Synthesis and antimicrobial activity of some new N-substituted-5-arylidene- thiazolidine-2,4-diones

Article abstract of DOI:10.1002/jhet.1726

A total of 17 new N-substituted derivatives (2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k and 3b, 3c, 3d, 3e, 3f, 3g, 3h) of 5-((2-phenylthiazol-4-yl) methylene) thiazolidine-2,4-dione (2a) and 5-(2,6-dichloro- benzylidene) thiazolidine-2,4-dione (3a) were synthesized. The structural elucidation of the newly synthesized compounds was based on elemental analysis and spectroscopic data (MS, ¹H NMR, ¹³C NMR), and their antimicrobial activities were assessed in vitro against several strains of Gram-positive and Gram-negative bacteria and one fungal strain (Candida albicans) as growth inhibition diameter. Some of them showed modest to good antibacterial activity against Gram-negative Escherichia coli and Salmonella typhimurium and Gram-positive Staphylococcus aureus, Bacillus cereus, and Enterococcus fecalis bacterial strains, whereas almost all the compounds were inactive against Listeria monocytogenes. All of the synthesized compounds showed moderate to very good activity against C. albicans.

Full text of DOI:10.1002/jhet.1726

March 2014
Synthesis and Antimicrobial Activity of Some New N-substituted-5-
arylidene-thiazolidine-2,4-diones
411
Anca Stana,a* Brînduşa Tiperciuc,a Mihaela Duma,b Laurian Vlase,a Ovidiu Crişan,a Adrian Pîrnău,c and Ovidiu Oniga,a
aDepartment of Pharmaceutical Chemistry,“Iuliu Haţieganu”, University of Medicine and Pharmacy, 12 Ion Creangă
Street, 400010 Cluj Napoca, Romania
bState Veterinary Laboratory for Animal Health and Food Safety, 400572 Cluj-Napoca, Romania
cNational Institute for Research and Development of Isotopic and Molecular Technologies, 400293 Cluj Napoca, Romania
*
E-mail: teodora_anca@yahoo.com
Received November 25, 2011
DOI 10.1002/jhet.1726
Published online 18 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
A total of 17 new N-substituted derivatives (2b–k and 3b–h) of 5-((2-phenylthiazol-4-yl)methylene)
thiazolidine-2,4-dione (2a) and 5-(2,6-dichloro- benzylidene)thiazolidine-2,4-dione (3a) were synthesized.
The structural elucidation of the newly synthesized compounds was based on elemental analysis and spectro-
scopic data (MS, 1H NMR, 13C NMR), and their antimicrobial activities were assessed in vitro against several
strains of Gram-positive and Gram-negative bacteria and one fungal strain (Candida albicans) as growth
inhibition diameter. Some of them showed modest to good antibacterial activity against Gram-negative
Escherichia coli and Salmonella typhimurium and Gram-positive Staphylococcus aureus, Bacillus cereus,
and Enterococcus fecalis bacterial strains, whereas almost all the compounds were inactive against Listeria
monocytogenes. All of the synthesized compounds showed moderate to very good activity against C. albicans.
J. Heterocyclic Chem., 51, 411 (2014).
INTRODUCTION
infections [6], pain [7], allergies, hypertension, schizophrenia,
as hypnotics, and as fibrinogen receptor antagonists with
antithrombotic activity [8,9].
Since their discovery, antibiotics have dramatically
improved public health by enabling millions of people to
live longer, more productive lives. The very success of
these drugs has often resulted in an inappropriate and irratio-
nal use of antimicrobial drugs that has led to the development
of antimicrobial resistance, a worldwide public health prob-
lem that continues to grow. In spite of the large number of
antibacterial agents available for medical use, the dramati-
cally increasing number of pathogens resistant to different
classes of antibiotics and chemotherapeutics, and emerging
infectious diseases over the past decades, lead to the
necessity for developing new approaches to antimicrobial
therapy, especially for seeking, testing, and validating
novel therapeutics with little or no cross-resistance [1].
Thiazoles and their derivatives (thiazolines, thiazolidines,
thiazolidinones, and thiazolidinediones) have attracted
continuous interest over the years because of their broad
spectrum of biological activities [2]. Recently, were found
applications of thiazoles in drug development for the treat-
ment of inflammation [3], bacterial [4], fungal [5], HIV
Thiazolidine-2,4-dione derivatives have been studied
extensively and found to serve as basic pharmacophore
for various biological profiles: antidiabetic, anticancer,
antimicrobial, analgesic, cardiotonic, aldose reductase inhi-
bitors, and anti-inflammatory [10]. Some thiazolidine-2,4-
dione compounds are used in the treatment of type II diabetes
by increasing the sensitivity towards insulin and give poten-
tial anti-inflammatory activity by inhibiting monocyte/
macrophage activation and expression of inflammatory
mediators [11]. In addition, thiazolidine-2,4-dione-based
molecules have remarkable antiproliferative effect on vascu-
lar smooth muscle, cause G0/G1 cell cycle arrest in cancer
[12] and show significant antibacterial and antifungal activi-
ties [13]. It has been reported that the insertion of arylidene
moieties at the fifth position of the thiazolidine-2,4-dione
ring enhanced the antimicrobial activity [14,15].
Prompted by these findings and as part of our efforts to
discover potentially active new antimicrobial agents, we
report in the present work, the synthesis of two series of
© 2013 HeteroCorporation

412
A. Stana, B. Tiperciuc, M. Duma, L. Vlase, O. Crişan, A. Pîrnău, and O. Oniga
Vol 51
5-arylidene-thiazolidine-2,4-diones, various substitution in
the third position, at the nitrogen atom and evaluation of their
antibacterial and antifungal activities.
continuous stirring at room temperature. The potassium salts
obtained were then treated with various halogenated deriva-
tives in DMF under continuous stirring at room temperature
to give the target compounds, N-substituted-5-arylidene-
thiazolidine-2,4-diones (2b–k and 3b–h, respectively) in
47–89% yields. The synthesis of the alkylating agents 4
and 5 was reported in a previous article [18].
RESULTS AND DISCUSSION
Chemistry.
The target compounds, N-substituted 5-
((2-phenylthiazol-4-yl)methylene)thiazolidine-2,4-diones
(2b–k) and N-substituted 5-(2,6-dichloro benzylidene)
thiazolidine-2,4-diones (3b–h) were prepared via the
route depicted in Schemes 1 and 2.
All newly synthesized compounds (2a–k and 3a–h) were
characterized by melting point, elemental analysis, and
spectroscopic data (1H NMR, 13C NMR, and MS). All
compounds gave very good CHNS quantitative elemental
analysis results. All spectral data were in accordance with
the assumed structures. The physical data, the yields, and
the spectral characterizations of the synthesized compounds
are presented in Experimental section, along with the details
of the synthetic procedures.
The general method known as Knoevenagel condensation
was used to synthesize the 5-arylidene-thiazolidine-2,4-diones
(2a and 3a) in good yields (85–95%). 5-((2-phenylthiazol-4-
yl)methylene)thiazolidine-2,4-dione (2a) was prepared by
Knoevenagel condensation of thiazolidine-2,4-dione with
2-phenylthiazole-4-carbaldehyde in refluxing glacial acetic
acid in the presence of anhydrous sodium accetate. 5-(2,
6-dichlorobenzylidene)thiazolidine-2,4-dione (3a) was prepared
according to the procedures described in the literature [16,17].
The 5-arylidene-2,4-thiazolidinediones (2a and 3a) were
considered for N-alkylation so they were converted into
potassium salts at the N3 position using anhydrous potas-
sium hydroxide in dimethylformamide (DMF) under
1H NMR spectra of synthesized compounds 2a–k and
3a–h showed one signal for the methylidene proton, as a
singlet at 7.7–7.95ppm, that supported the formation of 5-
arylidene-thiazolidine-2,4-diones. The NH proton appeared
1
as a singlet in the 12.5–12.8 ppm region in the H NMR
1
spectra of compounds 2a and 3a and was absent in the H
NMR spectra of 2b–k and 3b–h, thus substantiating the
formation of N-substituted derivatives. 13C NMR spectra of
Scheme 1
Scheme 2
Journal of Heterocyclic Chemistry
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March 2014 Synthesis and Antimicrobial Activity of Some New N-substituted-5-arylidene-thiazolidine-2,4-diones 413
the synthesized compounds were in accordance with the
assumed structures.
The tested compounds presented a modest inhibitory
activity against the Gram-positive and the Gram-negative
bacteria, except compound 3a that showed a good inhibitory
activity against the tested Gram-negative bacterial strains,
similar to that of ciprofloxacin (50 mg/well), used as standard
drug. 3a was the only compound that presented antibacterial
activity against L. monocytogenes. All of the synthesized
compounds are active and showed moderate activity
against E. fecalis, E. coli, and S. typhimurium (8–14 mm
inhibition zone). The 5-((2-phenylthiazol-4-yl)methylene)
thiazolidine-2,4-diones 2a–k were more active than the
5-(2,6-dichlorobenzylidene) thiazolidine-2,4-diones 3b–h,
suggesting that the presence of thiazole moiety increases
the antibacterial activity of the compounds. Compounds
2e–g were more active than compounds 2a–d,i against S.
typhimurium, suggesting that the substitution of N3 with
lipophilic alkyl groups enhances the antibacterial properties.
Regarding the antifungal activity, most of the synthesized
compounds showed good inhibition against C. albicans, at
test concentrations. The most active compounds were 2k,
with three thiazole rings in the structure, and the unsubsti-
tuted 5-(2,6-dichlorobenzylidene)thiazolidine-2,4-dione 3a,
which presented very good antifungal activity; the inhibitory
activity being significantly more powerful than that of fluco-
nazole (50 mg/well), used as standard drug. Concerning
the antibacterial and antifungal activities, the most active
compound was 3a, suggesting that the presence of chlorine
atoms on the aromatic ring, which increases the lipophilicity
of the compound, and also the unsubstituted nitrogen atom of
the 5-arylidene-thiazolidine-2,4-dione plays an important
role in enhancing the antimicrobial properties of this class
of compounds.
The mass spectra of the synthesized compounds gave
idea about the fragmentation of the final compounds
with their corresponding mass and showed the correct
molecular ions (M+ or M + 1), as suggested by their
molecular formulas.
Antibacterial/antifungal activity.
In vitro antimicro-
bial activity was evaluated by agar disc diffusion method
according to the National Committee for Clinical Laboratory
Standards guidelines. Antibacterial activity of newly
synthesized compounds 2a–k and 3`a–h was evaluated
against various pathogenic Gram-negative (Salmonella
typhimurium ATCC 13311 and Escherichia coli ATCC
25922) and Gram-positive (Listeria monocytogenes
ATCC 35152, Staphylococcus aureus ATCC 25923,
Bacillus cereus ATCC 13061, and Enterococcus fecalis
ATCC 29212) bacterial strains. Antifungal activity of the
aforementioned compounds was evaluated against a
strain of Candida albicans ATCC 90028.
For antibacterial testing, Mueller-Hinton agar medium
was used. For antifungal testing, Mueller-Hinton medium
supplemented with 2% glucose (providing adequate
growth of yeasts) and 0.5 mg/mL methylene blue (provid-
ing a better definition of the inhibition zone diameter)
was used. The inoculum was prepared by suspending five
representative colonies, obtained from an 18–24 h culture
on nonselective nutritive agar medium, in sterile distilled
water. The cell density was adjusted to the density of a
0.5 McFarland standard by measuring the absorbance in a
spectrophotometer at a wavelength of 530 nm and adding
sterile distilled water as required (corresponding to a popu-
lation of 1–5 ꢀ 106 CFU/mL). Six-millimeter diameter
wells were cut from the agar using a sterile cork borer,
and a predetermined volume of each compound solution
was delivered into the wells. A sterile swab was soaked
in suspension, and then, the Mueller-Hinton agar plates
were inoculated by streaking the entire surface. After
drying for 10–15 min, the 6-mm diameter wells were inoc-
ulated with 50 mL from 10 mg/mL solution in dimethyl
sulfoxide (DMSO) (Merck, Germany) of each compound
(50 mg/well). Ciprofloxacin (50 mg/well) and fluconazole
(50 mg/well) were used as standard drugs. The plates were
incubated at 35ꢁC. Zone diameters were measured to the
nearest whole millimeter at a point in which there will be
no visible growth after 24–48 h. The solvent used for the
preparation of the newly synthesized compound solutions,
DMSO, did not show inhibition against the tested bacterial
and fungal strains. Results were obtained in duplicate.
The results of antifungal and antibacterial activity of
5-arylidene-thiazolidine-2,4-diones (2a and 3a) and their
N-substituted derivatives (2b–k and 3b–h, respectively)
are reported in Table 1, in comparison with those of the
reference drugs, ciprofloxacin and fluconazole.
CONCLUSIONS
In conclusion, a series of new 5-((2-phenylthiazol-4-yl)
methylene)thiazolidine-2,4-dione and 5-(2,6-dichlorobenzyli-
dene)thiazolidine-2,4-dione derivatives have been synthesized
by the Knoevenagel condensation method starting from thia-
zolidine-2,4-dione and the corresponding aromatic aldehydes.
All compounds were characterized with the help of analytical
techniques: 1H NMR, 13C NMR, mass, and elemental analysis
and were evaluated for their antibacterial and antifungal activ-
ities against several Gram-positive, Gram-negative bacteria,
and C. albicans. The antimicrobial activity results indicated
that some of the tested compounds showed promising antibac-
terial and antifungal activities.
EXPERIMENTAL
Chemistry.
Solvents and some alkylating agents were
obtained from commercial sources. Compound 3a and the non-
commercially available variants of the alkylating agents 4-
(iodomethyl)-2-phenylthiazole (4) and 4-(iodomethyl)-20-phenyl-2,
Journal of Heterocyclic Chemistry
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A. Stana, B. Tiperciuc, M. Duma, L. Vlase, O. Crişan, A. Pîrnău, and O. Oniga
Vol 51
Table 1
Antimicrobial activity of the synthesized compounds 2a–k and 3a–h.
Inhibition zone in millimeters
Gram-positive bacteria
Gram-negative bacteria
Fungi
Staphylococus
aureus
Listeria
monocytogenes
Bacillus
cereus
Enterococcus
fecalis
Escherichia
coli
Salmonella
typhimurium
Candida
albicans
Compound
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
3a
3b
3c
3d
3e
10
11
8
8
8
8
10
8
8
7
14
20
-
7
10
8
-
-
-
20
-
-
-
-
-
-
-
-
-
-
-
-
20
-
-
-
-
-
-
14
14
11
8
7
8
10
11
8
8
8
10
8
10
10
10
8
8
10
8
8
6
6
8
6
6
8
8
6
8
10
8
8
6
8
12
12
11
13
15
15
15
12
10
11
10
11
11
9
20
22
16
12
17
10
16
11
10
12
35
35
10
16
18
16
18
16
15
-
8
8
-
12
20
8
7
7
8
11
9
10
22
-
10
16
10
10
8
9
8
10
12
10
8
22
-
3f
3g
3h
11
10
10
20
-
-
22
-
8
24
-
Ciprofloxacin
Fluconazole
25
Ciprofloxacine (50 mg/well) and fluconazole (50 mg/well) were used as standard drugs.
Hyphen (-) indicates the compound has no activity.
40-bisthiazole (5) were prepared according to methodologies
described in the literature [16–18].
(85%), light brown solid, mp 275ꢁC; 1H NMR (DMSO-d6,
500 MHz) d: 12.5 (s, 1H, NH), 8.29 (s, 1H, C5–thiazole–H),
8.08–8.013 (m, 2H, Ar-H), 7.77 (s, 1H, –CH═), 7.54–7.59
(m, 3H, Ar-H) ppm; 13C NMR (DMSO-d6) d: 123.84 (CH),
124.28 (CH), 126.80 (2CH), 127.36 (C), 129.95 (2CH), 131.48
(C), 132.49 (CH), 150.61 (C), 166.20 (C═O), 168.36 (C), 170.19
(C═O) ppm; MS (EI, 70eV) m/z (%): 289 (M + 1). Anal. Calcd
for C13H8N2O2S2: C, 54.15; H, 2.80; N, 9.72; S, 22.24. Found: C,
53.96; H, 2.62; N, 9.50 (9.72); S, 22.41 (22.24).
2-(2,4-Dioxo-5-((2-phenylthiazol-4-yl)methylene)thiazolidin-3-
yl)acetamide (2b). A 1mmol (288mg) of 2a was dissolved in
DMF (3.5 mL), and fine dispersed anhydrous potassium hydroxide
(84 mg, 1.5 mmol) was added. The mixture was stirred for 30 min
at room temperature to give the potassium salt of 5-((2-
phenylthiazol-4-yl)methylene)thiazolidine-2,4-dione. To the
resulting suspension was added 2-iodoacetamide as alkylating
agent (202 mg, 1.1 mmol). The mixture was stirred at room
temperature for 8 h. The reaction was monitored by TLC. After
completion of the reaction, the reaction mass was poured into
ice-cold water. The resulted precipitate was filtered, washed with
water, dried, and then recrystallized from absolute methanol. Yield
(82%), gray solid, mp 283ꢁC; 1H NMR (DMSO-d6, 500 MHz)
d: 8.395 (s, 1H, C5–thiazole–H), 8.038–8.058 (m, 2H, Ar-H), 7.81
(s, 1H, –CH═), 7.72 (s, 2H, NH2), 7.569–7.615 (m, 3H, Ar-H),
4.241 (s, 2H, CH2) ppm; 13C NMR (DMSO-d6) d: 43.82 (CH2),
123.75 (CH), 124.19 (CH), 126.75 (2CH), 127.26 (C), 129.82
(2CH), 131.53 (C), 132.41 (CH), 150.71 (C), 166.28 (C═O), 166.87
(C═O), 168.43 (C), 170.29 (C═O) ppm; MS (EI, 70 eV) m/z (%):
The melting points were taken with an electrothermal melting
point meter and are uncorrected. Analytical thin layer chromatography
(TLC) was used to monitor the reaction progress and was carried out
on precoated silica gel 60F254 sheets using heptane–ethyl–acetate 1:1
system and UV absorption for visualization. Yields were not opti-
mized. The 1H NMR spectra were recorded at room temperature on
a Bruker Avance NMR (Karlsruhe, Germany) spectrometer operating
at 400 and 500 MHz and were in accordance with the assigned struc-
tures. Chemical shift values were reported relative to tetramethylsilane
(TMS) as internal standard. The samples were prepared by dissolving
the compounds in DMSO-d6 (dH = 2.51 ppm) as solvent, and the spec-
tra were recorded using a single excitation pulse of 12 ms (1H NMR).
13C NMR spectra were recorded on Bruker spectrometer (125 MHz)
in DMSO-d6. GC–MS analyses were performed with an Agilent
(Darmstadt, Germany) gas chromatograph 6890 equipped with an
apolar Macherey Nagel Permabond (Dueren, Germany) SE 52
capillary column. Elemental analysis was registered with a Vario El
CHNS (Hanau, Germany) instrument.
5-((2-Phenylthiazol-4-yl)methylene)thiazolidine-2,4-dione (2a).
To a solution of 2-phenylthiazole-4-carbaldehyde (945 mg, 5 mmol)
in glacial acetic acid (2 mL) were added anhydrous sodium acetate
(820 mg, 10 mmol) and thiazolidine-2,4-dione (585 mg, 5 mmol).
The mixture was refluxed for 5 h. After cooling, the reaction mass
was poured into ice-cold water. The precipitated solid was filtered,
washed with water to remove the remaining traces of acetic acid,
and then dried. The product was recrystallized from ethanol. Yield
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March 2014 Synthesis and Antimicrobial Activity of Some New N-substituted-5-arylidene-thiazolidine-2,4-diones 415
346 (M + 1). Anal. Calcd for C15H11N3O3S2: C, 52.16; H, 3.21; N,
12.17; S, 18.57. Found: C, 51.96; H, 3.16; N, 12.00; S, 18.87.
3-Methyl-5-((2-phenylthiazol-4-yl)methylene)thiazolidine-2,4-
dione (2c). Using the procedure described earlier for 2b using
iodomethane (212mg, 1.5 mmol), we recrystallized the title
compound from absolute ethanol. Yield (59%), white solid, mp
228–230ꢁC; 1H NMR (DMSO-d6, 500 MHz) d: 8.366 (s, 1H, C5–
thiazole–H), 8.030–8.048 (m, 2H, Ar-H), 7.78 (s, 1H, –CH═),
7.579–7.595 (m, 3H, Ar-H), 3.106 (s, 3H, N–CH3) ppm; 13C
NMR (DMSO-d6) d: 28.72 (CH3), 123.86 (CH), 124.35 (CH),
126.95 (2CH), 127.30 (C), 129.86 (2CH), 131.55 (C), 132.45
(CH), 150.69 (C), 166.19 (C═O), 168.38 (C), 170.23 (C═O)
ppm; MS (EI, 70 eV) m/z (%): 303 (M + 1). Anal. Calcd for
C14H10N2O2S2: C, 55.61; H, 3.33; N, 9.26; S, 21.21. Found: C,
55.30; H, 3.02; N, 8.98; S, 21.16.
500 MHz) d: 8.362 (s, 1H, C5–thiazole–H), 8.03–8.04 (m, 2H,
Ar-H), 7.71 (s, 1H, –CH═), 7.48–7.59 (m, 3H, Ar-H), 3.26
(m, 2H, N–CH2), 1.64 (m, 1H, CH), 1.56 (m, 2H, CH2), 0.94 (d,
6H, 2CH3) ppm; 13C NMR (DMSO-d6) d: 22.66 (2CH3), 25.82
(CH), 36.39 (CH2), 39.96 (CH2), 123.70 (CH), 124.37 (CH),
126.83 (2CH), 127.42 (C), 129.93 (2CH), 131.51 (C), 132.47
(CH), 150.61 (C), 166.31 (C═O), 168.35 (C), 170.30 (C═O)
ppm; MS (EI, 70eV) m/z (%): 359 (M+ 1). Anal. Calcd for
C18H18N2O2S2: C, 60.31; H, 5.06; N, 7.81; S, 17.89. Found: C,
60.12; H, 5.01; N, 7.68; S, 18.11.
3-Pentyl-5-((2-phenylthiazol-4-yl)methylene)thiazolidine-2,4-
dione (2h). The title compound was prepared using the procedure
described for 2b using 1-iodopentane (297 mg, 1.5 mmol) and was
recrystallized from absolute ethanol. Yield (84%), light brown
solid, mp 110ꢁC; 1H NMR (DMSO-d6, 500MHz) d: 8.361 (s, 1H,
C5–thiazole–H), 8.03–8.04 (m, 2H, Ar-H), 7.71 (s, 1H, –CH═),
7.48–7.59 (m, 3H, Ar-H), 3.24 (m, 2H, N–CH2), 1.29–1.64
(m, 6H, 3CH2), 0.91 (t, 3H, CH3) ppm; 13C NMR (DMSO-d6) d:
14.27 (CH3), 22.12 (CH2), 27.26 (CH2), 28.76 (CH2), 41.41
(CH2), 123.70 (CH), 124.39 (CH), 126.84 (2CH), 127.41 (C),
129.94 (2CH), 131.52 (C), 132.48 (CH), 150.64 (C), 166.38
(C═O), 168.37 (C), 170.34 (C═O) ppm; MS (EI, 70 eV) m/z (%):
359 (M + 1). Anal. Calcd for C18H18N2O2S2: C, 60.31; H, 5.06; N,
7.81; S, 17.89. Found: C, 59.97; H, 4.84; N, 7.49; S, 18.17 (17.89).
3-(2-Oxopropyl)-5-((2-phenylthiazol-4-yl)methylene)thiazolidine-
2,4-dione (2i). The title compound was synthesized according to
the procedure described for 2b using 1-chloropropan-2-one
(185 mg, 2 mmol) and was recrystallized from absolute methanol.
Yield (80%), white solid, mp 215ꢁC; 1H NMR (DMSO-d6,
500 MHz) d: 8.407 (s, 1H, C5–thiazole–H), 8.042–8.061 (m, 2H,
Ar-H), 7.81 (s, 1H, –CH═), 7.585–7.601 (m, 3H, Ar-H), 4.663 (s,
2H, CH2), 2.258 (s, 3H, CH3) ppm; 13C NMR (DMSO-d6) d:
27.60 (CH3), 50.94 (CH2), 123.75 (CH), 124.42 (CH), 126.86
(2CH), 127.44 (C), 129.92 (2CH), 131.56 (C), 132.49 (CH),
150.68 (C), 166.39 (C═O), 168.39 (C), 170.31 (C═O), 200.71
(C═O) ppm; MS (EI, 70eV) m/z (%): 345 (M + 1). Anal. Calcd
for C16H12N2O3S2: C, 55.80; H, 3.51; N, 8.13; S, 18.62. Found:
C, 55.49; H, 3.31; N, 8.03; S, 18.94.
3-((2-Phenylthiazol-4-yl)methyl)-5-((2-phenylthiazol-4-yl)
methylene) thiazolidine-2,4-dione (2j). The title compound was
synthesized according to the procedure described for 2b using
4-(iodomethyl)-2-phenylthiazole [18] (301 mg, 1 mmol) and was
recrystallized from absolute methanol. Yield (67%), white
solid, mp 229–230ꢁC; 1H NMR (DMSO-d6, 500 MHz) d: 8.391
(s, 1H, C5–thiazole–H), 7.88 (s, 1H, –CH═), 7.57–8.04 (m, 10H,
Ar-H), 7.53 (s, 1H, C5–thiazole–H), 3.43 (s, 2H, CH2) ppm; 13C
NMR (DMSO-d6) d: 42.37 (CH2), 116.92 (CH), 122.61 (2CH),
126.97 (5CH), 128.17 (4CH), 130.06 (2C), 133.15 (C), 134.00
(C), 151.42 (C), 152.90 (C), 165.48 (C, C═O), 167.44 (C),
171.17 (C═O) ppm; MS (EI, 70eV) m/z (%): 462 (M+ 1). Anal.
Calcd for C23H15N3O2S3: C, 59.85; H, 3.28; N, 9.10; S, 20.84.
Found: C, 59.65; H, 3.17; N, 9.02; S, 21.12.
3-Ethyl-5-((2-phenylthiazol-4-yl)methylene)thiazolidine-2,4-
dione (2d).
The compound was prepared according to the
procedure for 2b using iodoethane (234 mg, 1.5 mmol), and
absolute ethanol was used for recrystallization. Yield (53%),
1
white solid, mp 165–168ꢁC; H NMR (DMSO-d6, 500 MHz) d:
8.371 (s, 1H, C5–thiazole–H), 8.035–8.051 (m, 2H, Ar-H), 7.76
(s, 1H, –CH═), 7.496–7.598 (m, 3H, Ar-H), 3.21 (m, 2H, CH2),
1.25 (t, 3H, CH3) ppm; 13C NMR (DMSO-d6) d: 13.31 (CH3),
36.55 (CH2), 123.81 (CH), 124.29 (CH), 126.82 (2CH), 127.34
(C), 129.92 (2CH), 131.49 (C), 132.47 (CH), 150.64 (C),
166.17 (C═O), 168.34 (C), 170.17 (C═O) ppm; MS (EI, 70 eV)
m/z (%): 317 (M + 1). Anal. Calcd for C15H12N2O2S2: C, 56.94;
H, 3.82; N, 8.85; S, 20.27. Found: C, 56.72; H, 3.65; N, 8.53;
S, 20.57.
5-((2-Phenylthiazol-4-yl)methylene)-3-propylthiazolidine-2,4-
dione (2e).
The compound was prepared according to the
procedure for 2b using 1-bromopropane (184 mg, 1.5 mmol).
Absolute ethanol was used for recrystallization. Yield (78%),
brown solid, mp 130ꢁC; 1H NMR (DMSO-d6, 500MHz) d:
8.368 (s, 1H, C5–thiazole–H), 8.028–8.044 (m, 2H, Ar-H), 7.75
(s, 1H, –CH═), 7.492–7.596 (m, 3H, Ar-H), 3.3 (m, 2H, N–
CH2), 1.62 (m, 2H, CH2), 0.94 (t, 3H, CH3) ppm; 13C NMR
(DMSO-d6) d: 13.61 (CH3), 26.76 (CH2), 38.52 (CH2), 123.89
(CH), 124.32 (CH), 126.88 (2CH), 127.39 (C), 129.97 (2CH),
131.46 (C), 132.41 (CH), 150.61 (C), 166.13 (C═O), 168.38 (C),
170.11 (C═O) ppm; MS (EI, 70 eV) m/z (%): 331 (M + 1). Anal.
Calcd for C16H14N2O2S2: C, 58.16; H, 4.27; N, 8.48; S, 19.41.
Found: C, 58.12; H, 4.18; N, 8.19; S, 19.71.
3-Butyl-5-((2-phenylthiazol-4-yl)methylene)thiazolidine-2,4-
dione (2f).
The compound was prepared according to the
procedure for 2b using 1-bromobutane (205 mg, 1.5 mmol) and
was recrystallized from absolute ethanol. Yield (81%), light
brown solid, mp 139ꢁC; 1H NMR (DMSO-d6, 500 MHz) d: 8.365
(s, 1H, C5–thiazole–H), 8.031–8.045 (m, 2H, Ar-H), 7.73 (s, 1H,
–CH═), 7.483–7.591 (m, 3H, Ar-H), 3.28 (m, 2H, N–CH2), 1.28–
1.51 (m, 4H, 2CH2), 0.96 (t, 3H, CH3) ppm; 13C NMR (DMSO-
d6) d: 13.95 (CH3), 19.90 (CH2), 29.69 (CH2), 41.20 (CH2),
123.72 (CH), 124.40 (CH), 126.85 (2CH), 127.44 (C), 129.97
(2CH), 131.54 (C), 132.49 (CH), 150.65 (C), 166.40 (C═O),
168.40 (C), 170.36 (C═O) ppm; MS (EI, 70 eV) m/z (%): 345
(M+ 1). Anal. Calcd for C17H16N2O2S2: C, 59.28; H, 4.68; N,
8.13; S, 18.62. Found: C, 59.18; H, 4.45, N, 8.06; S, 18.89.
3-((20-Phenyl-2,40-bisthiazol-4-yl)methyl)-5-((2-phenylthiazol-
4-yl)methylene) thiazolidine-2,4-dione (2k). A 1.7 mmol of 2a
(489 mg) was suspended in absolute methanol (2 mL), and a
suspension of anhydrous potassium hydroxide (96 mg, 1.7 mmol)
in absolute methanol (2 mL) was added. The resulting suspension
was stirred for 10 min. A suspension of 4-(iodomethyl)-20-phenyl-
2,40-bisthiazole [18] (646 mg, 1.7 mmol) in absolute methanol
(10mL) was added slowly, under continuous stirring to the
reaction mixture. The resultant was stirred for 10min at room
temperature and then refluxed for 12 h. After cooling, the reaction
3-Isopentyl-5-((2-phenylthiazol-4-yl)methylene)thiazolidine-
2,4-dione (2g). Using the procedure described for 2b using 1-
bromo-3-methylbutane (226 mg, 1.5 mmol), the title compound
was synthesized and recrystallized from absolute ethanol. Yield
1
(89%), light brown solid, mp 137–138ꢁC; H NMR (DMSO-d6,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

416
A. Stana, B. Tiperciuc, M. Duma, L. Vlase, O. Crişan, A. Pîrnău, and O. Oniga
Vol 51
mass was poured into ice-cold water. The precipitated solid
was filtered, washed with water, and dried. The product was
recrystallized from absolute methanol. Yield (48%), white solid,
mp 243ꢁC; 1H NMR (DMSO-d6, 500 MHz) d: 8.389 (s, 1H, C5–
thiazole–H), 8.22 (s, 1H, C5–thiazole–H), 7.85 (s, 1H, –CH═),
7.58–8.03 (m, 10H, Ar-H), 7.57 (s, 1H, C5–thiazole–H), 3.48
(s, 2H, CH2) ppm; 13C NMR (DMSO-d6) d: 39.97 (CH2), 114.12
(CH), 122.04 (2CH), 122.90 (CH), 123.77 (2CH), 124.26 (2CH),
127.35 (4CH), 130.14 (2C), 131.40 (C, CH), 133.33 (C, CH),
149.84 (2C), 151.19 (C), 162.20 (C═O), 167.03 (2C), 170.79
(C═O) ppm; MS (EI, 70 eV) m/z (%): 545 (M + 1). Anal. Calcd
for C26H16N4O2S4: C, 57.33; H, 2.96; N, 10.29; S, 23.55. Found:
C, 56.99; H, 2.61; N, 10.09; S, 23.42.
2-(5-(2,6-Dichlorobenzylidene)-2,4-dioxothiazolidin-3-yl)
acetamide (3b). To a solution of 3a (273 mg, 1 mmol) in DMF
(3.5mL) was added fine dispersed anhydrous potassium hydroxide
(84 mg, 1.5 mmol). The mixture was stirred for 30 min at room
temperature to give the potassium salt. To the resulting suspension
was added 2-iodoacetamide (202 mg, 1.1 mmol), and the mixture
was stirred at room temperature for 8 h. The reaction was
monitored by TLC. After completion of the reaction, the mass
was poured into ice-cold water under continuous stirring. The
resulted compound was washed with water, dried, and then
recrystallized from absolute ethanol. Yield (85%), white solid, mp
222–223ꢁC; 1H NMR (DMSO-d6, 500 MHz) d: 7.95 (s, 1H, –
CH═), 7.76 (s, 2H, NH2), 7.481–7.603 (m, 3H, Ar-H), 4.26 (s,
2H, CH2) ppm; 13C NMR (DMSO-d6) d: 44.00 (CH2), 129.31
(2CH), 129.59 (CH), 130.54 (C), 131.62 (CH), 132.48 (C),
133.51 (2C), 164.35 (C═O), 166.71 (C═O), 167.19 (C═O) ppm;
MS (EI, 70eV) m/z (%): 332 (M+ 1). Anal. Calcd for
C12H8Cl2N2O3S: C, 43.52; H, 2.43; N, 8.46; S, 9.68. Found: C,
43.33; H, 2.32; N, 8.36; S, 9.49.
(C═O), 166.97 (C═O) ppm; MS (EI, 70 eV) m/z (%): 317 (M + 1).
Anal. Calcd for C13H11Cl2NO2S: C, 49.38; H, 3.51; N, 4.43; S,
10.14. Found: C, 49.54; H, 3.41; N, 4.09; S, 9.84.
3-Butyl-5-(2,6-dichlorobenzylidene)thiazolidine-2,4-dione(3f).
The compound was prepared according to the procedure described
for 3b using 1-bromobutane (205 mg, 1.5 mmol). Yield (47%),
white solid, mp 31–32ꢁC; 1H NMR (DMSO-d6, 500 MHz) d:
7.92 (s, 1H, –CH═), 7.468–7.687 (m, 3H, Ar-H), 3.29 (m, 2H,
N–CH2), 1.25–1.52 (m, 4H, 2CH2), 0.97 (t, 3H, CH3) ppm; 13C
NMR (DMSO-d6) d: 13.91 (CH3), 19.91 (CH2), 29.58 (CH2),
42.05 (CH2), 129.12 (2CH), 129.27 (CH), 130.64 (C), 131.68
(CH), 132.41 (C), 133.52 (2C), 164.72 (C═O), 166.94 (C═O)
ppm; MS (EI, 70eV) m/z (%): 331 (M+ 1). Anal. Calcd for
C14H13Cl2NO2S: C, 50.92; H, 3.97; N, 4.24; S, 9.71. Found: C,
51.19; H, 3.72; N, 4.06; S, 9.64.
5-(2,6-Dichlorobenzylidene)-3-isopentylthiazolidine-2,4-dione
(3g).
The compound was prepared according to the procedure
described for 3b using 1-bromo-3-methylbutane (226 mg, 1.5 mmol).
Yield (60%), white solid, mp 65ꢁC; 1H NMR (DMSO-d6,
500 MHz) d: 7.90 (s, 1H, –CH═), 7.508–7.692 (m, 3H, Ar-H), 3.25
(m, 2H, N–CH2), 1.66 (m, 1H, CH), 1.57 (m, 2H, CH2), 0.93
(d, 6H, 2CH3) ppm; 13C NMR (DMSO-d6) d: 22.61 (2CH3), 25.85
(CH), 36.32 (CH2), 39.99 (CH2), 129.15 (2CH), 129.34 (CH),
130.63 (C), 131.66 (CH), 132.45 (C), 133.56 (2C), 164.76 (C═O),
166.98 (C═O) ppm; MS (EI, 70 eV) m/z (%): 345 (M + 1). Anal.
Calcd for C15H15Cl2NO2S: C, 52.33; H, 4.39; N, 4.07; S, 9.31.
Found: C, 52.43; H, 4.53; N, 3.87; S, 8.98.
5-(2,6-Dichlorobenzylidene)-3-(2-oxopropyl)thiazolidine-2,4-
dione (3h). The title compound was prepared according to the
procedure described for 3b using 1-chloropropan-2-one (185 mg,
2 mmol). Yield (81%), white solid, mp 140–141ꢁC; 1H NMR
(DMSO-d6, 500 MHz) d: 7.94 (s, 1H, –CH═), 7.464–7.529 (m,
3H, Ar-H), 4.693 (s, 2H, CH2), 2.278 (s, 3H, CH3) ppm; 13C
NMR (DMSO-d6) d: 27.54 (CH3), 50.98 (CH2), 129.32 (2CH),
130.06 (CH), 130.25 (C), 131.56 (CH), 132.54 (C), 133.50
(2C), 164.09 (C═O), 166.44 (C═O), 200.75 (C═O) ppm; MS
(EI, 70 eV) m/z (%): 331 (M + 1). Anal. Calcd for
C13H9Cl2NO3S: C, 47.29; H, 2.75; N, 4.24; S, 9.71. Found: C,
47.09; H, 2.45; N, 3.98; S, 9.35.
5-(2,6-Dichlorobenzylidene)-3-methylthiazolidine-2,4-dione (3c).
The compound was prepared according to the procedure described
for 3b using iodomethane (212 mg, 1.5 mmol) for alkylation of 3a
1
(273 mg, 1 mmol). Yield (69%), white solid, mp 94ꢁC; H NMR
(DMSO-d6, 500 MHz) d: 7.88 (s, 1H, –CH═), 7.496–7.622
(m, 3H, Ar-H), 3.431 (s, 3H, N–CH3) ppm; 13C NMR (DMSO-d6)
d: 28.51 (CH3), 128.92 (2CH), 129.27 (CH), 130.93 (C), 131.75
(CH), 132.39 (C), 133.52 (2C), 164.85 (C═O), 166.99 (C═O)
ppm; MS (EI, 70 eV) m/z (%): 289 (M + 1). Anal. Calcd for
C11H7Cl2NO2S: C, 45.85; H, 2.45; N, 4.86; S, 11.13. Found: C,
45.54; H, 2.38; N, 4.65; S, 11.01.
5-(2,6-Dichlorobenzylidene)-3-ethylthiazolidine-2,4-dione (3d).
The compound was prepared according to the procedure described
for 3b using iodoethane (234 mg, 1.5 mmol). Yield (78%), white
solid, mp 68–69ꢁC; 1H NMR (DMSO-d6, 500 MHz) d: 7.89
(s, 1H, –CH═), 7.482–7.654 (m, 3H, Ar-H), 3.384 (m, 2H, N–
CH2), 1.27 (t, 3H, CH3) ppm; 13C NMR (DMSO-d6) d: 13.16
(CH3), 37.48 (CH2), 129.06 (2CH), 129.27 (CH), 130.77 (C),
131.70 (CH), 132.40 (C), 133.53 (2C), 164.52 (C═O), 166.77
(C═O) ppm; MS (EI, 70eV) m/z (%): 303 (M+ 1). Anal. Calcd
for C12H9Cl2NO2S: C, 47.70; H, 3.00; N, 4.64; S, 10.61. Found:
C, 47.74; H, 2.81; N, 4.30; S, 10.35.
5-(2,6-Dichlorobenzylidene)-3-propylthiazolidine-2,4-dione (3e).
The compound was prepared according to the procedure described
for 3b using 1-bromopropane (184 mg, 1.5 mmol). Yield (73%),
white solid, mp 58–59ꢁC; 1H NMR (DMSO-d6, 500 MHz) d: 7.91
(s, 1H, –CH═), 7.468–7.687 (m, 3H, Ar-H), 3.36 (m, 2H, N–CH2),
1.68 (m, 2H, CH2), 0.98 (t, 3H, CH3) ppm; 13C NMR (DMSO-d6)
d: 11.53 (CH3), 20.96 (CH2), 43.88 (CH2), 129.12 (2CH), 129.27
(CH), 130.64 (C), 131.68 (CH), 132.40 (C), 133.53 (2C), 164.75
Acknowledgments. This research was financially supported by
the National University Research Council, Romania (Project PN
II–1271/2008 and PN II–ID 1348/2008). This support is
gratefully acknowledged.
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