Synthesis of Novel Highly Functionalized
4-Thiazolidinone Derivatives from
4-Phenyl-3-thiosemicarbazones

Abdelmadjid Benmohammed, Omar Khoumeri, Ayada Djafri, Thierry Terme,
Patrice Vanelle

► To cite this version:

Abdelmadjid Benmohammed, Omar Khoumeri, Ayada Djafri, Thierry Terme, Patrice Vanelle. Synthesis of Novel Highly Functionalized 4-Thiazolidinone Derivatives from 4-Phenyl-3-thiosemicarbazones. Molecules, 2014, 19 (3), pp.3068–3083. 10.3390/molecules19033068. hal-01460500

HAL Id: hal-01460500

https://amu.hal.science/hal-01460500

Submitted on 21 Jun 2023

**HAL** is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire **HAL**, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Synthesis of Novel Highly Functionalized 4-Thiazolidinone Derivatives from 4-Phenyl-3-thiosemicarbazones

Abdelmadjid Benmohammed<sup>1,2</sup>, Omar Khoumeri<sup>3</sup>, Ayada Djafri<sup>1</sup>, Thierry Terme<sup>3</sup> and Patrice Vanelle<sup>3,*</sup>

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

<footnote n="1">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.)</footnote>

<footnote n="2">² Département de Sciences et Techniques, Faculté des Sciences & Technologie, Université de Mascara, Mascara 29000, Algeria</footnote>

<footnote n="3">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.)</footnote>

<footnote>* Author to whom correspondence should be addressed; E-Mail: patrice.vanelle@univ-amu.fr; Tel.: +33-4-9183-5580; Fax: +33-4-9179-4677.</footnote>
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).

<figure><img src="image_2.png" /><figcaption>**Scheme 1.** Preparation of 4-phenyl-3-thiosemicarbazide (2).</figcaption></figure>

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.

<figure><img src="image_3.png" /><figcaption>**Scheme 2.** Preparation of 4-phenyl-3-thiosemicarbazones **4a–h**.</figcaption></figure>

The most characteristic signals in the ¹H-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].
<table><caption>**Table 1.** Reaction of **2** with various aromatic aldehydes **3a–h**.</caption><thead><tr><th>Carbonyl compound</th><th>Product</th><th>Product number</th><th>Reaction time (h)</th><th>Yield (%)</th></tr></thead><tbody><tr><td>3a</td><td>4a</td><td>1</td><td></td><td>70</td></tr><tr><td>3b</td><td>4b</td><td>3</td><td></td><td>90</td></tr><tr><td>3c</td><td>4c</td><td>2</td><td></td><td>93</td></tr><tr><td>3d</td><td>4d</td><td>1</td><td></td><td>90</td></tr><tr><td>3e</td><td>4e</td><td>1</td><td></td><td>91</td></tr><tr><td>3f</td><td>4f</td><td>2</td><td></td><td>89</td></tr><tr><td>3g</td><td>4g</td><td>2</td><td></td><td>91</td></tr><tr><td>3h</td><td>4h</td><td>1</td><td></td><td>89</td></tr></tbody></table>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

<figure><img src="image_14.png" /></figure>

<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /></figure>

<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /></figure>
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.

<figure><img src="image_20.png" /><figcaption>**Table 2.** Reactions of **4a–h** with ethyl 2-bromoacetate (5).</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Product</th><th>Product number</th><th>Reaction time (h)</th><th>Yield (%)</th></tr></thead><tbody><tr><td>4a</td><td><img src="image_0_0_0.png" alt="Chemical structure of 4a"></td><td>6a</td><td>1</td><td>91</td></tr><tr><td>4b</td><td><img src="image_0_0_1.png" alt="Chemical structure of 4b"></td><td>6b</td><td>3</td><td>68</td></tr><tr><td>4c</td><td><img src="image_0_0_2.png" alt="Chemical structure of 4c"></td><td>6c</td><td>3</td><td>82</td></tr><tr><td>4d</td><td><img src="image_0_0_3.png" alt="Chemical structure of 4d"></td><td>6d</td><td>2</td><td>86</td></tr><tr><td>4e</td><td><img src="image_0_0_4.png" alt="Chemical structure of 4e"></td><td>6e</td><td>2</td><td>80</td></tr></tbody></table>
<table><caption>**Table 2. Cont.**</caption><thead><tr><th>Compound</th><th>Product</th><th>Product number</th><th>Reaction time (h)</th><th>Yield (%)</th></tr></thead><tbody><tr><td>4f</td><td><img src="image_4f.png" alt="Chemical structure of 4f"></td><td>6f</td><td>3</td><td>89</td></tr><tr><td>4g</td><td><img src="image_4g.png" alt="Chemical structure of 4g"></td><td>6g</td><td>3</td><td>90</td></tr><tr><td>4h</td><td><img src="image_4h.png" alt="Chemical structure of 4h"></td><td>6h</td><td>2</td><td>88</td></tr></tbody></table>

The structures of all new compounds **6a–h** were established by analysis of their IR, ¹H-NMR and ¹³C-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 (NH) protons. On the other hand, the ¹H-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** occurred 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**.
**Scheme 4.** Preparation of **8a–h** with 4-phenyl-3-thiosemicarbazones **4a–h** and diethyl acetylenedicarboxylate.

<figure><img src="image_21.png" /><figcaption>**Table 3.** Reactions of **4a–h** with diethyl acetylenedicarboxylate.</figcaption></figure>

<table><thead><tr><th>Compound</th><th>Product</th><th>Product number</th><th>Yield (%)</th></tr></thead><tbody><tr><td>4a</td><td><img src="image_0_0_0.png" alt="Chemical structure of 4a"></td><td>8a</td><td>73</td></tr><tr><td>4b</td><td><img src="image_0_0_1.png" alt="Chemical structure of 4b"></td><td>8b</td><td>70</td></tr><tr><td>4c</td><td><img src="image_0_0_2.png" alt="Chemical structure of 4c"></td><td>8c</td><td>76</td></tr></tbody></table>
<table><caption>**Table 3. Cont.**</caption><thead><tr><th>Compound</th><th>Product</th><th>Product number</th><th>Yield (%)</th></tr></thead><tbody><tr><td>4d</td><td><img src="image_4d.png" alt="Chemical structure of 4d"></td><td>8d</td><td>74</td></tr><tr><td>4e</td><td><img src="image_4e.png" alt="Chemical structure of 4e"></td><td>8e</td><td>73</td></tr><tr><td>4f</td><td><img src="image_4f.png" alt="Chemical structure of 4f"></td><td>8f</td><td>75</td></tr><tr><td>4g</td><td><img src="image_4g.png" alt="Chemical structure of 4g"></td><td>8g</td><td>70</td></tr><tr><td>4h</td><td><img src="image_4h.png" alt="Chemical structure of 4h"></td><td>8h</td><td>71</td></tr></tbody></table>

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
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><img src="image_22.png" /><figcaption>**Figure 1.** ORTEP plots of **8b** and **8g**.</figcaption></figure>

The chemical structures of the reaction products **8a–h** were confirmed by their IR, $^{1}$H-NMR, $^{13}$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 at 1595–1622 cm$^{-1}$ are due to the C=N groups. The $^{1}$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 COOCH$_{2}$CH$_{3}$ 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, Faculté des Sciences site Saint-Jérome. $^{1}$H-NMR (200 MHz) and $^{13}$C-NMR (50 MHz) spectra were recorded on a Bruker ARX 200 spectrometer in CDCl$_{3}$ or D$_{2}$O at the Service Inter-Universitaire de RMN de la Faculté de Pharmacie de Marseille. The $^{1}$H-NMR chemical shifts were reported as parts per million downfield from tetramethylsilane (Me$_{4}$Si), and the $^{13}$C-NMR chemical shifts were referenced to the solvent peaks: CDCl$_{3}$ (76.9 ppm) or DMSO-d$_{6}$ (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).
### 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 (KBr) $v_{max}/cm^{-1}$: 3316 and 3138 (NH), 1543 (C=N), 1292 (C=S); $^{1}$H-NMR (DMSO-d$_{6}$): 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); $^{13}$C-NMR (DMSO-d$_{6}$): 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 $C_{14}H_{12}N_{4}O_{2}S$: 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 (KBr) $v_{max}/cm^{-1}$: 3316 and 3138 (NH), 1543 (C=N), 1292 (C=S); $^{1}$H-NMR (DMSO-d$_{6}$): 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); $^{13}$C-NMR (DMSO-d$_{6}$): 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 $C_{14}H_{11}N_{5}O_{4}S$: 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) $v_{max}/cm^{-1}$: 3226 and 3151 (NH), 1540 (C=N), 1247 (C=S); $^{1}$H-NMR (CDCl$_{3}$): 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); $^{13}$C-NMR (CDCl$_{3}$): 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 $C_{16}H_{14}N_{4}O_{2}S$: 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 solid; mp: 231 °C; IR (KBr) $v_{max}/cm^{-1}$: 3302 and 3283 (NH), 1547 (C=N), 1268 (C=S); $^{1}$H-NMR (DMSO-d$_{6}$): 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, 1H, *J* = 7.2 Hz, *J* = 1.2 Hz, Ar-H), 6.25 (s, 2H, CH$_{2}$); $^{13}$C-NMR (DMSO-d$_{6}$): 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 (CH$_{2}$); Anal. Calcd for $C_{15}H_{12}N_{4}O_{4}S$: 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 solid; mp: 161 °C; IR (KBr) $v_{max}/cm^{-1}$: 3291 and 3134 (NH), 1557 (C=N), 1262 (C=S); $^{1}$H-NMR (CDCl$_{3}$):
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 (s, 3H, OCH<sub>3</sub>), 3.91 (s, 6H, OCH<sub>3</sub>); <sup>13</sup>C-NMR (CDCl<sub>3</sub>): 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 (CH<sub>3</sub>), 56.3 (2CH<sub>3</sub>); Anal. Calcd for C<sub>17</sub>H<sub>19</sub>N<sub>3</sub>O<sub>3</sub>S: 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; IR (KBr) v<sub>max</sub>/cm<sup>-1</sup>: 3325 and 3150 (NH), 1542 (C=N), 1267 (C=S); <sup>1</sup>H-NMR (DMSO-d<sub>6</sub>): 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, CH<sub>3</sub>); <sup>13</sup>C-NMR (DMSO-d<sub>6</sub>): δ 177.0 (C), 141.7 (CH), 141.2 (CH), 139.44 (2C), 128.7 (2CH), 128.6 (2CH), 127.7 (2CH), 126.7 (2CH), 126.10 (CH), 43.9 (CH<sub>3</sub>); Anal. Calcd for C<sub>15</sub>H<sub>15</sub>N<sub>3</sub>O<sub>2</sub>S<sub>2</sub>: 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 (KBr) v<sub>max</sub>/cm<sup>-1</sup>: 3343 and 3152 (NH), 1541 (C=N), 1271 (C=S); <sup>1</sup>H-NMR (CDCl<sub>3</sub>): 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, *J* = 7.3 Hz, Ar-H), <sup>13</sup>C-NMR (DMSO-d<sub>6</sub>): 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 (CH<sub>3</sub>); Anal. Calcd for C<sub>15</sub>H<sub>15</sub>N<sub>3</sub>O<sub>2</sub>S<sub>2</sub>: 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) v<sub>max</sub>/cm<sup>-1</sup>: 3350 and 3138 (NH), 1542 (C=N), 1267 (C=S); <sup>1</sup>H-NMR (CDCl<sub>3</sub>): 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 (m, 4H, Ar-H), 7.43 (d, 2H, *J* = 7.4 Hz, Ar-H), 7.29 (t, 1H, *J* = 7.3 Hz, Ar-H); <sup>13</sup>C-NMR (CDCl<sub>3</sub>): 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 C<sub>15</sub>H<sub>12</sub>F<sub>3</sub>N<sub>3</sub>S: 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 (KBr) v<sub>max</sub>/cm<sup>-1</sup>: 1716 (C=O), 1662 (C=N); <sup>1</sup>H-NMR (CDCl<sub>3</sub>): δ 8.34 (s, 1H, CH=N), 8.25 (d, 2H,
$J = 8.8$ 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, $CH_2$); $^{13}$C-NMR (CDCl₃): $\delta$ 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 $C_{16}H_{12}N_4O_3S$: 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 (KBr) $v_{max}/cm^{-1}$: 1731 (C=O), 1592 (C=N); $^{1}$H-NMR (DMSO-d₆): $\delta$ 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, $CH_2$); $^{13}$C-NMR (DMSO-d₆): $\delta$ 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 ($CH_2$); Anal. Calcd for $C_{16}H_{11}N_5O_5S$: 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) $v_{max}/cm^{-1}$: 1732 (C=O), 1627 (C=N); $^{1}$H-NMR (CDCl₃): $\delta$ 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), 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, $CH_2$); $^{13}$C-NMR (CDCl₃): $\delta$ 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 ($CH_2$); Anal. Calcd for $C_{18}H_{14}N_4O_3S$: 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 solid; mp: 262 °C; IR (KBr) $v_{max}/cm^{-1}$: 1717 (C=O), 1602 (C=N); $^{1}$H-NMR (DMSO-d₆): $\delta$ 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, Ar-H), 6.27 (s, 2H, $CH_2$), 4.10 (s, 2H, $CH_2$); $^{13}$C-NMR (DMSO-d₆): $\delta$ 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 ($CH_2$), 32.9 ($CH_2$); Anal. Calcd for $C_{17}H_{12}N_4O_5S$: 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) $v_{max}/cm^{-1}$: 1720 (C=O), 1619 (C=N); $^{1}$H-NMR (DMSO-d₆): $\delta$ 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, $CH_2$), 3.78 (s, 6H, $OCH_3$), 3.70 (s, 3H, $OCH_3$); $^{13}$C-NMR (DMSO-d₆): $\delta$ 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 ($CH_3$), 56.3 (2$CH_3$), 32.7 ($CH_2$); Anal. Calcd for $C_{19}H_{19}N_3O_4S$: 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: 277 °C; IR (KBr) $v_{max}/cm^{-1}$: 1734 (C=O), 1615 (C=N); $^{1}$H-NMR (DMSO-d₆): $\delta$ 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 (m, 2H, Ar-H), 4.12 (s, 2H, $CH_2$), 3.22 (s, 3H, $CH_3$); $^{13}$C-NMR (DMSO-d₆): $\delta$ 172.5 (C), 167.8 (C),
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) vmax/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), 3.97 (s, 2H, CH₂), 2.50 (s, 3H, CH₃); ¹³C-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: 206 °C; IR (KBr) vmax/cm⁻¹: 1732 (C=O), 1616 (C=N); ¹H-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 (m, 2H, Ar-H), 3.99 (s, 2H, CH₂); ¹³C-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): yellow solid; mp: 206 °C; IR (KBr) vmax/cm⁻¹: 1730 (C=O), 1692 (C=O), 1623 (C=N); ¹H-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): yellow solid; mp: 193 °C; IR (KBr) vmax/cm⁻¹: 1727 (C=O), 1698 (C=O), 1620 (C=N); ¹H-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),
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) vmax/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, *J* = 7.1 Hz, CH₃); ¹³C-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) vmax/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, *J* = 7.1 Hz, CH₃); ¹³C-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) vmax/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, *J* = 7.0 Hz, CH₃); ¹³C-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) vmax/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) vmax/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,
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) vmax/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, *J* = 7.1 Hz, CH₃); ¹³C-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.

**References and Notes**

1. Pirrung, M.C.; Pansare, S.V.; das Sarma, K.; Keith, K.A.; Kern, E.R. Combinatorial optimization of isatin-β-thiosemicarbazones as anti-poxvirus agents. *J. Med. Chem.* **2005**, *48*, 3045–3050.

2. Hu, W.-X.; Zhou, W.; Xia, C.-N.; Wen, X. Synthesis and anticancer activity of thiosemicarbazones. *Bioorg. Med. Chem. Lett.* **2006**, *16*, 2213–2218.
3. Kolocouris, A.; Dimas, K.; Pannecouque, C.; Witvrouw, M.; Foscolos, G.B.; Stamatiou, G.; Fytas, G.; Zoidis, G.; Kolocouris, N.; Andrei, G.; et al. New 2-(1-adamantylcarbonyl) pyridine and 1-acetyladamantane thiosemicarbazones-thiocarbonohydrazones: Cell growth inhibitory, antiviral and antimicrobial activity evaluation. *Bioorg. Med. Chem. Lett.* **2002**, *12*, 723-727.

4. Tarasconi, P.; Capacchi, S.; Pelosi, G.; Cornia, M.; Albertini, R.; Bonati, A.; Dall'Aglio, P.P.; Lunghi, P.; Pinelli, S. Synthesis, spectroscopic characterization and biological properties of new natural aldehydes thiosemicarbazones. *Bioorg. Med. Chem.* **2000**, *88*, 157.

5. Pérez-Rebolledo, A.; Teixeira, L.R.; Batista, A.A.; Mangrich, A.S.; Aguirre, G.; Cerceretto, H.; González, M.; Hernández, P.; Ferreira, A.M.; Speziali, N.L.; et al. 4-Nitroacetophenone-derived thiosemicarbazones and their copper (II) complexes with significant *in vitro* anti-trypanosomal activity. *Eur. J. Med. Chem.* **2008**, *43*, 939-948.

6. Aguirre, G.; Boiani, L.; Cerecetto, H.; Fernández, M.; González, M.; Denicola, A.; Otero, L.; Gambino, D.; Rigol, C.; Olea-Azar, C.; et al. *In vitro* activity and mechanism of action against the protozoan parasite *Trypanosoma cruzi* of 5-nitrofuryl containing thiosemicarbazones. *Bioorg. Med. Chem.* **2004**, *12*, 4885-4893.

7. Du, X.; Guo, C.; Hansell, E.; Doyle, P.S.; Caffrey, C.R.; Holler, T.P.; McKerrow, J.H.; Cohen, E. Synthesis and structure-activity relationship study of potent trypanocidal thio- semicarbazone inhibitors of the trypanosomal cysteine protease cruzain. *J. Med. Chem.* **2002**, *45*, 2695-2707.

8. De Aquino, T.M.; Liesen, A.P.; da Silva, R.E.A.; Lima, V.T.; Carvalho, C.S.; de Faria, A.R.; de Araujo, J.M.; de Lima, J.G.; Alves, A.J.; de Melo, E.J.T.; et al. Synthesis, anti-*Toxoplasma-gondii* and antimicrobial activities of benzaldehyde 4-phenyl-3-thiosemicarbazones and 2-[(phenymethylene) hydrazono]-4-oxo-3-phenyl-5-thiazolidine acetic acids. *Bioorg. Med. Chem.* **2008**, *16*, 446-456.

9. Mayekar, S.A.; Mulwad, V.V. Synthesis and antibacterial activity of 6-(5phenyl-{1,3,4} thiadiazol-2-ylimino)-benzopyran-2-ones. *Ind. J. Chem.* **2008**, *47*, 1438-1442.

10. Omar, K.; Geronikaki, A.; Zoumpoulakis, P.; Camoutsis, C.; Sokovic, M.; Ciric, A.; Glamoclija, J.; Novel 4- thiazolidinone derivatives as potential antifungal and antibacterial drugs. *Bioorg. Med. Chem.* **2010**, *18*, 426-432.

11. Bhat, M.A.; Siddiqui, N.; Khan, S.A. Synthesis, anticonvulsant and neurotoxicity screening of 2-(substituted phenyl)-3-[3-(2-oxo-2H-chromen-3-yl)-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,3-thiazolidin-4-ones. *Ind. J. Het. Chem.* **2008**, *17*, 287-288.

12. Babaoglu, K.; Page, M.A.; Jones, V.C.; McNeil, M.R.; Dong, C.; Naismith, J.H.; Lee, R.E. Novel inhibitors of an emerging target in mycobacterium tuberculosis; substituted thiazolidinones as inhibitors of dTDP-rhamnose synthesis. *Bioorg. Med. Chem. Lett.* **2003**, *13*, 3227-3230.

13. Vigorita, M.G.; Ottanà, R.; Monforte, F.; Maccari, R.; Monforte, M.T.; Trovato, A.; Taviano, M.F.; Miceli, N.; de Luca, G.; Alcaro, S.; et al. Chiral 3,3'-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] with anti-inflammatory activity. Part 11: Evaluation of COX-2 selectivity and modeling. *Bioorg. Med. Chem.* **2003**, *11*, 999-1006.

14. Agrawal, V.K.; Sachan, S.; Khadikar, P.V. QSAR studies on antihistaminic activity of some thiazolidine-4-ones. *Acta Pharm.* **2000**, *50*, 281-290.

15. Diurno, M.V.; Mazzoni, O.; Correale, G.; Monterrey, I.G.; Calignano, A.; la Rana, G.; Bolognese, A. Synthesis and structure-activity relationships of 2-(substituted phenyl)-3-[3-(N,N-dimethylamino)-propyl]-1,3-thiazolidin-4-ones acting as H1-histamine antagonists. *Farmaco* **1999**, *54*, 579-583.
16. Suzuki, Y.; Akima, M.; Tamura, K. Effects of CP-060S, a novel cardioprotective drug, on cardiac function and myocardial oxygen consumption. *Gen. Pharmacol.* **1999**, *32*, 57–63.

17. Rawal, R.K.; Prabhakar, Y.S.; Katti, S.B.; de Clercq, E. 2-(Aryl)-3-furan-2-ylmethyl-thiazolidin-4-ones as selective HIV-RT inhibitors. *Bioorg. Med. Chem.* **2005**, *13*, 6771–6776.

18. Crozet, M.P.; Archaimbault, G.; Vanelle, P.; Nouguier, R. Reaction $S_{RN1}$ en serie heterocyclique: Reactivite des sels du dimethyl-2,2-nitro-5-dioxane-1,3. *Tetrahedron Lett.* **1985**, *26*, 5133–5134.

19. Amiri-Attou, O.; Terme, T.; Vanelle, P. Functionalization of 6-nitrobenzo[1,3]dioxole with carbonyl compounds via TDAE methodology. *Molecules* **2005**, *10*, 545–551.

20. Verhaeghe, P.; Azas, N.; Hutter, S.; Castera-Ducros, C.; Laget, M.; Dumètre, A.; Gasquet, M.; Reboul, J.P.; Rault, S.; Rathelot, P.; et al. Synthesis and *in vitro* antiplasmodial evaluation of 4-anilino-2-trichloromethylquinazolines. *Bioorg. Med. Chem.* **2009**, *17*, 4313–4322.

21. Crozet, M.D.; Botta, C.; Gasquet, M.; Curti, C.; Remusat, V.; Hutter, S.; Chapelle, O.; Azas, N.; de Méo, M.; Vanelle, P. Lowering of 5-nitroimidazole's mutagenicity: Towards optimal antiparasitic pharmacophore. *Eur. J. Med. Chem.* **2009**, *44*, 653–659.

22. Kabri, Y.; Azas, N.; Dumètre, A.; Hutter, S.; Laget, M.; Verhaeghe, P.; Gellis, A.; Vanelle, P. Original quinazoline derivatives displaying antiplasmodial properties. *Eur. J. Med. Chem.* **2010**, *45*, 616–622.

23. Huang, H.; Chen, Q.; Ku, X.; Meng, L.; Lin, L.; Wang, X.; Zhu, C.; Wang, Y.; Chen, Z.; Li, M.; et al. A series of α-heterocyclic carboxaldehyde thiosemicarbazones inhibit topoisomerase IIα catalytic activity. *J. Med. Chem.* **2010**, *53*, 3048–3064.

24. Serda, M.; Malecki, J.G.; Mrozek-Wilczkiewicz, A.; Musiol, R.; Polanski, J. Microwave assisted synthesis, X-ray crystallography and DFT calculations of selected aromatic thiosemicarbazones. *J. Mol. Struct.* **2013**, *1037*, 63–72.

25. Küçügüzel, G.; Kocayepe, A.; de Clercq, E.; Sahin, F.; Güllüce, M. Synthesis and biological activity of 4-thiazolidinones, thiosemicarbazides derived from diflunisal hydrazide. *Eur. J. Med. Chem.* **2006**, *41*, 353–359.

26. Vas'kevich, R.I.; Zborovskii, Y.L.; Staninets, V.I.; Chernega, A.N. Reaction of 4-Aryl-1-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thiosemicarbazides with Dimethyl Acetylenedicarboxylate. *Russ. J. Org. Chem.* **2004**, *40*, 1047–1052.

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.