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. 2006 Aug 10;11(8):597–602. doi: 10.3390/11080597

One-Pot Synthesis of 5-Arylidene-2-Imino-4-Thiazolidinones under Microwave Irradiation

Souad Kasmi-Mir 1,*, Ayada Djafri 3, Ludovic Paquin 2,†, Jack Hamelin 2, Mustapha Rahmouni 1,‡
PMCID: PMC6148661  PMID: 17971732

Abstract

A rapid and easy solvent free one-pot synthesis of 5-arylidene-2-imino-4-thiazolidinones by condensation of the thioureas with chloroacetic acid and an aldehyde under microwave-irradiation is described.

Keywords: 5-Arylidene-2-imino-4-thiazolidinones, one-pot synthesis, microwave-irradiation

Introduction

4-Thiazolidinone derivatives constitute an important class of heterocyclic compounds for their potential pharmaceutical applications [1,2,3,4,5,6,7,8]. Consequently, a large number of synthetic protocols leading to these compounds have been reported in the literature [9]. Recently, 5-arylidene-2-imino-4-thiazolidinones [10] were synthesized by the reaction of 2-imino-4-thiazolidinones and appropriate aldehydes under basic conditions in ethanol at reflux for about 24 hours. The 2-imino-thiazolidinones in turn were obtained by condensation of thiourea with chloroacetyl chloride in the presence of triethylamine in CHCl3 at room temperature. We have previously reported the synthesis of iminothiazolines [11] by Hantzsch cyclisation using microwave-irradiation. In similar fashion and following the same strategy, we describe herein the one-pot three component solvent-free reaction of the thioureas 1a,a’, chloroacetic acid and an appropriate aldehydes 2a-e under microwave-irradiation according to Scheme 1. Yields and reaction conditions are given in Table 1.

Scheme 1.

Scheme 1

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Synthesis of 5-arylidene-2-imino-4-thiazolidinones 3a-e, 4a-e.

Table 1.

Yields and reaction conditions used for the microwave syntheses of 3a-e and 4a-e

Compounds 3 R1 Time (min) Yields(%)(a)
3a Ph 20 89
3b Ph 15 64
3c Ph 20 73
3d Ph 20 71
3e, 3e’ Ph 20 75(b)
4a 4-methylpyridin-2-yl 20 79
4b 4-methylpyridin-2-yl 20 68
4c 4-methylpyridin-2-yl 10 77
4d 4-methylpyridin-2-yl 10 74
4e 4-methylpyridin-2-yl 15 61
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(a) Isolated product yields

(b) 3:1 mixture of isomers 3e/3e’

The structures of all new compounds 3a-e, 4a-e were established by analysis of their 1H- and 13C- NMR and mass spectra. The Z configuration of the exocyclic C=C bond was assigned on the basis of 1H-NMR spectroscopy, according to literature data for analogous 4-thiazolidinones [3,10,12]. The methine proton deshielded by the adjacent C=O was detected at 7.76-8.30 ppm, except for 3d and 4d. In the case of the reaction with aldehyde 2e a 3:1 mixture of two isomers 3e and 3e’ was obtained. When the synthesis was performed in EtOH at reflux, the major and the most stable isomer 3e was obtained. The 13C-NMR spectra of all compounds were characterized by the presence of the rhodanine C2 C=N at 150.99-154.90 ppm and C=O at the rhodanine C4 at 165.20-167.25 ppm.

Conclusions

A solvent-free synthesis coupled with focused microwave irradiation appears to be a simple, fast and high yielding method for the preparation of 5-arylidene-2-imino-4-thiazolidinones.

Experimental

General

Melting points were determined on a Koffler melting point apparatus and are uncorrected. 1H-NMR spectra were recorded on a Bruker ARX 200 (1H at 200 MHz) or Bruker AC 300P (1H and 13C at 300 and 75 MHz, respectively) spectrometers. Chemical shifts are expressed in parts per million downfield from tetramethylsilane used as an internal standard. The mass spectra were recorded on a Varian MAT 311 at a ionizing potential of 70eV at the “Centre de Mesures Physiques de l’Ouest” (CRMPO, Rennes). Reactions under microwaves were performed in a PROLABO Synthewave 402 (2.45 GHz) microwave reactor with a single focused system. All solvents and reagents were purchased from Acros Organics and Aldrich Chemical and used without further purification.

Preparation of Thioureas 1a,1a’

A mixture of the appropriate amine (0.1 mol) and phenylisothiocyanate (0.12 mol) was stirred in CH2Cl2 at room temperature for 24 h. The crude product was concentrated under vacuum and recrystallized from ethanol. 1.3-diphenylthiourea (1a): 93% yield; beige crystals; mp = 157°C; 1H-NMR (CDCl3/CF3COOH): δ 10.00 (bs, 2H, NH), 7.47 (m, 10H); 13C-NMR (CDCl3/CF3COOH) δ: 178.89 (C=S), 137.23, 129.12, 126.65, 124.79. 1-(4-methylpyridin-2yl)-3-phenylthiourea (1a’): 94% yield; beige crystals; mp = 160°C; 1H-NMR (CDCl3) δ: 13.91 (bs, 1H, NH), 9.72 (bs, 1H, NH), 8.07 (d, 1H, J=5.16Hz), 7.36 (m, 5H), 6.82 (d, 1H, J=6Hz), 6.80 (s, 1H); 13C-NMR (CDCl3) δ: 178.73 (C=S), 153.5 (C=N), 150.59, 150.09, 138.38, 128.73, 126.19, 125.02, 119.82, 112.72, 21.33 (CH3).

General procedure for the preparation of 5-arylidene-2-imino-4-thiazolidinones 3a-e, 4a-e.

The appropriate thiourea 1a-a’ (3 mmol), chloroacetic acid (3.6 mmol) and the aldehyde 2 (3 mmol) were placed successively in a cylindrical quartz tube (Ø = 1.5cm). Then the tube was introduced into the Synthwave ® 402 Prolabo microwave reactor and irradiated at 90-110°C for 10-20 min. The microwave is monitored by a computer which allows the temperature of the reaction mixture to be adjusted. After, cooling down to room temperature; the mixture was extracted with CH2Cl2. After elimination of the solvent under vacuum, the residue was purified by recrystallisation from EtOH/water. Reaction times and yields are listed in Table 1, while microwave power settings and reaction temperatures are given under each entry.

5-Benzylidene-3-phenyl-2-(phenylimino)thiazolidin-4-one (3a): 50W (110°C); yellow solid; mp = 216°C; 1H-NMR (CDCl3) δ: 7.88 (s, 1H, CH=C5rhod), 7.6-7.04 (m, 15H); 13C-NMR (CDCl3) δ: 166.6 (C=O), 151.05 (C=N), 148.23, 134.77 (CH=C5rhod), 134.51, 133.73, 133.28, 132.73, 131.58, 130.35, 129.46, 128.13, 127.36, 124.96, 121.37; 121.15 (C5rhod); HRMS, m/z found 356.0982 (calc. for C22H16N2OS: 356.09834)

5-(4-Methoxybenzylidene)-3-phenyl-2-(phenylimino)thiazoldin-4-one (3b): 50W (90°C); yellow powder; mp = 204°C; 1H-NMR (CDCl3) δ: 7.8 (s, 1H, CH=C5rhod), 7.32 (m, 10H), 7.04 (d, 2H, J= 7.3Hz), 6.9 (d, 2H, J=8.76Hz), 3.8 (s, 3H, CH3O); 13C-NMR (CDCl3) δ: 166.70 (C=O), 160.99, 151.36 (C=N), 148.49, 134.89 (CH=C5), 133.80, 133.12, 132.03, 129.29, 128.92, 127.12, 126.39, 124.88, 121.22, 121.27, 118.35 (C5rhod), 114.77 (C5rhod), 55.46 (CH3)2); HRMS, m/z found 386.1072 (calc. for C23H19N3O2S: 386.10890)

5-(4-(Dimethylamino)benzylidene)-3-phenyl-2-(phenylimino)thiazolidin-4-one (3c): 50W (110°C); yellow crystals; mp = 208°C; 1H-NMR (CDCl3) δ: 7.82 (s, 1H, CH=C5rhod), 7.58 -7.06 (m, 10H), 7.03 (d, 2H, J =8.03Hz), 6.76 (d, 2H, J=8.8Hz ), 3.02 (s, 6H, (CH3)2); 13C-NMR (CDCl3) δ: 167.03 (C=O), 151.92 (C=N), 151.15, 148.76, 135.19 (CH=C5rhod), 134.51, 132.72, 132 .46, 129.29, 128.72, 128.26, 127.50, 124.65, 121.35, 114.58 (C5rhod), 112.01, 40.06 (CH3)2); HRMS, m/z found 399.1406 (calc. for C2H21N3OS: 399.1053).

5-(3-(4(Dimethylamino)phenyl)allylidene)-3-phenyl-2-(phenylimino)thiazolidin-4-one (3d): 30W (110°C); purple crystals; mp = 246°C; 1H-NMR (CDCl3) δ: 7.62-7.47 (m, 10H), 7.39 (d, 2H, J= 7.61Hz), 7.20 (1H, dd, J=6Hz, J=2Hz), 7.02 (d, 2H, J=7.57Hz), 6.78 (d, 1H, J=3Hz), 6.57 (d, 1H, J= 3.4Hz), 3.06 (s, 6H, (CH3)2); 13C-NMR (CDCl3) δ: 166.06 (C=O), 151.54 (C=N), 48.60, 142.96, 134.98 (CH =C5), 134.77, 132.37, 131.31, 129.24, 129.20, 128.76, 128.09, 124.74, 121.25, 119.07 (C5rhod); 112.74, 40.68 (CH3)2); HRMS, m/z found 425.1567 (calc. for C26H23N3OS 425.15618).

5-((Benzo[d][1,3]dioxol-6-yl)methylene)-3-phenyl-2-(phenylimino)thiazolidin-4-one (3e, 3e’): 50W (110°C); a 3:1 mixture of 3e/3e’; yellow solid; mp = 218°C, after crystallisation with EtOH/water; 1H-NMR (CDCl3) δ: 7.90 (s, 1H, CH=C5rhod), 7.76 (s, 1H, CH=C5rhod), 7.57-6. 85 (m, 20H), 7.3 (s, 1H), 7.18 (d, 1H, J=8.0Hz), 7.10 (d, 1H, J = 8.2Hz), 7.03 (d, 1H, J = 8.3Hz), 7.01 (s, 1H), 6.02 (s, 2H, CH2), 6.01 (s, 2H, CH2); 13C-NMR (CDCl3) δ: 167.22 (C=O), 166.58 (C=O), 151.54 (C=N), 150.99 (C=N), 149.91, 149.20, 148.78, 148.40, 148.65, 148.38, 148.33, 148.30, 134.87, 134.80 (CH=C5rhod), 132.80, 131.42, 129.93, 129.34, 129.31, 129.22, 128.90, 126.15 , 127.51, 126.83 , 126.13, 124.90, 121.12, 119.04 (C5rhod), 119.02 (C5rhod), 109.80, 109.24, 109.20, 109.16, 109.10, 108.98, 102.02 (CH2), 101.80 (CH2). Isomer 3e is obtained in 80% yield after reflux in EtOH for 5 hours; yellow solid; mp = 265°C; 1H-NMR (CDCl3) δ: 7.76 (s, 1H, CH=C5rhod), 7.60-6.86 (m, 10H), 7.00 (s, 1H), 7.03 (d, 1H, J=8.4Hz), 6.86 (d, 1H, J=8.07Hz), 6.01 (s, 2H, CH2); 13C-NMR (CDCl3) δ: 166.58 (C=O), 150.99 (C= N), 149.20, 148.65, 148.38, 148.31, 134.81 (CH=C5rhod), 131.43, 129.93, 129.31, 128.90, 126.14, 124.90, 121.12, 119.02 (C5rhod), 109.20, 109.16, 108.98, 101.79 (CH2); HRMS, m/z found 400.0889 (calc. for C23H16N2O3S: 400.08816).

5-Benzylidene-3-(4-methylpyridin-2-yl)-2-(phenylimino)thiazolidin-4-one (4a): 50W (110°C); yellow solid; mp>260°C; 1H-NMR (CDCl3/CF3COOH) δ: 8.45 (d, 1H, J=6.7Hz), 8.17 (s, 1H, CH=C5rhod), 7.60 (s, 1H), 7.53 (m, 10H), 7.46 (d, 1H, J=5.7Hz), 2.70 (s, 3H, CH3); 13C-NMR (CDCl3) δ: 167.25 (C=O), 160.58, 153.05 (C=N), 148.75, 148.20, 139.10, 138.90, 135.90 (CH=C5rhod), 132.09, 130.58, 129.90, 129.56, 127.84, 122.96, 118.61 (C5rhod), 117.00, 116.9, 112.42, 22.54 (CH3); HRMS, m/z found 371.1083 (calc. for C22H17N3OS: 371.10923).

5-(4-Methoxybenzylidene)-3-(4-methyl-3-(4-methylpyridin-2-yl)-2-(phenylimino)thiazolidin-4-one (4b): 50W (90°C); yellow powder; mp = 207°C; 1H-NMR (CDCl3/CF3COOH) δ: 8.28 (d, 1H, J = 5.76Hz), 7.95 (s, 1H, CH=C5rhod), 7.9 (m, 5H), 7.3 (d, 2H, J=8.3Hz), 7.23 (d, 1H, J=5.6Hz), 7.19 (s, 1H), 6.97 (d, 2H, J=8.3Hz), 3.85 (s, 3H, CH3pyridine), 2.54 (s, 3H, CH3O); 13C-NMR (CDCl3) δ: 165.63 (C=O), 160.18, 154. 06 (C=N), 139.53, 136.14 (CH=C5rhod), 133.72, 132.52, 129.68, 127.89, 125.16, 122.42, 121.27, 118.53 (C5rhod), 117.45, 115.01, 113.63, 109.81, 55.51 (CH3O), 22.26 (CH3pyridine); HRMS, m/z found 401.1213 (calc. for C23H19N3O2S: 401.11980).

5-(4-(Dimethylaminobenzylidene)-3-(4-methylpyridin-2-yl)-2-(phenylimino)thiazolidin-4one (4c): 30W (90°C); red crystals; mp = 230°C; 1H-NMR (CDCl3/CF3COOH) δ: 8.45 (d, 1H, J=5.74Hz), 7.96 (s, 1H, CH=C5rhod), 7.62 (s, 1H), 7.58-7.50 (m, 5H), 7. 47 (d, 1H, J=4.12Hz), 7.33 (d, 2H, J=5.33Hz), 7.26 (d, 2H, J=5.43Hz), 3.10 (s, 6H (CH3)2), 2.35 (s, 3H, CH3pyridine); 13C-NMR (CDCl3/CF3COOH) δ: 165.20 (C=O), 159.65, 153.99 (C=N), 146.33, 139.67, 134.33 (CH=C5rhod), 133.21, 132.28, 130.20, 129.90, 129. 62, 127.77, 122.51, 118.72 (C5rhod), 118.63, 117.22, 113.41, 44.52 (CH3)2), 22.52 (CH3); HRMS, m/z = 414.1501 found (calc. for C24H22N4OS: 414.15143).

5-(3-(4-(Dimethylamino)phenyl)allylidene)-3-(4-methylpyridin-2-yl)-2-(phenylimino)thiazolidin-4-one (4d): 30W (90°C); red crystals; mp> 260°C; 1H-NMR (CDCl3) δ: 8.43 (d, 1H, J =5.74Hz), 7.58 (d, 1H, J=5.21Hz), 7.53 (t, 1H, J=3.91Hz), 7.47 (m, 5H), 7.04 (s, 1H), 6.94 (d, 2H, J=6.28Hz), 6.90 (d, 1H, J=3.23Hz), 6.83 (d, 1H, J=3.83Hz), 6.74 (d, 2H, J=8.7Hz), 3.08 (s, 6H, (CH3)2, 2.34 (s, 3H, CH3pyridine); 13C-NMR (CDCl3) δ: 165.96 (C=O), 158.01, 153.25 (C=N), 151.25, 149.28, 146.33, 143.34, 135.63, 133.59, 129.30, 129.05, 128.4, 124.10, 122.15, 121.2, 118.78 (C5rhod), 112.03, 40.23 (CH3)2), 20.79 (CH3pyridine); HRMS, m/z found 440.1657 (calc. for C26H24N4OS: 440.16708).

5-((Benzo[d][1,3]dioxol-6-yl)methylene)-3-(4-methylpyridin-2yl)-2-(phenylimino)thiazolidin-4-one (4e): 50W (90°C); yellow powder; mp = 217°C; 1H-NMR (CDCl3/CF3COOH) δ: 8.40 (d, 1H, J= 5.97Hz), 8.3 (s, 1H, CH=C5rhod), 7.86 (s, 1H), 7.5 (d, 1H, J=3Hz), 7.20 (m, 8H), 6.04 (s, 2H, CH2), 2.53 (s, 3 H); 13C-NMR (CDCl3) δ: 165.50 (C=O), 160.67, 154.9 (C=N), 150.15, 148.64, 141.07, 135.08 (CH=C5rhod), 133.67, 129.52, 127.98, 127.92, 127.13, 127.04, 122.22, 118.81 (C5rhod), 117.77, 116.44, 113.94, 108.99, 102.06, 22.26 (CH3); HRMS, m/z found 415.099 (calc. for C23H17N3O3S: 415.09906)

Acknowledgements

We thank Mr Pierre Guenot, responsible for the CRMPO and his group for mass spectrometry

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