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

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.


Scheme 2. Preparation of 4-phenyl-3-thiosemicarbazones 4a-h.
The most characteristic signals in the 1 H-NMR spectrum of this family of thiosemicarbazones were those corresponding to the CH=N and N-H protons. 1 H-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 1 H-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]. 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.
The structures of all new compounds 6a-h were established by analysis of their IR, 1 H-NMR and 13 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 1 H-NMR spectra, where it did not display signs of the 4-phenyl-3-thiosemicarbazone (NH) protons. On the other hand, the 1 H-NMR spectra exhibited resonances assigned to the SCH 2 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. Scheme 4. Preparation of 8a-h with 4-phenyl-3-thiosemicarbazones 4a-h and diethyl acetylenedicarboxylate.  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, 1 H-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. 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.

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).

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.

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).

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.