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

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.

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

Scheme 1. 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

^(a) Isolated product yields

^(b) 3:1 mixture of isomers 3e/3e’

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

^(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=C5_rhod), 7.6-7.04 (m, 15H); ¹³C-NMR (CDCl₃) δ: 166.6 (C=O), 151.05 (C=N), 148.23, 134.77 (CH=C5_rhod), 134.51, 133.73, 133.28, 132.73, 131.58, 130.35, 129.46, 128.13, 127.36, 124.96, 121.37; 121.15 (C5_rhod); 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=C5_rhod), 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 (C5_rhod), 114.77 (C5_rhod), 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=C5_rhod), 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 (C5_rhod); 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=C5_rhod), 7.76 (s, 1H, CH=C5_rhod), 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=C5_rhod), 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 (C5_rhod), 119.02 (C5_rhod), 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=C5_rhod), 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=C5_rhod), 131.43, 129.93, 129.31, 128.90, 126.14, 124.90, 121.12, 119.02 (C5_rhod), 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=C5_rhod), 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=C5_rhod), 132.09, 130.58, 129.90, 129.56, 127.84, 122.96, 118.61 (C5_rhod), 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, CH_3pyridine), 2.54 (s, 3H, CH₃O); ¹³C-NMR (CDCl₃) δ: 165.63 (C=O), 160.18, 154. 06 (C=N), 139.53, 136.14 (CH=C5_rhod), 133.72, 132.52, 129.68, 127.89, 125.16, 122.42, 121.27, 118.53 (C5_rhod), 117.45, 115.01, 113.63, 109.81, 55.51 (CH₃O), 22.26 (CH_3pyridine); 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=C5_rhod), 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, CH_3pyridine); ¹³C-NMR (CDCl₃/CF₃COOH) δ: 165.20 (C=O), 159.65, 153.99 (C=N), 146.33, 139.67, 134.33 (CH=C5_rhod), 133.21, 132.28, 130.20, 129.90, 129. 62, 127.77, 122.51, 118.72 (C5_rhod), 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, CH_3pyridine); 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 (C5_rhod), 112.03, 40.23 (CH₃)₂), 20.79 (CH_3pyridine); 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=C5_rhod), 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=C5_rhod), 133.67, 129.52, 127.98, 127.92, 127.13, 127.04, 122.22, 118.81 (C5_rhod), 117.77, 116.44, 113.94, 108.99, 102.06, 22.26 (CH₃); HRMS, m/z found 415.099 (calc. for C₂₃H₁₇N₃O₃S: 415.09906)