Synthesis and biological evaluation of some new polyfluorinated 4-thiazolidinone and α-aminophosphonic acid derivatives

Article abstract of DOI:10.1007/s00706-013-0934-6

A simple route for the synthesis of new polyfluorinated 4-thiazolidinones and 1,4-bis(4-thiazolidinone)phenylenes was achieved from one-pot three-component reaction of fluorinated aniline, mono- and dialdehyde and thioglycolic acid followed by fluorination with trifluoroacetamide and 4-fluorobenzaldehyde. Also, some new fluorinated α-aminophosphonates, 1,4-bis(α-aminophosphonate)phenylenes and their corresponding acids were synthesized via one-pot three-component reaction of fluorinated aniline, mono- and dialdehyde and diethyl phosphite followed by fluorination with trifluoroacetic anhydride. All the synthesized compounds were screened for their antifungal activity against Alternaria alternate and Fusarium oxysporium. Also, their effects on the enzymatic effect of cellobiase produced from Alternaria alternate and Fusarium oxysporium were estimated. Compounds that have trifluoromethyl groups recorded good inhibition against the fungal strains and also enhanced the enzymatic effect of cellobiase.

Full text of DOI:10.1007/s00706-013-0934-6

Monatsh Chem
DOI 10.1007/s00706-013-0934-6
ORIGINAL PAPER
Synthesis and biological evaluation of some new polyfluorinated
4-thiazolidinone and a-aminophosphonic acid derivatives
•
Reda M. Abdel-Rahman Tarik E. Ali
Received: 8 July 2012 / Accepted: 21 January 2013
Ó Springer-Verlag Wien 2013
Abstract A simple route for the synthesis of new poly-
fluorinated 4-thiazolidinones and 1,4-bis(4-thiazolidinone)-
phenylenes was achieved from one-pot three-component
reaction of fluorinated aniline, mono- and dialdehyde
and thioglycolic acid followed by fluorination with trifluo-
roacetamide and 4-fluorobenzaldehyde. Also, some new
fluorinated a-aminophosphonates, 1,4-bis(a-aminophospho-
nate)phenylenes and their corresponding acids were
synthesized via one-pot three-component reaction of fluori-
nated aniline, mono- and dialdehyde and diethyl phosphite
followed by fluorination with trifluoroacetic anhydride. All
the synthesized compounds were screened for their anti-
fungal activity against Alternaria alternate and Fusarium
oxysporium. Also, their effects on the enzymatic effect of
cellobiase produced from Alternaria alternate and Fusarium
oxysporium were estimated. Compounds that have trifluo-
romethyl groups recorded good inhibition against the fungal
strains and also enhanced the enzymatic effect of cellobiase.
Introduction
Fluorine occupies a unique place among all elements of the
periodic classification because of its high electronegativity
and its specific properties. Thus, organofluorine chemistry
is of great importance because of this singular nature of the
fluorine atom combined with the unique physical and
chemical properties that fluorine imparts to compounds that
contain it. The strong electronic contribution and negligible
steric demands of fluorine present interesting and unusual
properties. Indeed, the specific physicochemical properties
of fluorinated organic compounds are of huge interest in a
wide range of applications [1–5]. Consequently, organo-
fluorine chemistry has been steadily growing and today
possesses a distinctive role in highly diverse technologi-
cal developments (fluoropolymers, pharmaceutical and
agrochemical products, materials science, etc.) [6, 7].
Therefore, the development of new methods to introduce
fluorine into molecules is of great interest to organic and
medicinal chemists.
Keywords Synthesis ꢀ Antifungal ꢀ Fluorine ꢀ
4-thiazolidinone ꢀ a-Aminophosphonic acids
and their esters
4-Thiazolidinones are key structures in numerous com-
pounds of therapeutic importance as antimicrobial, plant
protection, anticancer and anti-AIDS activities [8–15]. On
the other hand, a-aminophosphonate derivatives are struc-
tural mimics of a-amino acids, and some of these
compounds exhibit very high potency in inhibiting the
enzymes that are involved in the metabolism of the cor-
responding amino acids. These compounds have already
been found to act as antibacterial agents, neuroactive
compounds, anticancer drugs and pesticides, with some of
them already being commercialized [16–22].
R. M. Abdel-Rahman
Department of Chemistry, Faculty of Science,
King Abdulaziz University, Jeddah, Saudi Arabia
Keeping in view the diverse biological activities associ-
ated with organofluorine compounds, 4-thiazolidinones and
a-aminophosphonates, it was intended to construct novel
fluorinated 4-thiazolidinones and a-aminophosphonates
T. E. Ali (&)
Department of Chemistry, Faculty of Education,
Ain Shams University, Roxy, 11711 Cairo, Egypt
e-mail: tarik_elsayed1975@yahoo.com
123

R. M. Abdel-Rahman, T. E. Ali
hoping to achieve additive effects toward their biological
activities. As an extension of our research work on the syn-
thesis of bioactive heterocycles [23–27], we wish to report
herein the synthesis of some new fluorinated 4-thiazolidi-
nines and a-aminophosphonates and evaluation of their
fungicidal properties and enzymatic effect on cellobiase.
thioglycolic acid. The different reaction conditions, such as
long-term heating with a dehydrant, using an acylation agent
or microwave-assistant organic synthesis, were described
[28, 29]. Based on the above-mentioned approach, we have
synthesized 2,3-bis(fluorinated substituted phenyl)thiazoli-
din-4-one (1a,b) from the reaction of fluorinated substituted
aniline, fluorinated substituted benzaldehyde and thiogly-
colic acid in dry dioxane in the presence of anhydrous zinc
chloride (Scheme 1).
Results and discussion
Compounds 1a,b contain an active methylene group in
position C-5 of the core ring, which opens wide opportu-
nities for their modification, taking into consideration the
critical influence of the presence and the nature of the C-5
position moieties on biological activity. The polyfluori-
nated 4-thiazolidione derivatives 2a,b and 3a,b have been
Chemistry
The most convenient method for the synthesis of 2,3-di-
substituted-4-thiazolidinones is the one-pot three-component
reaction of a primary amine, carbonyl compound and
Scheme 1
R1
R2
R3
R
+
NH2
HSCH2COOH
+
OHC
4
R
Dioxane
ZnCl2
R
R1
O
R2
N
S
4
R3
H
R
1a, 1b
F3CCONH2
CH3COOH
4-FC6H5CHO
EtONa-EtOH
R
R
R1
R1
O
O
R2
R2
N
N
O
S
S
H
F3C
H
R3
R3
H
4
4
R
R
2a, 2b
3a, 3b
F
a, R=F, R1=H, R2=H, R3=F, R4=H
b, R=F, R1=F, R2=F, R3=H, R4=Cl
123

Polyfluorinated 4-thiazolidinone and a-aminophosphonic acid derivatives
Scheme 2
2
F
+
NH2
OHC
CHO
HSCH2COOH
+
2
Dioxane ZnCl2
S
S
N
N
O
O
F
F
4
F3CCONH2
CH3COOH
4-FC6H5CHO
EtONa-EtOH
O
O
F
F
H
S
H
S
F3C
CF3
N
N
O
O
S
S
N
N
O
O
F
F
5
F
F
6
achieved via fluorination of compounds 1a,b with fluorine
reagents such as trifluoroacetamide and 4-fluorobenzaldehyde.
Thus, fusion of compounds 1 a,b with trifluoroacetamide in
the presence of glacial acetic acid afforded 2,3-bis(fluori-
nated substituted phenyl)-5-(trifluoroacetyl)thiazolidin-4-ones
(2a,b), while their condensation with 4-fluorobenzaldehyde
in ethanolic sodium ethoxide under Knoevenagel reaction
condition gave 5-(4-fluorobenzylidene)-2,3-bis(fluorinated
substituted phenyl)thiazolidin-4-ones (3a,b) (Scheme 1).
The main aim of this work is the combination of many
fluorinated rings together in a single molecular structure
hoping to achieve additive biocidal effects toward their
antifungal activity, where the fluorine atoms leads to a
strong polarization and changes various physical and bio-
logical properties of the molecules. Thus, one-pot three-
component reaction of 4-fluoroaniline, 1,4-terephthalalde-
hyde and thioglycolic acid in dry dioxane in the presence of
anhydrous zinc chloride as a catalyst under reflux afforded
2,20-(1,4-phenylene)bis[3-(4-fluorophenyl)thiazolidin-4-one]
(4) (Scheme 2). Furthermore, the latter bis-thiazolidinone 4
reacted with trifluoroacetamide and 4-fluorobenzaldehyde
under the same previously described conditions to yield
the interesting 2,20-(1,4-phenylene)bis[3-(4-fluorophenyl)-5-
(2,2,2-trifluoroacetyl)thiazolidin-4-one] (5) and 2,20-(1,4-
phenylene)bis[5-(4-fluorobezylidene)-3-(4-fluorophenyl)-
thiazolidin-4-one] (6), respectively (Scheme 2). The struc-
tures of the new thiazolidinone derivatives 1–6 were
assigned on the basis of their analytical and spectral data. The
characteristic C=O bands of the thiazolidinone rings
appeared in the region 1,656–1,696 cm-1 in the IR spectra of
the thiazolidinones 1–6, while C=O of the trifluoroacetyl
moiety in 2a,b and 5 appeared at 1,729, 1,730 and
1,731 cm-1, respectively. Furthermore, the compounds 1a,b
and 4 display doublets at 3.85–3.95 ppm because of the HA
and HB systems in their 1H NMR spectra. In the compounds
2a,b, 3a,b, 5 and 6. These HA and HB systems were absent,
123

R. M. Abdel-Rahman, T. E. Ali
Scheme 3
R1
R2
R3
R
NH2
H-P(O)(OEt)2
+
+
OHC
R4
70 oC
BF3.Et2O
O
EtO
OEt
R2
R
P
R1
N
H
H
4
R
R3
7a, 7b
(CF3CO)2O
CH3COONa
O
P
EtO
O
OEt
R2
R
HO
OH
R2
R
P
R1
R1
N
O
N
H
H
F3C
4
R3
F3C
4
R
R3
R
O
9a, 9b
8a, 8b
a, R=F, R1=H, R2=H, R3=F, R4=H
b, R=F, R1=F, R2=F, R3=H, R4=Cl
confirming that trifluoroacetylation and condensation reac-
tions had taken place on the 5-CH2 groups. Regarding
substituted anilines, fluorinated substituted benzaldehydes
and diethyl phosphite in the presence of BF3.Et2O as a
catalyst at 70 °C under Kabachink-Fields reaction condition
afforded the corresponding diethyl[(fluorinated substituted
phenylamino) (fluorinated substituted phenyl)methyl]phos-
phonates (7a,b) in high yield [37, 38] (Scheme 3). The
fluorination of the a-aminophosphonates 7a,b with trifluoro-
acetic anhydride in the presence of anhydrous sodium acetate
gave [2,2,2-trifluoro-N-(fluorinated substituted phenyl)acet-
amido] [fluorinated substituted phenyl]methyl phosphonic
acids (8a,b) and not the diesters 9a,b (Scheme 3). This
reaction underwent trifluoroacetylation of the NH group of
compounds7a,b followedbyhydrolysisofthediesterbecause
of the presence of the formed trifluoroacetic acid. Similarly,
applying the Kabachnik-Fields reaction to 4-fluoroaniline,
1,4-terephthalaldehyde and diethyl phosphite in the presence
of BF3.Et2O as a catalyst at 70 °C afforded diethyl 1,4-phe-
nylene-bis[N-(4-fluorophenyl)aminomethylphosphonate]
(10) (Scheme 4). The latter bis-aminophosphonate also
1
compounds 1–6, their H-NMR spectra showed singlets at
5.92–6.03 ppm because of a proton of 2-CH. Also, the 13C-
NMR spectra recorded the characteristic C=O bands of the
thiazolidinone rings at 170.6–171.4 ppm, while C=O of the
trifluoroacetyl moiety in 2a,b and 5 appeared at 195.0, 193.5
and 195.1 ppm, respectively.
Introduction of the fluorine-containing group in a bio-
molecule may change the ‘normal’ route of its interaction
with a biological target or the direction of binding.
Therefore, such an approach is very popular for the con-
struction of new biologically active molecules. However,
in contrast to the rather well-developed a-aminophos-
phonic acid area, only limited representatives of fluorine
containing a-aminophosphonates are currently known
[30–38]. Thus, the synthesis of new fluorinated a-amino-
phosphonates as potential drug candidates is of current
interest. One-pot three-component reaction of fluorinated
123

Polyfluorinated 4-thiazolidinone and a-aminophosphonic acid derivatives
Scheme 4
2
F
+
NH2
OHC
H-P(O)(OEt)2
CHO
2
+
BF3.Et2O
70 oC
O
OEt
H
EtO O
P
EtO
P
OEt
F
N
H
N
H
F
H
10
(CF3CO)2O
CH3COONa
HO O
O
OH
H
HO
P
N
P
OH
H
F
N
F
O
O
F3C
CF3
11
underwent trifluoroacetylation followed by acid hydrolysis
to give the novel interesting 1,4-phenylene-bis[N-(2,2,2-
trifluoroacetyl)-N-(4-fluorophenyl)aminomethylphosphonic
acid] (11) (Scheme 4). The chemical structures of a-am-
inophosphonic acid derivatives 7a,b, 8a,b, 10 and 11 were
confirmed by elemental analysis, IR, 1H-, 13C- and 31P-NMR
spectra. Compounds 7a,b and 10 exhibited characteristic
IR stretching frequencies in the region 3,339–3,100,
1,281–1,238 and 1,013–1,092 cm-1 for NH, P=O and P–O–
C functions, respectively. The P–CH protons of 7a,b and 10
resonated as doublets at d 4.69, 4.12 and 5.06 ppm
(JPCH = 23.9, 15.6 and 17.2 Hz), respectively, because of
their coupling with phosphorus. The ethyl groups of the
diethyl phosphonate moieties resonated as two distinct
triplets and quartets at d 1.19–1.28 and 3.69–4.20 ppm [38].
Also, the P–CH carbon atom shift signals for 7b and 10
appeared as doublets at d 44.0 and 43.3 ppm (JPCH = 143.8
and 150 Hz), respectively, in their 13C-NMR spectra, while
the phosphorus atoms were resonated in the 31P-NMR
spectrum as singlets at d 22.3 and 20.5 ppm, respectively.
Similarly, the spectroscopic data of 8a,b and 11 were in
complete agreement with the proposed structures. The
appearance of OH, C=O and P=O was at 3,200–3,365,
1,709–1,731 and 1,220–1,257 cm-1, respectively, in their IR
appeared as doublets at d 3.65, 4.00 and 4.61 (JPCH = 16.8,
19.2, and 19.2 Hz) for 8a,b and 11, respectively. Also, the
13C-NMR spectra were supported for the proposed struc-
tures, which exhibited the resonances of P–CH and C=O at
the region d 51.5, 50.6, 48.5 and 193, 195, 190.3 ppm,
respectively. The 31P-NMR spectra of 8b and 11 recorded
singlets for them at d 14.4 and 15.3 ppm, respectively.
Although the compounds 10 and 11 have two chiral centers,
they exist in only one diastereomeric form because of the
presence of one peak for each carbon and phosphorus of the
P–CH moiety in their NMR spectra [39].
Biological evaluation
In vitro antifungal activity
The newly synthesized compounds were evaluated for their
in vitro antifungal activity against two fungal strains,
Alternaria alternate and Fusarium oxysporium, by the
poisoned food method [40, 41]. Fluconazole was used as
the reference drug, and the results were recorded as the
percentage of growth inhibition (Table 1). The results
revealed that, in general, all the tested compounds pos-
sessed good antifungal activity. On the basis of percentage
of growth inhibition against the tested fungal strains, it
seems that replacement of the active methylene group in
1
spectra. Also, in their H-NMR spectra, the P–CH protons
123

R. M. Abdel-Rahman, T. E. Ali
Table 1 In vitro antifungal activity of the synthesized compounds on some fungi at concentrations of 250, 500 and 100 ppm
Compound
Percent of growth inhibition/%
Alternaria alternate
Fusarium oxysporium
250 ppm
500 ppm
1,000 ppm
250 ppm
500 ppm
1,000 ppm
1a
76.8
77.8
88.1
88.7
80.5
80.9
76.2
85.4
78.9
80.1
82.4
80.3
81.6
79.9
83.2
92.0
78.1
80.2
89.0
90.3
82.3
83.4
77.0
88.3
80.3
82.8
83.4
82.1
83.5
80.1
86.1
94.3
80.9
82.0
91.5
91.9
85.8
85.9
78.9
90.5
82.1
85.2
85.6
84.4
86.3
83.5
89.4
95.8
76.3
77.4
84.3
85.6
74.8
76.2
76.5
87.3
74.2
80.1
80.2
79.5
79.7
78.0
85.3
90.8
80.2
80.8
87.0
88.1
76.3
77.6
78.2
88.3
76.7
83.3
84.1
80.5
81.3
80.5
87.2
92.4
82.2
83.3
90.4
92.3
81.7
81.9
81.8
90.1
79.9
87.1
88.1
86.5
88.3
82.1
88.7
94.3
1b
2a
2b
3a
3b
4
5
6
7a
7b
8a
8b
10
11
Fluconazole
compounds 1a,b and 4 with trifluoroacetyl and 4-fluorob-
enzylidene exhibited a noticeable increase in the antifungal
activity. Also, trifluoroacetylation of the NH groups of
compounds 7a,b and 10 and transformation of ethoxy
groups into hydroxyl caused improvement the antifungal
activity.
antifungal activity against the tested fungi and also
enhanced the enzymatic effect of cellobiase. However,
none of the newly synthesized compounds was found to be
superior compared to the used references.
Experimental
The effect of the synthesized compounds on the enzymatic
effect on cellobiase
Melting points of the products were determined on Stuart
SMP3. A Perkins-Elmer model RXI-FT-IR system 55529
was used for recording the IR spectra of the prepared
The effect of synthesized compounds on cellobiase activity
produced by Alternaria alternate and Fusarium oxyspori-
um was estimated [42, 43]. The obtained results were
recorded in Table 2. Generally, at lower concentration, the
enzymatic effect of the tested compounds increased while
the higher concentration of the synthesized compounds
inhibited that enzymatic effect. Only compounds 2a,b, 5,
8b and 11 exhibited highly enzymatic effects at low con-
centration because of the hydrophobic character of CF3
groups that essentially improves the pharmacokinetic pro-
files of potential drugs.
1
compounds using CDCl3 and D2O solvents. H-, 13C- and
31P-NMR spectra were recorded on a Bruker 600 MHz
spectrometer operating at 600, 150 and 242 MHz, respec-
tively. The chemical shifts are reported in ppm with respect
to the references and were stated relative to tetramethyl-
silane (TMS) for 1H- and 13C-NMR and to 85 %
phosphoric acid for 31P-NMR. Mass spectra were recorded
on a gas chromatographic DI analysis Shimadzu instrument
Q-2010 Plus at 70 eV. The purity of the synthesized
compounds was checked by thin layer chromatography
(TLC) and elemental analysis. The biological activities
were measured at the Department of Biochemistry, Faculty
of Science, King Abdulaziz University.
Conclusions
In this article, some new fluorinated 4-thiazolidinone and
a-aminophosphonic acid derivatives were synthesized. All
the synthesized compounds were screened for their anti-
fungal activity and the enzymatic effect on cellobiase. Of
the tested compounds, 2a,b, 5 and 11 exhibited good
2,3-Bis(fluorinated substituted phenyl)thiazolidin-4-one
(1a,b)
A mixture of fluorinated substituted aniline (2.5 mmol) and
fluorinated substituted benzaldehyde (2.5 mmol) was
123

Polyfluorinated 4-thiazolidinone and a-aminophosphonic acid derivatives
Table 2 The effect of synthesized compounds on cellobiase activity produced by Alternaria alternate and Fusarium oxysporium
Compound*
Alternaria alternate
Fusarium oxysporium
10 lg/cm3
50 lg/cm3
100 lg/cm3
10 lg/cm3
50 lg/cm3
100 lg/cm3
1a
1b
2a
2b
3a
3b
4
0.32
0.33
0.35
0.36
0.29
0.31
0.28
0.38
0.30
0.31
0.32
0.34
0.36
0.34
0.41
0.30
0.32
0.33
0.33
0.25
0.27
0.26
0.35
0.28
0.28
0.30
0.31
0.33
0.32
0.36
0.25
0.26
0.30
0.32
0.22
0.24
0.22
0.31
0.22
0.25
0.27
0.29
0.29
0.28
0.32
0.31
0.33
0.33
0.34
0.26
0.26
0.26
0.35
0.28
0.30
0.32
0.28
0.30
0.30
0.37
0.30
0.31
0.31
0.32
0.22
0.23
0.24
0.33
0.25
0.28
0.27
0.26
0.29
0.27
0.33
0.26
0.26
0.27
0.25
0.18
0.17
0.22
0.30
0.22
0.24
0.21
0.22
0.23
0.25
0.31
5
6
7a
7b
8a
8b
10
11
* DMF as solvent recorded 0.04 lg/cm3
heated in dry dioxane (15 cm3) under reflux for 10 min,
followed by addition of a solution of thioglycolic acid
(3 mmol) in dry dioxane (5 cm3) and 1.5 g freshly fused
zinc chloride. The reaction mixture was heated under reflux
for an additional 6 h. The mixture was cooled then
neutralized with aqueous NaHCO3 (10 %, 30 cm3). The
formed solid was filtered off, washed with water three
times and crystallized from ethanol to give the pale yellow
crystals.
MS (70 eV): m/z = 344 (M?); anal. calcd. for
C15H9ClF3NOS (343.75): C, 52.41; H, 2.64; N, 4.07; S,
9.33. Found: C, 52.19; H, 2.53; N, 3.82; S, 9.11.
5-(2,2,2-Trifluoroacetyl)-2,3-bis(fluorinated substituted
phenyl)thiazolidin-4-one (2a,b)
A mixture of 2,3-bis(fluorinated substituted phenyl)thiazoli-
din-4-one (1a,b) (2.5 mmol) and 0.28 g trifluoroacetamide
(2.5 mmol) in the presence of few drops of glacial acetic acid
was fused at 120 °C for 1 h. The cooled reaction mixture was
poured onto 100 g of crushed ice. The formed solid was
filtered off, washed with water three times then crystallized
from aqueous ethanol to give the yellowish crystals.
2,3-Bis(4-fluorophenyl)thiazolidin-4-one
(1a, C15H11F2NOS)
Yield 0.45 g (62 %). M.p.: 98–100 °C; IR (CDCl3):
vꢀ = 1,656 (C=O), 1,239 (C–F) cm-1
;
1H NMR
5-(2,2,2-Trifluoroacetyl)-2,3-bis(4-fluorophenyl)thiazoli-
din-4-one (2a, C17H10F5NO2S)
(600 MHz, CDCl3): d = 3.88, 3.91 (dd, 2H, 5-CH2, AB
system), 6.02 (s, 1H, 2-CH), 6.96–6.99 (m, 4H, Ar–H),
7.02–7.09 (m, 2H, Ar–H), 7.27–7.29 (m, 2H, Ar–H) ppm;
13C NMR (150 MHz, CDCl3): d = 33.4 (5-CH2), 65.1
(2-CH), 116.0, 116.3, 127.8, 127.9, 133.0, 134.7, 160.4,
162.0, 171.0 (C=O) ppm; anal. calcd. for C15H11F2NOS
(291.32): C, 61.84; H, 3.81; N, 4.81; S, 11.01. Found: C,
61.66; H, 3.59; N, 4.71; S, 10.70.
Yield 0.78 g (81 %). M.p.: 122–124 °C; IR (CDCl3):
vꢀ = 1,729 (C=O), 1,669 (C=O), 1,222 (C–F) cm-1 1H
;
NMR (600 MHz, CDCl3): d = 4.20 (s, 1H, 5-CH), 6.03 (s,
1H, 2-CH), 6.95–6.99 (m, 4H, Ar–H), 7.00–7.10 (m, 2H, Ar–
H), 7.27–7.30 (m, 2H, Ar–H) ppm; 13C NMR (150 MHz,
CDCl3): d = 45.3 (5-CH), 65.1 (2-CH), 113.9 (CF3), 116.0,
116.3, 127.8, 127.9, 133.0, 134.7, 160.4, 162.0, 171.0 (C=O),
195.0(C=O)ppm. MS(70 eV): m/z = 387 (M?);anal. calcd.
for C17H10F5NO2S (387.33): C, 52.72; H, 2.60; N, 3.62; S,
8.28. Found: C, 52.47; H, 2.39; N, 3.36; S, 8.02.
2-(2-Chloro-6-fluorophenyl)-3-(3,4-difluorophenyl)thiaz-
olidin-4-one (1b, C15H9ClF3NOS)
Yield 0.51 g (60 %). M.p.: 70–72 °C; IR (CDCl3):
vꢀ = 1,660 (C=O), 1,203 (C–F) cm-1
;
1H NMR
(600 MHz, CDCl3): d = 3.85, 3.88 (dd, 2H, 5-CH2, AB
system), 6.00 (s, 1H, 2-CH), 6.99–7.10 (m, 6H, Ar–H)
ppm; 13C NMR (150 MHz, CDCl3): d = 33.5 (5-CH2),
58.5 (2-CH), 114.8, 115.6, 117.5, 121.1, 125.6, 127.6,
130.7, 130.9, 133.4, 160.6, 161.0, 162.3, 170.6 (C=O) ppm;
2-(2-Chloro-6-fluorophenyl)-3-(3,4-difluorophenyl)-5-
(2,2,2-trifluoroacetyl)thiazolidin-4-one
(2b, C17H8ClF6NO2S)
Yield 0.6 g (55 %). M.p.: 101–103 °C; IR (CDCl3):
vꢀ = 1,730 (C=O), 1,696 (C=O), 1,220 (C–F) cm-1 1H
;
123

R. M. Abdel-Rahman, T. E. Ali
NMR (600 MHz, CDCl3): d = 4.10 (s, 1H, 5-CH), 6.02 (s,
1H, 2-CH), 6.98–7.10 (m, 6H, Ar–H) ppm; 13C NMR
(150 MHz, CDCl3): d = 44.5 (5-CH), 64.7 (2-CH), 110.0
(CF3), 114.9, 115.7, 117.5, 121.1, 125.6, 127.6, 130.8,
130.9, 133.4, 160.6, 161.0, 162.3, 170.6 (C=O), 193.5
(C=O) ppm; anal. calcd. for C17H8ClF6NO2S (439.75): C,
46.43; H, 1.83; N, 3.19; S, 7.29. Found: C, 46.26; H, 1.54;
N, 2.87; S, 7.08.
tetrahydrofuran to give pale yellow crystals. Yield 0.41 g
(88 %). M.p.: 247–249 °C. IR (CDCl3): vꢀ = 1,665 (C=O),
1
1,227 (C–F); H NMR (600 MHz, CDCl3): d = 3.89, 3.95
(dd, 4H, 5-CH2, AA0BB0 system), 5.95 (s, 2H, 2-CH), 6.90–6.93
(m, 4H, Ar–H), 6.94–6.98 (m, 4H, Ar–H), 7.21–7.22 (m, 4H,
Ar–H) ppm; 13C NMR (150 MHz, CDCl3): d = 33.3(5-CH2),
65.2 (2-CH), 116.1, 127.8, 127.9, 132.9, 140.0, 162.0, 170.9 (2
C=O) ppm; MS (70 eV): m/z = 468 (M?); anal. calcd. for
C24H18F2N2O2S2 (468.55): C, 61.52; H, 3.87; N, 5.98; S,
13.69. Found: C, 61.32; H, 3.64; N, 5.77; S, 13.48.
5-(4-Fluorobenzylidene)-2,3-bis(fluorinated substituted
phenyl)thiazolidin-4-one (3a,b)
A mixture of 2,3-bis(fluorinated substituted phenyl)thiazoli-
din-4-one (1a,b) (2.5 mmol) and 0.31 g 4-fluorobenzaldehyde
(2.5 mmol) in ethanolic sodium ethoxide (0.2 g Na in 15 cm3
of ethanol) was heated under reflux for 10 h. The cooled
reaction mixture was poured onto ice cold water, then acidified
with diluted acetic acid. The formed solid was filtered off and
crystallized from ethanol to give the yellowish products.
2,20-(1,4-Phenylene)bis[3-(4-fluorophenyl)-5-(2,2,2-trifluo-
roacetyl) thiazoldin-4-one] (5, C28H16F8N2O4S2)
A mixture of 0.468 g 2,20-(1,4-phenylene)bis[3-(4-fluoro-
phenyl) thiazolidin-4-one) (4) (1 mmol) and 0.226 g
trifluoroacetamide (2 mmol) in the presence of a few drops
of glacial acetic acid was fused at 250 °C for 2 h. The
cooled reaction mixture was poured onto 100 g of crushed
ice. The formed solid was filtered off, washed with water
three times then crystallized from methanol to give white
crystals. Yield 0.48 g (74 %). M.p.: 202–204 °C. IR
(CDCl3): vꢀ = 1,731 (C=O), 1,667 (C=O), 1,222 (C–F)
5-(4-Fluorobenzylidene)-2,3-bis(4-fluorophenyl)thiazoli-
din-4-one (3a, C22H14F3NOS)
Yield 0.73 g (74 %). M.p.: 242–244 °C; IR (CDCl3):
vꢀ = 1,682 (C=O), 1,221 (C–F) cm-1; 1H NMR (600 MHz,
CDCl3): d = 5.95 (s, 1H, 2-CH), 6.90–7.30 (m, 13H, Ar–H
and =CH) ppm; 13C NMR (150 MHz, CDCl3): d = 65.1
(2-CH), 116.0, 116.1, 116.3, 127.8, 127.9, 129.1, 129.2,
133.0, 133.1, 134.7, 162.0, 162.1, 163.7, 171.0 (C=O) ppm;
anal. calcd. for C22H14F3NOS (397.41): C, 66.49; H, 3.55;
N, 3.52; S, 8.07. Found: C, 66.21; H, 3.38; N, 3.34; S, 7.94.
cm-1 1H NMR (600 MHz, CDCl3): d = 4.23 (s, 2H,
;
5-CH), 5.96 (s, 2H, 2-CH), 6.90–6.99 (m, 8H, Ar–H),
7.21–7.23 (m, 4H, Ar–H) ppm; 13C NMR (150 MHz,
CDCl3): d = 48.1 (5-CH), 65.2 (2-CH), 114.4 (CF3),
116.2, 127.7, 127.9, 133.0, 140.0, 162.0, 171.0 (C=O),
195.1 (C=O) ppm; anal. calcd. for C28H16F8N2O4S2
(660.57): C, 50.91; H, 2.44; N, 4.24; S, 9.71. Found: C,
50.66; H, 2.24; N, 3.97; S, 9.53.
2-(2-Chloro-6-fluorophenyl)-3-(3,4-difluorophenyl)-5-
(4-fluorobenzylidene) thiazolidin-4-one
(3b, C22H12ClF4NOS)
2,20-(1,4-Phenylene)bis[5-(4-fluorobenzylidene)-3-(4-fluo-
rophenyl) thiazolidin-4-one] (6, C38H24F4N2O2S2)
Yield 0.84 g (75 %). M.p.: 264–265 °C; IR (CDCl3):
A mixture of 0.468 g 2,20-(1,4-phenylene)bis[3-(4-fluoro-
phenyl) thiazolidin-4-one) (4) (1 mmol) and 0.248 g 4-
fluorobenzaldehyde (2 mmol) in ethanolic sodium ethoxide
(0.2 g Na in 30 cm3 of ethanol) was heated under reflux for
10 h. The cooled reaction mixture was poured onto ice cold
water then acidified with diluted acetic acid. The formed
solid was filtered off and crystallized from ethanol to give
yellow crystals. Yield 0.53 g (79 %). M.p.: 263–265 °C;
IR (CDCl3): vꢀ = 1,670 (C=O), 1,597 (C=C), 1,227 (C–F)
vꢀ = 1,667 (C=O), 1,600 (C=C), 1,231 (C–F) cm-1 1H
;
NMR(600 MHz, CDCl3):d = 5.92 (s, 1H, 2-CH), 6.78–7.23
(m, 11H, Ar–H and =CH) ppm; 13C NMR (150 MHz,
CDCl3): d = 58.6 (2-CH), 115.4, 115.5, 115.6, 117.5, 121.2,
121.3, 124.3, 124.4, 125.5, 125.6, 127.6, 130.7, 130.8, 130.9,
133.3, 133.4, 160.5, 161.0, 162.0, 162.2, 171.40 (C=O) ppm;
MS (70 eV): m/z = 450 (M?); anal. calcd. for
C22H12ClF4NOS (449.84): C, 58.74; H, 2.69; N, 3.11; S,
7.13. Found: C, 58.42; H, 2.42; N, 3.01; S, 6.92.
cm-1 1H NMR (600 MHz, CDCl3): d = 5.95 (s, 2H,
;
2,20-(1,4-Phenylene)bis[3-(4-fluorophenyl)thiazolidin-4-
one] (4, C24H18F2N2O2S2)
2-CH), 6.92–6.97 (m, 8H, Ar–H), 7.10–7.30 (m, 14H, Ar–
H and =CH) ppm; 13C NMR (150 MHz, CDCl3): d = 65.1
(2-CH), 116.1, 116.3, 127.83, 127.9, 128.1, 129.2, 133.0,
133.1, 134.7, 162.0, 163.7, 171.0 (2 C=O) ppm; anal. calcd.
for C38H24F4N2O2S2 (680.75): C, 67.05; H, 3.55; N, 4.12;
S, 9.42. Found: C, 66.83; H, 3.28; N, 3.94; S, 9.20.
A mixture of 0.22 g 4-fluoroaniline (2 mmol) and 0.134 g
1,4-terephthalaldehyde (1 mmol) was heated in dry diox-
ane (15 cm3) under reflux for 15 min, followed by addition
of a solution of thioglycolic acid (3 mmol) in dry dioxane
(5 cm3) and 1.5 g freshly fused zinc chloride. The reaction
mixture was heated under reflux for an additional 10 h. The
mixture was cooled then neutralized with aqueous
NaHCO3 (10 %, 30 cm3). The formed solid was filtered
off, washed with water three times and crystallized from
Diethyl [(fluorinated substituted phenylamino)(fluorinated
substituted phenyl)methyl]phosphonate (7a,b)
A mixture of fluorinated substituted anilines (1 mmol),
fluorinated substituted benzaldehyde (1 mmol) and diethyl
123

Polyfluorinated 4-thiazolidinone and a-aminophosphonic acid derivatives
phosphite (1.5 mmol) in the presence of BF3.Et2O
(0.1 cm3) was heated under reflux at 70 °C for 2 h. The
mixture was concentrated to dryness under reduced
pressure, and the residue was taken up with ethyl acetate.
The organic layer was washed with anhydrous sodium
sulfate, and the solvent was removed under vacuum to give
the crude product, which was recrystallized from ethanol to
give white crystals.
160.4, 162.0, 193.0 (C=O) ppm; MS (70 eV): m/z = 395
(M?); anal. calcd. For C15H11F5NO4P (395.23): C, 45.59; H,
2.81; N, 3.54. Found: C, 45.21; H, 2.63; N, 3.37.
{(2-Chloro-6-fluorophenyl)[(3,4-difluorophenyl)(2,2,2-tri-
fluoroacetyl)amino]methyl}phosphonic acid
(8b, C15H9ClF6NO4P)
Yield 0.32 g (72 %). M.p.: 232–234 °C; IR (KBr):
vꢀ = 3,200 (br, OH), 1,709 (C=O), 1,265 (C–F) 1,257
(P=O) cm-1; 1H NMR (600 MHz, D2O): d = 4.00 (d, 1H,
J = 19.2 Hz, CH–P), 6.78–7.19 (m, 6H, Ar–H) ppm; 13C
NMR (150 MHz, D2O): d = 50.6 (d, J = 158.7 Hz, CH–
P), 109.1 (CF3), 114.8, 115.6, 117.5, 121.1, 125.6, 127.6,
130.8, 130.9, 133.2, 160.7, 161.0, 162.5, 195.0 (C=O) ppm;
31P NMR (242 MHz, D2O): d = 14.4 ppm; anal. calcd. for
C15H9ClF6NO4P (447.65): C, 40.25; H, 2.03; N, 3.13.
Found: C, 40.03; H, 1.86; N, 2.97.
Diethyl [(4-fluorophenylamino)(4-fluoro-
phenyl)methyl]phosphonate (7a, C17H20F2NO3P)
Yield 0.34 g (96 %). M.p.: 80–82 °C (Lit [37]. 80–81 °C);
IR (CDCl3): vꢀ = 3,331 (NH), 1,273 (P=O), 1,231 (C–F),
1
1,014 (P–O–C) cm-1; H NMR (600 MHz, CDCl3): 1.19
(t, 3H, J = 7.14 Hz, CH3), 1.28 (t, 3H, J = 7.14 Hz, CH3),
3.69–4.20 (m, 4H, CH2), 4.69 (d, 1H, J = 23.9 Hz, CH–P),
6.49–6.60 (m, 2H, Ar–H), 6.78–6.86 (m, 2H, Ar–H),
6.99–7.49 (m, 5H, Ar–H and NH) [38]; anal. calcd. for
C17H20F2NO3P (355.32): C, 57.47; H, 5.67; N, 3.94.
Found: C, 57.12; H, 5.55; N, 3.71.
Diethyl 1,4-phenylenebis[N-(4-fluorophenyl)amino-
methylphosphonate] (10, C28H36F2N2O6P2)
A mixture of 0.22 g 4-fluoroaniline (2 mmol), 0.134 g 1,4-
terephthalaldehyde (1 mmol) and diethyl phosphite
(4 mmol,) in the presence of BF3.Et2O (0.15 cm3) was
heated under reflux at 70 °C for 2 h. The mixture was
concentrated to dryness under reduced pressure, and the
residue was taken up with ethyl acetate. The organic layer
was washed with anhydrous sodium sulfate, and the solvent
was removed under vacuum to give the crude product,
which was recrystallized from ethanol to give white
crystals. Yield 0.47 g (80 %). M.p.: 158–159 °C; IR
(CDCl3): vꢀ = 3,100 (NH), 1,238 (C–F), 1,230 (P=O),
Diethyl [(2-chloro-6-fluorophenyl)(3,4-difluorophenylami-
no)methyl] phosphonate (7b, C17H18ClF3NO3P)
Yield 0.33 g (83 %). M.p.: 90–92 °C; IR (CDCl3):
vꢀ = 3,339 (NH), 1,281 (P=O), 1,225 (C–F), 1,013 (P–O–
1
C) cm-1; H NMR (600 MHz, CDCl3): d = 1.25 (t, 6H,
J = 6 Hz, CH3), 3.90 (q, 4H, J = 6 Hz, CH2), 4.12 (d, 1H,
J = 15.6 Hz, CH–P), 6.78–7.20 (m, 6H, Ar–H), 8.00 (br,
1H, NH) ppm; 13C NMR (150 MHz, CDCl3): d = 13.8
(CH3), 44.0 (d, J = 143.8 Hz, CH–P), 62.4 (CH2), 114.9,
115.6, 117.5, 121.1, 125.5, 127.6, 130.7, 130.8, 133.4,
160.6, 161.0, 162.3 ppm; 31P NMR (242 MHz, CDCl3):
d = 22.3 ppm. MS (70 eV): m/z = 407 (M?); anal. calcd.
for C17H18ClF3NO3P (407.75): C, 50.08; H, 4.45; N, 3.44.
Found: C, 49.82; H, 4.18; N, 3.13.
1,092 (P–O–C) cm-1
;
1H NMR (600 MHz, CDCl3):
d = 1.25 (t, 12H, J = 7.2 Hz, CH3), 3.91–3.96 (m, 8H,
CH2), 5.06 (d, 2H, J = 17.2 Hz, CH–P), 6.00 (br, 2H, NH),
6.96–6.99 (m, 8H, Ar–H), 7.00–7.10 (m, 4H, Ar–H) ppm;
13C NMR (150 MHz, CDCl3): d = 13.1 (CH3), 43.3 (d,
J = 150 Hz, CH–P), 62.3 (CH2), 116.2, 127.7, 127.9,
133.0, 140.0, 162.0 ppm; 31P NMR (242 MHz, CDCl3):
d = 20.5 ppm; anal. calcd. forC28H36F2N2O6P2 (596.55):C,
56.38; H, 6.08; N, 4.70. Found: C, 56.13; H, 5.83; N, 4.39.
[2,2,2-Trifluoro-N-(aryl)acetamido][aryl]methylphosphon-
ic acid (8a,b)
A mixture of diethyl a-aminophosphonates 7a,b (1 mmol),
1 g freshly fused sodium acetate and 5 cm3 of trifluoro-
acetic anhydride was stirred and heated under reflux for
4 h. The cooled reaction mixture was poured onto 100 g of
crushed ice. The formed solid was filtered off, washed with
water three times then crystallized from ethyl acetate to
give white crystals.
1,4-Phenylenebis[N-(2,2,2-trifluoroacetyl)-N-(4-fluoro-
phenyl)aminomethylphosphonic acid]
(11, C24H18F8N2O8P2)
A mixture of 0.596 g diethyl 1,4-phenylenebis[N-(4-fluoro-
phenyl)aminomethylphosphonate] (9) (1 mmol), 2 g freshly
fused sodium acetate and 5 cm3 of trifluoroacetic anhydride
wasstirredandheatedunderrefluxfor5 h. Thecooledreaction
mixture was poured onto 100 g of crushed ice. The formed
solid was filtered off, washed with water three times then
crystallized from ethyl acetate to give white crystals. Yield
0.52 g (77 %). M.p.: 243–245 °C; IR (KBr): vꢀ = 3,357 (br,
OH), 1,731 (C=O), 1,244 (C–F), 1,230 (P=O) cm-1; 1H NMR
(600 MHz, D2O): d = 4.61 (d, 2H, J = 19.2 Hz, CH–P),
[2,2,2-Trifluoro-N-(4-fluorophenyl)acetamido][4-fluoro-
phenyl]methylphosphonic acid (8a, C15H11F5NO4P)
Yield 0.27 g (69 %). M.p.: 206–208 °C; IR (KBr):
vꢀ = 3,365 (br, OH), 1,729 (C=O), 1,248 (C–F) 1,220 (P=O)
cm-1 1H NMR (600 MHz, D2O): d = 3.56 (d, 1H,
;
J = 16.8 Hz, CH–P), 4.75 (br, 2H, OH), 6.96–6.99 (m, 4H,
Ar–H), 7.00–7.08 (m, 2H, Ar–H), 7.26–7.29 (m, 2H, Ar–H)
ppm; 13C NMR (150 MHz, D2O): d = 51.5 (d, J = 149 Hz,
CH–P), 113.9 (CF3), 116.0, 116.3, 127.8, 127.9, 133.1, 134.7,
123

R. M. Abdel-Rahman, T. E. Ali
6.96–6.99 (m, 8H, Ar–H), 7.00–7.10 (m, 4H, Ar–H) ppm; 13
C
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NMR (150 MHz, D2O): d = 48.5 (d, J = 163.5 Hz, CH–P),
110.2 (2 CF3), 116.2, 127.8, 127.9, 133.0, 140.0, 160.3, 190.3
(2 C=O) ppm; 31P NMR (242 MHz, D2O): d = 15.3 ppm;
anal. calcd. for C24H18F8N2O8P2 (676.35): C, 42.62; H, 2.68;
N, 4.14. Found: C, 42.38; H, 2.46; N, 3.89.
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The antifungal activity of newly synthesized compounds
was evaluated against the fungal strains Alternaria alter-
nate and Fusarium oxysporium in three replications by the
food poison technique [40, 41]. The molds were grown on
to potato-dextrose Agar (PDA) medium at 25 °C for 7 days
and used as inocula. Then 100 lM3 volume of each com-
pound, having three concentrations of 250, 500 and
1,000 ppm, was reconstituted in dry acetone and poured
into a sterile petri plate. The poisoned agar plates were
incubated at the center with fungal plugs obtained from the
actively growing colony and incubated at 25 °C for 7 days.
Dry acetone was used as solvent, and fluconazole was used
as the reference drug. The experiments were performed in
triplicates. The diameter of the fungal colonies was mea-
sured and expressed as percent inhibition determined by
applying the following formula: percent of growth inhibi-
tion % = (dc - dt)/dc 9 100 where dc = average diameter
of fungal colony in control plates; dt = average diameter of
fungal colony in experimental plates.
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The effect of the synthesized compounds on the enzymatic
effect on cellobiase
The effect of synthesized compounds on cellobiase activity
produced by Alternaria alternate and Fusarium oxysporium
was estimated. The procedure for determining cellobiase
activity was according to Tolan and Foody [42, 43]. Each
compound was dissolved in an appropriate amount of DMF at
concentrations of 10, 50 and 100 lg/cm3, then added sepa-
rately to the assay mixture consisting of 1 cm3 of 15 mM
cellobiose solution (prepared in 0.05 M citrate buffer pH 4.8)
and 1 cm3 ofthe diluted enzymesolutionat50 °C for 1 h. The
released reducing sugar (glucose) was estimated colorimet-
rically at 540 nm as an indication for the enzyme activity. The
obtained results are recorded in Table 2.
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123