N-6.94%.
a
b
), 9.15 (s, 1H, OH); 13
C
d
of alkene attched to carbonyl carbon), 148.5 (CH of alkene attched
to pyrazole), 162.5 (C–F of fluorophenyl ring), 164.2 (C–OH), 183.6
5.4. General procedure for the preparation of 5-(3-(4-fluorophenyl)-
1-phenyl-1H-pyrazol-4-yl)-3-(aryl)-4,5-dihydro-1H-pyrazole-1-
carbothioamides (3a–q)
(C55O); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.35 (s, 1F, 4-F);
LCMS (m/z): 384 (M+); Anal. calcd. for C24H17FN2O2: C-74.99,
H-4.46, N-7.29; Found: C-74.93, H-4.52, N-7.36%.
A suspension of chalcones (0.01 mol), sodium hydroxide
(0.025 mol) in ethanol (99.5%) (50 mL) and thiosemicarbazide
(0.01 mol) was added. The mixture was refluxed for 8 h. The
products were poured into crushed ice and the solid mass which
separated out was filtered, dried and crystallized from ethanol
(95%).
5.3.14. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-o-
tolylprop-2-en-1-one (2n)
Yield: 77%; m.p.: 194–196 8C; IR (KBr) n
max/cmÀ1: 3062 (C–H,
aromatic), 3009 (C–H stretching), 2932 (C–H stretching), 1578
(C55N), 1523 (C55C), 1385 (C–H bending), 1154 (C–F), 980 (C–H
bending); 1H NMR (300 MHz, DMSO-d6,
d
, ppm): 2.41 (s, 3H,
ÀCH3), 7.21–8.46 (m, 14H, Ar–H), 7.63 (d, 1H, J = 14.5, H- ), 8. 07
(d, 1H, J = 14.5, H- , ppm): 19.2
); 13C NMR (100 MHz, DMSO-d6,
5.4.1. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-phenyl-
a
4,5-dihydro-1H-pyrazole-1-carbothioamide (3a)
b
d
Yield: 63%; m.p.: 156–158 8C; IR (KBr)
(NH2), 3064 (C–H, aromatic), 1579 (C55N), 1513 (C55C), 1330
(C55S), 1150 (C–F); 1H NMR (300 MHz, DMSO-d6,
, ppm): 3.09 (dd,
n
max/cmÀ1: 3442, 3370
(CH3), 113.8–150.4 (Ar–C), 127.6 (CH of alkene attched to carbonyl
carbon), 148.4 (CH of alkene attched to pyrazole), 162.5 (C–F of
fluorophenyl ring), 184.6 (C55O); 19F NMR (282 MHz, DMSO-d6,
ppm): À118.27 (s, 1F, 4-F); LCMS (m/z): 382 (M+); Anal. calcd.
for C25H19FN2O: C-78.52, H-5.01, N-7.33; Found: C-78.58, H-5.08,
N-7.26%.
d
d
,
1H, J = 17.34 Hz, 3.01 Hz, C4-H pyrazoline), 3.86 (dd, 1H,
J = 17.35 Hz, 11.04 Hz, C4-H pyrazoline), 6.11 (dd, 1H,
J = 11.04 Hz, 3.01 Hz, C5-H pyrazoline), 6.88–8.17 (m, 14H, Ar–
H), 8.31 (s, 1H, pyrazole-H), 8.53 (s, 2H, NH2, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 43.2 (C4 of pyrazoline), 63.1 (C5 of
5.3.15. 3-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-p-
pyrazoline), 115.8–150.1 (Ar–C), 156.7 (C55N of pyrazoline), 162.1
(C–F of fluorophenyl ring), 176.3 (C55S); 19F NMR (282 MHz,
tolylprop-2-en-1-one (2o)
Yield: 72%; m.p.: 183–185 8C; IR (KBr)
n
max/cmÀ1: 3075 (C–H,
DMSO-d6,
d
, ppm): À118.38 (s, 1F, 4-F); LCMS (m/z): 441 (M+);
aromatic), 3010 (C–H stretching), 2924 (C–H stretching), 1585
(C55N), 1517 (C55C), 1382 (C–H bending), 1157 (C–F), 964 (C–H
Anal. Calcd. For C25H20FN5S: C-68.01, H-4.57, N-15.86; Found:
C-68.08, H-4.64, N-15.80%.
bending); 1H NMR (300 MHz, DMSO-d6,
d
, ppm): 2.36 (s, 3H, –CH3),
7.31–8.48 (m, 14H, Ar–H), 7.67 (d, 1H, J = 14.2, H- ), 8. 10 (d, 1H,
J = 14.2, H- , ppm): 19.2 (CH3),
); 13C NMR (100 MHz, DMSO-d6,
a
5.4.2. 3-(2-Chlorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
b
d
pyrazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3b)
114.2–150.6 (Ar–C), 127.3 (CH of alkene attched to carbonyl
carbon), 148.6 (CH of alkene attched to pyrazole), 162.8 (C–F of
Yield: 67%; m.p.: 198–200 8C; IR (KBr)
(NH2), 3061 (C–H, aromatic), 1583 (C55N), 1518 (C55C), 1322 (C55S),
1147 (C–F), 715 (C–Cl); 1H NMR (300 MHz, DMSO-d6,
, ppm): 3.19
(dd, 1H, J = 17.44 Hz, 3.08 Hz, C4-H pyrazoline), 3.92 (dd, 1H,
n
max/cmÀ1: 3450, 3365
fluorophenyl ring), 184.6 (C55O); 19F NMR (282 MHz, DMSO-d6,
d
,
d
ppm): À118.27 (s, 1F, 4-F); LCMS (m/z): 382 (M+); Anal. calcd. for

74
N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
J = 17.45 Hz, 11.13 Hz, C4-H pyrazoline), 6.02 (dd, 1H, J = 11.12 Hz,
3.08 Hz, C5-H pyrazoline), 6.90–8.21 (m, 13H, Ar–H), 8.29 (s, 1H,
pyrazole-H), 8.53 (s, 2H, NH2, D2O exch.); 13C NMR (100 MHz,
8.59 (s, 2H, NH2, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d,
ppm): 43.4 (C4 of pyrazoline), 63.2 (C5 of pyrazoline), 114.2–150.2
(Ar–C), 156.3 (C55N of pyrazoline), 159.6 (C–F of fluorophenyl ring),
162.7 (C–F of fluorophenyl ring), 163.1 (C–F of fluorophenyl ring),
DMSO-d6,
d, ppm): 43.4 (C4 of pyrazoline), 63.0 (C5 of pyrazoline),
115.3–150.4 (Ar–C), 156.2 (C55N of pyrazoline), 162.3 (C–F of
176.5 (C55S); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.15 (s, 1F,
fluorophenyl ring), 176.2 (C55S); 19F NMR (282 MHz, DMSO-d6,
d
,
4-F), À119.82 (s, 1F, 3-F); LCMS (m/z): 459 (M+); Anal. Calcd.
For C25H19F2N5S: C-65.34, H-4.17, N-15.24; Found: C-65.28, H-
4.11, N-15.30%.
ppm): À118.09 (s, 1F, 4-F); LCMS (m/z): 475 (M+); Anal. Calcd. For
C
25H19ClFN5S: C-63.09, H-4.02, N-14.71; Found: C-63.01, H-4.08,
N-14.64%.
5.4.7. 3-(4-Fluorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
5.4.3. 3-(3-Chlorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
pyrazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3g)
pyrazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3c)
Yield: 61%; m.p.: 180–182 8C; IR (KBr)
(NH2), 3064 (C–H, aromatic), 1585 (C55N), 1520 (C55C), 1336
(C55S), 1146 (C–F); 1H NMR (300 MHz, DMSO-d6,
, ppm): 3.28 (dd,
n
max/cmÀ1: 3461, 3370
Yield: 62%; m.p.: 177–179 8C; IR (KBr)
(NH2), 3068 (C–H, aromatic), 1577 (C55N), 1523 (C55C), 1327 (C55S),
1151 (C–F), 725 (C–Cl); 1H NMR (300 MHz, DMSO-d6,
, ppm): 3.14
n
max/cmÀ1: 3444, 3362
d
d
1H, J = 17.40 Hz, 3.01 Hz, C4-H pyrazoline), 3.97 (dd, 1H,
J = 17.40 Hz, 11.14 Hz, C4-H pyrazoline), 6.14 (dd, 1H,
J = 11.14 Hz, 3.02 Hz, C5-H pyrazoline), 7.10–8.22 (m, 13H, Ar–
H), 8.35 (s, 1H, pyrazole-H), 8.57 (s, 2H, NH2, D2O exch.); 13C NMR
(dd, 1H, J = 17.48 Hz, 3.07 Hz, C4-H pyrazoline), 3.83 (dd, 1H,
J = 17.48 Hz, 11.12 Hz, C4-H pyrazoline), 6.07 (dd, 1H, J = 11.11 Hz,
3.07 Hz, C5-H pyrazoline), 6.96–8.28 (m, 13H, Ar–H), 8.27 (s, 1H,
pyrazole-H), 8.51 (s, 2H, NH2, D2O exch.); 13C NMR (100 MHz,
(100 MHz, DMSO-d6, d, ppm): 43.7 (C4 of pyrazoline), 63.5 (C5 of
DMSO-d6,
d
, ppm): 43.2 (C4 of pyrazoline), 63.2 (C5 of pyrazoline),
pyrazoline), 115.4–151.0 (Ar–C), 156.6 (C55N of pyrazoline), 163.3
115.1–150.5 (Ar–C), 156.6 (C55N of pyrazoline), 162.1 (C–F of
(C–F of fluorophenyl ring), 165.1 (C–F of fluorophenyl ring), 176.8
fluorophenyl ring), 176.5 (C55S); 19F NMR (282 MHz, DMSO-d6,
d
,
(C55S); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.02 (s, 1F, 4-F),
ppm): À117.68 (s, 1F, 4-F); LCMS (m/z): 475 (M+); Anal. Calcd. For
À118.13 (s, 1F, 4-F); LCMS (m/z): 459 (M+); Anal. Calcd. For
C
25H19ClFN5S: C-63.09, H-4.02, N-14.71; Found: C-62.94, H-4.11,
C25H19F2N5S: C-65.34, H-4.17, N-15.24; Found: C-65.41, H-4.11,
N-14.80%.
N-15.19%.
5.4.4. 3-(4-Chlorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
5.4.8. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(2-
pyrazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3d)
nitrophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3h)
Yield: 60%; m.p.: 189–191 8C; IR (KBr)
(NH2), 3067 (C–H, aromatic), 1581 (C55N), 1525 (C55C), 1326 (C55S),
1156 (C–F); 1H NMR (300 MHz, DMSO-d6,
, ppm): 3.18 (dd, 1H,
n
max/cmÀ1: 3456, 3371
Yield: 66%; m.p.: 156–158 8C; IR (KBr)
(NH2), 3054 (C–H, aromatic), 1588 (C55N), 1517 (C55C), 1485, 1352
(NO2), 1333 (C55S), 1158 (C–F); 1H NMR (300 MHz, DMSO-d6,
n
max/cmÀ1: 3458, 3366
d
d,
J = 17.52 Hz, 3.02 Hz, C4-H pyrazoline), 3.67 (s, 3H, –OCH3), 3.87
(dd, 1H, J = 17.52 Hz, 11.16 Hz, C4-H pyrazoline), 6.04 (dd, 1H,
J = 11.16 Hz, 3.03 Hz, C5-H pyrazoline), 6.92–8.20 (m, 13H, Ar–H),
8.29 (s, 1H, pyrazole-H), 8.54 (s, 2H, NH2, D2O exch.); 13C NMR
ppm): 3.24 (dd, 1H, J = 17.36 Hz, 3.13 Hz, C4-H pyrazoline), 3.92
(dd, 1H, J = 17.36 Hz, 11.08 Hz, C4-H pyrazoline), 6.11 (dd, 1H,
J = 11.08 Hz, 3.13 Hz, C5-H pyrazoline), 7.08–8.30 (m, 13H, Ar–H),
8.33 (s, 1H, pyrazole-H), 8.54 (s, 2H, NH2, D2O exch.); 13C NMR
(100 MHz, DMSO-d6,
d
, ppm): 43.6 (C4 of pyrazoline), 63.0 (C5 of
(100 MHz, DMSO-d6, d, ppm): 43.4 (C4 of pyrazoline), 63.7 (C5 of
pyrazoline), 115.5–150.8 (Ar–C), 156.5 (C55N of pyrazoline), 162.3
(C–F of fluorophenyl ring), 176.2 (C55S); 19F NMR (282 MHz,
pyrazoline), 116.0–151.4 (Ar–C), 156.3 (C55N of pyrazoline), 163.1
(C–F of fluorophenyl ring), 176.4 (C55S); 19F NMR (282 MHz,
DMSO-d6,
d
, ppm): À117.88 (s, 1F, 4-F); LCMS (m/z): 475 (M+);
DMSO-d6,
d
, ppm): À117.73 (s, 1F, 4-F); LCMS (m/z): 486 (M+);
Anal. Calcd. For C25H19ClFN5S: C-63.09, H-4.02, N-14.71; Found:
C-63.16, H-4.07, N-14.77%.
Anal. Calcd. For C25H19FN6O2S: C-61.72, H-3.94, N-17.27; Found:
C-61.77, H-4.01, N-17.17%.
5.4.5. 3-(2-Fluorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
5.4.9. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(3-
pyrazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3e)
nitrophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3i)
Yield: 60%; m.p.: 177–179 8C; IR (KBr)
(NH2), 3077 (C–H, aromatic), 1575 (C55N), 1518 (C55C), 1331 (C55S),
1152 (C–F); 1H NMR (300 MHz, DMSO-d6,
, ppm): 3.23 (dd, 1H,
n
max/cmÀ1: 3459, 3378
Yield: 62%; m.p.: 188–190 8C; IR (KBr)
(NH2), 3070 (C–H, aromatic), 1576 (C55N), 1527 (C55C), 1480, 1354
(NO2), 1333 (C55S), 1160 (C–F); 1H NMR (300 MHz, DMSO-d6,
n
max/cmÀ1: 3474, 3355
d
d,
J = 17.44 Hz, 3.10 Hz, C4-H pyrazoline), 3.90 (dd, 1H, J = 17.44 Hz,
11.12 Hz, C4-H pyrazoline), 6.10 (dd, 1H, J = 11.12 Hz, 3.09 Hz, C5-H
pyrazoline), 6.92–8.20 (m, 13H, Ar–H), 8.29 (s, 1H, pyrazole-H),
8.54 (s, 2H, NH2, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d,
ppm): 3.23 (dd, 1H, J = 17.50 Hz, 3.08 Hz, C4-H pyrazoline), 3.90
(dd, 1H, J = 17.50 Hz, 11.04 Hz, C4-H pyrazoline), 6.13 (dd, 1H,
J = 11.04 Hz, 3.07 Hz, C5-H pyrazoline), 7.06–8.53 (m, 13H, Ar–H),
8.37 (s, 1H, pyrazole-H), 8.60 (s, 2H, NH2, D2O exch.); 13C NMR
ppm): 43.1 (C4 of pyrazoline), 63.5 (C5 of pyrazoline), 115.2–150.5
(Ar–C), 156.6 (C55N of pyrazoline), 159.3 (C–F of fluorophenyl ring),
162.3 (C–F of fluorophenyl ring), 176.5 (C55S); 19F NMR (282 MHz,
(100 MHz, DMSO-d6, d, ppm): 43.2 (C4 of pyrazoline), 63.4 (C5 of
pyrazoline), 115.8–151.7 (Ar–C), 156.5 (C55N of pyrazoline), 163.7
(C–F of fluorophenyl ring), 176.2 (C55S); 19F NMR (282 MHz,
DMSO-d6,
d
, ppm): À118.02 (s, 1F, 4-F), À121.40 (s, 1F, 2-F); LCMS
DMSO-d6,
d
, ppm): À118.12 (s, 1F, 4-F); LCMS (m/z): 486 (M+);
(m/z): 459 (M+); Anal. Calcd. For C25H19F2N5S: C-65.34, H-4.17, N-
Anal. Calcd. For C25H19FN6O2S: C-61.72, H-3.94, N-17.27; Found:
C-61.63, H-3.88, N-17.20%.
15.24; Found: C-65.40, H-4.01, N-15.33%.
5.4.6. 3-(3-Fluorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
5.4.10. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(4-
pyrazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3f)
nitrophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3j)
Yield: 69%; m.p.: 211–213 8C; IR (KBr)
(NH2), 3062 (C–H, aromatic), 1571 (C55N), 1511 (C55C), 1337 (C55S),
1158 (C–F); 1H NMR (300 MHz, DMSO-d6,
, ppm): 3.26 (dd, 1H,
n
max/cmÀ1: 3442, 3383
Yield: 68%; m.p.: 167–169 8C; IR (KBr)
(NH2), 3062 (C–H, aromatic), 1580 (C55N), 1523 (C55C), 1479, 1348
(NO2), 1327 (C55S), 1153 (C–F); 1H NMR (300 MHz, DMSO-d6,
n
max/cmÀ1: 3479, 3358
d
d,
J = 17.47 Hz, 3.07 Hz, C4-H pyrazoline), 3.94 (dd, 1H, J = 17.47 Hz,
11.18 Hz, C4-H pyrazoline), 6.16 (dd, 1H, J = 11.18 Hz, 3.07 Hz, C5-H
pyrazoline), 7.12–8.24 (m, 13H, Ar–H), 8.37 (s, 1H, pyrazole-H),
ppm): 3.25 (dd, 1H, J = 17.38 Hz, 3.06 Hz, C4-H pyrazoline), 3.94
(dd, 1H, J = 17.37 Hz, 11.18 Hz, C4-H pyrazoline), 6.15 (dd, 1H,
J = 11.18 Hz, 3.07 Hz, C5-H pyrazoline), 7.09–8.36 (m, 13H, Ar–H),

N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
75
8.40 (s, 1H, pyrazole-H), 8.59 (s, 2H, NH2, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, , ppm): 43.6 (C4 of pyrazoline), 63.8 (C5 of
pyrazoline), 115.3–151.4 (Ar–C), 156.3 (C55N of pyrazoline), 163.3
(C–F of fluorophenyl ring), 176.6 (C55S); 19F NMR (282 MHz,
ppm): 19.4 (CH3), 43.5 (C4 of pyrazoline), 63.3 (C5 of pyrazoline),
d
115.6–151.8 (Ar–C), 156.3 (C55N of pyrazoline), 163.6 (C–F of
fluorophenyl ring), 176.6 (C55S); 19F NMR (282 MHz, DMSO-d6,
d,
ppm): À118.04 (s, 1F, 4-F); LCMS (m/z): 455 (M+); Anal. Calcd.
For C26H22FN5S: C-68.55, H-4.87, N-15.37; Found: C-68.62, H-4.93,
N-15.30%.
DMSO-d6,
d
, ppm): À118.07 (s, 1F, 4-F); LCMS (m/z): 486 (M+);
Anal. Calcd. For C25H19FN6O2S: C-61.72, H-3.94, N-17.27; Found:
C-61.64, H-4.00, N-17.21%.
5.4.15. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-p-tolyl-
5.4.11. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(2-
4,5-dihydro-1H-pyrazole-1-carbothioamide (3o)
hydroxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3k)
Yield: 66%; m.p.: 211–213 8C; IR (KBr) n
max/cmÀ1: 3447, 3360
Yield: 60%; m.p.: 191–193 8C; IR (KBr)
(NH2), 3411 (O–H), 3061 (C–H, aromatic), 1589 (C55N), 1522 (C55C),
1337 (C55S), 1145 (C–F); 1H NMR (300 MHz, DMSO-d6,
, ppm):
n
max/cmÀ1: 3473, 3388
(NH2), 3046 (C–H, aromatic), 2928 (C–H, methyl), 1580 (C55N),
1511 (C55C), 1388 (C–H bending, methyl), 1331 (C55S), 1165 (C–F);
1H NMR (300 MHz, DMSO-d6,
d, ppm): 2.32 (s, 3H), 3.11 (dd, 1H,
d
3.25 (dd, 1H, J = 17.52 Hz, 3.02 Hz, C4-H pyrazoline), 3.94 (dd, 1H,
J = 17.52 Hz, 11.16 Hz, C4-H pyrazoline), 6.15 (dd, 1H, J = 11.15 Hz,
3.02 Hz, C5-H pyrazoline), 6.87–8.20 (m, 13H, Ar–H), 8.30 (s, 1H,
pyrazole-H), 8.50 (s, 2H, NH2, D2O exch.), 9.10 (s, 1H, OH); 13C NMR
J = 17.50 Hz, 3.11 Hz, C4-H pyrazoline), 3.82 (dd, 1H, J = 17.49 Hz,
11.28 Hz, C4-H pyrazoline), 6.12 (dd, 1H, J = 11.29 Hz, 3.10 Hz, C5-H
pyrazoline), 7.11–8.10 (m, 13H, Ar–H), 8.31 (s, 1H, pyrazole-H),
8.57 (s, 2H, NH2, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d,
(100 MHz, DMSO-d6,
d
, ppm): 43.1 (C4 of pyrazoline), 63.9 (C5 of
ppm): 21.6 (CH3), 43.6 (C4 of pyrazoline), 63.1 (C5 of pyrazoline),
pyrazoline), 115.3–151.2 (Ar–C), 152.7 (C–OH), 156.1 (C55N of
pyrazoline), 163.7 (C–F of fluorophenyl ring), 176.4 (C55S); 19F NMR
115.8–151.7 (Ar–C), 156.3 (C55N of pyrazoline), 163.2 (C–F of
fluorophenyl ring), 176.8 (C55S); 19F NMR (282 MHz, DMSO-d6,
d,
(282 MHz, DMSO-d6,
d
, ppm): À117.84 (s, 1F, 4-F); LCMS (m/z): 457
ppm): À117.78 (s, 1F, 4-F); LCMS (m/z): 455 (M+); Anal. Calcd.
For C26H22FN5S: C-68.55, H-4.87, N-15.37; Found: C-68.48, H-4.80,
N-15.44%.
(M+); Anal. Calcd. For C25H20FN5OS: C-65.63, H-4.41, N-15.31;
Found: C-65.69, H-4.31, N-15.23%.
5.4.12. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(3-
5.4.16. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(2-
hydroxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3l)
methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3p)
Yield: 61%; m.p.: 170–172 8C; IR (KBr)
(NH2), 3415 (O–H), 3075 (C–H, aromatic), 1574 (C55N), 1513 (C55C),
1329 (C55S), 1155 (C–F); 1H NMR (300 MHz, DMSO-d6,
, ppm):
n
max/cmÀ1: 3469, 3361
Yield: 68%; m.p.: 185–187 8C; IR (KBr) n
max/cmÀ1: 3449, 3357
(NH2), 3059 (C–H, aromatic), 2935 (C–H, methyl), 1575 (C55N),
1522 (C55C), 1410 (C–H bending, methyl), 1333 (C55S), 1211 (C–O–
C), 1154 (C–F); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 3.56 (s, 3H),
3.14 (dd, 1H, J = 17.44 Hz, 3.02 Hz, C4-H pyrazoline), 3.86 (dd, 1H,
J = 17.43 Hz, 11.14 Hz, C4-H pyrazoline), 6.14 (dd, 1H, J = 11.15 Hz,
3.03 Hz, C5-H pyrazoline), 6.95–8.17 (m, 13H, Ar–H), 8.36 (s, 1H,
pyrazole-H), 8.55 (s, 2H, NH2, D2O exch.); 13C NMR (100 MHz,
d
3.22 (dd, 1H, J = 17.38 Hz, 3.13 Hz, C4-H pyrazoline), 3.91 (dd, 1H,
J = 17.38 Hz, 11.14 Hz, C4-H pyrazoline), 6.12 (dd, 1H, J = 11.14 Hz,
3.13 Hz, C5-H pyrazoline), 7.01–8.12 (m, 13H, Ar–H), 8.33 (s, 1H,
pyrazole-H), 8.54 (s, 2H, NH2, D2O exch.), 9.14 (s, 1H, OH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 43.4 (C4 of pyrazoline), 63.3 (C5 of
pyrazoline), 114.7–151.5 (Ar–C), 156.1 (C55N of pyrazoline), 158.3
(C–OH), 163.5 (C–F of fluorophenyl ring), 176.7 (C55S); 19F NMR
DMSO-d6, d, ppm): 43.7 (C4 of pyrazoline), 54.7 (OCH3), 63.6 (C5 of
pyrazoline), 111.4–151.6 (Ar–C), 156.3 (C55N of pyrazoline), 160.4
(C–OCH3), 163.5 (C–F of fluorophenyl ring), 176.3 (C55S); 19F NMR
(282 MHz, DMSO-d6,
d
, ppm): À118.09 (s, 1F, 4-F); LCMS (m/z): 457
(M+); Anal. Calcd. For C25H20FN5OS: C-65.63, H-4.41, N-15.31;
Found: C-65.71, H-4.33, N-15.38%.
(282 MHz, DMSO-d6,
d
, ppm): À118.16 (s, 1F, 4-F); LCMS (m/z): 471
(M+); Anal. Calcd. For C26H22FN5OS: C-66.22, H-4.70, N-14.85;
Found: C-66.31, H-4.79, N-14.78%.
5.4.13. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(4-
hydroxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3m)
5.4.17. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(4-
Yield: 67%; m.p.: 145–147 8C; IR (KBr)
(NH2), 3410 (O–H), 3063 (C–H, aromatic), 1581 (C55N), 1524 (C55C),
1332 (C55S), 1151 (C–F); 1H NMR (300 MHz, DMSO-d6,
, ppm):
n
max/cmÀ1: 3456, 3348
methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (3q)
Yield: 66%; m.p.: 174–176 8C; IR (KBr) n
max/cmÀ1: 3455, 3363
d
(NH2), 3050 (C–H, aromatic), 2928 (C–H, methyl), 1584 (C55N),
1517 (C55C), 1416 (C–H bending, methyl), 1324 (C55S), 1204 (C–O–
C), 1143 (C–F); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 3.53 (s, 3H),
3.11 (dd, 1H, J = 17.36 Hz, 3.01 Hz, C4-H pyrazoline), 3.86 (dd, 1H,
J = 17.37 Hz, 11.16 Hz, C4-H pyrazoline), 6.17 (dd, 1H, J = 11.16 Hz,
3.00 Hz, C5-H pyrazoline), 7.03–8.21 (m, 13H, Ar–H), 8.38 (s, 1H,
pyrazole-H), 8.57 (s, 2H, NH2, D2O exch.); 13C NMR (100 MHz,
3.20 (dd, 1H, J = 17.40 Hz, 3.10 Hz, C4-H pyrazoline), 3.87 (dd, 1H,
J = 17.41 Hz, 11.18 Hz, C4-H pyrazoline), 6.17 (dd, 1H, J = 11.18 Hz,
3.11 Hz, C5-H pyrazoline), 6.83–8.17 (m, 13H, Ar–H), 8.29 (s, 1H,
pyrazole-H), 8.58 (s, 2H, NH2, D2O exch.), 9.11 (s, 1H, OH); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 43.2 (C4 of pyrazoline), 63.7 (C5 of
pyrazoline), 115.2–151.4 (Ar–C), 156.5 (C55N of pyrazoline), 160.3
(C–OH), 163.2 (C–F of fluorophenyl ring), 176.3 (C55S); 19F NMR
DMSO-d6, d, ppm): 43.5 (C4 of pyrazoline), 54.3 (OCH3), 63.5 (C5 of
(282 MHz, DMSO-d6,
d
, ppm): À117.92 (s, 1F, 4-F); LCMS (m/z): 457
pyrazoline), 114.2–151.6 (Ar–C), 156.5 (C55N of pyrazoline), 162.6
(C–OCH3), 163.4 (C–F of fluorophenyl ring), 176.8 (C55S); 19F NMR
(M+); Anal. Calcd. For C25H20FN5OS: C-65.63, H-4.41, N-15.31;
Found: C-65.58, H-4.47, N-15.26%.
(282 MHz, DMSO-d6,
d
, ppm): À117.82 (s, 1F, 4-F); LCMS (m/z): 471
(M+); Anal. Calcd. For C26H22FN5OS: C-66.22, H-4.70, N-14.85;
Found: C-66.17, H-4.63, N-14.78%.
5.4.14. 5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-o-tolyl-
4,5-dihydro-1H-pyrazole-1-carbothioamide (3n)
Yield: 62%; m.p.: 188–190 8C; IR (KBr)
n
max/cmÀ1: 3477, 3359
5.5. General procedure for the preparation of 2-(5-(3-(4-
fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(aryl)-4,5-dihydro-1H-
pyrazol-1-yl)thiazol-4(5H)-ones (4a–q)
(NH2), 3056 (C–H, aromatic), 2933 (C–H, methyl), 1588 (C55N),
1517 (C55C), 1401 (C–H bending, methyl), 1338 (C55S), 1160 (C–F);
1H NMR (300 MHz, DMSO-d6,
d, ppm): 2.43 (s, 3H), 3.16 (dd, 1H,
J = 17.44 Hz, 3.10 Hz, C4-H pyrazoline), 3.84 (dd, 1H, J = 17.43 Hz,
11.04 Hz, C4-H pyrazoline), 6.15 (dd, 1H, J = 11.03 Hz, 3.09 Hz, C5-H
pyrazoline), 7.05–8.12 (m, 13H, Ar–H), 8.37 (s, 1H, pyrazole-H),
8.53 (s, 2H, NH2, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d,
To suspension of compounds (3a–q) (0.01 mol) in ethanol
(99.9%), ethyl bromoacetate (0.01 mol) was added and refluxed for
1 h. After cooling, the separated product was filtered and washed.
The product was crystallized from ethanol (99.5%).

76
N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
5.5.1. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-
(s, 1F, 4-F); LCMS (m/z): 515 (M+); Anal. Calcd. For C27H19ClFN5OS:
phenyl-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4a)
C-62.85, H-3.71, N-13.57; Found: C-62.79, H-3.78, N-13.52%.
Yield: 52%; m.p.: 165–167 8C; IR (KBr) n
max/cmÀ1: 3067, 3041
(C–H, aromatic), 2861 (C–H, methylene), 1694 (C55O), 1573 (C55N),
1530 (C55C), 1465 (C–H bending, methylene), 1150 (C–F); LCMS
5.5.5. 2-(3-(2-Fluorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4e)
(m/z): 481 (M+); 1H NMR (300 MHz, DMSO-d6,
d
, ppm): 3.43 (dd,
Yield: 57%; m.p.: 190–192 8C; IR (KBr) n
max/cmÀ1: 3067, 3042
1H, J = 17.52 Hz, 3.13 Hz, C4-H pyrazoline), 3.94 (dd, 1H,
J = 17.51 Hz, 11.12 Hz, C4-H pyrazoline), 4.11 (s, 2H, thiazolone-
C5-H), 6.09 (dd, 1H, J = 11.11 Hz, 3.12 Hz, C5-H pyrazoline), 6.88–
8.13 (m, 14H, Ar–H), 8.32 (s, 1H, pyrazole-H); 13C NMR (100 MHz,
(C–H, aromatic), 2858 (C–H, methylene), 1688 (C55O), 1563 (C55N),
1518 (C55C), 1456 (C–H bending, methylene), 1150 (C–F); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 3.47 (dd, 1H, J = 17.48 Hz, 3.10 Hz,
C4-H pyrazoline), 3.95 (dd, 1H, J = 17.47 Hz, 11.29 Hz, C4-H
pyrazoline), 4.14 (s, 2H, thiazolone-C5-H), 6.16 (dd, 1H,
J = 11.28 Hz, 3.11 Hz, C5-H pyrazoline), 6.96–8.28 (m, 13H, Ar–
H), 8.34 (s, 1H, pyrazole-H); 13C NMR (100 MHz, DMSO-d6,
d, ppm):
DMSO-d6, d, ppm): 39.0 (C5 of thiazolone), 42.3 (C4 of pyrazoline),
60.4 (C5 of pyrazoline), 115.7–151.3 (Ar–C), 159.7 (C55N of
pyrazoline), 162.6 (C–F of fluorophenyl ring), 178.1 (C55N of
thiazolone), 187.5 (C55O of thiazolone); 19F NMR (282 MHz, DMSO-
39.3 (C5 of thiazolone), 42.7 (C4 of pyrazoline), 60.4 (C5 of
pyrazoline), 114.7–151.2 (Ar–C), 159.2 (C55N of pyrazoline), 159.8
(C–F), 162.5 (C–F of fluorophenyl ring), 178.4 (C55N of thiazolone),
d6,
d
, ppm): À118.18 (s, 1F, 4-F); LCMS (m/z): 481 (M+); Anal. Calcd.
For C27H20FN5OS: C-67.34, H-4.19, N-14.54; Found: C-67.42, H-
4.26, N-14.48%.
187.8 (C55O of thiazolone); 19F NMR (282 MHz, DMSO-d6,
d, ppm):
À117.99 (s, 1F, 4-F), À121.45 (s, 1F, 2-F); LCMS (m/z): 499 (M+);
Anal. Calcd. For C27H19F2N5OS: C-64.92, H-3.83, N-14.02; Found: C-
64.87, H-3.88, N-14.11%.
5.5.2. 2-(3-(2-Chlorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4b)
Yield: 50%; m.p.: 165–167 8C; IR (KBr) n
max/cmÀ1: 3059, 3035
(C–H, aromatic), 2855 (C–H, methylene), 1689 (C55O), 1568 (C55N),
1521 (C55C), 1455 (C–H bending, methylene), 1145 (C–F), 740 (C–
5.5.6. 2-(3-(3-Fluorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazols-4(5H)-one (4f)
Cl); 1H NMR (300 MHz, DMSO-d6,
d
,
ppm): 3.48 (dd, 1H,
Yield: 53%; m.p.: 202–204 8C; IR (KBr) n
max/cmÀ1: 3056, 3039
J = 17.40 Hz, 3.02 Hz, C4-H pyrazoline), 3.97 (dd, 1H, J = 17.40 Hz,
11.16 Hz, C4-H pyrazoline), 4.17 (s, 2H, thiazolone-C5-H), 6.11 (dd,
1H, J = 11.17 Hz, 3.02 Hz, C5-H pyrazoline), 6.93–8.27 (m, 13H, Ar–
(C–H, aromatic), 2861 (C–H, methylene), 1692 (C55O), 1570 (C55N),
1512 (C55C), 1467 (C–H bending, methylene), 1141 (C–F); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 3.50 (dd, 1H, J = 17.44 Hz, 3.18 Hz,
C4-H pyrazoline), 3.98 (dd, 1H, J = 17.44 Hz, 11.14 Hz, C4-H
pyrazoline), 4.17 (s, 2H, thiazolone-C5-H), 6.21 (dd, 1H,
J = 11.15 Hz, 3.17 Hz, C5-H pyrazoline), 7.12–8.24 (m, 13H, Ar–
H), 8.39 (s, 1H, pyrazole-H); 13C NMR (100 MHz, DMSO-d6,
d, ppm):
H), 8.34 (s, 1H, pyrazole-H); 13C NMR (100 MHz, DMSO-d6,
d
, ppm):
39.4 (C5 of thiazolone), 42.6 (C4 of pyrazoline), 60.1 (C5 of
pyrazoline), 115.2–150.8 (Ar–C), 159.4 (C55N of pyrazoline), 162.5
(C–F of fluorophenyl ring), 178.4 (C55N of thiazolone), 187.3 (C55O
of thiazolone); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.08 (s,
39.7 (C5 of thiazolone), 42.5 (C4 of pyrazoline), 60.7 (C5 of
pyrazoline), 114.1–151.4 (Ar–C), 159.1 (C55N of pyrazoline), 162.4
(C–F of fluorophenyl ring), 163.4 (C–F), 178.7 (C55N of thiazolone),
1F, 4-F); LCMS (m/z): 515 (M+); Anal. Calcd. For C27H19ClFN5OS: C-
62.85, H-3.71, N-13.57; Found: C-62.79, H-3.77, N-13.50%.
187.5 (C55O of thiazolone); 19F NMR (282 MHz, DMSO-d6,
d, ppm):
5.5.3. 2-(3-(3-Chlorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
À118.07 (s, 1F, 4-F), À119.3 (s, 1F, 3F); LCMS (m/z): 499 (M+); Anal.
Calcd. For C27H19F2N5OS: C-64.92, H-3.83, N-14.02; Found: C-
64.99, H-3.89, N-13.95%.
pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4c)
Yield: 58%; m.p.: 216–218 8C; IR (KBr) n
max/cmÀ1: 3051, 3030
(C–H, aromatic), 2850 (C–H, methylene), 1697 (C55O), 1575 (C55N),
1533 (C55C), 1451 (C–H bending, methylene), 1152 (C–F), 748 (C–
5.5.7. 2-(3-(4-Fluorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
Cl); 1H NMR (300 MHz, DMSO-d6,
d
,
ppm): 3.46 (dd, 1H,
pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4g)
J = 17.47 Hz, 3.07 Hz, C4-H pyrazoline), 3.91 (dd, 1H, J = 17.47 Hz,
11.18 Hz, C4-H pyrazoline), 4.15 (s, 2H, thiazolone-C5-H), 6.14 (dd,
1H, J = 11.18 Hz, 3.08 Hz, C5-H pyrazoline), 6.96–8.25 (m, 13H, Ar–
Yield: 56%; m.p.: 204–206 8C; IR (KBr) n
max/cmÀ1: 3050, 3037
(C–H, aromatic), 2850 (C–H, methylene), 1698 (C55O), 1566 (C55N),
1522 (C55C), 1458 (C–H bending, methylene), 1144 (C–F); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 3.47 (dd, 1H, J = 17.47 Hz, 3.07 Hz,
H), 8.31 (s, 1H, pyrazole-H); 13C NMR (100 MHz, DMSO-d6,
d
, ppm):
39.2 (C5 of thiazolone), 42.6 (C4 of pyrazoline), 60.3 (C5 of
pyrazoline), 115.6–150.5 (Ar–C), 159.7 (C55N of pyrazoline), 162.9
(C–F of fluorophenyl ring), 178.3 (C55N of thiazolone), 187.2 (C55O
C4-H pyrazoline), 3.95 (dd, 1H, J = 17.47 Hz, 11.18 Hz, C4-H
pyrazoline), 4.21 (s, 2H, thiazolone-C5-H), 6.25 (dd, 1H,
J = 11.18 Hz, 3.07 Hz, C5-H pyrazoline), 7.16–8.33 (m, 13H, Ar–
of thiazolone); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À117.97 (s,
H), 8.37 (s, 1H, pyrazole-H); 13C NMR (100 MHz, DMSO-d6,
d, ppm):
1F, 4-F); LCMS (m/z): 515 (M+); Anal. Calcd. For C27H19ClFN5OS:
39.5 (C5 of thiazolone), 42.7 (C4 of pyrazoline), 60.4 (C5 of
pyrazoline), 115.1–151.8 (Ar–C), 159.4 (C55N of pyrazoline), 162.5
(C–F of fluorophenyl ring), 165.1 (C–F), 178.5 (C55N of thiazolone),
C-62.85, H-3.71, N-13.57; Found: C-62.91, H-3.66, N-13.63%.
5.5.4. 2-(3-(4-Chlorophenyl)-5-(3-(4-fluorophenyl)-1-phenyl-1H-
187.3 (C55O of thiazolone); 19F NMR (282 MHz, DMSO-d6,
d, ppm):
pyrazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4d)
À118.03 (s, 1F, 4-F), À118.12 (s, 1F, 4-F); LCMS (m/z): 499 (M+);
Anal. Calcd. For C27H19F2N5OS: C-64.92, H-3.83, N-14.02; Found:
C-64.87, H-3.77, N-14.09%.
Yield: 53%; m.p.: 180–182 8C; IR (KBr) n
max/cmÀ1: 3041, 3035
(C–H, aromatic), 2861 (C–H, methylene), 1700 (C55O), 1567 (C55N),
1524 (C55C), 1461 (C–H bending, methylene), 1145 (C–F), 753 (C–
Cl); 1H NMR (300 MHz, DMSO-d6,
d
,
ppm): 3.42 (dd, 1H,
5.5.8. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(2-
J = 17.42 Hz, 3.10 Hz, C4-H pyrazoline), 3.94 (dd, 1H, J = 17.41 Hz,
11.29 Hz, C4-H pyrazoline), 4.18 (s, 2H, thiazolone-C5-H), 6.18 (dd,
1H, J = 11.28 Hz, 3.10 Hz, C5-H pyrazoline), 6.92–8.20 (m, 13H, Ar–
nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4h)
Yield: 51%; m.p.: 184–186 8C; IR (KBr) n
max/cmÀ1: 3067, 3046
(C–H, aromatic), 2868 (C–H, methylene), 1694 (C55O), 1561 (C55N),
1512 (C55C), 1462 (C–H bending, methylene), 1481, 1359 (NO2),
1153 (C–F); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 3.44 (dd, 1H,
J = 17.34 Hz, 3.13 Hz, C4-H pyrazoline), 3.93 (dd, 1H, J = 17.35 Hz,
11.04 Hz, C4-H pyrazoline), 4.18 (s, 2H, thiazolone-C5-H), 6.23 (dd,
1H, J = 11.05 Hz, 3.13 Hz, C5-H pyrazoline), 7.06–8.27 (m, 13H,
H), 8.36 (s, 1H, pyrazole-H); 13C NMR (100 MHz, DMSO-d6,
d, ppm):
39.6 (C5 of thiazolone), 42.2 (C4 of pyrazoline), 60.8 (C5 of
pyrazoline), 115.1–150.7 (Ar–C), 159.3 (C55N of pyrazoline), 162.6
(C–F of fluorophenyl ring), 178.5 (C55N of thiazolone), 187.7 (C55O
of thiazolone); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.11

N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
77
Ar–H), 8.34 (s, 1H, pyrazole-H); 13C NMR (100 MHz, DMSO-d6,
d
,
1586 (C55N), 1516 (C55C), 1466 (C–H bending, methylene), 1154
(C–F); 1H NMR (300 MHz, DMSO-d6,
, ppm): 3.34 (dd, 1H,
J = 17.40 Hz, 3.08 Hz, C4-H pyrazoline), 3.81 (dd, 1H, J = 17.41 Hz,
11.28 Hz, C4-H pyrazoline), 4.14 (s, 2H, thiazolone-C5-H), 6.12 (dd,
1H, J = 11.28 Hz, 3.07 Hz, C5-H pyrazoline), 7.02–8.14 (m, 13H, Ar–
H), 8.31 (s, 1H, pyrazole-H), 9.15 (s, 1H, OH); 13C NMR (100 MHz,
ppm): 39.2 (C5 of thiazolone), 42.4 (C4 of pyrazoline), 60.7 (C5 of
pyrazoline), 115.7–151.2 (Ar–C), 159.7 (C55N of pyrazoline), 162.3
(C–F of fluorophenyl ring), 178.4 (C55N of thiazolone), 187.1 (C55O
d
of thiazolone); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.10 (s,
1F, 4-F); LCMS (m/z): 526 (M+); Anal. Calcd. For C27H19FN6O3S:
C-61.59, H-3.64, N-15.96; Found: C-61.67, H-3.70, N-15.90%.
DMSO-d6, d, ppm): 39.2 (C5 of thiazolone), 42.4 (C4 of pyrazoline),
60.7 (C5 of pyrazoline), 115.3–151.6 (Ar–C), 159.5 (C55N of
pyrazoline), 158.4 (C–OH), 162.2 (C–F of fluorophenyl ring),
178.3 (C55N of thiazolone), 187.6 (C55O of thiazolone); 19F NMR
5.5.9. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(3-
nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4i)
Yield: 51%; m.p.: 176–178 8C; IR (KBr)
n
max/cmÀ1: 3062, 3040
(282 MHz, DMSO-d6,
d
, ppm): À118.11 (s, 1F, 4-F); LCMS (m/z): 497
(C–H, aromatic), 2877 (C–H, methylene), 1698 (C55O), 1568
(C55N), 1517 (C55C), 1457 (C–H bending, methylene), 1485, 1352
(NO2), 1160 (C–F); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 3.42 (dd,
(M+); Anal. Calcd. For C27H20FN5O2S: C-65.18, H-4.05, N-14.08;
Found: C-65.13, H-4.12, N-14.01%.
1H, J = 17.42 Hz, 3.10 Hz, C4-H pyrazoline), 3.96 (dd, 1H,
J = 17.43 Hz, 11.12 Hz, C4-H pyrazoline), 4.21 (s, 2H, thiazolone-
C5-H), 6.20 (dd, 1H, J = 11.13 Hz, 3.10 Hz, C5-H pyrazoline), 7.01–
8.54 (m, 13H, Ar–H), 8.40 (s, 1H, pyrazole-H); 13C NMR (100 MHz,
5.5.13. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(4-
hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one
(4m)
Yield: 48%; m.p.: 188–190 8C; IR (KBr) n
max/cmÀ1: 3417 (O–H),
DMSO-d6,
d
, ppm): 39.5 (C5 of thiazolone), 42.1 (C4 of pyrazoline),
3070, 3044 (C–H, aromatic), 2866 (C–H, methylene), 1693 (C55O),
1578 (C55N), 1521 (C55C), 1468 (C–H bending, methylene), 1158
60.8 (C5 of pyrazoline), 115.7–151.7 (Ar–C), 159.6 (C55N of
pyrazoline), 162.1 (C–F of fluorophenyl ring), 178.7 (C55N of
thiazolone), 187.7 (C55O of thiazolone); 19F NMR (282 MHz,
(C–F); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 3.31 (dd, 1H,
J = 17.44 Hz, 3.00 Hz, C4-H pyrazoline), 3.77 (dd, 1H, J = 17.45 Hz,
11.15 Hz, C4-H pyrazoline), 4.11 (s, 2H, thiazolone-C5-H), 6.17 (dd,
1H, J = 11.16 Hz, 3.01 Hz, C5-H pyrazoline), 6.81–8.15 (m, 13H, Ar–
H), 8.29 (s, 1H, pyrazole-H), 9.09 (s, 1H, OH); 13C NMR (100 MHz,
DMSO-d6,
d
, ppm): À118.16 (s, 1F, 4-F); LCMS (m/z): 526 (M+);
Anal. Calcd. For C27H19FN6O3S: C-61.59, H-3.64, N-15.96; Found:
C-61.54, H-3.58, N-15.89%.
DMSO-d6, d, ppm): 39.4 (C5 of thiazolone), 42.7 (C4 of pyrazoline),
5.5.10. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(4-
60.3 (C5 of pyrazoline), 115.1–151.4 (Ar–C), 159.5 (C55N of
pyrazoline), 160.3 (C–OH), 162.5 (C–F of fluorophenyl ring),
178.5 (C55N of thiazolone), 187.3 (C55O of thiazolone); 19F NMR
nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4j)
Yield: 50%; m.p.: 152–154 8C; IR (KBr) n
max/cmÀ1: 3057, 3047
(C–H, aromatic), 2871 (C–H, methylene), 1693 (C55O), 1561 (C55N),
1519 (C55C), 1466 (C–H bending, methylene), 1488, 1357 (NO2),
1152 (C–F); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 3.46 (dd, 1H,
(282 MHz, DMSO-d6,
d
, ppm): À118.17 (s, 1F, 4-F); LCMS (m/z): 497
(M+); Anal. Calcd. For C27H20FN5O2S: C-65.18, H-4.05, N-14.08;
Found: C-65.25, H-4.01, N-14.18%.
J = 17.51 Hz, 3.10 Hz, C4-H pyrazoline), 3.94 (dd, 1H, J = 17.51 Hz,
11.14 Hz, C4-H pyrazoline), 4.17 (s, 2H, thiazolone-C5-H), 6.18 (dd,
1H, J = 11.15 Hz, 3.10 Hz, C5-H pyrazoline), 7.07–8.35 (m, 13H, Ar–
5.5.14. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(2-
methylphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4n)
H), 8.47 (s, 1H, pyrazole-H); 13C NMR (100 MHz, DMSO-d6,
d
, ppm):
Yield: 46%; m.p.: 220–222 8C; IR (KBr) n
max/cmÀ1: 3081, 3049
39.0 (C5 of thiazolone), 42.4 (C4 of pyrazoline), 60.3 (C5 of
pyrazoline), 115.5–151.2 (Ar–C), 159.4 (C55N of pyrazoline), 162.6
(C–F of fluoro phenylring), 178.3 (C55N of thiazolone), 187.6 (C55O
(C–H, aromatic), 2921, 2866 (C–H, methyl, methylene), 1690
(C55O), 1574 (C55N), 1515 (C55C), 1401, 1460 (C–H bending, methyl,
methylene), 1155 (C–F); 1H NMR (300 MHz, DMSO-d6,
d, ppm):
2.41 (s, 3H), 3.34 (dd, 1H, J = 17.34 Hz, 3.15 Hz, C4-H pyrazoline),
3.74 (dd, 1H, J = 17.34 Hz, 11.12 Hz, C4-H pyrazoline), 4.14 (s, 2H,
thiazolone-C5-H), 6.13 (dd, 1H, J = 11.13 Hz, 3.14 Hz, C5-H pyrazo-
line), 7.02–8.18 (m, 13H, Ar–H), 8.36 (s, 1H, pyrazole-H); 13C NMR
of thiazolone); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À117.95 (s,
1F, 4-F); LCMS (m/z): 526 (M+); Anal. Calcd. For C27H19FN6O3S:
C-61.59, H-3.64, N-15.96; Found: C-61.63, H-3.60, N-16.02%.
5.5.11. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(2-
hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one
(4k)
(100 MHz, DMSO-d6, d, ppm): 19.7 (CH3), 39.7 (C5 of thiazolone),
42.3 (C4 of pyrazoline), 60.5 (C5 of pyrazoline), 116.1–151.2 (Ar–C),
159.4 (C55N of pyrazoline), 162.5 (C–F of fluorophenyl ring), 178.6
(C55N of thiazolone), 187.2 (C55O of thiazolone); 19F NMR
Yield: 46%; m.p.: 185–187 8C; IR (KBr) n
max/cmÀ1: 3415 (O–H),
3070, 3050 (C–H, aromatic), 2863 (C–H, methylene), 1690 (C55O),
1577 (C55N), 1523 (C55C), 1462 (C–H bending, methylene), 1144
(282 MHz, DMSO-d6,
d
, ppm): À118.07 (s, 1F, 4-F); LCMS (m/z):
495 (M+); Anal. Calcd. For C28H22FN5OS: C-67.86, H-4.47, N-14.13;
Found: C-67.92, H-4.53, N-14.21%.
(C–F); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 3.38 (dd, 1H,
J = 17.38 Hz, 3.02 Hz, C4-H pyrazoline), 3.83 (dd, 1H, J = 17.39 Hz,
11.11 Hz, C4-H pyrazoline), 4.16 (s, 2H, thiazolone-C5-H), 6.17 (dd,
1H, J = 11.11 Hz, 3.03 Hz, C5-H pyrazoline), 6.85–8.24 (m, 13H, Ar–
H), 8.43 (s, 1H, pyrazole-H), 9.13 (s, 1H, OH); 13C NMR (100 MHz,
5.5.15. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(4-
methylphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4o)
Yield: 53%; m.p.: 195–197 8C; IR (KBr) n
max/cmÀ1: 3067, 3040
DMSO-d6,
d
, ppm): 39.5 (C5 of thiazolone), 42.7 (C4 of pyrazoline),
(C–H, aromatic), 2917, 2860 (C–H, methyl, methylene), 1696
60.6 (C5 of pyrazoline), 115.3–151.7 (Ar–C), 159.7 (C55N of
pyrazoline), 162.2 (C–F of fluorophenyl ring), 163.2 (C–OH),
178.7 (C55N of thiazolone), 187.2 (C55O of thiazolone); 19F NMR
(C55O), 1582 (C55N), 1524 (C55C), 1392, 1462 (C–H bending, methyl,
methylene), 1148 (C–F); 1H NMR (300 MHz, DMSO-d6,
d, ppm):
2.44 (s, 3H), 3.28 (dd, 1H, J = 17.40 Hz, 3.18 Hz, C4-H pyrazoline),
3.71 (dd, 1H, J = 17.41 Hz, 11.18 Hz, C4-H pyrazoline), 4.10 (s, 2H,
thiazolone-C5-H), 6.16 (dd, 1H, J = 11.19 Hz, 3.17 Hz, C5-H pyrazo-
line), 6.93–8.15 (m, 13H, Ar–H), 8.37 (s, 1H, pyrazole-H); 13C NMR
(282 MHz, DMSO-d6,
d
, ppm): À118.05 (s, 1F, 4-F); LCMS (m/z): 497
(M+); Anal. Calcd. For C27H20FN5O2S: C-65.18, H-4.05, N-14.08;
Found: C-65.24, H-4.13, N-14.02%.
(100 MHz, DMSO-d6, d, ppm): 21.4 (CH3), 39.4 (C5 of thiazolone),
5.5.12. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(3-
42.6 (C4 of pyrazoline), 60.2 (C5 of pyrazoline), 116.1–150.8 (Ar–C),
159.6 (C55N of pyrazoline), 162.3 (C–F of fluorophenyl ring), 178.2
(C55N of thiazolone), 187.7 (C55O of thiazolone); 19F NMR
hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (4l)
Yield: 53%; m.p.: 179–181 8C; IR (KBr)
3066, 3042 (C–H, aromatic), 2857 (C–H, methylene), 1696 (C55O),
n
max/cmÀ1: 3411 (O–H),
(282 MHz, DMSO-d6,
d
, ppm): À117.88 (s, 1F, 4-F); LCMS (m/z):

78
N.C. Desai et al. / Journal of Fluorine Chemistry 142 (2012) 67–78
495 (M+); Anal. Calcd. For C28H22FN5OS: C-67.86, H-4.47, N-14.13;
Found: C-67.80, H-4.51, N-14.18%.
[4] J.P. Begue, D. Bonnet-Delpon, Journal of Fluorine Chemistry 127 (2006) 992–1012.
[5] K.L. Kirk, Journal of Fluorine Chemistry 127 (2006) 1013–1029.
[6] E. Akbas, I. Berber, European Journal of Medicinal Chemistry 40 (2005) 401–405.
[7] S. Manfredini, R. Bazzanini, P.G. Baraldi, M. Guarneri, D. Simoni, M.E. Marongiu, A.
Pani, P.L. Colla, E. Tramontano, Journal of Medicinal Chemistry 35 (1992)
917–924.
[8] C.W. Noell, C.C. Cheng, Journal of Medicinal Chemistry 14 (1971) 1245–1246.
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Chemistry 44 (2009) 3480–3487.
[10] Z. Ozdemir, H.B. Kandilici, B. Gumusel, U. Calis, A. Bilgin, European Journal of
Medical Chemistry 42 (2007) 373–379.
[11] L. Xinhua, Z. Jing, P. Chunxiu, S. Bao’an, L. Bo, Frontiers of Chemistry in China 3
(2008) 418–421.
5.5.16. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(2-
methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one
(4p)
Yield: 51%; m.p.: 210–212 8C; IR (KBr) n
max/cmÀ1: 3075, 3033
(C–H, aromatic), 2937, 2867 (C–H, methyl, methylene), 1690
(C55O), 1586 (C55N), 1530 (C55C), 1418, 1467 (C–H bending, methyl,
methylene), 1214 (C–O–C), 1152 (C–F); 1H NMR (300 MHz, DMSO-
[12] D. Castagnolo, A. De Logu, M. Radi, B. Bechi, F. Manetti, M. Magnani, et al.
Bioorganic and Medicinal Chemistry 16 (2008) 8587–8591.
[13] A. Palomer, F. Cabre, J. Pascual, J. Campos, M.A. Trujillo, A. Entrena, M.A. Gallo, L.
Garcia, D. Mauleon, A. Espinosa, Journal of Medicinal Chemistry 45 (2002)
1402–1411.
d6, d, ppm): 3.53 (s, 3H), 3.25 (dd, 1H, J = 17.42 Hz, 3.10 Hz, C4-H
pyrazoline), 3.73 (dd, 1H, J = 17.43 Hz, 11.28 Hz, C4-H pyrazoline),
4.13 (s, 2H, thiazolone-C5-H), 6.18 (dd, 1H, J = 11.29 Hz, 3.11 Hz,
C5-H pyrazoline), 6.93–8.18 (m, 13H, Ar–H), 8.32 (s, 1H, pyrazole-
H); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 39.7 (C5 of thiazolone),
[14] S.G. Kucukguzel, S. Rollas, H. Erdeniz, M. Kiraz, A.C. Ekinci, A. Vidin, European
Journal of Medical Chemistry 35 (2000) 761–771.
42.3 (C4 of pyrazoline), 54.6 (OCH3), 60.1 (C5 of pyrazoline), 111.3–
151.4 (Ar–C), 159.5 (C55N of pyrazoline), 160.6 (C–OCH3), 162.6 (C–
F of fluorophenyl ring), 178.4 (C55N of thiazolone), 187.2 (C55O of
[15] M.J. Genin, D.A. Allwine, D.J. Anderson, M.R. Barbachyn, D.E. Emmert, S.A. Garmon,
D.R. Graber, et al. Journal of Medicinal Chemistry 43 (2000) 953–970.
[16] T.S. Jeong, K.S. Kim, S.J. An, K.H. Cho, S. Lee, W.S. Lee, Bioorganic and Medicinal
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Chemistry Letters 14 (2004) 2719–2723.
thiazolone); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À117.95 (s, 1F,
4-F); LCMS (m/z): 511 (M+); Anal. Calcd. For C28H22FN5O2S:
[18] K.D. Hargrave, F.K. Hess, J.T. Oliver, Journal of Medicinal Chemistry 26 (1983)
1158–1163.
C-65.74, H-4.33, N-13.69; Found: C-65.81, H-4.40, N-13.63%.
[19] W.C. Patt, H.W. Hamilton, M.D. Taylor, M.J. Ryan, D.G. Taylor Jr., C.J.C. Connolly,
A.M. Doherty, S.R. Klutchko, I. Sircar, B.A. Steinbaugh, B.L. Batley, C.A. Painchaud,
S.T. Rapundalo, B.M. Michniewicz, S.C. Olson, Journal of Medicinal Chemistry 35
(1992) 2562–2572.
[20] B.S. Holla, K.V. Malini, B.S. Rao, B.K. Sarojini, N.S. Kumari, European Journal of
Medicinal Chemistry 38 (2003) 313–318.
[21] J.C. Jaen, L.D. Wise, B.W. Caprathe, H. Tecle, S. Bergmeier, C.C. Humblet, T.G.
Heffner, L.T. Meltzner, T.A. Pugsley, Journal of Medicinal Chemistry 33 (1990)
311–317.
[22] K. Tsuji, H. Ishikawa, Bioorganic and Medicinal Chemistry Letters 4 (1994) 1601–
1606.
[23] F.W. Bell, A.S. Cantrell, M. Hogberg, S.R. Jaskunas, N.G. Johansson, C.L. Jordon, M.D.
Kinnick, P. Lind, J.M. Morin Jr., R. Noreen, B. Oberg, J.A. Palkowitz, C.A. Parrish, P.
Pranc, C. Sahlberg, R.J. Ternansky, R.T. Vasileff, L. Vrang, S.J. West, H. Zhang,
Journal of Medicinal Chemistry 38 (1995) 4929–4936.
[24] V. Ergenc, G. Capan, N.S. Gunay, S. Ozkirimli, M. Gungor, S. Ozbey, E. Kendi,
Archiv der Pharmazie – Pharmaceutical and Medicinal Chemistry 332 (1999)
343–347.
[25] J.S. Carter, S. Kramer, J.J. Talley, T. Penning, P. Collins, M.J. Graneto, K. Seibert, C.M.
Koboldt, J. Masferrer, B. Zweifel, Bioorganic and Medicinal Chemistry Letters 9
(1999) 1171–1174.
[26] A. Badorc, M.F. Bordes, P. De Cointet, P. Savi, A. Bernat, A. Lale, M. Petitou, J.P.
Maffrand, J.M. Herbert, Journal of Medicinal Chemistry 40 (1997) 3393–3401.
[27] J. Rudolph, H. Theis, R. Hanke, R. Endermann, L. Johannsen, F.U. Geschke, Journal of
Medicinal Chemistry 44 (2001) 619–626.
5.5.17. 2-(5-(3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(4-
methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one
(4q)
Yield: 55%; m.p.: 184–186 8C; IR (KBr) n
max/cmÀ1: 3071, 3044
(C–H, aromatic), 2930, 2864 (C–H, methyl, methylene), 1695
(C55O), 1582 (C55N), 1536 (C55C), 1410, 1458 (C–H bending, methyl,
methylene), 1210 (C–O–C), 1144 (C–F); 1H NMR (300 MHz, DMSO-
d6, d, ppm): 3.57 (s, 3H), 3.22 (dd, 1H, J = 17.50 Hz, 3.18 Hz, C4-H
pyrazoline), 3.77 (dd, 1H, J = 17.51 Hz, 11.29 Hz, C4-H pyrazoline),
4.11 (s, 2H, thiazolone-C5-H), 6.14 (dd, 1H, J = 11.28 Hz, 3.18 Hz,
C5-H pyrazoline), 7.02–8.24 (m, 13H, Ar–H), 8.37 (s, 1H, pyrazole-
H); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 39.7 (C5 of thiazolone),
42.3 (C4 of pyrazoline), 54.8 (OCH3), 60.4 (C5 of pyrazoline), 114.1–
151.7 (Ar–C), 159.2 (C55N of pyrazoline), 160.4 (C–OCH3), 162.4 (C–
F of fluorophenyl ring), 178.5 (C55N of thiazolone), 187.5 (C55O of
thiazolone); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.14 (s, 1F,
4-F); LCMS (m/z): 511 (M+); Anal. Calcd. For C28H22FN5O2S:
C-65.74, H-4.33, N-13.69; Found: C-65.69, H-4.28, N-13.75%.
[28] S. Oncu, M. Punar, H. Eraksoy, Chemotherapy 50 (2004) 98–100.
[29] N.C. Desai, K.M. Rajpara, V.V. Joshi, H.V. Vaghani, H.M. Satodiya, Anti-Infective
Agents 10 (2012) 75–86.
Acknowledgment
[30] N.C. Desai, M.R. Pandya, K.M. Rajpara, V.V. Joshi, H.V. Vaghani, H.M. Satodiya,
Medicinal Chemistry Research (2012), http://dx.doi.org/10.1007/s00044-012-
9988-y.
[31] N.C. Desai, D.D. Pandya, V.V. Joshi, K.M. Rajpara, H.V. Vaghani, H.M. Satodiya,
Medicinal Chemistry Research (2012), http://dx.doi.org/10.1007/s00044-012-
9990-4.
We express sincere gratitude to the Department of Chemistry,
Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavna-
gar University, Bhavnagar for providing research and library
facilities.
[32] N.C. Desai, D.D. Pandya, H.M. Satodiya, K.M. Rajpara, V.V. Joshi, H.V. Vaghani,
Medicinal Chemistry Research (2012), http://dx.doi.org/10.1007/s00044-012-
9980-6.
Appendix A. Supplementary data
[33] N.C. Desai, A.S. Maheta, K.M. Rajpara, V.V. Joshi, H.V. Vaghani, H.M. Satodiya,
Journal of Saudi Chemical Society (2011), http://dx.doi.org/10.1016/j.jscs.2011.
11.021.
[34] D.I. Brahmbhatt, A.R. Kaneria, A.K. Patel, N.H. Patel, Indian Journal of Chemistry
49B (2010) 971–977.
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.jfluchem.2012.06.021.
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Broth Dilution Antifungal Testing of Yeasts, Proposed Standard, NCCLS Document
M27-P, Villanova, PA, 1992.
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