Synthesis and antimicrobial activity of some novel 2-(substituted fluorobenzoylimino)-3-(substituted fluorophenyl)-4-methyl-1,3-thiazolines

Article abstract of DOI:10.1016/j.jfluchem.2009.11.005

The synthesis of several 2-(substituted fluorobenzoylimino)-3-(substituted fluorophenyl)-4-methyl-1,3-thiazolines (2a-t) was carried out by base-catalyzed cyclization of corresponding 1-(fluorobenzoyl)-3-(fluorophenyl)thioureas (1a-t) with 2-bromoacetone in aqueous medium. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. All synthesized compounds were evaluated for in vitro antibacterial activity using Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa). The minimum inhibitory concentration (MIC) was determined for the most active compounds. In vitro antifungal activity was also determined against the five fungal species (Rhizopus oryzae, Fusarium oxysporum, Aspergillus terreus, A. niger and A. fumigatus).

Full text of DOI:10.1016/j.jfluchem.2009.11.005

Journal of Fluorine Chemistry 131 (2010) 333–339
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and antimicrobial activity of some novel 2-(substituted
fluorobenzoylimino)-3-(substituted fluorophenyl)-4-methyl-1,3-thiazolines
a
b
b
Aamer Saeed a, , Uzma Shaheen , Abdul Hameed , Faiza Kazmi
*
a Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan
b Department of Microbiology, Quaid-I-Azam University, Islamabad 45320, Pakistan
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of several 2-(substituted fluorobenzoylimino)-3-(substituted fluorophenyl)-4-methyl-
1,3-thiazolines (2a–t) was carried out by base-catalyzed cyclization of corresponding 1-(fluorobenzoyl)-
3-(fluorophenyl)thioureas (1a–t) with 2-bromoacetone in aqueous medium. The structures of the
synthesized compounds were confirmed by spectral and elemental analysis. All synthesized compounds
were evaluated for in vitro antibacterial activity using Gram-positive bacteria (Staphylococcus aureus,
Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa). The minimum
inhibitory concentration (MIC) was determined for the most active compounds. In vitro antifungal
activity was also determined against the five fungal species (Rhizopus oryzae, Fusarium oxysporum,
Aspergillus terreus, A. niger and A. fumigatus).
Received 11 August 2009
Received in revised form 10 November 2009
Accepted 11 November 2009
Available online 17 November 2009
Keywords:
Antimicrobial activity
Fluorinated imino-1
3-Thiazolines
ß 2009 Elsevier B.V. All rights reserved.
Fluorinated 1,3-disubstituted thioureas
1. Introduction
applications in medicinal chemistry. 2-Thiazolylimino-5-aryli-
dene-4-thiazolidinones show noticeable antimicrobial activity
There has been an increasing interest in recent years in
introduction of fluorine into organic compounds [1]. Incorpora-
tion of one or several fluorine atoms into an organic molecule can
enhance their biological potency, bioavailability, metabolic
stability and lipophilicity. Enhanced lipophilicity may lead to
easier absorption and transportation of molecules within
biological systems. More than 200 fluorinated pharmaceuticals
are available and still others are appearing [2]. Fluorinated
compounds usually have size and shape comparable to their non-
fluorinated analogues and this favors interaction at a given
biological molecular recognition site. Thus they tend to have
similar inherent biological activities. Moreover, the fluorinated
compounds tend to be more resistant to metabolic degradation
due to the high bond energies and heats of formation of the H–O
and C–O bonds relative to those of the F–O bond [3]. Fluorine
substitution at a certain position in a drug molecule can influence
not only pharmacokinetic properties such as absorption, tissue
distribution, secretion and the route and rate of biotransformation
but also its pharmacodynamics, toxicology and can improve the
efficacy of drugs [4].
against bacteria, yeasts and moulds [5]. 3-Substituted 2-(cyanoi-
mino)thiazolidines can be used in agriculture due to their
neonicotinoid insecticidal activity [6]. 3-Substituted thiazolidines
show radioprotective properties against
g-radiations [7]. A
quantitative structural-activity relationship (QSAR) study for
fungicidal activities of 2-imino-1,3-thiazoline derivatives against
rice blast fungus Pyricularia oryzae [8] has revealed their potent use
as fungicides. KHG22394, a 2-imino-1,3-thiazoline derivative,
significantly inhibits melanin production in a dose-dependent
manner thus acting as a skin whitening agent [9] and pifithrin-a,
another imino thiazoline, is a reversible inhibitor of p53-mediated
apoptosis and p53-dependent gene transcription [10]. Amidine
derivatives synthesized by the condensation of 2-cyanopyridine
with various 3,4-diaryl-2-imino-4-thiazolines exhibited good anti-
inflammatory and analgesic activity [11]. The 3-alkyl-3-H-thiazo-
line derivative, PS 028, a GP IIb/IIIa receptor antagonist, is a lead
compound for the development of orally active potent platelet
aggregation inhibitors [12]. Acridinyl-thiazoline derivatives have
been found to exhibit moderate CDK1 inhibition [13]. Sydnonyl
substituted thiazoline derivatives exhibit potent DPPH radical
scavenging activity [14]. 2-Acylimino-1,3-thiazolines show
bleaching herbicidal activity against up-land weeds and selectivity
against crops [15]. The above mentioned biological and synthetic
significance prompted us to carry out the synthesis of some
new (substituted fluorobenzoylimino)-3-aryl-4-methyl-1,3-thia-
zolines.
The 2-imino-1,3-thiazoline nucleus is found in a variety of
biologically active natural products and has found extensive
* Corresponding author.
E-mail address: aamersaeed@yahoo.com (A. Saeed).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.11.005

334
A. Saeed et al. / Journal of Fluorine Chemistry 131 (2010) 333–339
2. Results and discussion
zolines. The structures were confirmed by a slight shifting of
carbonyl absorption bands to 1585–1660 cmꢀ1 and appearance of
a characteristic C55N stretching at 1440–1480 cmꢀ1 in the IR
spectra, in addition to the absence of thiourea NHs absorptions.
2.1. Synthesis
Scheme 1 outlines the synthesis of the title compounds. The
The emergence of characteristic 1H quartet for H-5 at
d 6.34–6.46
cyclocondensation of 1-aroyl-3-arylthioureas with
a
-halocarbonyl
and a three-proton doublet for the 4-CH3 of the thiazoline ring at d
compounds is classically achieved in the presence of bromine in
basic medium in rigorously dry solvents like acetone, dichlor-
omethane, N,N,-dimethylformamide or acetonitrile under an inert
atmosphere [16–19]. However these conventional non-aqueous
conditions require long reaction times (3–5 h reflux) and give only
modest yields. Reaction in water not only shortens the reaction
times but also increases product purities and yields compared to
non-aqueous media. In recent years aqueous chemistry has
fascinated the synthetic organic chemists, not only for the reason
that water is the most abundant, cheapest and environmentally
friendly solvent but also because water exhibits exclusive
reactivity and selectivity, which is different from those obtained
in conventional organic solvents. The considerable enhancement
in the rate of reaction in water has been ascribed to hydrophobic
packing, solvent polarity, hydration, and hydrogen bonding
[20,21]. The precursor 1-(fluorobenzoyl)-3-(fluorophenyl)thiour-
eas (1a–t) were prepared according to the reported procedure
involving the reaction of a fluorobenzoyl chloride with potassium
thiocyanate in anhydrous acetone, followed by the condensation of
the resulting fluorobenzoyl isothiocyanate intermediate with a
suitable fluoroaniline [22]. In their IR spectra the 1-(fluoroben-
zoyl)-3-(fluorophenyl)thioureas are characterized by absorptions
bands at 3351, 3200 cmꢀ1 for free and associated NH stretching, at
1670 for carbonyl and at 1240 cmꢀ1 for thiocarbonyl functional-
2.06–2.16, respectively, due to the mutually coupled protons with
an allylic coupling constant of 0.9–1.2 Hz was noted in the 1H NMR.
13C NMR reveals the characteristic signals for olefinic carbon at
d
104.4–105.1 and for methyl carbon at
d 14.2–15.1 in conjunction
with signals for aromatic protons which agreed to the proposed
structures (Table 1). In the EIMS, in addition to the molecular ion
peaks, the base peaks were observed at m/z 123, 139 and 195
corresponding to aroyl fragments [FPhCO]+, [ClPhCO]+ and
[(CH3O)3PhCO]+ respectively (Table 2).
2.2. Biological activities
2.2.1. Antibacterial activity
The antibacterial activities of all synthesized fluorinated
iminothiazolines were investigated against four strains of bacteria
(Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 10197,
Bacillus subtilis DSM 3256, Staphylococcus aureus ATCC 25923). The
results of the antimicrobial evaluation of the tested compounds are
presented in Table 3. Most of the tested compounds displayed
significant efficacy against the Gram-positive bacterial strain
Bacillus subtilis (B. S.) and the Gram-negative bacterial strain
Pseudomonas aeruginosa (P. A.). Compound 2d was most active
against B. S., while 2o was the least active. In the cases of P. A. 2p
exhibited highest activity and 2n the lowest activity. Imipenem
(molecular mass 299.347) was used as the standard drug. It is an
ities; singlets at d 9.0 and 12 for HN(1) and HN(3) and peaks at 170,
179 for carbonyl and thiocarbonyl are observed in their 1H and 13
NMR spectra, respectively.
C
intravenous b-lactam antibiotic (subgroup carbapenems) having
an extremely broad spectrum of activity (Fig. 1).
Cyclization of thioureas (1a–t) with 2-bromoacetone in water
in basic medium led to the formation of the corresponding three
series of isomeric (fluorobenzoylimino)-3-aryl-4-methyl-1,3-thia-
Based on the results of the preliminary antimicrobial evalua-
tion, compounds 2a, 2b, 2d, 2e, 2i, 2n, 2p, 2r, 2s and 2t were
selected for further assessment. Significant results were obtained
Scheme 1. Synthesis of some 2-(substituted fluorobenzoylimino)-3-(substituted fluorophenyl)-4-methyl-1,3-thiazolines.

Table 1
Spectroscopic data of thiazolines (2a–t).
Compd.
R1
R2
IR spectral data (
n
/cmꢀ1
)
1H and 13C NMR spectral data (
d)
2a
2-Cl
2-F
1589 (C5O), 1555
1H NMR:
13C NMR:
d
d
7.81 (dd, 1H, J = 1.8, 7.65Hz, Ar–H), 7.55–7.16 (m, 7H, Ar–H), 6.43 (q, 1H, J = 1.2 Hz, CH5C), 2.12 (d, 3H, J = 1.2 Hz, CH3).
(Ar–C5C), 1448 (C5N),
174.1 (C5O), 170.2 (C5N), 157.6 (d, 1J = 251 Hz), 136.0, 134.3, 133.6, 131.5 (d, 3J = 8.25 Hz), 131.2, 131.0, 130.7, 126.3,
1261 (C–S), 1165 (C–N)
125.1, 124.8 (d, 3J = 12.75 Hz), 124.6 (d, 4J = 3.75Hz), 116.8 (d, 2J = 19.5 Hz), 104.6 (CH5C), 14.32 (CH3).
2b
2c
2d
3,4,5-triO-CH3
2-F
2-F
2-F
1595 (C5O), 1558 (Ar–C5C),
1451 (C5N), 1273 (C–S),
1125 (C–N)
1H NMR:
3.86 (s, 3H, OCH3), 3.77 (s, 6H, 2[OCH3]), 3.23 (d, 3H, J = 1.2 Hz, CH3). 13C NMR:
d
7.58–7.51 (m, 1H, Ar–H), 7.44 (dt, 1H, J = 1.8, 7.8 Hz, Ar–H), 7.39–7.31 (m, 4H, Ar–H), 6.43 (q, 1H, J = 1.2 Hz, CH5C),
173.6 (C5O), 169.6 (C5N), 157.7 (d, 1J = 251Hz),
d
152.5 (2C), 140.8, 133.9, 132.0, 131.2 (d, 3J = 7.5 Hz), 130.5, 125.1 (d, 3J = 12.75 Hz), 124.6 (d, 4J = 3.75 Hz), 116.7 (d, 2J = 19.5 Hz),
106.2 (2C), 104.3 (CH5C), 60.8 (OCH3), 55.77 (2C, 2[OCH3]), 14.26 (CH3).
2-F-
1606 (C5O), 1561 (Ar–C5C),
1458 (C5N), 1275 (C–S),
1130 (C–N)
1H NMR:
13C NMR:
d
d
7.88 (dt, 1H, J = 1.8, 7.8 Hz, Ar–H), 7.55–7.02 (m, 7H, Ar–H), 6.43 (q, 1H, J = 1.2 Hz, CH5C), 2.16 (d, 3H, J = 1.2 Hz, CH3).
173.4 (C5O), 169.7 (C5N), 162.3 (d, 1J = 257 Hz), 157.6 (d, 1J = 251 Hz), 134.0, 132.6 (d, 3J = 8.25 Hz),
132.1 (d, 4J = 0.75 Hz), 131.2 (d, 3J = 8.75 Hz), 130.3, 125.1 (d, 3J = 7.5 Hz), 124.7 (d, 4J = 3.75 Hz), 123.4 (d, 4J = 3.75 Hz),
116.8 (d, 2J = 19.5 Hz), 116.7 (d, 2J = 22.5 Hz), 104.4 (CH5C), 14.29 (CH3).
3-F-
1598 (C5O), 1564 (Ar–C5C),
1479 (C5N), 1262 (C–S),
1128 (C–N)
1H NMR: 7.31–7.69 (m, 8H, Ar–H), 6.43 (q, 1H, J = 1.2 Hz, CH5C), 2.12 (d, 3H, J = 1.2 Hz, CH3). 13C NMR:
d d 173.3 (C5O),
169.6 (C5N), 162.4 (d, 1J =256 Hz), 157.9 (d, 1J = 251 Hz), 134.0, 132.6 (d, 3J = 8.75 Hz), 132.2 (d, 4J = 0.75 Hz), 131.1 (d, 3J = 9 Hz),
130.3, 125.1 (d, 3J = 7.5 Hz), 124.6 (d, 4J = 3 Hz), 123.3 (d, 4J = 3.75 Hz), 116.9 (d, 2J = 21 Hz), 116.6 (d, 2J = 22.5 Hz),
105.1 (CH5C), 14.96 (CH3).
2e
2f
4-F-
2-F
3-F
1605 (C5O), 1569 (Ar–C5C),
1461 (C5N), 1265 (C–S),
1148 (C–N)
1H NMR: 8.07–6.95 (m, 8H, Ar–H), 6.43 (q, 1H, J =1.2 Hz, CH5C), 2.12 (d, 3H, J = 1.2 Hz, CH3). 13C NMR:
d d 173.4 (C5O),
170.0 (C5N), 165.1 (d, 1J = 250 Hz), 157.5 (d, 1J = 251 Hz), 134.1, 133.0 (d, 4J =3 Hz), 131.7, 131.1 (d, 2C, 3J = 8.25 Hz),
130.2, 124.9 (d, 4J = 3 Hz), 124.8 (d, 3J = 6.75 Hz), 116.9 (d, 2J = 19.5 Hz), 114.8 (d, 2C, 2J = 21.75 Hz), 104.5 (CH5C), 14.30 (CH3).
2-Cl-
1589 (C5O), 1554 (Ar–C5C),
1452 (C5N), 1272 (C–S),
1252 (C–N)
1H NMR:
2.16 (d, 3H, J = 1.2 Hz, CH3). 13C NMR:
d 7.82 (dd, 1H, J = 1.8, 7.7 Hz, Ar–H), 7.57 (q, 1H, J = 8.1 Hz, Ar–H), 7.34–7.12 (m, 6H, Ar–H), 6.42 (q, 1H, J = 1.2 Hz, CH5C),
d
172.3 (C5O), 169.3 (C5N), 162.7 (d, 1J = 247 Hz), 138.4 (d, 3J = 9.75 Hz), 135.9, 134.4,
133.6, 131.8, 131.2, 130.9, 130.6 (d, 3J = 9 Hz), 126.2, 123.9 (d, 4J = 3.5 Hz), 116.5 (d, 2J = 21Hz), 115.9 (d, 2J = 22.5 Hz),
105.0 (CH5C), 14.93 (CH3).
2g
3,4,5-triO-CH3
3-F
1603 (C5O), 1565 (Ar–C5C),
1452 (C5N), 1273 (C–S),
1126 (C–N)
1H NMR:
6.42 (q, 1H, J = 1.2Hz, CH5C), 3.87 (s, 3H, OCH3), 3.67 (s, 6H, 2[OCH3]), 2.10 (d, 3H, J = 1.2 Hz, CH3). 13C NMR:
169.5 (C5N), 162.7 (d, 1J =247 Hz), 152.5 (2C), 140.7, 138.6 (d, 3J = 9.75 Hz), 133.9, 132.0, 130.5 (d, 3J = 8.25Hz),
123.9 (d, 4J = 3.75 Hz), 116.5 (d, 2J = 21.5 Hz), 115.2 (d, 2J = 22.5 Hz), 106.2 (2C), 104.3 (CH5C), 60.7 (OCH3),
55.7 (2C, 2[OCH3]), 14.21 (CH3).
d
7.56 (q, 1H, J = 8.1 Hz, Ar–H), 7.37 (s, 2H, Ar–H), 7.29–7.20 (m, 1H, Ar–H), 7.14 (dt, 1H, J = 2.1, 8.1 Hz, Ar–H),
172.4 (C5O),
d
2h
2i
2-F-
3-F-
4-F-
3-F
3-F
3-F
1608 (C5O), 1569 (Ar–C5C),
1443 (C5N), 1277 (C–S),
1152 (C–N)
1H NMR:
13C NMR:
d
d
7.87 (dt, 1H, J = 1.8, 7.8 Hz, Ar–H), 7.60–7.01 (m, 7H, Ar–H), 6.43 (q, 1H, J = 1.2 Hz, CH5C), 2.10 (d, 3H, J = 1.2 Hz, CH3).
172.4 (d, J = 3.3 Hz, C5O), 169.9 (C5N), 162.8 (d, 1J = 247 Hz), 162.3 (d, 1J = 251 Hz), 138.4 (d, 3J = 9.75 Hz), 133.9,
132.7 (d, 3J = 8.25 Hz), 132.2 (d, 4J = 0.75 Hz), 130.7 (d, 3J =9 Hz), 125.2 (d, 3J = 7.75 Hz), 123.9 (d, 4J =4.5 Hz),
123.4 (d, 2J = 18.75 Hz), 116.7 (d, 2J = 22.5 Hz), 116.3 (d, 2J = 21 Hz), 115.9 (d, 2J = 23.25 Hz), 105.1 (CH5C), 14.59 (CH3).
1606 (C5O), 1559 (Ar–C5C),
1473 (C5N), 1260 (C–S),
1132 (C–N)
1H NMR: 7.68–7.26 (m, 8H, Ar–H), 6.43 (q, 1H, J =0.9 Hz, CH5C), 2.11 (d, 3H, J = 0.9 Hz, CH3). 13C NMR:
d d 173.7 (C5O),
169.2 (C5N), 162.6 (d, 1J =257 Hz), 157.9 (d, 1J = 257 Hz), 134.1, 132.5 (d, 3J = 8.75 Hz), 132.1 (d, 4J =3.75 Hz),
131.2 (d, 3J = 8.75 Hz), 130.4, 125.2 (d, 3J = 8.75 Hz), 124.7 (d, 4J = 0.75 Hz), 123.4 (d, 4J = 3 Hz), 116.9 (d, 2J = 18.75 Hz),
116.6 (d, 2J = 21 Hz), 104.8 (CH5C), 15.01 (CH3).
2j
1602 (C5O), 1562 (Ar–C5C),
1450 (C5N), 1269 (C–S),
1142 (C–N)
1H NMR:
7.06–6.96 (m, 2H, Ar–H), 6.44 (q, 1H, J = 1.2 Hz, CH5C), 2.14 (d, 3H, J = 1.2 Hz, CH3). 13C NMR:
164.9 (d, 1J = 250 Hz), 162.7 (d, 1J = 247 Hz), 138.4 (d, 1C, 3J = 9.75 Hz), 133.9, 133.0 (d, 2C, 3J = 8 Hz), 131.6, 130.3 (d, 3J =9 Hz),
124.0 (d, 4J =4.5 Hz), 116.6 (d, 2J = 21 Hz), 115.9 (d, 2J = 23.25 Hz), 114.8 (d, 2C, 2J = 21.25 Hz), 105.1 (CH5C), 14.83 (CH3).
d 8.08–8.05 (m, 2H, Ar–H), 7.57 (q, 1H, J = 8.1 Hz, Ar–H), 7.30–7.24 (m, 2H, Ar–H), 7.17 (q, 1H, J = 8.1 Hz, Ar–H),
d
170.4 (C5O), 169.9 (C5N),
2k
2l
2-Cl-
4-F
4-F
1587 (C5O), 1503 (Ar–C5C),
1447 (C5N), 1279 (C–S),
1223 (C–N)
1H NMR:
13C NMR:
d
d
7.81 (dd, J = 2.1, 7.7 Hz, Ar–H), 7.36–7.15 (m, 7H, Ar–H), 6.44 (q, 1H, J = 1.2 Hz, CH5C), 2.06 (d, 3H, J = 1.2 Hz, CH3).
174.0 (C5O), 170.2 (C5N), 162.6 (d, 1J = 248 Hz), 136.0, 134.4, 133.5, 126.2, 133.1 (d, 4J = 3 Hz), 131.8, 131.0,
130.8, 129.9 (d, 2C, JC–F = 8.25 Hz), 126.2, 116.6 (d, 2C, 2J = 22.5 Hz), 104.9 (CH5C), 15.04 (CH3).
3
3,4,5-triO-CH3
1603 (C5O), 1562 (Ar–C5C),
1452 (C5N), 1262 (C–S),
1151 (C–N)
1H NMR:
d 7.39–7.35 (m, 4H, Ar–H), 7.28 (dt, 2H, J = 2.1, 8.25 Hz, Ar–H), 6.41 (q, 1H, J =1.2 Hz, CH5C), 3.86 (s, 3H, OCH3),
3.79 (s, 6H, 2[OCH3]), 2.11 (d, 3H, J =1.2 Hz, CH3). 13C NMR:
d
173.0 (C5O), 169.9 (C5N), 162.6 (d, 1J = 248 Hz), 152.5 (2C), 140.8,
134.1, 133.3 (d, 4J = 3 Hz), 132.1, 130.2 (d, 3J = 8.25 Hz), 116.3 (d, 2J = 23 Hz), 106.1 (2C), 104.5 (CH5C), 60.85 (OCH3),
55.77 (2C, 2[OCH3]), 15.01 (CH3).

Table 1 (Continued )
Compd.
R1
R2
IR spectral data (
n
/cmꢀ1
)
1H and 13C NMR spectral data (
1H NMR: 7.89–7.01 (m, 8H, Ar–H), 6.43 (q, 1H, J =0.9 Hz, CH5C), 2.09 (d, 3H, J = 0.9 Hz, CH3). 13C NMR:
d 172.4 (d, J = 3 Hz, C5O),
d)
2m
2-F-
4-F
1602 (C5O), 1563 (Ar–C5C),
1455 (C5N), 1269 (C–S),
1153 (C–N)
d
170.1 (C5N), 162.6 (d, 1J = 248 Hz), 162.3 (d, 1J =257 Hz), 134.2, 133.1 (d, 4J = 3 Hz), 132.7 (d, 3J = 9 Hz), 132.1 (d, 4J = 0.75 Hz),
129.9 (d, 2C, 3J = 9 Hz), 125.2 (d, 3J = 8.25 Hz), 123.4 (d, 4J = 3.75 Hz), 116.7 (d, 2J = 22.5 Hz), 116.6 (d, 2C, 2J = 22.5 Hz),
104.9 (CH5C), 15.04 (CH3).
2n
2o
3-F-
4-F-
4-F
4-F
1599 (C5O), 1566 (Ar–C5C),
1454 (C5N), 1259 (C–S),
1154 (C–N)
1H NMR: 7.71–7.30 (m, 8H, Ar–H), 6.46 (q, 1H, J =1.2 Hz, CH5C), 2.11 (d, 3H, J = 1.2 Hz, CH3). 13C NMR:
d d 173.8 (C5O),
169.5 (C5N), 162.7 (d, 1J =251 Hz), 157.8 (d, 1J = 257 Hz), 134.1, 132.5 (d, 3J = 9 Hz), 132.2 (d, 4J = 3.75 Hz), 131.2 (d, 3J = 9 Hz),
130.3, 124.6 (d, 4J = 3 Hz), 125.1 (d, 3J = 8.75 Hz), 123.3 (d, 4J = 3.75 Hz), 116.9 (d, 2J = 22.5 Hz), 116.7 (d, 2J = 22.5 Hz),
104.6 (CH5C), 15.04 (CH3).
1660 (C5O), 1566 (Ar–C5C),
1453 (C5N), 1275 (C–S),
1148 (C–N)
1H NMR:
2.07 (d, 3H, J = 1.2 Hz, CH3). 13C NMR:
d 8.07–7.35 (m, 4H, Ar–H), 7.28 (dt, 2H, J = 2.1, 7.8 Hz, Ar–H), 7.02–6.95 (m, 2H, Ar–H), 6.42 (q, 1H, J = 1.2 Hz, CH5C),
d
173.8 (C5O), 169.9 (C5N), 164.9 (d, 1J = 250 Hz), 162.6 (d, 1J =248 Hz), 134.1,
133.4 (d, 4J = 3 Hz), 133.0 (d, 2C, 3J = 8 Hz), 131.6, 130.2 (d, 2C, 3J =8.25 Hz), 116.3 (d, 2C, 2J = 23 Hz),
114.9 (d, 2C, 2J = 21.75 Hz), 104.4 (CH5C), 15.02 (CH3).
2p
2q
2-Cl-
3-Cl, 4-F
3-Cl, 4-F
1596 (C5O), 1555 (Ar–C5C),
1456 (C5N), 1265 (C–S),
1136 (C–N)
1H NMR:
13C NMR:
d
d
7.82 (dd, 1H, J = 2.1, 7.65Hz, Ar–H), 7.39–7.19 (m, 6H, Ar–H), 6.45 (q, 1H, J = 0.9 Hz, CH5C), 2.11 (d, 3H, J = 0.9 Hz, CH3).
174.1 (C5O), 170.2 (C5N), 158.3 (d, 1J = 251 Hz), 135.9, 134.2, 133.5, 133.4 (d, 4J = 3 Hz), 131.8, 130.7, 130.6,
128.2 (d, 3J = 7.5 Hz), 126.3, 122.1 (d, 2J = 19.5 Hz), 121.8, 117.4 (d, 2J = 22.5 Hz), 105.2 (CH5C), 15.02 (CH3).
3,4,5-triO-CH3
1598 (C5O), 1565 (Ar–C5C),
1474 (C5N), 1264 (C–S),
1125 (C–N)
1H NMR:
3.82 (s, 6H, 2[OCH3]), 2.14 (d, 3H, J =1.2 Hz, CH3). 13C NMR:
133.6 (d, 4J = 3.75 Hz), 133.5, 131.8, 131.0, 128.2 (d, 3J = 7.5 Hz), 121.8 (d, 2J = 18.75 Hz), 117.1 (d, 2J =21.7 Hz), 106.1 (2C),
104.8 (CH5C), 60.87 (OCH3), 55.8(2C, 2[OCH3]), 15.02 (CH3).
d 7.57 (dd, 1H, J = 2.7, 6.3 Hz, Ar–H), 7.39–7.24 (m, 4H, Ar–H), 6.42 (q, 1H, J = 1.2 Hz, CH5C), 3.87 (s, 3H, OCH3),
d
173.6 (C5O), 169.9 (C5N), 158.2 (d, 1J = 251 Hz), 152.6 (2C), 140.9,
2r
2s
2t
2-F-
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
1600 (C5O), 1575 (Ar–C5C),
1461 (C5N), 1273 (C–S),
1152 (C–N)
1H NMR:
6.43 (q, 1H, J = 1.2 Hz, CH5C), 2.10 (d, 3H, J = 1.2 Hz, CH3). 13C NMR:
d 7.88 (dt, 1H, J = 1.8, 7.8 Hz, Ar–H), 7.46 (dd, 1H, J = 2.4, 6.3 Hz, Ar–H), 7.42–7.02 (m, 5H, Ar–H),
d
172.4 (d, J =3 Hz, C5O), 170.1 (C5N), 162.3 (d, 1J = 256 Hz),
158.3 (d, 1J = 255 Hz), 133.8, 133.4 (d, 4J = 3.75 Hz), 132.8 (d, 3J =9 Hz), 132.1, 130.5, 128.2 (d, 3J = 7.5 Hz), 125.0 (d, 3J = 7.5 Hz),
123.5 (d, 4J = 4.5 Hz), 122.1 (d, 2J = 18.75 Hz), 117.4 (d, 2J = 22.5 Hz), 116.7 (d, 2J = 22.5 Hz), 104.6 (CH5C), 15.02 (CH3).
4-F-
1600 (C5O), 1571 (Ar–C5C),
1452 (C5N), 1278 (C–S),
1144 (C–N)
1H NMR:
2.13 (d, 3H, J = 1.2 Hz, CH3). 13C NMR:
d 8.08–8.01 (m, 2H, Ar–H), 7.46 (dd, 1H, J = 2.4, 6.3 Hz, Ar–H), 7.40–6.94 (m, 4H, Ar–H), 6.44 (q, 1H, J = 1.2 Hz, CH5C),
d
172.4 (C5O), 170.1 (C5N), 164.8 (d, 1J = 250 Hz), 158.2 (d, 1J =255 Hz), 134.1,
133.5 (d, 4J = 3.75 Hz), 133.0 (d, 2C, 3J = 8.25 Hz), 131.7, 130.5, 128.3 (d, 3J = 7.5 Hz), 122.1 (d, 2J = 18.75 Hz), 117.4 (d, 2J =22.5 Hz),
114.6 (d, 2C, 2J = 21.75 Hz), 105.1 (CH5C), 14.98 (CH3).
t-Butyl
1588 (C5O), 1540 (Ar-C5C),
1457 (C5N), 1258 (C–S),
1178 (C–N)
1H NMR:
13C NMR:
d
d
7.41–7.28 (m, 2H, Ar–H), 7.21 (s, 1H, Ar–H), 6.34 (s, 1H, CH5C), 2.08 (s, 3H, CH3), 1.11 (s, 9H, 3[CH3]).
174.6 (C5O), 169.0 (C5N), 158.1 (d, 1J = 251 Hz), 128.2 (d, 3J = 7.5 Hz), 121.7 (d, 2J = 18.5 Hz), 117.1 (d, 2J = 22.5 Hz),
104.3 (CH5C), 40.7, 27.5 (3C, 3[CH3]), 15.05 (CH3).

Table 2
Physicochemical and mass spectral data of thiazolines (2a–t).
Compound
R1
R2
Yield (%)
Rfa
Mp (8C)
Molecular formula (MW)
EIMS [M+]
Analysis (Calcd./Found) (%)
C
H
N
S
2a
2b
2c
2d
2e
2f
2-Cl
2-F
65
75
78
73
81
65
68
76
75
69
87
71
76
81
67
72
77
52
62
82
0.25
0.12
0.45
0.53
0.31
0.22
0.11
0.43
0.51
0.25
0.21
0.10
0.40
0.50
0.43
0.44
0.10
0.41
0.44
0.56
135–136
153–155
133–134
117–119
103–105
129–131
172–173
173–174
166–168
147–150
184–186
179–181
207–209
174–175
178–180
174–176
137–139
187–188
185–187
124–125
C17H12N2OSFCl (346.81)
C20H19N2O4SF (402.44)
346.0
402.0
330.0
330.0
330.0
346.0
402.0
330.0
330.0
330.0
346.0
402.0
330.0
330.0
330.0
380.0
436.0
364.0
364.0
326.0
58.87/58.85
59.69/59.61
61.81/61.82
61.81/61.86
61.81/61.83
58.87/58.80
59.69/59.65
61.81/61.85
61.81/61.74
61.81/61.85
58.87/58.82
59.69/59.71
61.81/61.84
61.81/61.77
61.81/61.80
53.56/53.49
54.98/54.93
55.97/55.90
55.97/55.96
55.13/55.07
3.49/3.51
4.76/4.79
3.66/3.68
3.66/3.64
3.66/3.61
3.49/3.39
4.76/4.77
3.66/3.69
3.66/3.68
3.66/3.62
3.49/3.45
4.76/4.73
3.66/3.61
3.66/3.69
3.66/3.61
2.91/2.85
4.15/4.16
3.04/3.10
3.04/3.07
4.93/4.90
8.08/8.06
6.96/6.99
8.48/8.45
8.48/8.47
8.48/8.52
8.08/8.10
6.96/6.95
8.48/8.43
8.48/8.40
8.48/8.41
8.08/8.11
6.96/6.91
8.48/8.47
8.48/8.56
8.48/8.45
7.35/7.41
6.41/6.46
7.68/7.59
7.68/7.65
8.57/8.62
9.25/9.27
7.97/7.98
9.71/9.73
9.71/9.73
9.71/9.74
9.25/9.28
7.97/7.99
9.71/9.68
9.71/9.77
9.71/9.78
9.25/9.27
7.97/8.08
9.71/9.66
9.71/9.79
9.71/9.73
8.41/8.44
7.34/7.30
9.81/8.88
8.79/8.77
9.81/9.82
3,4,5-Tri-OCH3
2-F
2-F
2-F
C
C
C
C
17H12N2OSF2 (330.35)
17H12N2OSF2 (330.35)
17H12N2OSF2 (330.35)
17H12N2OSFCl (346.81)
3-F
2-F
4-F
2-F
2-Cl
3-F
2g
2h
2i
3,4,5-Tri-OCH3
3-F
C17H17N2O4SF (364.39)
2-F
3-F
C
C
C
C
17H12N2OSF2 (330.35)
17H12N2OSF2 (330.35)
17H12N2OSF2 (330.35)
17H12N2OSFCl (346.81)
3-F
3-F
2j
4-F
3-F
2k
2l
2-Cl
4-F
3,4,5-Tri-OCH3
4-F
C17H17N2O4SF (364.39)
2m
2n
2o
2p
2q
2r
2s
2t
2-F
4-F
C
C
17H12N2OSF2 (330.35)
17H12N2OSF2 (330.35)
3-F
4-F
4-FC6H4
2-Cl
4-F
C17H12N2OSF2 (330.35)
17H11N2OSFCl2 (381.25)
C20H18N2O4SFCl (436.88)
3-Cl-4-F
3-Cl-4-F
3-Cl-4-F
3-Cl-4-F
3-Cl-4-F
C
3,4,5-Tri-OCH3
2-F
C
C
C
17H11N2OSF2Cl (364.8)
17H11N2OSF2Cl (364.8)
15H16N2OSFCl (326.82)
4-F
t-Butyl
a
Solvent system: n-hexane:ethyl acetate (6:4 v/v). Recrystallization solvent: ethanol.

338
A. Saeed et al. / Journal of Fluorine Chemistry 131 (2010) 333–339
Table 5
Antifungal bioassay screening of thiazolines (2a–t).
Compound
Antifungal activity
Rhizopus oryzae
Aspergillus terreus
Fusarium oxysporum
Aspergillus niger
Aspergillus fumigatus
Zone of
% inhibition
Zone of
% inhibition
Zone of
% inhibition
Zone of
% inhibition
Zone of
% inhibition
inhibition
inhibition
inhibition
inhibition
inhibition
2a
7.5
9.0
9.0
8.5
8.0
8.5
7.5
8.0
6.5
9.0
8.0
8.5
9.0
9.0
9.0
7.0
8.5
7.5
8.5
3.5
9.0
0
16.7
–
1.5
5.5
4.0
4.0
3.2
5.7
5.0
4.0
5.4
5.0
2.0
4.5
6.5
5.0
3.5
0.5
5.0
4.5
3.5
3.5
8.0
0
81.3
31.3
50.0
50.0
60.0
28.8
37.5
50.0
32.5
37.5
75.0
43.8
18.8
37.5
56.3
93.7
37.5
43.8
56.3
56.3
–
3.5
5.4
4.0
3.5
4.5
4.0
5.0
3.5
6.0
5.4
3.5
6.0
8.0
3.5
6.0
2.0
4.0
3.5
3.0
3.2
8.0
0
56.3
32.5
50.0
56.3
43.8
50.0
37.5
56.3
25.0
32.5
56.3
25.0
–
7.0
6.5
6.0
9.0
8.0
9.0
9.0
5.0
9.0
7.0
5
22.2
27.7
33.3
–
7.5
6.0
8.0
8.0
8.0
7.0
8.0
6.0
8.0
7.5
5.5
9.0
7.0
5.0
5.0
4.0
9.0
9.0
5.0
4.5
9.0
0
16.6
33.3
11.1
11.1
11.1
22.2
11.1
33.3
11.1
16.6
38.8
–
2b
2c
–
2d
5.60
11.2
5.60
2e
11.1
–
2f
2g
16.7
11.2
27.8
–
–
2h
44.4
–
2i
2j
22.2
44.4
–
2k
11.2
2l
5.60
9.0
6.5
4.5
7.0
2.0
9.0
9.0
7.0
5.0
9.0
0
2m
2n
2o
–
–
27.7
50.0
22.2
77.7
–
22.2
44.4
44.4
55.5
–
56.3
25.0
75.0
50.0
56.3
62.5
60.0
–
–
2p
22.3
2q
5.60
16.7
5.60
2r
–
–
2s
22.2
44.4
–
44.4
50.0
–
2t
61.2
–
Control
Nystatin
100
100
100
100
100
100ꢀfungal growth in test sample
fungal growth in control ðcmÞ
Zone of inhibition in cm. percentage of fungal inhibition ¼
ðcmÞ ꢁ 100. Concentration used: 2 mg/1 ml. (–) = No activity.
Fig. 1. Antibacterial activity of the synthesized compounds.
antifungal activities against A.T. The ortho- and para-fluorine
substitution on the aryl ring significantly improves the antifungal
efficacy compared to the meta-substitution. Nystatin (mol. mass
926.09), a polyene antifungal drug isolated from Streptomyces
noursei was used as negative control (as standard drug) with no
growth (100% inhibition) of all fungal strains at the same
concentration (Fig. 2).
3. Conclusion
Some new substituted fluorobenzoylimino-3-(fluoroaryl)-4-
methyl-1,3-thiazolines were synthesized by base-catalyzed cyclo-
condensation of corresponding thioureas with 2-bromoacetone in
unconventional aqueous medium. The compounds exhibit mod-
erate to potent in vitro antimicrobial efficacy. In general, the
antifungal activity of compounds was better than their anti-
bacterial activity.
4. Experimental
Melting points were recorded using a digital Gallenkamp
(SANYO) model MPD BM 3.5 apparatus and are uncorrected. 1H
Fig. 2. Antifungal activity of the synthesized compounds.

A. Saeed et al. / Journal of Fluorine Chemistry 131 (2010) 333–339
339
NMR spectra were determined as CDCl3 solutions at 300 MHz using
a Bruker AM-300 spectrophotometer using TMS as an internal
reference and 13C NMR spectra were determined at 75 MHz using a
Bruker75 MHzNMR spectrometer inCDCl3 solution. IRspectrawere
recorded using an Shimadzu IR 460 as KBr pellets; Mass Spectra (EI,
70 eV) on a GC–MS instrument Agilent technologies.
fungal strains, i.e., Aspergillus terreus, Rhizopus oryzae, Fusarium
oxysporum, Aspergillus niger and Aspergillus fumigatus. 2 mg of
compounds were dissolved in 1 ml of DMSO. All fungal strains
were grown on saboraud dextrose agar SDA (pH 5.7) at 28 8C.
To perform the antifungal assay SDA medium petri plates were
prepared. 50
ml of test samples were added to the respective petri
plates using a micropipette and were dispersed using a spreader
and were allowed to absorb for some time. These were inoculated
with fungal strains and incubated at 30 8C. For every fungal strain, a
control containing no test sample was also prepared. After 4–6
days of incubation, the diameter of the fungal strains was
measured in each petri plate and percentage of fungal inhibition
was calculated using the formulae:
4.1. General procedure for the preparation of 2-(substituted
fluorobenzoylimino)-3-aryl-4-methyl-1,3-thiazolines (2a–t)
A vigorously stirred mixture of thioureas (1a–t) (1 mmol), 2-
bromoacetone (1 mmol) and triethylamine (1 mmol) in water
(20 ml) was refluxed for 40–50 min. The progress of the reaction
was followed by TLC examination using hexane ethyl acetate (6:4,
v/v). On completion of the reaction the products were either
filtered directly or extracted using ethyl acetate followed by drying
and concentration. Recrystallization using ethanol or methanol
afforded the 2-(substituted fluorobenzoylimino)-3-aryl-4-methyl-
1,3-thiazolines (2a–t) as crystalline solids. Tables 1 and 2 give the
physicochemical and characteristic spectral data (IR, 1H, 13C NMR,
EIMS) of products.
percentage of fungal inhibition
100 ꢀ fungal growth in test sample ðcmÞ
¼
ꢁ 100:
fungal growth in control ðcmÞ
References
[1] W.R. Dolbier Jr., J. Fluorine Chem. 126 (2005) 157–163.
[2] J.M. Antelo, J. Crugeiras, J.R. Leis, A. Rios, J. Chem. Soc., Perkin Trans. 2 (2000)
2071–2076.
[3] P.N. Edwards, Uses of fluorine in chemotherapy, in: R.E. Banks, B. Smart, J.C.
Tatlow (Eds.), Organofluorine Chemistry: Principles and Commercial Applica-
tions, Plenum Press, New York, 1994, pp. 543–554.
5. Biological assay
5.1. Antibacterial activity
[4] C. Wakselman, Ann. Pharm. Fr. 57 (1999) 108–115;
B.E. Smart, J. Fluor. Chem. 109 (2001) 3–11.
The antibacterial activity of all synthesized fluorinated imi-
nothiazolines has been investigated against four bacterial strains
by the Agar well diffusion assay. Imipenum was used as a standard
antibiotic. 2 mg of compounds were dissolved in 1 ml of DMSO. In
nutrient broth medium 24 h fresh bacterial was prepared. To
compare the turbidity of bacterial culture McFarland 0.5% barium
sulphate solution was used (as turbidity standard).
[5] P. Vicini, A. Geronikaki, K. Anastasia, M. Incerti, F. Zani, Bioorg. Med. Chem. 14
(2006) 3859–3864.
[6] A. Zhang, H. Kaiser, P. Maienfisch, J.E. Casida, J. Neurochem. 75 (2000) 1294–1303;
P. Maienfisch, J. Haettenschwiler, A. Rindlisbacher, A. Decock, H. Wellmann, H.
Kayser, Chimia 57 (2003) 710–714.
[7] S.J. Hosseinimehr, A. Shafiee, H. Mozdarani, S. Akhlagpour, J. Radiat. Res. 42 (2001)
401–408;
S.J. Hosseinimehr, A. Shafiee, H. Mozdarani, S. Akhlagpour, M. Froughizadeh, J.
Radiat. Res. 43 (2002) 293–300.
[8] S. Bae, H.-G. Hahn, K.D. Nam, J. Comb. Chem. 7 (2005) 7–12.
[9] D.-S. Kim, Y.-M. Jeong, I.-K. Park, H.-G. Hahn, H.-K. Lee, S.-B. Kwon, S.J. Yang, U.D.
Sohn, K.-C. Park, Biol. Pharm. Bull. 30 (2007) 180–183.
[10] P. Nicolas, M. Anice, D. Rosanna, L. Paul, P. Veronique, L. Fabienne, B. Mathias, K.
Jean-Louis, M. Flavio, J. Med. Chem. 49 (2006) 3645–3652.
[11] S.M. Sondhi, S. Singh, J. Kumar, H. Jamal, P.P. Gupta, Eur. J. Med. Chem. 44 (2009)
1010–1015.
[12] A. Manaka, M. Sato, M. Aoki, M. Tanaka, T. Ikeda, Y. Toda, Y. Yamanane, S. Nakaike,
Bioorg. Med. Chem. Lett. 11 (2001) 1031–1035.
[13] S.M. Sondhi, N. Singh, A.M. Lahoti, K. Bajaj, A. Kumar, O. Lozach, L. Meijer, Bioorg.
Med. Chem. 13 (2005) 4291–4299.
[14] M.-H. Shih, F.-Y. Ke, J. Bioorg. Med. Chem. 12 (2004) 4633–4638.
[15] Y. Sanemitsu, S. Kawamura, J. Satoh, T. Katayama, S. Hashimoto, J. Pestic. Sci. 31
(2006) 305–310.
[16] A.A. Aly, E.K. Ahmed, K.M. El-Mokadem, J. Sulfur Chem. 27 (2006) 419–426;
R.-S. Zeng, J.-P. Zou, S.-J. Zhi, J. Chen, Q. Shen, Org. Lett. 5 (2003) 1657–1659.
[17] C.B. Singh, S. Murru, V. Kavala, B.K. Patel, Org. Lett. 8 (2006) 5397–5399.
[18] J.P. Germanas, S. Wang, A. Miner, W. Hao, J.M. Ready, Bioorg. Med. Chem. Lett. 17
(2007) 6871–6875.
To perform the antibacterial assay, nutrient agar petri plates
were prepared with sterile cotton swabs, respective bacterial
colony lawns were prepared with sterile cork borrer (4 mm). Using
a micropipette, 30
ml of test solution were poured into respective
wells and these petri plates were incubated at 37 8C for 24 h. After
24 h of incubation, the radius of the clear zones showing no
bacterial growth was measured around each well. The zones of
inhibition (mm) were calculated and compared with the standard
drug imipenum.
The primary screen was carried out by agar disc-diffusion
method using nutrient agar medium. The minimum inhibitory
concentration for the most active compounds 2a, 2b, 2d, 2e, 2i, 2n,
2p, 2r, 2s, and 2t against the same microorganisms used in the
preliminary screening was carried out using the microdilution
susceptibility method.
[19] Z.P. Demko, K.B. Sharpless, Org. Chem. 66 (2001) 7945–7951;
C.J. Li, Chem. Rev. 105 (2005) 3095–4007.
[20] T. Rispens, J.B.F.N. Engberts, J. Org. Chem. 67 (2001) 7369–7372;
J.S. Yadav, S.T. Swami, B.V.S. Reddy, D. Krishna Rao, J. Mol. Catal. A: Chem. 274
(2007) 116–126.
[21] A. Saeed, S. Zaman, M. Bolte, Synth. Commun. 38 (2008) 2185–2199.
[22] A. Saeed, M. Parvez, Cent. Eur. J. Chem. 3 (2005) 780–791.
5.2. Antifungal activity
The antifungal activity of all the synthesized fluorinated 1-
aroyl-3-aryl thioureas has been investigated against five different