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Short Note

Synthesis and Characterization of Novel Thiazolidinones and Thioxothiazolidinones Derived from Substituted Indole

by
Nawel Rekiba
1,2,
Abdelmadjid Benmohammed
1,3,
Sofiane Khanoussi
1,
Ayada Djafri
1 and
Jérôme Thibonnet
4,*
1
Laboratoire de Synthèse Organique Appliquée (LSOA), Department of Chemistry, Faculté des Sciences Exactes et Appliquées, Université Oran1 Ahmed Ben Bella, BP 1524 El M’Naouer, Oran 31000, Algeria
2
Hôpital Militaire Régional Universitaire d’Oran Dr. Amir Mohamed Benaissa, BP 35 Ahmed Medeghri, Oran 31000, Algeria
3
Department of Chemistry, Faculty of Exact Sciences, University of Mascara, Mascara 29000, Algeria
4
Laboratoire Synthèse et Isolement de Molécules BioActives (SIMBA, EA7502), Faculté des Sciences et Techniques, Université de Tours, Parc de Grandmont, 32 Av. Monge, 37200 Tours, France
*
Author to whom correspondence should be addressed.
Molbank 2021, 2021(4), M1284; https://doi.org/10.3390/M1284
Submission received: 24 August 2021 / Revised: 24 September 2021 / Accepted: 27 September 2021 / Published: 30 September 2021
Browse Figures
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Abstract

:
Based on recent discoveries concerning the numerous biological properties of thiazolidinones and thiosemicarbazones, new N-substituted heterocyclic derivatives have been designed by combining the indole ring with thioxothiazolidinone, thiazolidinone or thiosemicarbazone. Thus, a series of new thioxothiazolidinone, thiazolidinone, or thiosemicarbazone derivatives bearing indole-based moiety have been designed, synthesized, and developed in good yields.

Graphical Abstract

1. Introduction

The indolic nucleus is a heteroaromatic organic compound that is highly common in nature. This structural unit is present in many bioactive molecules, whether natural or synthetic. Indoles are an important class of heterocyclic compounds, and this kind of structure has been revealed to have antimicrobial [1,2], antifungal [3], anti-inflammatory and analgesic [4,5,6], anticonvulsant [7], anticancer [8,9], and anti-malarial properties [10]. The 4-thiazolidinone derivatives are one of the heterocyclic types which play an important role in therapeutical chemistry, due to their variety in biological activity, as antiviral [11], anti-inflammatory [12], anticancer [13], antimicrobial [14,15], antidiabetic [16], antioxidant [17], anti-HIV agents [18]. Moreover, the 5-arylidene-2-thioxothiazolidin-4-one or 5-arylidenerhodanine derivatives represent particularly privileged moieties in drug discovery because of their inherent tendency for biological activity [19,20,21]. For example, it was reported that the incorporation of indolyl moiety as in N′-[(1H-indol-3-yl)methylene]-isonicotinohydrazide derivative showed excellent to good anti-tubercular activity (compound I, Figure 1) [22]. Compound II displayed potent broad-spectrum antibacterial and antifungal activities [15]. Moreover, benzyl-1H-indole derivatives (indibulin III) also possess prominent antitumor activity, for example, acting as a novel synthetic microtubule inhibitor [23].
A new series of thiosemicarbazones 5a–e was prepared by the reaction of substituted indole-3-carbaldehyde 3a–e on 4-chlorophenylthiosemicarbazide in ethanol, with acetic acid as a catalyst. Substituted thiazolidinones compounds 7a–e were prepared by a cycling reaction in ethanol with sodium acetate. The arylidenerhodanines 10a–e were also prepared by condensation reactions of 2-thioxothiazolidin-4-one on several substituted indole-3-carbaldehyde compounds. In the previous work [24], we synthesized new indole derivatives of potential biological interest. The biological activity of this kind of compound will be interesting for further work. The synthesis of the target compounds (A, B, or C series) was carried out as outlined in Scheme 1. The spectral data and elemental analysis results of the synthesized compounds were in agreement with the proposed structures.

2. Results and Discussion

2.1. Synthesis of N-Benzylindole-3-carboaldehyde Derivatives

Substituted N-benzylindole-3-carboxaldehyde derivatives 3a–e were prepared with 90–95% yield by the reaction of the indole-3-carboxaldehyde 1 with various substituted benzyl halides 2a–e with K2CO3 as a base, in N,N-dimethylformamide (DMF) (Scheme 2) [25]. The structures of the synthesized compounds 3a–e were confirmed by their 1H-NMR and 13C-NMR spectral data. The 1H-NMR spectrum of compounds 3a–e shows characteristic signals near δ 5.70 and 10.00 assignable to CH2 and CHO. Further confirmation was achieved by the 13C-NMR spectrum, which showed signals at δ 49.78 and 185.0 due to CH2 and CHO, respectively (see Supporting Information).

2.2. Synthesis of Thiosemicarbazones

The reaction of 4-(4-chlorophenyl)-3-thiosemicarbazide 4 with indole-3-carbaldehyde derivatives 3a–e with a few drops of acetic acid, stirred for 3 h at 80 °C, lead to the corresponding 4-(4-chlorophenyl)-3-thiosemicarbazone derivatives 5a–e in good yields (Scheme 3). In the 1H-RMN spectrum, the most characteristic signals of thiosemicarbazones 5a–e correspond to the CH=N and the N–H protons. The 1H-RMN studies show that the N–H protons of thiosemicarbazones 5a–e are in the range of 9.62 to 11.68 ppm for the N–H adjacent to the mono-substituted phenyl ring and for the N–H adjacent to the CH=N fraction, while CH=N protons are in the range of 8.41 to 8.53 ppm. All synthesized compounds are in the E configuration, which was confirmed by the 1H-RMN spectroscopy, because the NH group signal is in the range of 9 to 12 ppm, compared to the Z isomer, which has a characteristic signal between 14 and 15 ppm [26,27].

2.3. Synthesis of Thiazolidin-4-One Derivatives

The resulting thiosemicarbazones 5a–e were cyclized with ethyl bromoacetate in ethanol and sodium acetate under reflux for 3 h to give 1,3-thiazolidin-4-one derivatives 7a–e, and final products were obtained in good yield (85–94%) (Scheme 4). The structures of new compounds 7a–e were defined by their 1H-NMR and 13C-NMR data. The 1H-NMR spectra present resonances assigned to the SCH2 group of the thiazolidine ring, and this signal appears as a singlet at 4.08 ppm due to the methylene protons. The CH=N protons in these kinds of structures were observed at 8.45 and 8.46 ppm.
At the final step for the synthesis of products 10a–e, the 2-thioxothiazolidin-4-one 9 has undergone a condensation with indole-3-carbaldehydes 3a–e. The interaction was realized in boiling alcohol with piperidine as a base, and final products were obtained with moderate to good yields (85–73%) (Scheme 5).
In the 1H-NMR spectrum, a large singlet at δ = 13.57 ppm was assigned to the –NH group, and the 13C-NMR spectrum showed signals at δ = 169.1 and 194.6 ppm assigned to the (C=O) and (C=S) functionalities for the compound 10a. The arylidenerhodanines synthesis 10a–e leads to two isomers, Z and E. Z-isomers are predominant (Z > 75%) and thermodynamically more stable [26,27]. The exocyclic C=CH double bond configuration can be determined by NMR spectroscopy. The Z-configuration of the 5-arylidene 10a–e derivatives was confirmed by the signal for the C=CH methine proton with a higher chemical shift between 7.90 and 7.95 ppm in a singlet form [28,29,30,31,32,33].

3. Materials and Methods

3.1. General Information

The reagents were purchased from commercial suppliers and used without further purification. Melting points were determined on Büchi B-540 apparatus and are uncorrected. All solvents were dried following the procedure described by Armarego and Chai [34]. 1H-NMR and 13C-NMR spectra were recorded on a Bruker Avance 300 MHz at 300 and 75 MHz, respectively. 1H-NMR spectra were recorded in CDCl3 referenced to the residual CHCl3 at 7.26 ppm, and 13C-NMR spectra were referenced to the central peak of CDCl3 at 77.0 ppm. 19F-NMR was recorded at 282 MHz on the same instrument, using the CFCl3 as internal reference (δ 0.0). Chemical shifts were reported in parts per million (ppm, δ), and coupling constants (J) were given in Hertz (Hz). Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; dd, doublet of doublets; dq, doublet of quartets; m, multiplet. High-resolution mass spectra (HRMS) were obtained by electrospray ionization time-of-flight (ESI) mass spectrometry. Thin-layer chromatography (TLC) was performed on TLC silica gel 60 F254. Compounds were visualized with UV light (λ = 254 nm) and/or by immersion in a KMnO4 solution followed by heating. Products were purified by flash column chromatography on silica gel (0.04–0.063 mm) using various mixtures of EtOAc and petroleum ether (35–60 °C fraction) as eluent. Heating was performed using a magnetic stirrer hotplate and an appropriately sized heating block. The compound names follow the IUPAC recommendations.

3.2. Experimental Section

3.2.1. General Procedure for the Synthesis of 1-Substituted-1H-indole-3-carbaldehydes (3a–e) (35)

1-Substituted-1H-indole-3-carbaldehyde was synthesized by reaction of 1H-indole-3-carbaldehyde 1 (1.45 g, 0.01 mol), the corresponding benzyl chloride 2a–e (0.011 mol), and anhydrous K2CO3 (2.76 g, 0.02 mol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred at 90 °C for 6 h, and the reaction was monitored by thin-layer chromatography. The reaction was stopped and cooled at room temperature, and the mixture was poured into ice-cold water. The resulting precipitate was collected by filtration and washed with water. The crude product was purified by recrystallization from ethanol and dried under vacuum to give the desired compounds (3a–e).
1-Benzyl-1H-indole-3-carbaldehyde (3a): White solid, 90%, 2.21 g. mp 107–109 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.99 (s, 1H, CHO), 8.36–8.32 (m, 1H, indole C7-H), 7.69 (s, 1H, indole C2-H), 7.36–7.29 (m, 6H), 7.21–7.15 (m, 2H), 5.34 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, CDCl3): δ = 184.7 (CHO), 138.6 (indole C2), 137.5 (Cquat), 135.4 (Cquat), 129.2 (2 CH), 128.5 (CH), 127.3 (2 CH), 125.6 (Cquat), 124.3 (CH), 123.1 (CH), 122.2 (CH), 118.6 (Cquat), 110.5 (indole C7), 51.0 (CH2) ppm.
1-(4-Fluorobenzyl)-1H-indole-3-carbaldehyde (3b): White solid, 93%, 2.35 g. mp 117–119 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.98 (s, 1H, CHO), 8.35–8.30 (m, 1H, indole C7-H), 7.69 (s, 1H, indole C2-H), 7.36–7.29 (m, 3H, indole C4-H, C5-H and C6-H), 7.18–7.14 (m, 2H, 2H phenyl), 7.03 (t, J = 8.6 Hz, 2H, 2H phenyl), 5.32 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, CDCl3): δ = 184.8 (CHO), 138.5 (indole C2), 137.4 (Cquat), 136.6 (Cquat), 131.6 (q, J = 32.5 Hz, Cquat), 130.4 (q, J = 1.1 Hz, CH), 129.9 (CH), 125.6 (Cquat), 125.4 (q, J = 3.7 Hz, CH), 124.6 (CH), 123.9 (q, J = 3.8 Hz, CH), 123.8 (q, J = 272 Hz, Cquat), 123.4 (CH), 122.4 (CH), 118.9 (Cquat), 110.3 (indole C7), 50.5 (CH2) ppm.
1-(4-(Trifluoromethyl)benzyl)-1H-indole-3-carbaldehyde (3c): White solid, 94%, 2.85 g. mp 133–13509 °C. 1H-NMR (300 MHz, CDCl3): δ = 10.02 (s, 1H, CHO), 8.37–8.32 (m, 1H, indole C7-H), 7.74 (s, 1H, indole C2-H), 7.60 (d, J = 7.8 Hz, 2H, 2H phenyl), 7.51 (bs, 1H, 1H phenyl), 7.46 (t, J = 7.8 Hz, 1H, 1H phenyl), 7.37–7.26 (m, 4H, C4-H, C5-H, C6-H and 1H phenyl), 5.43 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, CDCl3): δ = 184.7 (CHO), 138.6 (indole C2), 137.5 (Cquat), 135.4 (Cquat), 129.2 (2 CH), 128.5 (CH), 127.3 (2 CH), 125.6 (Cquat), 124.3 (CH), 123.1 (CH), 122.2 (CH), 118.6 (Cquat), 110.5 (indole C7), 51.0 (CH2) ppm.
1-(3-Chlorobenzyl)-1H-indole-3-carbaldehyde (3d): White solid, 93%, 2.50 g. mp 79–81 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.99 (s, 1H, CHO), 8.36–8.31 (m, 1H, indole C7-H), 7.72 (s, 1H, indole C2-H), 7.36–7.25 (m, 5H, indole C4-H, C5-H, C6-H, 2H phenyl), 7.17 (bs, 1H, 1H phenyl), 7.04–7.00 (m, 1H, 1H phenyl), 5.32 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, CDCl3): δ = 184.8 (CHO), 138.6 (indole C2), 137.5 (Cquat), 137.4 (Cquat), 135.1 (Cquat), 130.5 (CH), 128.7 (CH), 127.3 (CH), 125.5 (Cquat), 125.3 (CH), 124.5 (CH), 123.3 (CH), 122.3 (CH), 118.7 (Cquat), 110.4 (indole C7), 50.4 (CH2) ppm.
2-((3-Formyl-1H-indol-1-yl)methyl)benzonitrile (3e): White solid, 94%, 2.44 g. mp 133–135 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.99 (s, 1H, CHO), 8.45 (s, 1H, indole C2-H), 8.18 (d, J = 8 Hz, 1H, indole C4-H), 7.97 (d, 1H, J = 8 Hz, 1H, indole C7-H), 7.67 (1H, td, J = 1.4 Hz, J = 7.7 Hz, Ar-H), 7.60–7.52 (m, 2H, Ar-H), 7.35–7.25 (m, 2H, Ar-H), 7.07 (1H, d, J = 7.58 Hz, Ar-H), 5.83 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, CDCl3): δ = 185.0 (CHO), 141.2 (indole C2), 140.0 (Cquat), 137.1 (Cquat), 133.8 (CH), 133.5 (CH), 128.7 (CH), 127.8 (CH), 124.7 (CH), 123.9 (CH), 122.8 (CH), 121.2 (CH), 117.7 (Cquat), 117.2 (Cquat), 111.1 (Cquat), 110.4 (CH), 48.2 (CH2) ppm.

3.2.2. General Procedure for the Synthesis of Thiosemicarbazones (5a–e) (35)

To a solution of 4-chlorophenylthiosemicarbazide 4 (0.605 g, 3 mmol, 1 equiv) in ethanol (33 mL) were added the 1-substituted-1H-indole-3-carbaldehyde (6.3 mmol, 1.05 equiv) and acetic acid (0.50 mL). The mixture was stirred and heated under reflux for 3 h. The reaction was stopped and cooled to room temperature. After, the solid was filtered and recrystallized from ethanol-DMF (3:1) to give compounds 5a–e.
(E)-2-((1-Benzyl-1H-indol-3-yl)methylene)-N-(4-chlorophenyl)hydrazine-1-carbothioamide (5a): Beige solid, 93%, 0.97 g. mp 203–205 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 11.68 (bs, 1H, NH), 9.68 (bs, 1H, NH), 8.41 (s, 1H, indole C2-H), 8.26 (d, 1H, J = 7.3 Hz, Ar-H), 8.10 (s, 1H, CH=N), 7.68 (d, 2H, J = 8.7 Hz, Ar-H), 7.52 (d, 1H, J = 7.6 Hz, Ar-H), 7.42 (d, 2H, J = 8.7 Hz, Ar-H), 7.36–7.14 (m, 7H, Ar-H), 5.47 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 174.5 (CS), 141.0 (CH), 138.3 (Cquat), 137.4 (Cquat), 136.9 (Cquat), 134.3 (CH), 128.9 (Cquat), 128.6 (2CH), 127.9 (2CH), 127.6 (CH), 127.1 (2CH), 126.9 (2CH), 124.7 (Cquat), 122.9 (CH), 122.2 (CH), 121.1 (CH), 110.7 (CH), 110.6 (Cquat), 49.4 (CH2) ppm. HRMS (ESI): calcd. for C23H20ClN4S [M + H]+ 419.10972; found 419.10981.
(E)-N-(4-Chlorophenyl)-2-((1-(4-fluorobenzyl)-1H-indol-3-yl)methylene)hydrazine-1-carbothioamide (5b): Beige solid, 92%, 0.97 g. mp 211–213 °C. 1H-NMR (300 MHz, Acetone-d6): δ = 10.5 (bs, 1H, NH), 9.62 (bs, 1H, NH), 8.51 (s, 1H, indole C2-H), 8.28 (dd, 1H, J = 7.1 Hz, J = 1.3 Hz, Ar-H), 7.96 (s, 1H, CH=N), 7.90–7.83 (m, 2H, Ar-H), 7.51 (d, 1H, J = 7.4 Hz, Ar-H), 7.40 (d, 2H, J = 8.8 Hz, Ar-H), 7.37–7.31 (m, 2H, Ar-H), 7.29–7.18 (m, 2H, Ar-H), 7.11 (t, 2H, J = 8.8 Hz, Ar-H), 5.53 (s, 2H, PhCH2) ppm. 19F-NMR (282 MHz, DMSO-d6): δ = −116.3 ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 174.5 (CS), 161.5 (d, J = 244 Hz, Cquat), 140.9 (CH), 138.3 (Cquat), 136.8 (Cquat), 134.2 (CH), 133.6 (d, J = 3.1 Hz, Cquat), 129.3 (d, J = 3.2 Hz, 2CH), 128.9 (Cquat), 127.9 (2CH), 126.8 (2CH), 124.8 (Cquat), 122.9 (CH), 122.3 (CH), 121.1 (CH), 115.4 (d, J = 21.6 Hz, 2CH), 110.7 (Cquat), 110.6 (CH), 48.6 (CH2) ppm. HRMS (ESI): calcd. for C23H19ClFN4S [M + H]+ 437.10030; found 437.10029.
(E)-N-(4-Chlorophenyl)-2-((1-(3-(trifluoromethyl)benzyl)-1H-indol-3-yl)methylene)hydrazine-1-carbothioamide (5c): White solid, 89%, 1.00 g. mp 224–226 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 11.68 (bs, 1H, NH), 9.69 (bs, 1H, NH), 8.42 (s, 1H, indole C2-H), 8.28 (d, 1H, J = 7.1 Hz, Ar-H), 8.12 (s, 1H, CH=N), 7.67 (d, 2H, J = 8.7 Hz, Ar-H), 7.54 (d, 1H, J = 7.7 Hz, Ar-H), 7.42 (d, 2H, J = 8.7 Hz, Ar-H), 7.38–7.32 (m, 3H, Ar-H), 7.27–7.15 (m, 3H, Ar-H), 5.49 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 174.6 (CS), 140.9 (CH), 138.9 (Cquat), 138.3 (Cquat), 136.8 (Cquat), 134.3 (CH), 131.2 (CH), 129.8 (CH), 129.3 (q, J = 31.7 Hz, Cquat), 128.9 (Cquat), 127.9 (2CH), 126.9 (2CH), 124.7 (Cquat), 124.4 (q, J = 3.6 Hz, CH), 124.0 (q, J = 272 Hz, Cquat), 123.7 (q, J = 3.8 Hz, CH), 123.1 (CH), 122.4 (CH), 121.2 (CH), 110.9 (Cquat), 110.5 (CH), 48.7 (CH2) ppm. HRMS (ESI): calcd. for C24H19ClF3N4S [M + H]+ 487.09710; found 487.09720.
(E)-2-((1-(3-Chlorobenzyl)-1H-indol-3-yl)methylene)-N-(4-chlorophenyl)hydrazine-1-carbothioamide (5d): Beige solid, 93%, 0.97 g. mp 203–205 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 11.68 (bs, 1H, NH), 9.68 (bs, 1H, NH), 8.41 (s, 1H, indole C2-H), 8.26 (d, 1H, J = 7.3 Hz, Ar-H), 8.10 (s, 1H, CH=N), 7.68 (d, 2H, J = 8.7 Hz, Ar-H), 7.52 (d, 1H, J = 7.6 Hz, Ar-H), 7.42 (d, 2H, J = 8.7 Hz, Ar-H), 7.36–7.14 (m, 7H, Ar-H), 5.47 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 174.6 (CS), 140.9 (CH), 139.9 (Cquat), 138.3 (Cquat), 136.8 (Cquat), 134.3 (CH), 133.2 (Cquat), 130.6 (CH), 128.9 (Cquat), 127.9 (2CH), 127.6 (CH), 127.0 (CH), 126.9 (2CH), 125.8 (CH), 124.7 (Cquat), 123.1 (CH), 122.3 (CH), 121.2 (CH), 110.8 (Cquat), 110.6 (CH), 48.7 (CH2) ppm. HRMS (ESI): calcd. for C23H19Cl2N4S [M + H]+ 453.07075; found 453.07083.
(E)-N-(4-Chlorophenyl)-2-((1-(2-cyanobenzyl)-1H-indol-3-yl)methylene)hydrazine-1-carbothioamide (5e): Beige solid, 89%, 1.00 g. mp 229–231 °C. 1H-NMR (300 MHz, Acetone-d6): δ = 10.56 (bs, 1H, NH), 9.64 (bs, 1H, NH), 8.53 (s, 1H, indole C2-H), 8.31 (d, 1H, J = 7.2 Hz, Ar-H), 7.99 (s, 1H, CH=N), 7.90–7.82 (m, 3H, Ar-H), 7.63 (td, 1H, J = 7.6 Hz, J = 1.4 Hz, Ar-H), 7.58–7.50 (m, 2H, Ar-H), 7.40 (d, 2H, J = 8.8 Hz, Ar-H), 7.32–7.22 (m, 2H, Ar-H), 7.09–7.04 (m, 1H, Ar-H), 5.78 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, CHCl3): δ = 174.7 (CS), 140.8 (CH), 140.7 (Cquat), 138.3 (Cquat), 137.0 (Cquat), 134.5 (CH), 133.8 (CH), 133.4 (CH), 128.9 (Cquat), 128.6 (CH), 127.9 (2CH), 127.6 (CH), 126.9 (2CH), 124.7 (Cquat), 123.3 (CH), 122.5 (CH), 121.4 (CH), 117.2 (Cquat), 111.2 (Cquat), 110.4 (CH), 110.3 (Cquat), 47.8 (CH2) ppm. HRMS (ESI): calcd. for C24H19ClN4S [M + H]+ 444.10497; found 444.10489.

3.2.3. General Procedure for the Synthesis of Thiazolidin-4-ones (7a–e)

A mixture of compound 5a–e (1.5 mmol, 1 eq), ethyl 2-bromoacetate 6 (0.24 mL, 1.5 mmol), and anhydrous sodium acetate (0.37 g, 4.5 mmol, 3 eq) in ethanol (30 mL) was stirred at 80 °C for 6 h. The reaction mixture was cooled at room temperature, poured into ice cold water, and the solid was filtered, washed with water, and recrystallized from a mixture of ethanol-DMF (3:1).
2-(2-((1-Benzyl-1H-indol-3-yl)methylene)hydrazono)-3-(4-chlorophenyl)thiazolidin-4-one (7a): Yellow solid, 94%, 0.43 g. mp 250–252 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.45 (s, 1H, indole C2-H), 8.43–8.40 (m, 1H, Ar-H), 7.85 (s, 1H, CH=N), 7.56 (d, 2H, J = 8.9 Hz, Ar-H), 7.52–7.46 (m, 3H, Ar-H), 7.36–7.22 (m, 7H, Ar-H), 5.52 (s, 2H, PhCH2), 4.06 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 172.2 (CO), 161.8, 153.9, 137.9, 137.7, 135.3, 134.6, 133.6, 130.6, 129.5, 129.1, 127.6, 125.8, 123.4, 122.7, 121.6, 111.3, 50.0 (CH2), 32.7 (CH2) ppm. HRMS (ESI): calcd. for C25H20ClN4OS [M + H]+ 459.10463; found 459.10475.
2-(2-((1-(4-Fluorobenzyl)-1H-indol-3-yl)methylene)hydrazono)-3-(4-chlorophenyl)thiazolidin-4-one (7b): Brown solid, 94%, 0.42 g. mp 242–244 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.45 (s, 1H, indole C2-H), 8.27–8.24 (m, 1H, Ar-H), 7.96 (s, 1H, CH=N), 7.61 (d, 2H, J = 8.9 Hz, Ar-H), 7.57–7.46 (m, 1H, Ar-H), 7.46 (d, 2H, J = 8.7 Hz, Ar-H), 7.33–7.28 (m, 2H, Ar-H), 7.25–7.21 (m, 2H, Ar-H), 7.15 (t, 2H, J = 8.9 Hz, Ar-H), 5.46 (s, 2H, PhCH2), 4.08 (s, 2H, CH2) ppm. 19F-NMR (282 MHz, DMSO-d6): δ = −114.9 ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 171.9 (CO), 161.7 (Cquat), 161.5 (d, J = 243 Hz, Cquat), 153.3, 136.9, 134.8, 134.0, 133.5 (d, J = 3.2 Hz, Cquat), 133.1, 130.2, 129.3 (d, J = 8.3 Hz), 129.1, 125.2, 123.0, 122.3, 121.3, 115.4 (d, J = 21.5 Hz), 111.6, 110.8, 48.6 (CH2), 32.7 (CH2) ppm. HRMS (ESI): calcd. for C25H19ClFN4OS [M + H]+ 477.09521; found 477.09528.
2-(2-((1-(3-(Trifluoromethyl)benzyl)-1H-indol-3-yl)methylene)hydrazono)-3-(4-chlorophenyl)thiazolidin-4-one (7c): Beige solid, 91%, 0.48 g. mp 230–232 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.46 (s, 1H, indole C2-H), 8.29–8.26 (m, 1H, Ar-H), 8.02 (s, 1H, CH=N), 7.66–7.58 (m, 4H, Ar-H), 7.56–7.53 (m, 3H, Ar-H), 7.47 (d, 2H, J = 8.7 Hz, Ar-H), 7.28–7.20 (m, 2H, Ar-H), 5.60 (s, 2H, PhCH2). 4.09 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 171.8 (CO), 161.8, 153.3, 138.9, 136.9, 134.9, 134.0, 133.1, 131.1, 130.2, 129.8, 129.7 (q, J = 31 Hz), 129,1, 125.2, 124.4 (q, J = 3.7 Hz), 124.0 (q, J = 272 Hz), 123.7 (q, J = 4 Hz), 123.1, 122.3, 121.4, 111.8, 110.7, 48.7 (CH2), 32.3 (CH2) ppm. HRMS (ESI): calcd. for C26H19ClF3N4OS [M + H]+ 527.09202; found 527.09212.
2-(2-((1-(3-Chlorobenzyl)-1H-indol-3-yl)methylene)hydrazono)-3-(4-chlorophenyl)thiazolidin-4-one (7d): Yellow solid, 90%, 0.44 g. mp 252–254 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.45 (s, 1H, indole C2-H), 8.27–8.24 (m, 1H, Ar-H), 7.96 (s, 1H, CH=N), 7.60 (d, 2H, J = 8.8 Hz, Ar-H), 7.56–7.51 (m, 1H, Ar-H), 7.47 (d, 2H, J = 8.7 Hz, Ar-H), 7.33–7.20 (m, 6H, Ar-H), 5.47 (s, 2H, PhCH2), 4.09 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 171.9 (CO), 161.7, 153.4, 137.4, 137.1, 135.0, 134.1, 133.1, 130.2, 129.1, 128.8 (2CH), 127.6, 127.1 (2CH), 125.2, 123.0, 122.3, 121.3, 111.5, 110.9, 49.4 (CH2), 32.3 (CH2) ppm. HRMS (ESI): calcd. for C25H19Cl2N4OS [M + H]+ 493.06566; found 493.06574.
2-(2-((1-(2-Cyanobenzyl)-1H-indol-3-yl)methylene)hydrazono)-3-(4-chlorophenyl)thiazolidin-4-one (7e): Beige solid, 85%, 0.41 g. mp 253–255 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.46 (s, 1H, indole C2-H), 8.31–8.28 (s, 1H, Ar-H), 7.93 (s, 1H, CH=N), 7.91–7.90 (m, 1H, Ar-H), 7.62–7.58 (m, 3H, Ar-H), 7.52–7.45 (m, 4H, Ar-H), 7.25–7.22 (m, 1H, Ar-H), 5.72 (s, 2H, PhCH2), 4.09 (s, 2H, CH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 171.8 (CO), 161.9 (Cquat), 153.3 (CH), 140.6 (Cquat), 137.2 (Cquat), 135.1 (CH), 134.0 (Cquat), 133.7 (CH), 133.4 (CH), 133.1 (Cquat), 130.2 (2CH), 129.1 (2CH), 128,5 (CH), 127.7 (CH), 125.1 (Cquat), 123.2 (CH), 122.4 (CH), 121.5 (CH), 117.2 (Cquat), 112.0 (Cquat), 110.6 (CH), 110.3 (Cquat), 47.8 (CH2), 32.3 (CH2) ppm. HRMS (ESI): calcd. for C26H19ClN5OS [M + H]+ 484.09988; found 484.09994.

3.2.4. General Procedure for the Synthesis of Thioxothiazolinones (10a–e)

We mixed 2-thioxothiazolidin-4-one 9 (0.2 g, 1.5 mmol, 1 equiv) and indole-3-carbaldehyde (3a–e) (1.65 mmol, 1.1 equiv) in a two-neck round-bottom flask, with a sufficient quantity of ethanol for the dissolution of the starting reagents. The reaction mixture was heated at reflux at 80 °C, and 10 mol% of piperidine was added. The reaction was followed by TLC and at the end of the reaction, the reaction was stopped, and the mixture was cooled to room temperature. The final product was filtered and washed with distilled water to remove traces of piperidine.
(Z)-5-((1-Benzyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one (10a): Yellow solid, 85%, 0.45 g. mp 243–245 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 13.58 (s, 1H, NH), 8.11 (s, 1H), 7.97 (dd, 1H, J = 7.0 Hz, J = 1.6 Hz, Ar-H), 7.91 (s, 1H), 7.57 (dd, 1H, J = 7.0 Hz, J = 1.5 Hz, Ar-H), 7.36–7.20 (m, 7H, Ar-H), 5.60 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 194.6 (CS), 169.1 (CO), 136.9 (Cquat), 136.1 (Cquat), 132.7 (CH), 128.7 (2CH), 127.7 (CH), 127.5 (Cquat), 127.3 (2CH), 123.8 (CH), 123.4 (CH), 121.7 (CH), 118.8 (Cquat), 118.5 (CH), 111.4 (CH), 110.5 (Cquat), 49.8 (CH2) ppm. HRMS (ESI): calcd. for C19H15N2OS2 [M + H]+ 351.06258; found 351.06264.
(Z)-5-((1-(4-Fluorobenzyl)-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one (10b): Yellow solid, 74%, 0.41 g. mp 219–221°C. 1H-NMR (300 MHz, DMSO-d6): δ = 13.58 (s, 1H, NH), 8.12 (s, 1H), 7.96 (dd, 1H, J = 7.0 Hz, J = 1.4 Hz, Ar-H), 7.91 (s, 1H), 7.59 (dd, 1H, J = 7.3 Hz, J = 1.1 Hz, Ar-H), 7.43–7.36 (m, 2H, Ar-H), 7.29–7.14 (m, 4H, Ar-H) 5.58 (s, 2H, PhCH2) ppm. 19F-NMR (282 MHz, DMSO-d6): δ = −114.8 ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 194.6 (CS), 169.1 (CO), 161.9 (d, J = 243 Hz, Cquat), 136.5 (Cquat), 133.1 (d, J = 3.1 Hz, Cquat), 132.6 (CH), 129.5 (d, J = 8.3 Hz, CH), 127.6 (Cquat), 123.8 (CH), 123.5 (CH), 121.8 (CH), 118.8 (CH), 118.6 (Cquat), 115.4 (d, J = 21.5 Hz, CH), 113.4 (CH), 110.6 (Cquat), 49.0 (CH2) ppm. HRMS (ESI): calcd. for C19H14FN2OS2 [M + H]+ 369.05316; found 369.05319.
(Z)-2-Thioxo-5-((1-(3-(trifluoromethyl)benzyl)-1H-indol-3-yl)methylene)thiazolidin-4-one (10c): Yellow solid, 85%, 0.50 g. mp 208–210 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.08 (s, 1H), 7.91–7.87 (m, 1H, Ar-H), 7.87 (s, 1H), 7.73 (bs, 1H, Ar-H), 7.64 (d, 1H, J = 7.8 Hz, Ar-H), 7.59–7.53 (m, 2H, Ar-H), 7.46 (d, 1H, J = 7.6 Hz, Ar-H), 7.28–7.17 (m, 2H, Ar-H), 5.69 (s, 2H, PhCH2) ppm. 19F-NMR (282 MHz, DMSO-d6): δ = −61.1 ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 179.6 (CS), 172.4 (CO), 138.9 (Cquat), 136.1 (Cquat), 131.0 (CH), 130.3 (CH), 129.8 (CH), 129.2 (q, J = 31.7 Hz, Cquat), 127.5 (Cquat), 124.3 (q, J = 3.8 Hz, CH), 124.0 (q, J = 272 Hz, Cquat), 123.7 (q, J = 3.8 Hz, CH), 123.5 (Cquat), 123.1 (CH), 121.1 (CH), 120.7 (CH), 118.7 (CH), 111.0 (Cquat), 110.9 (CH), 48.9 (CH2) ppm. HRMS (ESI): calcd. for C20H14ClF3N2OS2 [M + H]+ 419.04996; found 419.05003.
(Z)-5-((1-(3-Chlorobenzyl)-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one (10d): Yellow solid, 73%, 0.42 g. mp 265–267 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 13.6 (bs, 1H, NH), 8.13 (s, 1H), 7.97 (d, J = 7.7 Hz, Ar-H), 7.90 (s, 1H), 7.58 (d, 1H, J = 7.8 Hz, Ar-H), 7.41–7.22 (m, 5H, Ar-H), 5.61 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 179.6 (CS), 161.1 (CO), 140.0, 136.5, 133.7, 133.0, 131.2, 131.1, 128.3, 128.2, 127.6, 126.4, 124.0, 122.3, 119.4, 111.8, 111.3, 49.6 (CH2) ppm. HRMS (ESI): calcd. for C19H14ClN2OS2 [M + H]+ 385.02361; found 385.02372.
(Z)-2-((3-((4-Oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indol-1-yl)methyl)benzonitrile e (10e): Yellow solid, 73%, 0.42 g. mp 244–246 °C. 1H-NMR (300 MHz, DMSO-d6): δ = 8.04 (s, 1H), 7.95–7.91 (d, J = 7.7 Hz, Ar-H), 7.88 (s, 1H), 7.60 (td, 1H, J = 7.7 Hz, J = 1.4 Hz, Ar-H), 7.51–7.46 (m, 2H, Ar-H), 7.28–7.20 (m, 2H, Ar-H), 6.84 (d, J = 7.7 Hz, Ar-H), 5.83 (s, 2H, PhCH2) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 179.6 (CS), 172.3 (CO), 140.8 (Cquat), 136.3 (Cquat), 133.8 (CH), 133.4 (CH), 130.8 (CH), 128.4 (CH), 127.4 (Cquat), 127.2 (CH), 123.7 (Cquat), 123.3 (CH), 121.3 (CH), 120.6 (CH), 118.8 (CH), 117.3 (Cquat), 111.2 (Cquat), 110.8 (CH), 110.1 (Cquat), 48.7 (CH2) ppm. HRMS (ESI): calcd. for C20H14N3OS2 [M + H]+ 376.05783; found 376.05788.

4. Conclusions

In summary, we have developed an effective new protocol for the preparation of indole substituted at position 1 and 3 for the series A. Knoevenagel-type condensation affords a new series of thiosemicarbazones or thioxothiazolinones with excellent yields according to the procedures described in [35]. The cyclization of thiosemicarbazones with ethyl bromoacetate furnished a new series of thiazolidinones also with a good yield. In vitro studies of the antimicrobial activity of all these molecules on various pathogenic bacteria (Staphylococcus aureus and Pseudomonas aeruginosa) are in progress in our laboratory.

Supplementary Materials

The following are available online. 1H- & 13C-NMR for compounds 3a–e, 4a, 5a–e, 7a–e, and 10a–e.

Author Contributions

Conceptualization, A.B. and A.D.; data curation, N.R. and A.B.; formal analysis, N.R., J.T. and A.B.; investigation, A.B.; methodology, N.R. and S.K.; project administration, A.B.; validation, A.D.; resources, J.T.; writing—original draft preparation, J.T. and A.B.; writing—review and editing, J.T. and A.B.; visualization, J.T. and A.B.; supervision, J.T. All authors discussed the results and commented on the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

We acknowledge Frédéric Montigny (Analysis Department, Tours University) for HRMS analysis. We acknowledge the Algeria Minister of Higher Education and Scientific Research for the financial support.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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Molbank 2021 m1284 g001 550
Figure 1. Selected biologically active compounds bearing indole-based moiety.
Figure 1. Selected biologically active compounds bearing indole-based moiety.
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Scheme 1. Preparation of A, B, or C series.
Scheme 1. Preparation of A, B, or C series.
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Scheme 2. Preparation of N-benzylindole-3-carboaldehyde derivatives 3a–e.
Scheme 2. Preparation of N-benzylindole-3-carboaldehyde derivatives 3a–e.
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Molbank 2021 m1284 sch003 550
Scheme 3. Preparation of thiosemicarbazones 5a–e.
Scheme 3. Preparation of thiosemicarbazones 5a–e.
Molbank 2021 m1284 sch003
Molbank 2021 m1284 sch004 550
Scheme 4. Preparation of thiazolidin-4-one derivatives 7a–e.
Scheme 4. Preparation of thiazolidin-4-one derivatives 7a–e.
Molbank 2021 m1284 sch004
Molbank 2021 m1284 sch005 550
Scheme 5. Preparation of thioxothiazolinones 10a–e.
Scheme 5. Preparation of thioxothiazolinones 10a–e.
Molbank 2021 m1284 sch005
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MDPI and ACS Style

Rekiba, N.; Benmohammed, A.; Khanoussi, S.; Djafri, A.; Thibonnet, J. Synthesis and Characterization of Novel Thiazolidinones and Thioxothiazolidinones Derived from Substituted Indole. Molbank 2021, 2021, M1284. https://doi.org/10.3390/M1284

AMA Style

Rekiba N, Benmohammed A, Khanoussi S, Djafri A, Thibonnet J. Synthesis and Characterization of Novel Thiazolidinones and Thioxothiazolidinones Derived from Substituted Indole. Molbank. 2021; 2021(4):M1284. https://doi.org/10.3390/M1284

Chicago/Turabian Style

Rekiba, Nawel, Abdelmadjid Benmohammed, Sofiane Khanoussi, Ayada Djafri, and Jérôme Thibonnet. 2021. "Synthesis and Characterization of Novel Thiazolidinones and Thioxothiazolidinones Derived from Substituted Indole" Molbank 2021, no. 4: M1284. https://doi.org/10.3390/M1284

APA Style

Rekiba, N., Benmohammed, A., Khanoussi, S., Djafri, A., & Thibonnet, J. (2021). Synthesis and Characterization of Novel Thiazolidinones and Thioxothiazolidinones Derived from Substituted Indole. Molbank, 2021(4), M1284. https://doi.org/10.3390/M1284

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