Synthesis of novel highly functionalized 4-thiazolidinone derivatives from 4-phenyl-3-thiosemicarbazones

Article abstract of DOI:10.3390/molecules19033068

We present herein the synthesis in good yields of two series of highly functionalized thiazolidinone derivatives from the reactions of various 4-phenyl-3-thio-semicarbazones with ethyl 2-bromoacetate and diethyl acetylenedicarboxylate, respectively.

Full text of DOI:10.3390/molecules19033068

Molecules 2014, 19, 3068-3083; doi:10.3390/molecules19033068
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Novel Highly Functionalized 4-Thiazolidinone
Derivatives from 4-Phenyl-3-thiosemicarbazones
Abdelmadjid Benmohammed 1,2, Omar Khoumeri 3, Ayada Djafri 1, Thierry Terme 3 and
Patrice Vanelle 3,*
1
Laboratoire de Synthèse Organique Appliquée, BP 1524, El Menaouer, Département de Chimie,
Faculté des Sciences Exactes et Appliquées, Université d’Oran, Oran 31000, Algeria;
E-Mails: medmadjid@yahoo.fr (A.B.); djafriayada@yahoo.fr (A.D.)
2
Département de Sciences et Techniques, Faculté des Sciences & Technologie,
Université de Mascara, Mascara 29000, Algeria
3
Aix-Marseille Université, Institut de Chimie Radicalaire ICR, UMR CNRS 7273,
Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin,
Marseille cedex 05 13385, France; E-Mails: omar.khoumeri@univ-amu.fr (O.K.);
thierry.terme@univ-amu.fr (T.T.)
* Author to whom correspondence should be addressed; E-Mail: patrice.vanelle@univ-amu.fr;
Tel.: +33-4-9183-5580; Fax: +33-4-9179-4677.
Received: 7 February 2014; in revised form: 27 February 2014 / Accepted: 4 March 2014 /
Published: 11 March 2014
Abstract: We present herein the synthesis in good yields of two series of highly functionalized
thiazolidinone derivatives from the reactions of various 4-phenyl-3-thio-semicarbazones
with ethyl 2-bromoacetate and diethyl acetylenedicarboxylate, respectively.
Keywords: 4-phenyl-3-thiosemicarbazones; thiazolidinones derivatives; ethyl 2-bromoacetate;
diethyl acetylenedicarboxylate
1. Introduction
Thiosemicarbazones are a class of small molecules that have been evaluated over the last 50 years
as antiviral [1] and as antitumoral agents [2–4], in addition to their antiparasitic and bacterial action
against Trypanasoma cruzi [5–7] and Toxoplasma gondii and several bacterial strains [8].
Thiosemicarbazones have been used as intermediates for a great variety of heterocyclic products, such

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as thiazolidinones, thiohydantoins, thioxopyrimidinediones. It is reported that thiazolidinones exhibit
antibacterial [9], antifungal [10], anticonvulsant [11], antitubercular [12], anti-inflammatory [13],
antihistaminic [14,15], cardiovascular [16] and anti-HIV [17] activities. As part of our research
program on new bioactive compounds [18–22], we report herein an efficient synthesis of some new
highly functionalized thiazolidinones derived from 4-phenyl-3-thiosemicarbazones.
2. Results and Discussion
The starting materials, 4-phenyl-3-thiosemicarbazones 4a–h, were synthesized in two steps.
The first step was the preparation of 4-phenyl thiosemicarbazide (2) in 86% yield from phenyl
isothiocyanate (1) and hydrazine hydrate in ethanol at room temperature [23] (Scheme 1).
Scheme 1. Preparation of 4-phenyl-3-thiosemicarbazide (2).
The reaction of 4-phenyl-3-thiosemicarbazide (2) with various aromatic aldehydes 3a–h in the presence
of few drops of acetic acid at 85 °C for 1–3 h, led to the corresponding 4-phenyl-3-thiosemicarbazone
derivatives 4a–h in good yields (70%–93%), as shown in Scheme 2 and Table 1.
Scheme 2. Preparation of 4-phenyl-3-thiosemicarbazones 4a–h.
1
The most characteristic signals in the H-NMR spectrum of this family of thiosemicarbazones
were those corresponding to the CH=N and N-H protons. 1H-NMR studies showed the CH=N protons
in the 7.86–8.62 ppm range, whereas thiourea N-H protons are found in the 9.13–11.78 ppm interval
for N-H adjacent to the monosubstituted phenyl ring and for the N-H adjacent to the CH=N moiety,
respectively. All of the synthesized compounds were in the E-configuration, which was confirmed
using 1H-NMR spectroscopy, as the signal of the NH group was in the 9–12 ppm range, in comparison
to the Z-isomer, which possesses a characteristic NH signal in the 14–15 ppm range [24].

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Table 1. Reaction of 2 with various aromatic aldehydes 3a–h.
Product Reaction
Yield (%)
Carbonyl compound
Product
number
time (h)
O
H
H
N
N
NO2
N
N
N
H
4a
1
70
S
S
S
NO2
NO2
3a
O
NO2
H
N
H
N
NO2
H
4b
3
90
93
O2N
3b
O
H
N
H
N
H
4c
2
O2N
O2N
3c
H
N
H
N
O
O
N
4d
1
90
S
O2N
3d
OCH3
H
H
N
N
OCH3
O
N
OCH3
OCH3
4e
4f
1
2
91
89
S
H
OCH3
OCH3
3e
H
H
N
N
N
O
O
O
S
S CH3
O
S CH3
O
H
3f
O
H
CH3
S
H
N
H
N
N
4g
4h
2
1
91
89
S
CH3
S
3g
3h
O
H
H
N
N
CF3
N
H
S
CF3

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The reaction of various 4-phenyl thiosemicarbazones 4a–h with ethyl 2-bromoacetate (5) as
cyclizing reagent in boiling absolute ethanol containing three equivalents of anhydrous sodium acetate
during 1–3 h, afforded to the thiazolidin-4-ones 6a–h in good yields (68%–91%) as shown in
Scheme 3 and Table 2.
Scheme 3. Preparation of thiazolidinones 6a–h.
Table 2. Reactions of 4a–h with ethyl 2-bromoacetate (5).
Product
number
Reaction
time (h)
Yield
(%)
Compound
4a
Product
O2N
S
N
N
O
N
6a
6b
1
3
91
68
O2N
S
N
N
O
N
4b
4c
4d
NO2
NO2
S
N
O
O
N
N
N
6c
3
2
82
86
NO2
N
O
O
S
N
6d
4e
6e
2
80

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Table 2. Cont.
Product
number
Reaction
time (h)
Yield
(%)
Compound
Product
O
S
H3C
S
O
N
N
O
4f
N
N
6f
6g
6h
3
3
2
89
90
N
S
H3C
S
O
N
4g
4h
F3C
S
N
O
N
N
88
1
The structures of all new compounds 6a–h were established by analysis of their IR, H-NMR
13
and C-NMR data. The IR spectra of the thiazolidin-4-ones 6a–h showed absorption bands at about
1,734–1,716 cm−1 characteristic of (amide group) C=O stretching vibrations. Further support was
obtained from the 1H-NMR spectra, where it did not display signs of the 4-phenyl-3-thiosemicarbazone
1
(NH) protons. On the other hand, the H-NMR spectra exhibited resonances assigned to the SCH2
group of the thiazolidine ring appearing as a singlet at 3.97–4.10 ppm due to the methylene protons.
The CH=N protons in these structures were observed in the 7.67–8.57 ppm region. The formation of
thiazolidinones 6a–h ocurred in two steps: the first step of this reaction is thought to be S-alkylation of
thiosemicarbazide in its thiol form due to the sodium acetate used. Second step involved loss of ethanol
to give the thiazolidin-4-one. The electronic and steric properties of the substituent at the 4-position of
the thiosemicarbazones seems to be a determining factor for the formation of the thiazolidinone ring.
Previous reports on these types of compounds reveal a small substituent such as phenyl or alkyl leads
to a 4-thiazolidinone ring by loss of ethanol [25].
The next cyclization reaction of 4-phenyl-3-thiosemicarbazones derivatives 4a–h was conducted
using diethyl acetylenedicarboxylate in methanol for 1 h [26], as shown in Scheme 4 and Table 3.
In this reaction both of the sulfur group and the amino group are capable of reacting with diethyl
acetylenedicarboxylate. It was found that the 4-phenyl thiosemicarbazone derivatives 4a–h reacted
with diethyl acetylenedicarboxylate exclusively with the sulfur atom. In this reaction the intermediate
7 undergoes an intramolecular cyclization which leads to the compounds 8a–h.

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Scheme 4. Preparation of 8a–h with 4-phenyl-3-thiosemicarbazones 4a–h and diethyl
acetylenedicarboxylate.
Table 3. Reactions of 4a–h with diethyl acetylenedicarboxylate.
Compound
Product number
Yield (%)
Product
CH3
O
O
O2N
S
4a
8a
73
N
N
O
N
CH3
O
O
O2N
S
4b
8b
70
N
N
O
N
NO2
CH3
O
O
NO2
S
4c
8c
76
N
N
O
N

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Table 3. Cont.
Compound
Product number
Yield (%)
Product
CH3
O
O
NO2
O
O
S
4d
8d
74
N
N
O
N
4e
8e
73
75
70
CH3
O
O
O
S
H3C
S
4f
8f
O
N
O
N
N
CH3
O
O
S
H3C
S
4g
8g
N
O
N
N
CH3
O
O
F3C
S
4h
8h
71
N
O
N
N
Although the two geometrical E- or Z- isomers of 8a–h could be formed in almost equal amounts
from the reaction of diethyl acetylenedicarboxylate with 4a–h, 1H-NMR revealed the presence of only

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one singlet at 6.8 ppm (vinyl proton) indicating that only one E- or Z-isomer was formed. The
structures of compound 8b and 8g obtained by X-ray structure analysis confirmed the Z-configuration
for the double bond in the 5-position of the thiazolidin-4-ones (Figure 1) [27,28], probably due to the
steric effect of the ester group.
Figure 1. ORTEP plots of 8b and 8g.
The chemical structures of the reaction products 8a–h were confirmed by their IR,
13
1H-NMR, C-NMR spectra. The IR spectrum of compound 8a, for example, showed absorptions at
1730, 1692 cm−1 due to the C=O functions of the ester and cyclic amide, respectively. Similarly, bands
1
at 1595–1622 cm−1 are due to the C=N groups. The H-NMR spectrum of 8a showed a triplet at
δ = 1.28 ppm and a quartet at δ = 4.28 ppm is due to the COOCH2CH3 protons. A singlet at δ = 6.80 ppm is
due to C=CH. Aromatic protons appeared as a multiplet at δ = 7.38–7.60 ppm.
3. Experimental
3.1. General
Melting points were determined on Büchi B-540 apparatus and are uncorrected. IR spectra were
recorded as KBr pellets on a JASCO FT/IR4200 Fourier Transform infrared spectrometer and the
reported wavenumbers are given in cm−1. Elemental analyses were carried out at the Spectropole,
1
Faculté des Sciences site Saint-Jérome. H-NMR (200 MHz) and 13C-NMR (50 MHz) spectra were
recorded on a Bruker ARX 200 spectrometer in CDCl3 or D2O at the Service Inter-Universitaire de
RMN de la Faculté de Pharmacie de Marseille. The 1H-NMR chemical shifts were reported as parts per
13
million downfield from tetramethylsilane (Me4Si), and the C-NMR chemical shifts were referenced
to the solvent peaks: CDCl3 (76.9 ppm) or DMSO-d6 (39.6 ppm). Silica gel 60 (Merck, 230–400 mesh)
was used for column chromatography: Thin-layer chromatography was performed with silica gel
Merck 60F-254 (0.25 mm layer thickness).

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3.2. General Procedure for the Preparation of Compounds 4a–h
To a solution of 4-phenylthiosemicarbazide (2, 1 g, 6 mmol, 1 eq) in ethanol (33 mL) were added
the benzaldehyde derivative (6.3 mmol, 1.05 eq) and acetic acid (0.50 mL). The mixture was stirred
under reflux for 1–3 h and then cooled to room temperature. After, the solid separated was filtered and
recrystallized from ethanol-DMF (3:1) to give compounds 4a–h.
(E)-2-(4-Nitrobenzylidene)-N-phenylhydrazinecarbothioamide (4a): yellow solid; mp: 234 °C; IR
1
(KBr) νmax/cm−1: 3316 and 3138 (NH), 1543 (C=N), 1292 (C=S); H-NMR (DMSO-d6): δ 10.32
(s, 1H, NH), 8.24 (d, 2H, J = 9.2 Hz, Ar-H), 8.22 (s, 1H, CH=N), 8.17 (d, 2H, J = 9.2 Hz, Ar-H), 7.52
(d, 2H, J = 7.9 Hz, Ar-H), 7.38 (dd, 2H, J = 7.9 Hz, J = 7.2 Hz, Ar-H), 7.22 ( t, 1H J = 7.2 Hz, Ar-H);
13C-NMR (DMSO-d6): δ 177.0 (C), 148.1 (C), 141.0 (C), 140.6 (CH), 139.4 (C), 128.9 (2CH), 128.6
(2CH), 126.7 (2CH), 126.1 (CH), 124.4 (2CH); Anal. Calcd for C14H12N4O2S: C, 55.99; H, 4.03; N,
18.65; S, 10.68. Found: C, 55.98; H, 4.06; N, 18.49; S, 10.68.
(E)-2-(2,4-Dinitrobenzylidene)-N-phenylhydrazinecarbothioamide (4b): yellow solid; mp: 219 °C; IR
1
(KBr) νmax/cm−1: 3316 and 3138 (NH), 1543 (C=N), 1292 (C=S); H-NMR (DMSO-d6): δ 10.40 (s,
1H, NH), 8.87 (d, 1H, J = 8.8 Hz, Ar-H), 8.75 (d, 1H, J = 2.2 Hz, Ar-H), 8.62 (s, 1H, CH=N),
8.45 (dd, 1H, J = 8.8 Hz, J = 2.2 Hz, Ar-H), 7.52 (d, 2H, J = 7.7 Hz, Ar-H), 7.39 (dd, 2H, J = 7.7 Hz,
J = 7.3 Hz, Ar-H), 7.24 (t, 1H, J = 7.3 Hz, Ar-H); 13C-NMR (DMSO-d6): δ 177.2 (C), 148.3 (C), 147.5
(C), 139.2 (C), 136.4 (CH), 134.6 (C), 130.3 (CH), 128.7 (2CH), 127.4 (CH), 126.6 (2CH), 126.3
(CH), 120.8 (CH); Anal. Calcd for C14H11N5O4S: C, 48.69; H, 3.21; N, 20.28; S, 9.29. Found: C,
48.83; H, 3.22; N, 20.08; S, 9.05.
(E)-2-((E)-3-(2-Nitrophenyl)allylidene)-N-phenylhydrazinecarbothioamide (4c): brown solid; mp: 185 °C;
IR (KBr) νmax/cm−1: 3226 and 3151 (NH), 1540 (C=N), 1247 (C=S); 1H-NMR (CDCl3): δ 9.67 (s, 1H,
NH), 9.14 (s, 1H, NH), 8.02 (dd, 1H, J = 8.2 Hz, J = 1.2 Hz, Ar-H), 7.76-7.59 (m, 5H, Ar-H), 7.52-
7.37 (m, 4H, Ar-H), 7.25–7.29 (m, 1H, Ar-H), 6.87 (dd, 1H, J = 15.9 Hz, J = 9.2 Hz, CH);
13C-NMR (CDCl3): δ 175.6 (C), 147.8 (C), 143.3 (CH), 137.7 (C), 134.8 (CH), 133.3 (CH), 131.3 (C),
129.4 (CH), 129.0 (CH), 128.8 (2CH), 128.2 (CH), 126.2 (CH), 125.0 (CH), 124.2 (2CH); Anal. Calcd
for C16H14N4O2S: C, 58.88; H, 4.32; N, 17.17; S, 9.82. Found: C, 59.13; H, 4.40; N, 17.07; S, 9.78.
(E)-2-((6-Nitrobenzo[d][1,3]dioxol-5-yl)methylene)-N-phenylhydrazinecarbothioamide (4d): yellow
1
solid; mp: 231 °C; IR (KBr) νmax/cm−1: 3302 and 3283 (NH), 1547 (C=N), 1268 (C=S); H-NMR
(DMSO-d6): δ 10.21 (s, 1H, NH), 8.58 (s, 1H, Ar-H), 8.17 (s, 1H, CH=N), 7.61 (s, 1H, Ar-H),
7.50 (dd, 2H, J = 7.8 Hz , J = 1.2 Hz , Ar-H), 7.37 (dd, 2H, J = 7.8 Hz , J = 7.2 Hz, Ar-H), 7.21 (td,
13
1H, J = 7.2 Hz, J = 1.2 Hz, Ar-H), 6.25 (s, 2H, CH2); C-NMR (DMSO-d6): δ 176.9 (C), 152.2 (C),
149.2 (C), 143.9 (C), 139.4 (C), 138.5 (CH), 128.6 (2CH), 126.94 (2CH), 126.1 (CH), 125.9 (C), 106.6
(CH), 105.3 (CH), 104.1 (CH2); Anal. Calcd for C15H12N4O4S: C, 52.32; H, 3.51; N, 16.27; S, 9.31.
Found: C, 52.35; H, 3.46; N, 16.01; S, 9.20.
(E)-N-Phenyl-2-(3,4,5-trimethoxybenzylidene)hydrazinecarbothioamide (4e): white solide; mp:
1
161 °C; IR (KBr) νmax/cm−1: 3291 and 3134 (NH), 1557 (C=N), 1262 (C=S); H-NMR (CDCl3):

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δ 10.36 (s, 1H, NH), 9.14 (s, 1H, NH), 7.93 (s, 1H, CH=N), 7.63 (d, 2H, J = 7.8 Hz, Ar-H), 7.44
(dd, 2H, J = 7.8 Hz, J = 7.2 Hz, Ar-H), 7.30 (t, 1H, J = 7.2 Hz, Ar-H ), 6.90 (s, 2H, Ar-H ), 3.90
13
(s, 3H, OCH3), 3.91 (s, 6H, OCH3); C-NMR (CDCl3): δ 175.6 (C), 153.6 (2C), 143.7 (CH), 140.5
(C), 137.7 (C), 129.0 (2CH), 128.4 (C), 126.6 (CH), 125.2 (2CH), 104.7 (2CH), 61.1 (CH3), 56.3
(2CH3); Anal. Calcd for C17H19N3O3S: C, 59.11; H, 5.54; N, 12.17; S, 9.28. Found: C, 59.25; H, 5.65;
N, 12.06; S, 9.19.
(E)-2-(4-(Methylsulfonyl)benzylidene)-N-phenylhydrazinecarbothioamide (4f): yellow solid; mp: 225 °C;
1
IR (KBr) νmax/cm−1: 3325 and 3150 (NH), 1542 (C=N), 1267 (C=S); H-NMR (DMSO-d6):
δ 10.30 (s, 1H, NH), 8.22 (s, 1H, CH=N ), 8.19 (d, 2H, J = 8.4 Hz, Ar-H), 7.95 (d, 2H, J = 8.4 Hz,
Ar-H), 7.55 (d, 2H, J = 7.60 Hz, Ar-H), 7.39 (dd, 2H, J = 7.2 Hz, J = 7.60 Hz, Ar-H), 7.23 ( t, 1H,
J =7.2 Hz, Ar-H), 3.26 ( s, 3H, CH3 ); 13C-NMR (DMSO-d6): δ 177.0 (C), 141.7 (C), 141.2 (CH),
139.44 (2C), 128.7 (2CH), 128.6 (2CH), 127.7 (2CH), 126.7 (2CH), 126.10 (CH), 43.9 (CH3);
Anal. Calcd for C15H15N3O2S2: C, 54.03; H, 4.53; N, 12.60; S, 19.23. Found: C, 54.11; H, 4.55; N,
12.45; S, 19.21.
(E)-2-(4-(Methylthio)benzylidene)-N-phenylhydrazinecarbothioamide (4g): yellow solid; mp: 178 °C; IR
1
(KBr) νmax/cm−1: 3343 and 3152 (NH), 1541 (C=N), 1271 (C=S); H-NMR (CDCl3): δ 11.78 (s, 1H,
NH), 10.08 (s, 1H, NH), 8.09 (s, 1H, CH=N), 7.82 (d, 2H, J = 8.4 Hz, Ar-H), 7.54 (d, 2H, J = 8.0 Hz,
Ar-H), 7.35 (dd, 2H, J = 7.3 Hz, J = 8.0 Hz, Ar-H), 7.27 (d, J = 8.4 Hz, 2H, Ar-H), 7.18 (dd, 1H,
13
J = 7.3 Hz, Ar-H), C-NMR (DMSO-d6): δ 175.4 (C), 143.1 (CH), 142.5 (C), 137.8 (C), 129.6 (C),
128.9 (2CH), 127.8 (2CH), 126.3 (CH), 125.8 (2CH), 124.8 (2CH), 15.1 (CH3); Anal. Calcd for
C15H15N3O2S2: C, 59.77; H, 5.02; N, 13.94; S, 21.28. Found: C, 59.68; H, 5.04; N, 13.78; S, 21.33.
(E)-N-Phenyl-2-(4-(trifluoromethyl)benzylidene)hydrazinecarbothioamide (4h): white solid; mp: 195 °C;
IR (KBr) νmax/cm−1: 3350 and 3138 (NH), 1542 (C=N), 1267 (C=S); 1H-NMR (CDCl3):
δ 10.36 (s, 1H, NH), 9.18 (s, 1H, NH), 8.03 (s, 1H, CH=N), 7.85 (d, 2H, J = 8.1 Hz, Ar-H), 7.69–7.51
13
(m, 4H, Ar-H), 7.43 (d, 2H, J = 7.4 Hz, Ar-H), 7.29 (t, 1H, J = 7.3 Hz, Ar-H); C-NMR (CDCl3):
δ 176.0 (C), 141.4 (CH), 137.5 (C), 133.9 (C), 131.5 (q, J = 32.9 Hz, C), 129.5 (CH), 128.9 (3CH),
127.0 (q, J = 3.6 Hz, CH), 126.6 (CH), 124.9 (2CH), 123.9 (q, J = 3.6 Hz, CH), 123.7 (q, J = 272.6 Hz,
C); Anal. Calcd for C15H12F3N3S: C, 55.72; H, 3.74; N, 13.00; S, 9.92. Found: C, 55.79; H, 3.66; N,
12.86; S, 9.81.
3.3. General Procedure for the Preparation of Compounds 6a–h
A mixture of compound 4a–h (1.5 mmol, 1 eq), ethyl 2-bromoacetate (0.24 mL, 1.5 mmol) and
anhydrous sodium acetate (0.37 g, 4.5 mmol, 3 eq) in ethanol (30 mL) was stirred until reflux; the
mixture was stirred under the same conditions till the completion of the reaction (1–3 h). The reaction
mixture was left to cool, poured into ice cold water, and the separated solid was filtered, washed with
water and recrystallized from a mixture of ethanol-DMF (3:1).
2-((4-Nitrobenzylidene)hydrazono)-3-phenylthiazolidin-4-one (6a): yellow solid; mp: 258 °C; IR
1
(KBr) νmax/cm−1: 1716 (C=O), 1662 (C=N); H-NMR (CDCl3): δ 8.34 (s, 1H, CH=N), 8.25 (d, 2H,

Molecules 2014, 19
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J = 8.8 Hz , Ar-H), 7.88 (d, 2H, J = 8.8 Hz , Ar-H), 7.59-7.44 (m, 3H, Ar-H), 7.35 (dd, 2H, J = 7.7 Hz,
J = 1.9 Hz, Ar-H), 4.00 (s, 2H, CH2); 13C-NMR (CDCl3): δ 171.6 (C), 166.9 (C), 156.2 (CH),
148.9 (C), 140.0 (C), 134.3 (C), 129.4 (2CH), 129.3 (CH), 128.6 (2CH), 127.7 (2CH), 124.0 (2CH),
32.55 (CH2); Anal. Calcd for C16H12N4O3S: C, 56.46; H, 3.55; N, 16.46; S, 9.42. Found: C, 56.44; H,
3.5; N, 16.53; S, 9.53.
2-((2,4-Dinitrobenzylidene)hydrazono)-3-phenylthiazolidin-4-one (6b): yellow solid; mp: 275 °C; IR
1
(KBr) νmax/cm−1: 1731 (C=O), 1592 (C=N); H-NMR (DMSO-d6): δ 8.74 (d, 1H, J = 2.3 Hz,
Ar-H), 8.58 (dd, 1H, J = 8.4 Hz, J = 2.3 Hz , Ar-H), 8.57 (s, 1H, HC=N), 8.20 (d, 1H, J = 8.4 Hz,
Ar-H), 7.54–7.45 (m, 3H, Ar-H), 7.41–7.36 (m, 2H, Ar-H), 4.14 (s, 2H, CH2); 13C-NMR (DMSO-d6):
δ 172.6 (C), 170.1 (C), 152.8 (CH), 148.4 (C), 148.3 (C), 135.3 (C), 133.7 (C), 131.2 (CH), 129.4
(2CH), 129.3 (CH), 128.7 (2CH), 128.1 (CH), 120.6 (CH), 33.1 (CH2); Anal. Calcd for C16H11N5O5S:
C, 49.87; H, 2.88; N, 18.17; S, 8.32.Found: C, 49.99; H, 2.87; N, 17.93; S, 8.25.
2-(3-(2-Nitrophenyl)allylidene)hydrazono)-3-phenylthiazolidin-4-one (6c): orange solid; mp: 265 °C; IR
(KBr) νmax/cm−1: 1732 (C=O), 1627 (C=N); 1H-NMR (CDCl3): δ 8.13 (d, 1H, J = 9.5 Hz, CH=N), 8.0
(dd, 1H, J = 8.2 Hz, J = 1.0 Hz, Ar-H), 7.75–7.57 (m, 3H, Ar-H), 7.53–7.43 (m, 4H, Ar-H),
13
7.39–7.32 (m, 2H, Ar-H), 7.01 (dd, 1H, J = 15.8 Hz, J = 9.5 Hz, CH), 3.98 (s, 2H, CH2); C-NMR
(CDCl3): δ 171.6 (C), 164.5 (C), 160.2 (CH), 148.00 (C), 135.8 (CH), 134.4 (C), 133.3 (2CH),
131.4 (C), 130.1 (CH), 129.4 (2CH), 129.1 (CH), 128.3 (CH), 127.7 (2CH), 125.0 (CH), 32.5 (CH2);
Anal. Calcd for C18H14N4O3S: C, 59.01; H, 3.85; N, 15.29; S, 8.75. Found: C, 58.96; H, 3.92; N,
15.18; S, 8.50.
2-(3,4-(Methylenedioxy)-6-nitrobenzaldehyde)hydrazono)-3-phenylthiazolidin-4-one (6d): yellow
1
solid; mp: 262 °C; IR (KBr) νmax/cm−1: 1717 (C=O), 1602 (C=N); H-NMR (DMSO-d6): δ 8.47 (s,
1H, Ar-H), 7.64 (s, 1H, HC=N), 7.56–7.44 (m, 3H, Ar-H), 7.35–7.40 (m, 1H, Ar-H), 7.36 (m, 2H,
13
Ar-H), 6.27 (s, 2H , CH2), 4.10 (s, 2H, CH2); C-NMR (DMSO-d6): δ 172.5 (C), 167.7 (C), 154.0
(CH), 152.0 (C), 149.8 (C), 144.0 (C), 135.4 (C), 129.6 (2CH), 129.3 (CH), 128.7 (2CH), 125.4 (C),
106.6 (CH), 105.6 (CH), 104.4 (CH2), 32.9 (CH2); Anal. Calcd for C17H12N4O5S: C, 53.12; H, 3.15; N,
14.58; S, 8.34. Found: C, 53.15; H, 3.10; N, 14.67; S, 8.26.
2-((3,4,5-Trimethoxybenzylidene)hydrazono)-3-phenylthiazolidin-4-one (6e): white solid; mp:
174 °C; IR (KBr) νmax/cm−1: 1720 (C=O), 1619 (C=N); 1H-NMR (DMSO-d6): δ 8.21 (s, 1H, HC=N),
7.55–7.44 (m, 3H, Ar-H), 7.39–7.35 (m, 2H, Ar-H), 7.06 (s, 2H, Ar-H), 4.08 (s, 2H, CH2) , 3.78 (s,
6H, OCH3), 3.70 (s, 3H, OCH3); 13C-NMR (DMSO-d6): δ 172.6 (C), 165.4 (C), 158.0 (CH), 153.6
(2C), 140.3 (C), 135.5 (C), 130.0 (C), 129.5 (2CH), 129.1 (CH), 128.7 (2CH), 105.5 (2CH), 60.6
(CH3), 56.3 (2CH3), 32.7 (CH2); Anal. Calcd for C19H19N3O4S: C, 59.21; H, 4.97; N, 10.90; S, 8.32.
Found: C, 59.29; H, 5.08; N, 10.64; S, 8.21.
2-(4-(Methylsulfonyl)benzylidene)hydrazono)-3-phenylthiazolidin-4-one (6f): yellow solid; mp:
1
277 °C; IR (KBr) νmax/cm−1: 1734 (C=O), 1615 (C=N); H-NMR (DMSO-d6): δ 8.43 (s, 1H, HC=N),
8.00 (d, 2H, J = 9.2 Hz, Ar-H), 7.94 (d, 2H, J = 9.2 Hz, Ar-H), 7.54–7.44 (m, 3H, Ar-H), 7.41–7.36
13
(m, 2H, Ar-H), 4.12 (s, 2H, CH2), 3.22 (s, 3H, CH3); C-NMR (DMSO-d6): δ 172.5 (C), 167.8 (C),

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156.76 (CH), 142.5 (C), 139.2 (C), 135.4 (C), 129.6 (2CH), 129.2 (CH), 128.7 (4CH) , 128.0 (2CH),
43.8 (CH3), 32.9 (CH2); Anal. Calcd for C17H15N3O3S2: C, 54.67; H, 4.05; N, 11.25; S, 17.17. Found:
C, 54.71; H, 4.05; N, 11.19; S, 17.14.
2-(4-(Methylthio)benzylidene)hydrazono)-3-phenylthiazolidin-4-one (6g): yellow solid; mp: 223 °C;
IR (KBr) νmax/cm−1: 1732 (C=O), 1609 (C=N); 1H-NMR (CDCl3): δ 8.25 (s, 1H, HC=N), 7.64 (d, 2H,
J = 8.5 Hz, Ar-H), 7.53–7.45 (m, 3H, Ar-H), 7.38–7.34 (m, 2H, Ar-H), 7.21 (d, 2H, J = 8.5 Hz, Ar-H),
13
3.97 (s, 2H, CH2), 2.50 (s, 3H, CH3); C-NMR (CDCl3): δ 171.8 (C), 163.9 (C), 158.4 (CH), 142.6
(C), 134.5 (C), 130.7 (C), 129.4 (2CH), 129.1 (CH), 128.4 (2CH) , 127.8 (2CH), 125.8 (2CH), 32.5
(CH2), 15.2 (CH3); Anal. Calcd for C17H15N3OS2: C, 59.80; H, 4.43; N, 12.31; S, 18.78. Found: C,
59.67; H, 4.43; N, 12.20; S, 18.88.
2-(4-(Trifluoromethyl)benzylidene)hydrazono)-3-phenylthiazolidin-4-one (6h): white solid; mp:
1
206 °C; IR (KBr) νmax/cm−1: 1732 (C=O), 1616 (C=N); H-NMR (CDCl3): δ 8.33 (s, 1H, HC=N),
7.84 (d, 2H, J = 8.2 Hz, Ar-H), 7.65 (d, 2H, J = 8.2 Hz, Ar-H), 7.59–7.43 (m, 3H, Ar-H), 7.39–7.32
13
(m, 2H, Ar-H), 3.99 (s, 2H, CH2); C-NMR (CDCl3): δ 171.7 (C), 165.8 (C), 157.3 (CH), 137.4 (C),
134.4 (C), 132 (q, J = 32.4 Hz, C), 129.4 (2CH), 129.2 (CH), 128.2 (2CH), 127.8 (3CH), 125.6 (q,
J = 3.8 Hz, CH), 123.8 (q, J = 272.3 Hz, C), 32.5 (CH2); Anal. Calcd for C17H12F3N3OS: C, 56.19; H,
3.33; N, 11.56; S, 8.82.Found: C, 56.17; H, 3.66; N, 12.82; S, 9.96.
3.4. General Procedure for the Preparation of Compounds 8a–h
An equimolar mixture of 4a–h (1.5 mmol) and diethyl acetylenedicarboxylate (1.5 mmol) in
methanol (20 mL) was refluxed for 1 h. After completion of the reaction, the reaction mixture was
allowed to cool to the room temperature. The solid thus separated was collected by filtration and
recrystallized using ethanol-DMF mixture.
(Z)-Ethyl-2-(2-((4-nitrobenzylidene)hydrazono)-4-oxo-3-phenylthiazolidin-5-ylidene) acetate (8a):
1
yellow solid; mp: 206 °C; IR (KBr) νmax/cm−1: 1730 (C=O), 1692 (C=O), 1623 (C=N); H-NMR
(DMSO-d6): δ 8.60 (s, 1H, CH=N), 8.32 (d, 2H, J = 8.8 Hz, Ar-H), 8.01 (d, 2H, J = 8.8 Hz, Ar-H),
7.58–7.48 (m, 5H, Ar-H), 6.80 (s, 1H, C=CH), 4.28 (q, 2H, J = 7.0 Hz, CH2), 1.28 (t, 3H, J = 7.0 Hz,
CH3). 13C-NMR (DMSO-d6): δ 166.0 (C), 164.6 (C), 163.6 (C), 158.5 (CH), 149.2 (C), 141.7 (C),
140.0 (C), 134.5 (C), 129.6 (3CH), 129.5 (2CH), 128.6 (2CH), 124.6 (2CH), 116.2 (CH), 62.0 (CH2),
14.5 (CH3); Anal. Calcd for C20H16N4O5S: C, 56.60; H, 3.80; N, 13.20; S, 7.55. Found: C, 55.68; H,
4.59; N, 10.67; S, 5.44.
(Z)-Ethyl-2-(2-((E)-2,4-dinitrobenzylideneamino)-4-oxo-3-phenylthiazolidin-5-ylidene) acetate (8b):
1
yellow solid; mp: 193 °C; IR (KBr) νmax/cm−1: 1727 (C=O), 1698 (C=O), 1620 (C=N); H-NMR
(DMSO-d6): δ 8.77 (d, 1H, J = 2.2 Hz, Ar-H), 8.7 (s, 1H, CH=N), 8.64 (dd, 1H, J = 8.6 Hz, J = 2.2 Hz,
Ar-H), 8.25 (d, 1H, J = 8.6 Hz, Ar-H), 7.60-7.46 (m, 5H, Ar-H), 6.83 (s, 1H, C=CH), 4.29 (q, 2H,
J = 7.1 Hz, CH2), 1.28 (t, 3H, J = 7.1 Hz, CH3); 13C-NMR (DMSO-d6): δ 165.9 (C), 165.2 (C), 164.7
(C), 155.2 (CH), 148.6 (C), 141.5 (C), 134.5 (C), 133.3 (C), 131.4 (CH), 129.8 (CH), 129.7 (3CH),

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128.7 (2CH), 128.3 (CH), 120.7 (CH), 116.6 (CH), 62.1 (CH2), 14.5 (CH3); Anal. Calcd for
C20H15N5O7S: C, 51.17; H, 3.22; N, 14.92; S, 6.83. Found: C, 51.29; H, 3.15; N, 14.78; S, 6.77.
(Z)-Ethyl-2-(2-((E)-3-(2-nitrophenyl)allylidene)amino)-4-oxo-3-phenylthiazolidin-5-ylidene) acetate
(8c): yellow solid; mp: 251 °C; IR (KBr) νmax/cm−1: 1727 (C=O), 1692 (C=O), 1618 (C=N); 1H-NMR
(DMSO-d6): δ 8.27 (d, 1H, J = 9.4 Hz, CH), 8.01 (ddd, 2H, J = 7.1 Hz, J = 7.9 Hz,
J = 1.1 Hz, Ar-H), 7.73 (dd, 1H, J = 7.9 Hz, J = 7.1 Hz, Ar-H), 7.63-7.42 (m, 7H, Ar-H), 7.20 (dd, 1H,
J = 15.7 Hz, J = 9.4 Hz, Ar-H), 6.77 (s, 1H, C=CH), 4.27 (q, 2H, J = 7.1 Hz, CH2), 1.27 (t, 3H,
13
J = 7.1 Hz, CH3); C-NMR (DMSO-d6): δ 166.0 (C), 164.6 (C), 162.1 (CH), 161.5 (C), 148.6 (C),
141.9 (C), 137.3 (CH), 134.6 (C), 134.0 (CH), 130.7 (CH), 130.4 (C), 129.8 (CH), 129.6 (3CH),
129.0 (CH), 128.6 (2CH), 125.0 (CH), 115.9 (CH), 62.0 (CH2), 14.5 (CH3). Anal. Calcd for
C22H18N4O5S: C, 58.66; H, 4.03; N, 12.44; S, 7.12. Found: C, 58.47; H, 3.92; N, 12.05; S, 6.64
(Z)-Ethyl-2-(2-((E)-(4-nitrobenzo[d][1,3]dioxol-5-yl)methyleneamino)-4-oxo-3-phenylthiazolidin-5-
ylidene) acetate (8d): yellow solid; mp: 251 °C; IR (KBr) νmax/cm−1: 1721 (C=O) 1702 (C=O), 1597
(C=N); 1H-NMR (DMSO-d6): δ 8.59 (s, 1H, Ar-H), 7.70 (s, 1H, Ar-H), 7.54–7.47 (m, 5H, Ar-H), 7.38
(s, 1H, Ar-H), 6.80 (s, 1H, C=CH), 6.30 (s, 2H, CH2 ), 4.27 (q, 2H, J = 7.1 Hz, CH2), 1.27 (t, 3H,
13
J = 7.1 Hz, CH3); C-NMR (DMSO-d6): δ 166.0 (C), 164.7 (C), 163.0 (C), 156.5 (CH), 152.1 (C),
150.3 (C), 144.3 (C), 141.8 (C), 137.2 (C), 134.6 (C), 129.7 (2CH), 128.7 (2CH), 124.9 (CH), 116.2
(CH), 106.8 (CH), 105.8 (CH), 104.6 (CH2), 62.0 (CH2), 14.5 (CH3); Anal. Calcd for C21H16N4O7S: C,
53.84; H, 3.44; N, 11.96; S, 6.85. Found: C, 53.79; H, 3.42; N, 11.98; S, 6.75.
(Z)-Ethyl-2-(2-((E)-3,4,5-trimethoxybenzylideneamino)-4-oxo-3-phenylthiazolidin-5-ylidene) acetate
(8e): yellow solid; mp: 145 °C; IR (KBr) νmax/cm−1: 1721 (C=O), 1689 (C=O), 1622 (C=N); 1H-NMR
(DMSO-d6): δ 8.35 (s, 1H, CH=N), 7.58–7.47 (m, 5H, Ar-H), 7.11 (s, 2H, Ar-H), 6.77
(s, 1H, C=CH), 4.27 (q, 2H, J = 7.0 Hz, CH2), 3.80 (s, 6H, OCH3), 3.70 (s, 3H, OCH3), 1.28 (t, 3H,
13
J = 7.0 Hz, CH3); C-NMR (DMSO-d6): δ 165.9 (C), 164.6 (C), 160.6 (C), 160.4 (CH), 153.6 (2C),
142.0 (C), 140.9 (C), 134.7 (C), 129.6 (3CH), 129.4 (C), 128.6 (2CH), 115.7 (CH), 105.9 (2CH), 62.0
(CH2), 60.6 (CH3), 56.3 (2CH3), 14.5 (CH3); Anal. Calcd for C23H23N3O6S: C, 58.84; H, 4.94; N, 8.95;
S, 6.83. Found: C, 58.47; H, 4.93; N, 8.77; S, 6.64.
(Z)-Ethyl-2-(2-((E)-4-(methylsulfonyl)benzylideneamino)-4-oxo-3-phenylthiazolidin-5-ylidene)
acetate
(8f): yellow solid; mp: 254 °C; IR (KBr) νmax /cm−1: 1722 (C=O), 1687 (C=O), 1611 (C=N);
1H-NMR (DMSO-d6): δ 8.58 (s, 1H, CH=N), 8.02 (s, 4H, Ar-H), 7.59–7.45 (m, 5H, Ar-H), 6.81 (s,
1H, C=CH), 4.29 (q, 2H, J = 7.1 Hz, CH2), 3.24 (s, 3H, CH3), 1.28 (t, 3H, J = 7.1 Hz, CH3); 13C-NMR
(DMSO-d6): δ 166.0 (C), 164.7 (C), 163.2 (C), 159.0 (CH), 143.0 (C), 141.8 (C), 138.6 (C), 134.6 (C),
129.7 (3CH), 129.1 (2CH), 128.7 (2CH), 128.1 (2CH), 116.1 (CH), 62.1 (CH2), 43.9 (CH3), 14.5
(CH3); Anal. Calcd for C21H19N3O5S2: C, 55.13; H, 4.19; N 9.18; S, 14.02. Found: C, 55.18; H, 4.19;
N, 8.96; S, 14.11.
(Z)-Ethyl-2-(2-((E)-4-(methylthio)benzylideneamino)-4-oxo-3-phenylthiazolidin-5-ylidene)acetate
(8g): yellow solid; mp: 210 °C; IR (KBr) νmax/cm−1: 1720 (C=O), 1696 (C=O), 1604 (C=N); 1H-NMR
(DMSO-d6): δ 8.40 (s, 1H, CH=N), 8.70 (d, 2H, J = 8.4 Hz, Ar-H), 7.58–7.44 (m, 5H, Ar-H), 7.33 (d,

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2H, J = 8.4 Hz, Ar-H), 6.77 (s, 1H, C=CH), 4.28 (q, 2H, J = 7.1 Hz, CH2), 3.31 (s, 3H, CH3), 1.28
(t, 3H, J = 7.1 Hz, CH3); 13C-NMR (DMSO-d6): δ 166.0 (C), 164.6 (C), 160.9 (C), 160.0 (CH), 143.5
(C), 142.1 (C), 134.7 (C), 130.3 (C), 129.6 (3CH), 128.9 (2CH), 128.7 (2CH), 126.0 (2CH), 115.6
(CH), 62.0 (CH2), 14.6 (CH3), 14.5 (CH3); Anal. Calcd for C21H19N3O3S2: C, 59.27; H, 4.50; N 9.87;
S, 15.07. Found: C, 59.10; H, 4.48; N, 9.74; S, 14.86.
(Z)-Ethyl-2-(2-((E)-4-(trifluoromethyl)benzylideneamino)-4-oxo-3-phenylthiazolidin-5-ylidene) acetate
(8h): yellow solid; mp: 154 °C; IR (KBr) νmax/cm−1: 1721 (C=O), 1690 (C=O), 1619 (C=N); 1H-NMR
(DMSO-d6): δ 8.56 (s, 1H, CH=N), 8.00 (d, 2H, J = 8.2 Hz, Ar-H), 7.84 (d, 2H, J = 8.2 Hz, Ar-H),
7.58-7.45 (m, 5H, Ar-H), 6.80 (s, 1H, C=CH), 4.30 (q, 2H, J = 7.1 Hz, CH2), 1.28 (t, 3H,
13
J = 7.1 Hz, CH3); C-NMR (DMSO-d6): δ 166.0 (C), 164.6 (C), 162.9 (C), 159.1 (CH), 141.9 (C),
137.9 (C), 134.6 (C), 131.3 (q, J = 32.2 Hz, C), 129.6 (q, J = 272.2 Hz, C), 129.5 (3CH), 129.1 (2CH),
128.7 (2CH), 126.3 (q, J = 3.2Hz, 2CH), 116.0 (CH), 62.0 (CH2), 14.5 (CH3); Anal. Calcd for
C21H16F3N3O3S: C, 56.37; H, 3.60; N, 9.39; S, 7.17. Found: C, 56.33; H, 3.51; N, 9.17; S, 7.10.
4. Conclusions
In conclusion, we have prepared a series of 4-phenyl-3-thiosemicarbazone derivatives from
4-phenyl-3-thiosemicarbazide and various aromatic aldehydes substituted with different electron-donor
and -withdrawing groups. In a second step, these 4-phenyl-3-thiosemicarbazone derivatives were
reacted with 2-ethyl bromoacetate and diethyl acetylenedicarboxylate, respectively, to afford an
original series of highly functionalized thiazolidinone derivatives in good yields. The antiparasitic and
antibacterial evaluations of all synthesized compound are under investigation.
Acknowledgments
This work was supported by the CNEPRU (Ministry of Higher Education and Scientific Research
Algeria). We express our thanks to Vincent Remusat for recording the 1H and 13C-NMR spectra.
Author Contributions
A.D.; T.T. and P.V. conceived and designed the study. A.B. and O.K. designed the experiments and
interpreted the results. A.B.; O.K.; A.D.; T.T. and P.V. wrote the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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27. CCDC contains the supplementary crystallographic data of compound 8b for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
28. CCDC contains the supplementary crystallographic data of compound 8g for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
Sample Availability: Samples of the compounds 4a–h, 6a–h and 8a–h are available from the authors.
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