Microwave induced synthesis of fluorobenzamides containing thiazole and thiazolidine as promising antimicrobial analogs

Article abstract of DOI:10.1016/j.jfluchem.2012.10.012

New 5-arylidene derivatives, which bear a fluorine atom in the 4th position of the benzoyl group as starting compound, have been synthesized by the condensation of 4-fluoro-N-(4-methyl-5-(2-(4-oxo-3-phenylthiazolidin-2-ylidene) hydrazinecarbonyl)thiazol-2-yl)benzamide and Knoevenagel condensation with aromatic aldehydes to form N-(5-(2-(5-(arylidene)-4-oxo-3-phenylthiazolidin-2- ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-fluorobenzamides (6a-o) through conventional and microwave methods. The structures of synthesized compounds were established by spectroscopic as well as spectrometric techniques (IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR spectroscopy and mass spectrometry). Antimicrobial screening of 5-arylidene derivatives 6a-o was done against Gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and fungi (Candida albicans, Aspergillus niger, and Aspergillus clavatus) using serial broth dilution method. Compounds 6g and 6j were found to be most active at MIC 12.5 μg/mL against selected bacterial strains and compound 6e was found to be most active at MIC 25 μg/mL against selected fungal strains. It has been further observed that the presence of fluorine atom at the 4th position of the benzoyl group in the final compounds is essential for enhancing the antimicrobial activity.

Full text of DOI:10.1016/j.jfluchem.2012.10.012

Journal of Fluorine Chemistry 145 (2013) 102–111
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Microwave induced synthesis of fluorobenzamides containing thiazole and
thiazolidine as promising antimicrobial analogs
*
N.C. Desai , K.M. Rajpara, V.V. Joshi
Division of Medicinal Chemistry, Department of Chemistry, Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji 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:
New 5-arylidene derivatives, which bear a fluorine atom in the 4th position of the benzoyl group as
starting compound, have been synthesized by the condensation of 4-fluoro-N-(4-methyl-5-(2-(4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)thiazol-2-yl)benzamide and Knoevenagel condensa-
tion with aromatic aldehydes to form N-(5-(2-(5-(arylidene)-4-oxo-3-phenylthiazolidin-2-ylidene)hy-
drazinecarbonyl)-4-methylthiazol-2-yl)-4-fluorobenzamides (6a–o) through conventional and
microwave methods. The structures of synthesized compounds were established by spectroscopic as
well as spectrometric techniques (IR, 1H NMR, 13C NMR, 19F NMR spectroscopy and mass spectrometry).
Antimicrobial screening of 5-arylidene derivatives 6a–o was done against Gram-positive bacteria
(Staphylococcus aureus and Streptococcus pyogenes), Gram-negative bacteria (Escherichia coli and
Pseudomonas aeruginosa) and fungi (Candida albicans, Aspergillus niger, and Aspergillus clavatus) using
Received 21 June 2012
Received in revised form 6 October 2012
Accepted 17 October 2012
Available online 29 October 2012
Keywords:
Thiazole
Thiazolidine
Microwave
Antibacterial activity
Antifungal activity
MIC
serial broth dilution method. Compounds 6g and 6j were found to be most active at MIC 12.5
mg/mL
against selected bacterial strains and compound 6e was found to be most active at MIC 25 g/mL against
m
selected fungal strains. It has been further observed that the presence of fluorine atom at the 4th position
of the benzoyl group in the final compounds is essential for enhancing the antimicrobial activity.
ß 2012 Elsevier B.V. All rights reserved.
1. Introduction
attractive aspect in the development of more active and selective
drug candidates.
Previously from our laboratory [1], we have reported N-(5-(2-
(5-(arylidene)-4-oxo-3-phenylthiazolidin-2-ylidene)hydrazine-
carbonyl)-4-methylthiazol-2-yl)benzamides (NCD1-15) and these
compounds were screened against Gram-positive, Gram-negative
bacteria and fungi. In an effort to improve the antimicrobial
activity through continued broad screen evaluation, we have been
interested in the effect of structural variations on the 4th position
of the benzoyl group by introducing fluorine atom. There are no
reports of antimicrobial activity of N-(5-(2-(5-(arylidene)-4-oxo-
3-phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthia-
zol-2-yl)-4-fluorobenzamides (6a–o). Fluorine has played a pivotal
role in novel drug discovery for modulating physical and biological
properties of the molecules [2–5]. Incorporation of one or several
fluorine atoms into an organic molecule may enhance its biological
activity, bioavailability, metabolic stability and lipophilicity.
Intrinsic properties of fluorine atom, such as high electronegativi-
ty, small atomic radius, and low polarizability of the C–F bond [6]
impart significant improvement on the biological activity of
fluorinated molecules. Thus, fluorine substitution remains an
Thiazoles and their derivatives have attracted continuing
interest over the years because of their varied biological activities
[7,8], and have recently found prominent place in drug develop-
ment for the treatment of allergies [9], hypertension [10],
inflammation [11], bacterial [12], HIV infections [13], hypnotics
[14], treatment of pain [15] and as new inhibitors of bacterial DNA
gyrase B [16]. Thiazole derivatives are also widely used for the
synthesis of sulfathiazole [17] and penicillin (antibiotic). They
showed promising antifungal activity [18].
The microwave-oven induced enhancement of organic
reactions is currently a focus of attention for chemists due to
the decreased reaction times, improved yields and easier work
up, as compared to conventional methods [19–21]. To avoid
accidents in microwave synthesis, low boiling, toxic, and
poisonous solvents are often avoided. The use of microwave
for the synthesis of organic compounds has proved to be
efficient, safe and an environmentally benign technique with
shorter reaction time [22]. In view of the above findings, we
have identified fluorine containing novel candidates that may be
of value in development of new, potent, selective and less toxic
antimicrobial agents. In the present paper, we have tried to
explore the possibility of a greener route with the help of
microwave assisted techniques for the synthesis of hybrid
* 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.2012.10.012

N.C. Desai et al. / Journal of Fluorine Chemistry 145 (2013) 102–111
103
Fig. 1. Structure relevance of compounds.
molecules in the form of fluorinated thiazole based thiazolidine
2. Results and discussion
derivatives as possible antimicrobial agents which may furnish
better results. Therefore, this paper describes, for the first time,
microwave synthesis, characterization and in vitro antimicrobial
(antibacterial and antifungal) activity of the synthesized
compounds (6a–o). We have observed some interesting effects
of placing various substituents on the phenyl rings of the
compounds (Fig. 1). A comparison of the results obtained from
the two synthetic approaches indicate that the effect of
microwave irradiation is not purely thermal, besides giving
decreased reaction times and improved yields (Table 3).
2.1. Chemistry
The synthetic pathways to obtain intermediate and target
compounds in this study are depicted in Scheme 1. Ethyl 2-(4-
fluorobenzamido)-4-methylthiazole-5-carboxylate (2) was pre-
pared by the reaction of 2-amino-4-methylthiazole-5-carboxylate
(1) and 4-fluorobenzoyl chloride by conventional and microwave
methods.Whencompound2wasreactedwithhydrazinehydrate, 4-
fluoro-N-(5-(hydrazinecarbonyl)-4-methylthiazol-2-yl)benzamide
Scheme 1. Synthetic route for the synthesis of final compounds 6a–o by conventional and microwave methods.

104
N.C. Desai et al. / Journal of Fluorine Chemistry 145 (2013) 102–111
Scheme 2. Plausible mechanistic pathway for the synthesis of compound 5.
(3) was obtained. Reacting hydrazide (3) with phenyl isothiocyanate
afforded 4-fluoro-N-(4-methyl-5-(2-(phenylcarbamothioyl)hydra-
zinecarbonyl)thiazol-2-yl)benzamide (4). The structure of com-
pound 4 was determined by spectral data. Next, the obtained
product 4 was furtherconvertedinto compound 5bytreatment with
monochloro acetic acid and anhydrous sodium acetate. A Mecha-
nism for formation of intermediate compound 5 is shown in Scheme
2. The structure of4-fluoro-N-(4-methyl-5-(2-(4-oxo-3-phenylthia-
zolidin-2-ylidene)hydrazinecarbonyl)thiazol-2-yl)benzamide (5)
was confirmed with the help of analytical techniques, viz., IR
spectrum which showed strong absorption bands at 1686, 1693 and
1715 cmÀ1 due to carbonyl groups. The high frequency region of IR
spectrum contains secondary amines stretching vibration at 3273
and 3225 cmÀ1. In addition, 1H NMR spectrum revealed the
1716 cmÀ1 were characteristic of carbonyl groups. Its 1H NMR
spectrum revealed singlet at
linkage and absence of peak at
d
= 7.86 ppm assignable to CH55C
d
= 3.79 and 4.10 ppm confirmed the
formation of Knoevenagel product. Protons of methyl group
displayed a singlet at = 2.46 ppm. Protons of secondary amines
in amide linkages appeared as a singlet at = 7.94 and 10.20 ppm,
d
d
which were confirmed by the disappearance of peak when
exchanged withD2O. Aromatic protons showed a multiplet centered
on
revealed twenty three nonequivalent carbons. The carbonyl carbons
displayedchemicalshiftsat = 166.5, 167.3and168.5 ppm.Another
important signal was displayed at = 145.7 ppm which is charac-
teristic of CH55C. Carbon C5 of thiazolidinone displayed a chemical
shift at = 116.5 ppm and the absence of a peak at = 30.2 ppm
d
= 7.28–8.14 ppm. The 13C NMR spectrum of compound 6a
d
d
d
d
appearance of peaks (two doublets) at
integratingtwoprotonsofmethylenegroup ofthiazolidineringwith
coupling constant of nearly 15.60 Hz. 13C NMR spectrum confirmed
d
= 3.79 and 4.10 ppm
confirmed the formation of Knoevenagel product. Moreover, the
mass spectrum of compound 6a showed a molecular ion peak at m/
z = 557 (M+) corresponding to molecular formula C28H20FN5O3S2.
The spectral values for all the compounds and C, H, and N analyses
are given in Section 4.
the proposed structure due to appearance of signal at
of carbonyl carbon as well as appearance of signal around
= 30.2 ppm assignable to methylene group of thiazolidine ring.
d = 171.7 ppm
d
Moreover, the mass spectrum of compound 5 showed a molecular
ion peak at m/z = 469 (M+) corresponding to a molecular formula
2.2. Antimicrobial activity
C
21H16FN5O3S2. The resulting intermediate 5 was subjected to
All of the newly synthesized compounds were evaluated
against Gram-positive bacteria (Staphylococcus aureus and Staphy-
lococcus pyogenes), Gram-negative bacteria (Escherichia coli and
Pseudomonas aeruginosa) and fungi (Candida albicans, Aspergillus
niger and Aspergillus clavatus). Individual minimum inhibitory
Knoevenagel condensation with aromatic aldehydes to form target
compounds N-(5-(2-(5-(arylidene)-4-oxo-3-phenylthiazolidin-2-
ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-chlorobenza-
mides (6a–o). Structures of products 6a–o were confirmed on basis
of spectral data. For example, the IR spectrum of compound 6a
showed characteristic absorption bands of secondary amines at
3364 and 3329 cmÀ1. Absorption bands displayed at 1682, 1694 and
concentration (MIC,
mg/mL) values of tested compounds 6a–o
against the test microbes are listed in Tables 1 and 2. Results
revealed that the majority of synthesized compounds showed
Table 1
Results of antibacterial screening of compounds 6a–o.
Sr. No.
-R
Minimum inhibitory concentration (MIC) for bacteria (
mg/mL) Æ SD
E. coli MTCC 443
P. aeruginosa MTCC 1688
S. aureus MTCC 96
S. pyogenes MTCC 442
6a
6b
6c
6d
6e
6f
-H
500 Æ 4.16
250 Æ 2.58**
500 Æ 4.04*
50 Æ 1.60
100 Æ 3.21
100 Æ 4.04*
50 Æ 1.60**
100 Æ 3.78
25 Æ 1.16**
500 Æ 3.64
50 Æ 1.05***
50 Æ 3.78*
250 Æ 4.60**
100 Æ 3.64*
250 Æ 4.04
100 Æ 4.16
500 Æ 3.78**
250 Æ 3.52*
50 Æ 1.60***
100 Æ 2.64*
250 Æ 2.58
50 Æ 2.58***
500 Æ 1.60
500 Æ 4.72**
500 Æ 4.16*
500 Æ 4.04
1000 Æ 2.88
100 Æ 1.52
500 Æ 2.88
50 Æ 3.60***
250 Æ 3.64
100 Æ 4.50
25 Æ 3.52**
250 Æ 4.72
12.5 Æ 3.56*
50 Æ 2.60**
100 Æ 4.50**
25 Æ 1.50*
500 Æ 4.04**
250 Æ 3.78
250 Æ 2.05
250 Æ 3.52
500 Æ 3.78*
100 Æ 2.08
-2-OH
-3-OH
-4-OH
-2-CH3
-3-CH3
-4-CH3
-2-OCH3
-3-OCH3
-4-OCH3
-2-Cl
100 Æ 3.21
250 Æ 2.60*
25 Æ 1**
6g
6h
6i
250 Æ 3.78
100 Æ 2.60**
12.5 Æ 1.18***
250 Æ 2.04
500 Æ 3.78
1000 Æ 1.60
500 Æ 4.16**
250 Æ 3.78**
250 Æ 2.15
100 Æ 1.20**
100 Æ 1.52
500 Æ 4.16*
250 Æ 2.05*
250 Æ 3.52***
1000 Æ 2.56
250 Æ 4.61
100 Æ 0.98
6j
6k
6l
-4-Cl
6m
6n
6o
-2-NO2
-4-NO2
-4-F
Ampicillin
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.

N.C. Desai et al. / Journal of Fluorine Chemistry 145 (2013) 102–111
105
Table 2
Results of antifungal screening of compounds 6a–o.
Sr. No.
-R
Minimum inhibitory concentration (MIC) for fungi (
m
g/mL) Æ SD
C. albicans MTCC 227
A. niger MTCC 282
A. clavatus MTCC 1323
6a
6b
6c
6d
6e
6f
-H
1000 Æ 4.16
100 Æ 2.05
250 Æ 3.46*
50 Æ 3.52***
100 Æ 4.04**
250 Æ 3.60
100 Æ 4.50**
250 Æ 1.16
500 Æ 1.60
100 Æ 3.46*
1000 Æ 4.50
500 Æ 4.72**
500 Æ 1.18**
500 Æ 2.64
250 Æ 4.16**
500 Æ 0.58
250 Æ 3.78
50 Æ 3.46**
50 Æ 2.50***
250 Æ 4.16
25 Æ 1**
250 Æ 2.05*
100 Æ 3.78
250 Æ 4.16*
100 Æ 3.78*
25 Æ 3.60*
-2-OH
-3-OH
-4-OH
-2-CH3
-3-CH3
-4-CH3
-2-OCH3
-3-OCH3
-4-OCH3
-2-Cl
100 Æ 4.04**
100 Æ 1.50
50 Æ 2.05***
250 Æ 4.04
100 Æ 2.88*
250 Æ 1.58
1000 Æ 4.16
1000 Æ 2.64*
500 Æ 3.78*
250 Æ 2.64*
100 Æ 1.16
250 Æ 4.04
50 Æ 2.64***
50 Æ 3.78**
100 Æ 4.72**
50 Æ 1.60*
6g
6h
6i
6j
6k
6l
250 Æ 3.52***
500 Æ 4.04
1000 Æ 1.00
250 Æ 4.70**
1000 Æ 2.52
100 Æ 1.10
-4-Cl
6m
6n
6o
-2-NO2
-4-NO2
-4-F
Griseofulvin
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.
Table 3
Reaction conditions and physical parameters for compounds 6a–o.
Sr. No.
-R
Reaction time (h) for
conventional method
Yield (%) for
Reaction time (min) for
microwave method
Yield (%) for
M.P. (8C)
conventional method
microwave method
6a
6b
6c
6d
6e
6f
-H
5
4
6
4
5
4
6
5
4
6
7
5
5
6
7
46
42
44
42
48
45
41
46
43
43
40
45
42
44
42
3
5
4
3
6
4
3
6
4
3
5
6
4
3
5
53
55
52
50
57
59
54
56
53
52
50
57
59
58
51
167–169
199–201
178–180
200–202
192–194
220–222
172–174
245–247
234–236
210–212
187–189
197–199
215–217
179–181
204–206
-2-OH
-3-OH
-4-OH
-2-CH3
-3-CH3
-4-CH3
-2-OCH3
-3-OCH3
-4-OCH3
-2-Cl
6g
6h
6i
6j
6k
6l
-4-Cl
6m
6n
6o
-2-NO2
-4-NO2
-4-F
varying degrees of inhibition against the test panel of species. The
assessed antimicrobial activity of compounds could be correlated
to structural variations and ramifications. Intermediate compound
3, showed poor antibacterial activity against almost all tested
and 6h (2-OCH3) exhibited good activity at MIC = 50
against S. pyogenes.
MIC values of antifungal activity exhibited similar trend as
antibacterial activity. Intermediate 3 showed poor inhibitory effect
mg/mL
bacterial strains at MIC ꢀ 1000
m
g/mL and intermediate
4
against C. albicans and A. clavatus (MIC = 1000
strains). Similarly intermediate 4 exhibited poor inhibitory effect
against A. niger and A. clavatus (MIC = 1000 g/mL for the both
strains). Thiazolidine precursor 5 displayed moderate inhibitory
action against A. clavatus (MIC = 250 g/mL). Table 2 reveals that
mg/mL for both
displayed mild antibacterial activity at MIC = 500
m
g/mL against
E. coli, S. aureus and S. pyogenes. Furthermore, thiazolidine
intermediate 5 displayed feeble antibacterial activity against P.
aeruginosa and S. pyogenes at MIC = 500
m
m
g/mL and moderate
m
activity against S. aureus at MIC = 250 g/mL. Table 1 shows that
final Knoevenagel compounds 6a–o were found to be broad
spectrum antibacterials and displayed significant activity. Com-
m
final compounds 6a–o were found to possess significant activity
against nearly all the tested fungal strains. Compounds 6b (2-OH),
6e (2-CH3), 6g (4-CH3) and 6j (4-OCH3) showed significant activity
pound 6j (4-OCH3) was the most potent at MIC = 12.5
while compounds 6g (4-CH3) and 6d (4-OH) showed excellent
inhibition at MIC = 25 and 50 g/mL, respectively, against E. coli.
Compounds 6e (2-CH3) exhibited excellent activity at MIC = 25 g/
mL, while compounds 6c (3-OH), 6g (4-CH3) and 6h (2-OCH3)
exhibited inhibition at MIC = 50 g/mL against P. aeruginosa.
Compounds 6g (4-CH3) and 6j (4-OCH3) displayed very good
inhibition at MIC = 50 g/mL against S. aureus. Compound 6g (4-
CH3) exhibited highest inhibition at MIC = 12.5 g/mL, while
compounds 6e (2-CH3) and 6j (4-OCH3) exhibited excellent
inhibition at MIC = 25 g/mL, whereas compounds 6b (2-OH)
m
g/mL,
at MIC = 100
activity at MIC = 50
OH), 6c (3-OH) and 6h (2-OCH3) exhibited inhibition at
MIC = 50 g/mL, while compound 6e (2-CH3) exhibited enhance-
ment in activity at MIC = 25 g/mL against A. niger. Compounds 6g
(4-CH3), 6h (2-OCH3) and 6j (4-OCH3) were found to be active at
MIC = 50 g/mL, while compound 6e (2-CH3) exhibited improved
activity at MIC = 25 g/mL against A. clavatus. The MIC (minimum
m
g/mL and, compound 6d (4-OH) exhibited excellent
m
g/mL against C. albicans. Compounds 6b (2-
m
m
m
m
m
m
m
m
m
inhibitory concentration) values were determined by comparison
with ampicillin and griseofulvin as reference drugs for antibacte-
rial and antifungal activities.
m

106
N.C. Desai et al. / Journal of Fluorine Chemistry 145 (2013) 102–111
2.3. Structure activity relationship
standard drugs used for screening of bacterial and fungal strains.
The electronic effect also played a role in activity, as can be seen for
the compounds having electron donor character such as methyl
and methoxy groups. Thus, in the future, this class of thiazole
intermediates and new thiazole based thiazolidines may be used as
templates for generating better lead molecules to fight against
bacterial and fungal infections.
Antimicrobial activity of final compounds and precursors
suggested that 4-flourobenzoyl chloride starting material must
be essential for broad spectrum antimicrobial activity. This could
be noticed from our previously observed results on antimicrobial
activity of N-(5-(2-(5-(arylidene)-4-oxo-3-phenylthiazolidin-2-
ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)benzamides [1]
that the presence of fluorine atom at the 4th position of the benzoyl
group was responsible for increasing the activity. Eventually, it can
be inferred from Tables 1 and 2 that compound without any
substitution 6a did not exhibit antimicrobial activity against panel of
microorganisms. Consideration of the relationships between the
structure of the heterocyclic scaffolds 6a–o and the antimicrobial
property, the identity of individual substitutions proved to be
important parameters for influencing the activity of the reported
compounds. In the present case, substitution of the phenyl ring by an
electrondonatinggroups seems tobe better thanthat by the electron
withdrawing substitutions. Compounds bearing 2-CH3, 4-CH3, 4-OH
and 4-OCH3 exhibited excellent activity and were even more potent
than reference drugs. Furthermore, compounds 6d, 6g and 6j were
the most active compounds against C. albicans, S. pyogenes and E. coli,
respectively. Incorporation of bulky electron-withdrawing nitro and
chlorogroupsstronglydiminished theantimicrobialproperty. Itmay
be observed that methyl and methoxy substituents bearing
derivatives are most suitable compounds for achieving the best
antimicrobial spectrum. The reason for this result may be explained
by electron density of the compounds. It has been reported that
electron donating groups increase the electron density which makes
compounds effective against microorganisms and enhance the
antimicrobial activity [23]. Thus, for a compound optimum electron
density is inevitable soastogainsignificantantimicrobial activity. As
a result it can be thought that electron donating ability of methyl and
methoxy leads the compounds 6g and 6j to reach an optimum
density which is important for antimicrobial activity. The enhanced
antimicrobial potency across broad panel of Gram-positive bacteria,
Gram-negative bacteria and fungi may be explained as due to
presence of fluorine atom at the 4th position of the benzoyl group as
the starting compound. In general, compounds 6b, 6d, 6e, 6g and 6j
emerged as compounds exhibiting more noteworthy results due to
the presence of fluorine atom in heterocyclic frame work.
4. Experimental
4.1. General
All reactions except those in aqueous media were carried out by
standard techniques for 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. 1H NMR spectra were recorded on
Varian Gemini 300 MHz and 13C NMR spectra on Varian Mercury-
400 100 MHz in DMSO-d6 as a solvent and tetramethylsilane (TMS)
as an internal standard. All chemical shifts are expressed in ppm,
coupling constants (J) are 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. Synthos-3000, Anton Paar reaction system was used
for microwave synthesis. Anhydrous reactions were carried out in
oven-dried glassware in nitrogen atmosphere.
4.2. Antibacterial assay
Newly synthesized compounds (6a–o) were screened for their
antibacterial activity against Gram-positive bacteria (Staphylococ-
cus aureus (MTCC-96), Streptococcus pyogenes (MTCC-442)) and
Gram-negative bacteria (Escherichia coli (MTCC-443), Pseudomonas
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) [25–28]. 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
3. Conclusion
In conclusion, salient feature of our approach is coupling
microwaves with solvent free technique keeping modernization
and simplification over classical procedure for avoiding the
generation of volatile and toxic organic solvents, which are
corrosive, and an efficient and cheap technology to synthesize
thiazole and thiazolidines. In continuation of our previously
published results [1] and as a part of our current research work,
focus has been given on the development of new fluorine
containing bio-active heterocyclic compounds to pursue more
active scaffolds. Synthesis and preliminary antimicrobial screening
of newer thiazole based thiazolidines have been demonstrated. We
have observed that hydrophobic nature of fluorine atom influence
as substituent group’s physicochemical properties on the activity
of the compounds. This property is useful to a compound to diffuse
through the biological membranes and reach to its site of action.
Due to this reason, hydrophobicity was found to be directly related
to the antimicrobial activity [24]. The presence of hydrophobic
substituent at 4th position of benzoyl moiety provides a positive
influence on antimicrobial activity. Thus, the 4-fluorobenzoyl
group consistently leads to greater activity in the synthesized
compounds. Owing to encouraging results, it was found that
synthesized compounds have a broader range of activity than
concentrations of 1000, 500 and 250
found to be active in primary screening were similarly diluted to
obtain 200, 125, 100, 62.5, 50, 25 and 12.5 g/mL concentrations
mg/mL. The compounds
m
for secondary screening to test in a second set of dilution against all
microorganisms. Inoculum size for test strain was adjusted to
106 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 were used against microbial strains. Synthesized compounds
were diluted to 1000
mg/mL concentration, as a stock solution.
Control tube containing no antibiotic was immediately subcul-
tured [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 inculcated at 37 8C for 24 h for
bacteria. 10
mg/mL suspensions were further inoculated on an
appropriate media and growth was noted after 24 and 48 h. The
highest dilution (lowest concentration) preventing appearance

N.C. Desai et al. / Journal of Fluorine Chemistry 145 (2013) 102–111
107
of turbidity was considered as minimum inhibitory concentra-
tion (MIC, g/mL), i.e., the amount of growth from the control
concentrated in vacuum. The residue was purified by column
chromatography using n-hexane–ethyl acetate (4:1) as eluent to
afford the title compound. Yield: 67%.
Brown crystals; m.p.: 168–170 8C; IR (KBr)
3245 (NH), 3072, 3044 (C–H, aromatic), 2931 (C–H, methyl), 1731
m
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 was greatly affected by size of the
inoculum. Test mixture should contain 106 CFU/mL organisms.
Standard drug used in the present study was ‘ampicillin’ for
evaluating antibacterial activity which showed 250, 100, 100
n
max/cmÀ1 3281,
(C55O) 1580 (C55N), 1521 (C55C), 1394 (C–H bending, methyl), 1151
(C–F stretching); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 1.31 (t,
J = 7.1 Hz, 3H), 2.35 (s, 3H), 4.25 (q, J = 7.1 Hz, 2H), 7.42 (d,
J = 7.6 Hz, 2H), 8.12 (d, J = 7.4 Hz, 2H), 10.23 (brs, 1H, D2O exch.);
13C NMR (100 MHz, DMSO-d6,
d, ppm): 16.7 (ester–CH3), 64.3
and 100
pyogenes, respectively.
m
g/mL MIC against E. coli, P. aeruginosa, S. aureus and S.
(ester–CH2), 18.7 (thiazole–C4–CH3), 115.3 (thiazole–C5), 115.1–
129.4 (Ar–C), 158.4 (thiazole–C4), 163.1 (thiazole–C2), 165.3 (C–F),
164.4 (C55O of ester), 168.3 (C55O of amide); 19F NMR (282 MHz,
4.3. Antifungal assay
DMSO-d6,
d
, ppm): À118.41 (s, 1F, 4-F); LCMS (m/z): 308 (M+);
Anal. Calcd. For C14H13FN2O3S: C-54.54, H-4.25, N-9.09; Found: C-
54.60, H-4.31, N-9.04%.
Same compounds (6a–o) were tested for antifungal activity as
primary screening in six sets against C. albicans, A. niger and A.
clavatus at various concentrations of 1000, 500 and 250
Compounds found to be active in primary screening were similarly
diluted to obtain 200, 125, 100, 62.5, 50, 25 and 12.5 g/mL
m
g/mL.
4.6. Preparation of N-(5-(hydrazinecarbonyl)-4-methylthiazol-2-yl)-
4-fluorobenzamide (3)
m
concentrations for secondary screening to test in a second set of
dilution against all microorganisms. Griseofulvin was used as a
standard drug for antifungal activity, which showed 500, 100 and
4.6.1. Conventional method
A solution of compound 2 (2.28 g, 0.01 mol) in ethanol (95%)
(20 mL) was heated under reflux with hydrazine hydrate (1.5 g,
0.03 mol) for 4 h. The reaction mixture was kept at room
temperature and the deposited solid was filtered, washed, dried,
and recrystallized by ethanol (95%). The crystals were purified by
column chromatography using n-hexane–ethyl acetate (4:1) as
eluent to afford the title compound. Yield: 60%.
100
mg/mL MIC against Candida albicans (MTCC 227), Aspergillus
niger (MTCC 282) and Aspergillus clavatus (MTCC 1323). For fungal
growth, in the present protocol, we used Sabourauds dextrose
broth at 28 8C in aerobic condition for 48 h.
4.4. Statistical analysis
4.6.2. Microwave method
Standard deviation was expressed in terms of ÆSD. On the
basis of calculated value by using one-way ANOVA followed by
independent two Sample t test, it was observed that differences
below 0.001 level were considered statistically significant.
Compounds (6a–o) were screened for their antibacterial and
antifungal activities in six sets (n) against bacteria and fungi used
in the present protocol.
A homogeneous mixture of compound 2 (2.28 g, 0.01 mol) and
hydrazine hydrate (1.5 g, 0.03 mol) in DMF (4 mL) was introduced
into microwave reaction vessel equipped with a magnetic stirrer
(Synthos-3000). The vessel was sealed and the reaction mixture
was irradiated by 50 W intermittently at 30 s interval for 1 min.
The solid formed was washed with water and crystallized from
ethanol (95%). The crystals were purified by column chromatogra-
phy using n-hexane–ethyl acetate (4:1) as eluent to afford the title
compound. Yield: 66%.
4.5. Preparation of ethyl 2-(4-fluorobenzamido)-4-methylthiazole-5-
carboxylate (2)
White crystals, m.p.: 201–203 8C; IR (KBr) n
max/cmÀ1: 3442,
3426 (NH2), 3262, 3226 (NH), 3074, 3035 (C–H, aromatic), 2937
4.5.1. Conventional method
(C–H, methyl), 1728 (C55O), 1682 (C55O), 1584 (C55N), 1516 (C55C),
To a solution of ethyl 2-amino-4-methylthiazole-5-carboxyl-
ate (1) (2.00 g, 0.01 mol) in anhydrous dichloromethane (40 mL)
was added pyridine (2.50 g, 0.03 mol), followed by the drop wise
addition of 4-fluorobenzoyl chloride (1.90 g, 0.01 mmol) at 0–
5 8C temperature. The reaction mixture was stirred at ambient
temperature for 18 h, then washed sequentially with 1 N
hydrochloric acid (15 mL), saturated aqueous sodium bicarbon-
ate (30 mL), and water (15 mL), dried over anhydrous sodium
sulfate and filtered. The filtrate was concentrated in vacuum.
The residue was purified by column chromatography using
n-hexane–ethyl acetate (4:1) as eluent to afford the title
compound. Yield: 61%.
1389 (C–H bending, methyl); 1H NMR (300 MHz, DMSO-d6,
d,
ppm): 2.43 (s, 3H), 7.45 (d, J = 7.8 Hz, 2H), 7.81 (brs, 1H, NH, D2O
exch.), 8.15 (d, J = 7.8 Hz, 2H), 9.28 (brs, 2H, D2O exch.), 10.27 (brs,
1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 18.5
(thiazole–C4–CH3), 115.3–129.4 (Ar–C), 132.5 (thiazole–C5), 155.4
(thiazole–C4), 161.5 (C55O), 163.6 (thiazole–C2), 165.1 (C–F), 165.5
(C55O linked to phenyl ring); 19F NMR (282 MHz, DMSO-d6,
d,
ppm): À118.38 (s, 1F, 4-F); LCMS (m/z): 294 (M+); Anal. Calcd. For
C12H11FN4O2S: C-48.97, H-3.77, N-19.04; Found: C-48.92, H-3.62,
N-19.09%.
4.7. Preparation of 4-fluoro-N-(4-methyl-5-(2-
(phenylcarbamothioyl)hydrazinecarbonyl) thiazol-2-yl)benzamide
4.5.2. Microwave method
(4)
To a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate
(1) (2.00 g, 0.01 mol) in glacial acetic acid was added drop wise in
4-fluorobenzoyl chloride (1.90 g, 0.01 mmol) at 0–5 8C tempera-
ture. The reaction mixture was introduced into microwave
4.7.1. Conventional method
To a solution of compound 3 (1.1 g, 0.05 mol) in pyridine
(15 mL), was added phenyl isothiocyanate (0.06 mol) and the
mixture was refluxed for 6 h. The reaction mixture was poured on
crushed ice and the separated solid product was filtered, washed
with water, dried, and recrystallized from ethanol (95%). The
crystals were purified by column chromatography using chloro-
form–methanol (4:1) as eluent to afford the title compound. Yield:
57%.
reaction vessel equipped with
a magnetic stirrer (Synthos-
3000). The vessel was sealed and the reaction mixture was
irradiated by 60 W intermittently at 30 s intervals for 2 min, then
washed sequentially with 1 N hydrochloric acid (15 mL), saturated
aqueous sodium bicarbonate (30 mL), and water (15 mL), dried
over anhydrous sodium sulfate and filtered. The filtrate was

108
N.C. Desai et al. / Journal of Fluorine Chemistry 145 (2013) 102–111
4.7.2. Microwave method
LCMS (m/z): 469 (M+); Anal. Calcd. For C21H16FN5O3S2: C-53.72, H-
A mixture of compound 3 (1.1 g, 0.05 mol), phenyl isothiocya-
nate (0.06 mol) and gla. acetic acid (4 mL) was introduced into
microwave reaction vessel equipped with a magnetic stirrer
(Synthos-3000). The vessel was sealed and the reaction mixture
was irradiated by 100 W intermittently at 30 s intervals for 4 min.
The solid formed was washed with cold methanol and crystallized
from ethanol (95%). The crystals were purified by column
chromatography using chloroform–methanol (4:1) as eluent to
afford the title compound. Yield: 63%.
3.43, N-14.92; Found: C-53.79, H-3.48, N-14.86%.
4.9. General procedure for preparation of N-(5-(2-(5-(arylidene)-4-
oxo-3-phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-
methylthiazol-2-yl)-4-fluorobenzamides (6a–o)
4.9.1. Conventional method
A mixture containing compound 5 (0.90 g, 0.002 mol), substi-
tuted benzaldehydes (0.002 mol) and piperidine (2 drops) in dry
dioxane (10 mL) was refluxed for 4–7 h, then allowed to cool room
temperature. The separated crystals were filtered, air dried and
recrystallized from ethanol (95%). The crystals were purified by
column chromatography using chloroform–methanol (4:1) as
eluent to afford the title compounds.
Light pink crystals, m.p.: 214–216 8C; IR (KBr) n
max/cmÀ1: 3272,
3255 (NH), 3071, 3048 (C–H, aromatic), 2930 (C–H, methyl), 1718,
1693 (C55O, amide), 1686 (C55O), 1585 (C55N), 1513 (C55C), 1390
(C–H bending, methyl), 1253, 1035, 997 (NCS), 1157 (C–F); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 2.46 (s, 3H), 6.09 (s, 1H, D2O exch.),
6.82 (t, J = 8.0 Hz, 1H), 7.24 (t, J = 7.2 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H),
7.75 (d, J = 8.2 Hz, 2H), 7.90 (brs, 1H, NH, D2O exch.), 8.11 (d,
4.9.2. Microwave method
J = 8.4 Hz, 2H), 8.58 (s, 1H, D2O exch.), 10.27 (s, 1H, D2O exch.); 13
C
A mixture of compound 5 (0.90 g, 0.002 mol), substituted
aromatic aldehydes (0.002 mol), DMF (1 mL) and catalytic amount
of silica gel was introduced into microwave reaction vessel
equipped with a magnetic stirrer (Synthos-3000). The vessel
was sealed and the reaction mixture was irradiated by 200 W
intermittently at 30 s intervals for specified time give in Table 3.
The solid formed was washed with cold methanol and crystallized
from ethanol (95%). The crystals were purified by column
chromatography using chloroform–methanol (4:1) as eluent to
afford the title compounds.
NMR (100 MHz, DMSO-d6, d, ppm): 18.5 (thiazole–C4–CH3), 115.1–
137.4 (Ar–C), 132.4 (thiazole–C5), 155.7 (thiazole–C4), 163.6
(thiazole–C2), 165.5 (C–F), 161.4 (C55O linked to phenyl ring),
168.4 (C55O of amide), 179.5 (C55S); 19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.29 (s, 1F, 4-F); LCMS (m/z): 429 (M+); Anal. Calcd.
For C19H16FN5O2S2: C-53.13, H-3.75, N-16.30; Found: C-53.18, H-
3.81, N-16.37%.
4.8. Preparation of 4-fluoro-N-(4-methyl-5-(2-(4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazine carbonyl)thiazol-2-
yl)benzamide (5)
4.9.3. N-(5-(2-(5-Benzylidene-4-oxo-3-phenylthiazolidin-2-
ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-
fluorobenzamide (6a)
4.8.1. Conventional method
A mixture containing compound 4 (0.82 g, 0.002 mol), mono-
chloro acetic acid (0.28 g, 0.003 mol) and anhydrous sodium
acetate (0.35 g, 0.005 mol) in glacial acetic acid (20 mL) was
refluxed for 4 h, and then poured onto crushed ice. The formed
precipitate was filtered, washed with water and crystallized from
acetone. The crystals were purified by column chromatography
using n-hexane–ethyl acetate (4:1) as eluent to afford the title
compound. Yield: 54%.
White crystals; IR (KBr) n
max/cmÀ1: 3364, 3329 (NH), 3052,
3032 (C–H, aromatic), 3012 (C–H, CH55C), 2924 (C–H, methyl),
1716, 1694 (C55O of amide), 1682 (C55O of thiazolidinone), 1604
(C55N), 1568 (C55C), 1383 (C–H bending, methyl), 1133 (C–F
stretching), 989 (C–H, CH55C); 1H NMR (300 MHz, DMSO-d6,
d,
ppm): 2.46 (s, 3H), 7.28 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 8.6 Hz, 1H),
7.41 (d, J = 8.2 Hz, 2H), 7.46 (t, J = 8.6 Hz, 2H), 7.57 (d, J = 8.0 Hz,
2H), 7.64 (t, J = 8.8 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.86 (s, 1H), 7.94
(brs, 1H, NH, D2O exch.), 8.14 (d, J = 7.2 Hz, 2H), 10.20 (s, 1H, D2O
4.8.2. Microwave method
exch.); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 18.3 (thiazole–C4–
A homogeneous mixture of compound 4 (0.82 g, 0.002 mol),
monochloro acetic acid (0.28 g, 0.003 mol) and anhydrous sodium
acetate (0.35 g, 0.005 mol) and catalytic amount of THF (1 mL) was
introduced into microwave reaction vessel equipped with a
magnetic stirrer (Synthos-3000). The vessel was sealed and the
reaction mixture is irradiated by 100 W intermittently at 30 s
intervals for 5 min. The solid formed was washed with cold
methanol and crystallized from DMF. The crystals were purified by
column chromatography using n-hexane–ethyl acetate (4:1) as
eluent to afford the title compound. Yield: 60%.
CH3), 116.5 (thiazolidinone–C5), 115.6–135.4 (Ar–C), 132.6 (thia-
zole–C5), 145.7 (CH55C), 150.6 (thiazolidinone–C2), 154.5 (thia-
zole–C4), 163.3 (thiazole–C2), 166.5 (C55O linked to phenyl ring),
165.2 (C–F), 167.3 (thiazolidinone–C4), 168.5 (C55O of amide); 19
F
NMR (282 MHz, DMSO-d6,
d
, ppm): À118.30 (s, 1F, 4-F); LCMS (m/
z): 557 (M+); Anal. Calcd. For C28H20FN5O3S2: C-60.31, H-3.61, N-
12.56; Found: C-60.36, H-3.55, N-12.62%.
4.9.4. N-(5-(2-(5-(2-Hydroxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-
yl)-4-fluorobenzamide (6b)
Light brown crystals, m.p.: 189–191 8C; IR (KBr)
n :
max/cmÀ1
3273, 3225 (NH), 3073, 3054 (C–H, aromatic), 2932, 2851 (C–H,
methyl, methylene), 1715, 1693 (C55O, amide), 1686 (C55O of
thiazolidinone), 1584 (C55N), 1557 (C55C), 1409, 1457 (C–H
bending, methyl, methylene), 1148 (C–F); 1H NMR (300 MHz,
Light brown crystals; IR (KBr) n
max/cmÀ1: 3412 (O–H, Ar–OH),
3367, 3335 (NH), 3057, 3038 (C–H, aromatic), 3010 (C–H, CH55C),
2927 (C–H, methyl), 1712, 1691 (C55O of amide), 1686 (C55O of
thiazolidinone), 1589 (C55N), 1572 (C55C), 1387 (C–H bending,
methyl), 1145 (C–F), 979 (C–H, CH55C); 1H NMR (300 MHz, DMSO-
DMSO-d6,
d, ppm): 2.41 (s, 3H), 3.79 (d, J = 15.60 Hz, 1H,
thiazolidin–C5–HA), 4.10 (d, J = 15.60 Hz, 1H, thiazolidin–C5–HB),
6.57 (d, J = 8.6 Hz, 2H), 6.84 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 8.4 Hz, 2H),
7.44 (d, J = 7.2 Hz, 2H), 7.90 (brs, 1H, NH, D2O exch.), 8.15 (d,
J = 8.1 Hz, 2H), 10.22 (s, 1H, D2O exch.); 19F NMR (282 MHz, DMSO-
d6, d, ppm):2.42(s, 3H), 6.75(d,J = 8.4 Hz,1H), 6.94(t, J = 7.6 Hz, 1H),
7.16 (t, J = 8.2 Hz, 1H), 7.27 (t, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H),
7.61 (d, J = 8.8, 1H), 7.72 (t, J = 7.0 Hz, 2H), 7.79 (d, J = 7.6 Hz, 2H),
7.90(brs,1H,NH,D2O exch.), 7.97(s, 1H), 8.08(d,J = 8.0 Hz, 2H), 9.18
(s, 1H, D2O exch.), 10.27 (s, 1H, D2O exch.); 13C NMR (100 MHz,
d6,
d
, ppm): À118.33 (s, 1F, 4-F); 13C NMR (100 MHz, DMSO-d6,
d,
ppm): 18.7 (thiazole–C4–CH3), 30.2 (thiazolidinone–C5), 115.4–
136.4 (Ar–C), 149.7 (thiazolidinone–C2), 132.5 (thiazole–C5), 154.4
(thiazole–C4), 163.2 (thiazole–C2), 165.7 (C–F), 166.7 (C55O linked
to phenyl ring), 169.4 (C55O of amide), 171.7 (thiazolidinone C55O);
DMSO-d6, d, ppm): 18.4 (thiazole–C4–CH3), 116.4 (thiazolidinone–
C5), 115.2–132.7 (Ar–C), 132.6 (thiazole–C5), 145.4 (CH55C), 150.6
(thiazolidinone–C2), 157.2 (C–OH), 166.5 (C55O linked to phenyl
ring), 154.3 (thiazole–C4), 163.2 (thiazole–C2), 165.3 (C–F), 167.6

N.C. Desai et al. / Journal of Fluorine Chemistry 145 (2013) 102–111
109
(thiazolidinone–C4), 168.2 (C55O of amide); 19F NMR (282 MHz,
168.7 (C55O of amide); 19F NMR (282 MHz, DMSO-d6,
d
, ppm):
DMSO-d6,
d
, ppm): À118.33 (s, 1F, 4-F); LCMS (m/z): 573 (M+); Anal.
À117.09 (s, 1F, 4-F); LCMS (m/z): 571 (M+); Anal. Calcd. For
C29H22FN5O3S2: C-59.23, H-3.88, N-12.25; Found: C-59.17, H-3.82,
N-12.28%.
Calcd. For C28H20FN5O4S2: C-58.63, H-3.51, N-12.21; Found: C-
58.70, H-3.46, N-12.25%.
4.9.5. N-(5-(2-(5-(3-Hydroxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-
yl)-4-fluorobenzamide (6c)
4.9.8. N-(4-Methyl-5-(2-(5-(3-methylbenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)thiazol-2-yl)-4-
fluorobenzamide (6f)
Light brown crystals; IR (KBr)
n
max/cmÀ1: 3417 (O–H, Ar–OH),
Light reddish brown crystals; IR (KBr) n
max/cmÀ1: 3365, 3342
3363, 3330 (NH), 3053, 3047 (C–H, aromatic), 3014 (C–H, CH55C),
2931 (C–H, methyl), 1710, 1687 (C55O of amide), 1683 (C55O of
thiazolidinone), 1586 (C55N), 1548 (C55C), 1392 (C–H bending,
methyl), 1152 (C–F), 993 (C–H, CH55C); 1H NMR (300 MHz, DMSO-
(NH), 3062, 3048 (C–H, aromatic), 3010 (C–H, CH55C), 2927 (C–H,
methyl), 1713, 1688 (C55O of amide), 1680 (C55O of thiazolidinone),
1586 (C55N), 1537 (C55C), 1402 (C–H bending, methyl), 1154 (C–F),
977 (C–H, CH55C); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 2.39 (s,
d6,
d
, ppm): 2.42 (s, 3H), 6.72 (s, 1H), 6.84 (d, J = 8.6 Hz, 1H), 7.13 (d,
3H), 2.43 (s, 3H), 3.85 (s, 3H), 7.00 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H),
7.12 (t, J = 9.2 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 7.36 (d, J = 8.8, 1H),
7.43 (d, J = 8.4 Hz, 2H), 7.64 (t, J = 7.6 Hz, 2H), 7.75 (d, J = 8.4 Hz,
2H), 7.85 (s, 1H), 7.95 (brs, 1H, NH, D2O exch.), 8.11 (d, J = 8.2 Hz,
J = 8.7 Hz, 2H), 7.24 (t, J = 8.6 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.61 (t,
J = 8.8, 1H), 7.68 (t, J = 7.0 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.89 (s,
1H), 7.91 (brs, 1H, NH, D2O exch.), 8.11 (d, J = 8.1 Hz, 2H), 9.13 (s,
1H, D2O exch.), 10.14 (s, 1H, D2O exch.); 13C NMR (100 MHz,
2H), 10.25 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d,
DMSO-d6,
d
, ppm): 18.2 (thiazole–C4–CH3), 116.3 (thiazolidinone–
ppm): 18.6 (thiazole–C4–CH3), 21.4 (CH3), 116.5 (thiazolidinone–
C5), 115.1–138.4 (Ar–C), 132.6 (thiazole–C5), 145.6 (CH55C), 150.2
(thiazolidinone–C2), 154.6 (thiazole–C4), 163.8 (thiazole–C2),
165.4 (C–F), 165.8 (C55O linked to phenyl ring), 167.3 (thiazoli-
C5), 112.7–136.4 (Ar–C), 132.5 (thiazole–C5), 145.4 (CH55C), 150.5
(thiazolidinone–C2), 154.2 (thiazole–C4), 158.4 (C–OH), 163.5
(thiazole–C2), 165.1 (C–F), 165.6 (C55O linked to phenyl ring),
167.6 (thiazolidinone–C4), 168.2 (C55O of amide); 19F NMR
dinone–C4), 168.6 (C55O of amide); 19F NMR (282 MHz, DMSO-d6,
d,
(282 MHz, DMSO-d6,
d
, ppm): À118.26 (s, 1F, 4-F); LCMS (m/z):
ppm): À118.17 (s, 1F, 4-F); LCMS (m/z): 571 (M+); Anal. Calcd. For
C29H22FN5O3S2: C-59.23, H-3.88, N-12.25; Found: C-59.29, H-3.94,
N-12.19%.
573 (M+); Anal. Calcd. For C28H20FN5O4S2: C-58.63, H-3.51, N-
12.21; Found: C-58.67, H-3.56, N-12.16%.
4.9.6. N-(5-(2-(5-(4-Hydroxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-
yl)-4-fluorobenzamide (6d)
4.9.9. N-(4-Methyl-5-(2-(5-(4-methylbenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)thiazol-2-yl)-4-
fluorobenzamide (6g)
Light pink crystals; IR (KBr)
n
max/cmÀ1: 3412 (O–H, Ar–OH),
Light pink crystals; IR (KBr) n
max/cmÀ1: 3366, 3340 (NH), 3073,
3373, 3343 (NH), 3062, 3046 (C–H, aromatic), 3010 (C–H,
CH55C), 2927 (C–H, methyl), 1715, 1689 (C55O of amide), 1680
(C55O of thiazolidinone), 1582 (C55N), 1548 (C55C), 1397 (C–H
bending, methyl), 1156 (C–F), 986 (C–H, CH55C); 1H NMR
3047 (C–H, aromatic), 3013 (C–H, CH55C), 2927 (C–H, methyl),
1714, 1692 (C55O of amide), 1684 (C55O of thiazolidinone), 1604
(C55N), 1554 (C55C), 1395 (C–H bending, methyl), 1157 (C–F), 987
(C–H, CH55C); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 2.37 (s, 3H),
(300 MHz, DMSO-d6,
d
, ppm): 2.47 (s, 3H), 6.62 (d, J = 7.4 Hz,
2.46 (s, 3H), 7.14 (d, J = 8.2 Hz, 2H), 7.23 (t, J = 9.0 Hz, 1H), 7.44 (d,
J = 7.6 Hz, 2H), 7.59 (d, J = 7.4, 2H), 7.61 (t, J = 7.8 Hz, 2H), 7.75 (d,
J = 8.4 Hz, 2H), 7.85 (s, 1H), 7.92 (brs, 1H, NH, D2O exch.), 8.14 (d,
J = 8.4 Hz, 2H), 10.08 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-
2H), 7.24 (t, J = 8.6 Hz, 1H), 7.42 (d, J = 7.4 Hz, 2H), 7.57 (d, J = 7.8,
2H), 7.65 (t, J = 7.6 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H),
7.94 (brs, 1H, NH, D2O exch.), 8.14 (d, J = 8.2 Hz, 2H), 9.11 (s, 1H,
D2O exch.), 10.14 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 18.6 (thiazole–C4–CH3), 21.2 (CH3), 116.5 (thiazoli-
d6,
d
, ppm): 18.3 (thiazole–C4–CH3), 116.5 (thiazolidinone–C5),
dinone–C5), 115.3–137.4 (Ar–C), 132.3 (thiazole–C5), 145.5
(CH55C), 150.2 (thiazolidinone–C2), 154.3 (thiazole–C4), 163.4
(thiazole–C2), 165.1 (C–F), 166.3 (C55O linked to phenyl ring),
167.1 (thiazolidinone–C4), 168.2 (C55O of amide); 19F NMR
115.1–132.5 (Ar–C), 132.8 (thiazole–C5), 145.5 (CH55C), 150.4
(thiazolidinone–C2), 154.6 (thiazole–C4), 157.6 (C–OH), 163.5
(thiazole–C2), 165.0 (C–F), 165.5 (linked to phenyl ring), 167.4
(thiazolidinone–C4), 168.5 (C55O of amide); 19F NMR (282 MHz,
(282 MHz, DMSO-d6,
d
, ppm): À118.13 (s, 1F, 4-F); LCMS (m/z):
DMSO-d6,
d
, ppm): À118.34 (s, 1F, 4-F); LCMS (m/z): 573 (M+);
571 (M+); Anal. Calcd. For C29H22FN5O3S2: C-59.23, H-3.88, N-
12.25; Found: C-59.27, H-3.83, N-12.31%.
Anal. Calcd. For C28H20FN5O4S2: C-58.63, H-3.51, N-12.21;
Found: C-58.58, H-3.43, N-12.27%.
4.9.10. N-(5-(2-(5-(2-Methoxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-
yl)-4-fluorobenzamide (6h)
4.9.7. N-(4-Methyl-5-(2-(5-(2-methylbenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)thiazol-2-yl)-4-
fluorobenzamide (6e)
Light yellow crystals; IR (KBr)
n
max/cmÀ1: 3374, 3336 (NH),
Light yellow crystals, yield; IR (KBr)
n
max/cmÀ1: 3378, 3339
3074, 3056 (C–H, aromatic), 3009 (C–H, CH55C), 2922 (C–H,
methyl), 1718, 1690 (C55O of amide), 1689 (C55O of thiazolidinone),
1603 (C55N), 1557 (C55C), 1393 (C–H bending, methyl), 1158 (C–F),
975 (C–H, CH55C); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 2.40 (s,
(NH), 3071, 3058 (C–H, aromatic), 3013 (C–H, CH55C), 2932 (C–H,
methyl), 1717, 1695 (C55O of amide), 1686 (C55O of thiazolidinone),
1601 (C55N), 1576 (C55C), 1404 (C–H bending, methyl), 1149 (C–F),
985 (C–H, CH55C); 1H NMR (300 MHz, DMSO-d6,
d
, ppm): 2.39 (s,
3H), 3.82 (s, 3H), 6.94 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 7.21
(t, J = 7.6 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.64
(t, J = 7.8 Hz, 2H), 7.70 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 7.4 Hz, 2H),
7.89 (brs, 1H, NH, D2O exch.), 8.15 (d, J = 8.2 Hz, 2H), 7.95 (s, 1H),
3H), 2.44 (s, 3H), 7.01 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.21
(t, J = 8.4 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.8, 1H), 7.45 (d,
J = 8.6 Hz, 2H), 7.68 (t, J = 7.2 Hz, 2H), 7.72 (d, J = 9.2 Hz, 2H), 7.87
(brs, 1H, NH, D2O exch.), 7.92 (s, 1H), 8.16 (d, J = 9.0 Hz, 2H), 10.23
10.18 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d, ppm):
(s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d
, ppm): 18.3
18.2 (thiazole–C4–CH3), 54.7 (OCH3), 116.3 (thiazolidinone–C5),
114.3–129.4 (Ar–C), 132.6 (thiazole–C5), 145.4 (CH55C), 150.2
(thiazolidinone–C2), 154.7 (thiazole–C4), 165.3 (C–F), 163.5 (thia-
zole–C2), 165.2 (C–F), 166.5 (C55O linked to phenyl ring), 167.6
(thiazolidinone–C4), 168.3 (C55O of amide); 19F NMR (282 MHz,
(thiazole–C4–CH3), 19.4 (CH3), 116.5 (thiazolidinone–C5), 115.2–
136.3 (Ar–C), 132.7 (thiazole–C5), 145.4 (CH55C), 150.7 (thiazoli-
dinone–C2), 154.3 (thiazole–C4), 163.6 (thiazole–C2), 165.4 (C–F),
165.9 (C55O linked to phenyl ring), 167.5 (thiazolidinone–C4),

110
N.C. Desai et al. / Journal of Fluorine Chemistry 145 (2013) 102–111
DMSO-d6,
d
, ppm): À118.15 (s, 1F, 4-F); LCMS (m/z): 587 (M+);
(m/z): 591 (M+); Anal. Calcd. For C28H19ClFN5O3S2: C-56.80, H-3.23,
N-11.83; Found: C-56.74, H-3.18, N-11.78%.
Anal. Calcd. For C29H22FN5O4S2: C-59.27, H-3.77, N-11.92; Found:
C-59.33, H-3.72, N-11.96%.
4.9.14. N-(5-(2-(5-(4-Chlorobenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-
yl)-4-fluorobenzamide (6l)
4.9.11. N-(5-(2-(5-(3-Methoxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-
yl)-4-fluorobenzamide (6i)
Light brown crystals; IR (KBr)
n
max/cmÀ1: 3368, 3345 (NH),
Light yellow crystals; IR (KBr)
n
max/cmÀ1: 3370, 3325 (NH),
3078, 3041 (C–H, aromatic), 3011 (C–H, CH55C), 2924 (C–H,
methyl), 1707, 1691 (C55O of amide), 1683 (C55O of thiazolidinone),
1601 (C55N), 1538 (C55C), 1404 (C–H bending, methyl), 987 (C–H,
CH55C), 767 (C–Cl); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 2.39 (s,
3H), 7.25 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 7.2 Hz, 2H), 7.46 (d, J = 8.6 Hz,
2H), 7.61 (t, J = 9.0 Hz, 2H), 7.69 (d, J = 8.8, 2H), 7.75 (d, J = 7.4 Hz,
2H), 7.84 (s, 1H), 7.96 (brs, 1H, NH, D2O exch.), 8.16(d, J = 7.4 Hz,
2H), 10.22 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d,
3071, 3050 (C–H, aromatic), 3011 (C–H, CH55C), 2931 (C–H,
methyl), 1715, 1693 (C55O of amide), 1689 (C55O of thiazolidinone),
1607 (C55N), 1567 (C55C), 1395 (C–H bending, methyl), 1206 (C–O–
C), 984 (C–H, CH55C); 1H NMR (300 MHz, DMSO-d6,
d
, ppm): 2.41
(s, 3H), 3.85 (s, 3H), 6.86 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 7.20 (d,
J = 8.2 Hz, 1H), 7.27 (t, J = 8.6 Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.57 (t,
J = 7.3, 1H), 7.65 (t, J = 7.5 Hz, 2H), 7.76 (d, J = 7.4 Hz, 2H), 7.88 (s,
1H), 7.92 (brs, 1H, NH, D2O exch.), 8.14 (d, J = 8.0 Hz, 2H), 10.28 (s,
ppm): 18.3 (thiazole–C4–CH3), 116.5 (thiazolidinone–C5), 115.1–
133.4 (Ar–C), 132.5 (thiazole–C5), 145.7 (CH55C), 150.4 (thiazoli-
dinone–C2), 154.2 (thiazole–C4), 163.5 (thiazole–C2), 165.4 (C–F),
166.3 (C55O linked to phenyl ring), 167.2 (thiazolidinone–C4),
1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 18.6
(thiazole–C4–CH3), 54.3 (OCH3), 116.5 (thiazolidinone–C5), 113.6–
136.4 (Ar–C), 132.8 (thiazole–C5), 145.4 (CH55C), 150.7 (thiazoli-
dinone–C2), 154.6 (thiazole–C4), 160.7 (C–OCH3), 163.2 (thiazole–
C2), 165.3 (C–F), 166.4 (C55O linked to phenyl ring), 167.5
(thiazolidinone–C4), 168.4 (C55O of amide); 19F NMR (282 MHz,
168.4 (C55O of amide); 19F NMR (282 MHz, DMSO-d6,
d, ppm):
À118.20 (s, 1F, 4-F); LCMS (m/z): 591 (M+); Anal. Calcd. For
C28H19ClFN5O3S2: C-56.80, H-3.23, N-11.83; Found: C-56.86, H-
DMSO-d6,
d
, ppm): À118.09 (s, 1F, 4-F); LCMS (m/z): 587 (M+);
3.27, N-11.90%.
Anal. Calcd. For C29H22FN5O4S2: C-59.27, H-3.77, N-11.92; Found:
C-59.22, H-3.61, N-11.88%.
4.9.15. N-(5-(2-(5-(2-Nitrobenzylidene)-4-oxo-3-phenylthiazolidin-
2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-
fluorobenzamide (6m)
4.9.12. N-(5-(2-(5-(4-Methoxybenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-
yl)-4-fluorobenzamide (6j)
Orange crystals; IR (KBr) n
max/cmÀ1: 3275, 3237 (NH), 3081,
3056 (C–H, aromatic), 3015 (C–H, CH55C), 2932 (C–H, methyl),
1718, 1692 (C55O of amide), 1686 (C55O of thiazolidinone), 1587
(C55N), 1534 (C55C), 1482, 1354 (NO2), 1385 (C–H bending,
Light reddish crystals; IR (KBr) n
max/cmÀ1: 3380, 3356 (NH),
3056, 3041 (C–H, aromatic), 3007 (C–H, CH55C), 2925 (C–H,
methyl), 1718, 1694 (C55O of amide), 1682 (C55O of thiazolidi-
none), 1603 (C55N), 1545 (C55C), 1405 (C–H bending, methyl),
1202 (C–O–C), 1158 (C–F), 978 (C–H, CH55C); 1H NMR (300 MHz,
methyl), 982 (C–H, CH55C); 1H NMR (300 MHz, DMSO-d6,
d,
ppm): 2.38 (s, 3H), 7.28 (t, J = 7.4 Hz, 1H), 7.43 (d, J = 7.2 Hz, 2H),
7.65 (t, J = 8.4 Hz, 2H), 7.74 (d, J = 9.0 Hz, 2H), 7.85 (t, J = 7.2 Hz, 1H),
7.94 (brs, 1H, NH, D2O exch.), 7.97 (t, J = 8.4 Hz, 1H), 8.01 (d,
J = 9.2 Hz, 1H), 8.12 (d, J = 7.4 Hz, 2H), 8.29 (d, J = 7.8, 1H), 8.37 (s,
DMSO-d6, d, ppm): 2.38 (s, 3H), 3.81 (s, 3H), 6.94 (d, J = 7.6 Hz,
2H), 7.24 (t, J = 7.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.56 (t,
J = 7.2 Hz, 2H), 7.65 (d, J = 7.4, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.84
(s, 1H), 7.97 (brs, 1H, NH, D2O exch.), 8.10 (d, J = 9.0 Hz, 2H),
10.21 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d, ppm):
18.6 (thiazole–C4–CH3), 55.3 (OCH3), 116.5 (thiazolidinone–C5),
114.1–132.8 (Ar–C), 132.4 (thiazole–C5), 145.4 (CH55C), 150.5
(thiazolidinone–C2), 154.3 (thiazole–C4), 159.2 (C–OCH3), 163.5
(thiazole–C2), 165.5 (C55O linked to phenyl ring), 167.4
(thiazolidinone–C4), 168.5 (C55O of amide); 19F NMR
1H), 10.28 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d,
ppm): 18.3 (thiazole–C4–CH3), 116.6 (thiazolidinone–C5), 115.1–
135.2 (Ar–C), 132.4 (thiazole–C5), 145.4 (CH55C), 147.5 (C–NO2),
150.4 (thiazolidinone–C2), 154.5 (thiazole–C4), 163.7 (thiazole–
C2), 165.4 (C–F), 166.4 (C55O linked to phenyl ring), 167.4
(thiazolidinone–C4), 168.7 (C55O of amide); 19F NMR (282 MHz,
DMSO-d6,
d
, ppm): À118.22 (s, 1F, 4-F); LCMS (m/z): 602 (M+);
Anal. Calcd. For C28H19FN6O5S2: C-55.81, H-3.18, N-13.95; Found:
C-55.76, H-3.12, N-13.88%.
(282 MHz, DMSO-d6,
d
, ppm): À118.21 (s, 1F, 4-F); LCMS (m/
z): 587 (M+); Anal. Calcd. For C29H22FN5O4S2: C-59.27, H-3.77, N-
11.92; Found: C-59.31, H-3.70, N-11.97%.
4.9.16. N-(5-(2-(5-(4-Nitrobenzylidene)-4-oxo-3-phenylthiazolidin-
2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-
fluorobenzamide (6n)
4.9.13. N-(5-(2-(5-(2-Chlorobenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-
yl)-4-fluorobenzamide (6k)
Dark yellowish orange crystals; IR (KBr) n
max/cmÀ1: 3372, 3328
(NH), 3067, 3055 (C–H, aromatic), 3010 (C–H, CH55C), 2938 (C–H,
methyl), 1710, 1694 (C55O of amide), 1685 (C55O of thiazolidinone),
1604 (C55N), 1517 (C55C), 1483, 1354 (NO2), 1383 (C–H bending,
methyl), 1152 (C–F), 968 (C–H, CH55C); 1H NMR (300 MHz, DMSO-
Light yellow crystals; IR (KBr)
n
max/cmÀ1: 3372, 3237 (NH),
3085, 3053 (C–H, aromatic), 3005 (C–H, CH55C), 2932 (C–H,
methyl), 1714, 1691 (C55O of amide), 1686 (C55O of thiazolidinone),
1605 (C55N), 1545 (C55C), 1406 (C–H bending, methyl), 979 (C–H,
CH55C), 789 (C–Cl); 1H NMR (300 MHz, DMSO-d6,
d6, d, ppm): 2.40 (s, 3H), 7.24 (t, J = 7.0 Hz, 1H), 7.47 (d, J = 7.7 Hz,
d
, ppm): 2.35 (s,
2H), 7.63 (t, J = 8.2 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.86 (s, 1H), 7.95
(brs, 1H, NH, D2O exch.), 8.03 (d, J = 8.1, 2H), 8.15 (d, J = 8.6 Hz, 2H),
8.21 (d, J = 7.6 Hz, 2H), 10.26 (s, 1H, D2O exch.); 13C NMR (100 MHz,
3H), 7.18 (t, J = 8.4 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.29 (t, J = 8.0 Hz,
1H), 7.37 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 7.6,
1H), 7.65 (t, J = 9.0 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.87 (brs, 1H,
NH, D2O exch.), 7.99 (s, 1H), 8.05 (d, J = 8.0 Hz, 2H), 10.20 (s, 1H,
DMSO-d6, d, ppm): 18.2 (thiazole–C4–CH3), 116.4 (thiazolidinone–
C5), 115.2–141.1 (Ar–C), 145.7 (CH55C), 132.4 (thiazole–C5), 147.3
(C–NO2), 150.4 (thiazolidinone–C2), 154.7 (thiazole–C4), 161.8
(C55O), 163.5 (thiazole–C2), 165.1 (C–F), 165.9 (C55O linked to
D2O exch.); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 18.5 (thiazole–
C4–CH3), 116.4 (thiazolidinone–C5), 115.2–134.5 (Ar–C), 145.7
(CH55C), 150.4 (thiazolidinone–C2), 132.2 (thiazole–C5), 154.5
(thiazole–C4), 163.5 (thiazole–C2), 165.2 (C–F), 165.7 (C55O linked
to phenyl ring), 167.5 (thiazolidinone–C4), 168.4 (C55O of amide);
phenyl ring), 167.5 (thiazolidinone–C4), 168.5 (C55O of amide); 19
F
NMR (282 MHz, DMSO-d6,
d
, ppm): À118.09 (s, 1F, 4-F); LCMS (m/
z): 602 (M+); Anal. Calcd. For C28H19FN6O5S2: C-55.81, H-3.18, N-
19F NMR (282 MHz, DMSO-d6,
d
, ppm): À118.12 (s, 1F, 4-F); LCMS
13.95; Found: C-55.87, H-3.23, N-13.90%.

N.C. Desai et al. / Journal of Fluorine Chemistry 145 (2013) 102–111
111
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4.9.17. N-(5-(2-(5-(4-Fluorobenzylidene)-4-oxo-3-
phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-
yl)-4-fluorobenzamide (6o)
[6] B.E. Smart, R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.), Organofluorine Chemistry.
Principles and Commercial Applications, Plenum Press, New York, 1994 , pp.
57–88.
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1606.
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R. Bone, D. Green, T. Randall, M. Zhang, F.A. Lewandowski, Z. Zhou, C. Sharp, D.
Maguire, B. Grasberger, R.L. DesJarlais, J. Spurlino, Bioorganic and Medicinal
Chemistry Letters 11 (2001) 915–918.
Light yellow crystals; IR (KBr)
n
max/cmÀ1: 3380, 3358 (NH),
3071, 3026 (C–H, aromatic), 3014 (C–H, CH55C), 2925 (C–H,
methyl), 1715, 1693 (C55O of amide), 1689 (C55O of thiazolidinone),
1589 (C55N), 1547 (C55C), 1422 (C–H bending, methyl), 1156 (C–F),
971 (C–H, CH55C); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 2.44 (s,
3H), 7.12 (d, J = 8.4 Hz, 2H), 7.27 (t, J = 8.2 Hz, 1H), 7.44 (d, J = 7.4,
2H), 7.64 (t, J = 8.6 Hz, 2H), 7.70 (d, J = 7.2 Hz, 2H), 7.79 (d,
J = 8.0 Hz, 2H), 7.86 (s, 1H), 7.98 (brs, 1H, NH, D2O exch.), 8.14 (d,
J = 9.0 Hz, 2H), 10.21 (s, 1H, D2O exch.); 13C NMR (100 MHz, DMSO-
[11] F. Haviv, J.D. Ratajczyk, R.W. DeNet, F.A. Kerdesky, R.L. Walters, S.P. Schmidt, J.H.
Holms, P.R. Young, G.W. Carter, Journal of Medicinal Chemistry 31 (1988) 1719–
1728.
[12] F.W. Bell, A.S. Cantrell, M. Hoegberg, S.R. Jaskunas, N.G. Johansson, C.L. Jordan,
M.D. Kinnick, P. Lind, J.M. Morin Jr., Journal of Medicinal Chemistry 38 (1995)
4929–4936.
[13] X.H. Gu, X.Z. Wan, B. Jiang, Bioorganic and Medicinal Chemistry Letters 9 (1999)
569–572.
[14] B. Jiang, X.H. Gu, Bioorganic and Medicinal Chemistry 8 (2000) 363–371.
[15] Y. Kumar, R. Green, K.Z. Borysko, D.S. Wise, L.L. Wotring, L.B. Townsend, Journal of
Medicinal Chemistry 36 (1993) 3843–3848.
[16] E. Medime, G. Capan, II Farmaco 49 (1994) 449–451.
[17] V.E. Borisenko, A. Koll, E.E. Kolmakov, A.G. Rjasnyi, Journal of Molecular Structure
783 (2006) 101–115.
d6,
d, ppm): 18.5 (thiazole–C4–CH3), 116.3 (thiazolidinone–C5),
115.1–132.2 (Ar–C), 132.8 (thiazole–C5), 145.5 (CH55C), 150.7
(thiazolidinone–C2), 154.8 (thiazole–C4), 161.5 (C55O), 162.3 (C–F),
163.4 (thiazole–C2), 165.5, 166.7 (C55O linked to phenyl ring),
167.3 (thiazolidinone–C4), 168.5 (C55O of amide); 19F NMR
(282 MHz, DMSO-d6,
1F, 4-F); LCMS (m/z): 575 (M+); Anal. Calcd. For C28H19F2N5O3S2: C-
d
, ppm): À118.04 (s, 1F, 4-F), À118.17 (s,
58.42, H-3.33, N-12.17; Found: C-58.50, H-3.28, N-12.11%.
[18] P. Beuchet, M. Varache-Lembege, A. Neveu, J.M. Leger, J. Vercauteren, S. Larrou-
ture, G. Deffieux, A. Nuhrich, European Journal of Medical Chemistry 34 (1999)
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Acknowledgement
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