A solvent- and catalyst-free domino reaction for the efficient synthesis of 3-arylthiazolidine-2-thiones under microwave irradiation

Abstract

A facile synthesis of 4-hydroxy-3-arylthiazolidine-2-thiones through novel domino reactions of aryl isothiocyanates and 1,4-dithiane-2,5-diol under solvent- and catalyst-free microwave irradiation is reported. This highly atom efficient reaction presumably proceeds via 2-mercaptoacetaldehyde generation/thia-Michael addition/regioselective hemiaminalization domino sequence. This reaction also proceeds in good yields with aryl isocyanates affording 3-phenylthiazol-2(3H)-ones.

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Introduction

In recent years, synthetic organic chemists have made tremendous efforts to design environmentally benign protocols for the assembly of biologically and medicinally active compounds. In particular, solvent- and catalyst-free methodologies¹ play a crucial role in pharmaceutical industries. These protocols significantly reduce the use of organic solvents and minimize waste generation.

Microwave irradiation has emerged as an important facet of green chemistry and one of the most powerful synthetic tools in the field of drug discovery and new methodology development research. Compared to conventional heating, microwave heating has better homogeneity, shorter reaction time, enhanced reaction rate, higher yield and improved purity rendering this process greener.²

Domino reactions³ constitute another important synthetic tool in drug discovery programmes especially in the synthesis of heterocycles and total synthesis of natural products.⁴ These reactions allow the generation of combinatorial libraries of high levels of structural diversity and complexity by two or more bond forming reactions under the same reaction conditions without adding additional reagents and catalysts. These reactions are endowed with (a) operational simplicity, (b) easy automation, (c) resource effectiveness, (e) atom economy and (f) minimal waste generation bringing them under the purview of green chemistry.

Drug-like small heterocycles are amongst the most ubiquitous pharmacophores⁵ and hence have attracted great interest in chemical and medical communities. Rhodamine and its derivatives, known from the beginning of 20^th century, constitute one of the most privileged scaffolds that possess a wide range of medicinal activities⁶ like antiviral,⁷ antimicrobial,⁸ antimalarial,⁹ anticancer¹⁰ and inhibitory activities against HIV-1,¹¹ HIV-1 gp41,¹² JSP-1,¹³ IKKβ,¹⁴ PRL-3,¹⁵ and cholesterol esterase.¹⁶ The 3-phenylthiazole-2(3H)-thiones act as COX-2 inhibitors,¹⁷ tyrosinaseinhibitors¹⁸ and combretastatin analogs.¹⁹

The previously reported methods for the construction of 4-hydroxy-3-arylthiazolidine-2-thione (Scheme 1) include (i) the reaction of [N-4-methylphenyl]ammonium dithiocarbamate and chloro-acetaldehyde in ethanol–water mixture,²⁰ (ii) the reaction between primary amines, carbon disulphide and ethyl bromopyruvate in solvent-free condition,²¹ (iii) the reaction between amines, carbon disulphide and α-bromoketone under solvent-free condition^22a as well as in the presence of K₂CO₃ in water^22b and (iv) the reaction between aliphatic amines, carbon disulphide and dibenzoyl acetylene under neutral condition in water/DCM mixture.²³

Scheme 1 Some strategies for the synthesis of 4-hydroxy-3-arylthiazolidine-2-thiones.

These synthetic methods, however, suffer from one or more disadvantages like limited diversity, polymeric nature of precursor (chloroacetaldehyde), need for excess amount of one of the reactants, longer reaction time, toxic solvents, moderate yields, mixture of products, need for chromatographic separation and laborious workup. Therefore, from the perspective of green chemistry, evolution of new eco-friendly synthetic protocols is highly desirable. Consequently, we describe in this manuscript our findings on the synthesis of a library of 4-hydroxy-3-arylthiazolidine-2-thiones through two-component solvent- and catalyst-free microwave irradiation as a continuation of our interest in the construction of biologically relevant heterocycles employing tandem/domino/sequential processes and green transformations.²⁴ It is to be noted that 1,4-dithiane-2,5-diol has been used as the sulfur source instead of the conventional carbon disulfide.

Results and discussion

We started our investigation on the reaction between 1-chloro-4-isothiocyanatobenzene 1b (1.0 mmol) and 1,4-dithiane-2,5-diol 2 (0.5 mmol) in the presence of a catalytic amount of TEA (25 mol%) in ethanol under reflux condition.

This reaction proceeded smoothly furnishing 82% yield (entry 1) of 3-(4-chlorophenyl)-4-hydroxythiazolidine-2-thione 3b. Then we investigated the reaction of an equimolar mixture of the reactants under microwave irradiation which gave a slightly enhanced 85% yield of 3b (entry 2) compared to that obtained under reflux condition. Then reaction was examined in several solvents viz. EtOH, MeOH, DMF, CH₃CN, THF and water (entries 3–7) as well as under solvent-free (entry 8) condition with microwave irradiation at 100 °C. The results showed that the reaction under solvent-free condition is as good as that in EtOH affording 3b in 86% yield. We then investigated the reaction in the presence of several bases like DIPEA, DBU, DABCO, K₂CO₃ and KF/Al₂O₃ (entries 9–13) which led to no further improvement in the yield of the product. Interestingly, in the absence of any base (entry 14), this reaction afforded an excellent yield, 88% of 3b. The reaction of an equimolar mixture of the reactants upon irradiation with microwaves at 110 °C for 3 min led to 90% yield of 3b, while the same reaction at 120 °C for 3 min resulted in 89% yield (entries 15 and 16). The data listed in Table 1 show that the solvent- and catalyst-free microwave irradiation at 110 °C is optimal reaction condition for the synthesis of 4-hydroxy-3-arylthiazolidine-2-thiones. With these optimized reaction conditions, we explored the scope of the reaction employing a series of arylisothiocyanates bearing different substituents in the aryl ring (Table 2). It is found that the arylisothiocyanates having highly electron-withdrawing/electron-releasing groups such as 4-NO₂, 4-CF₃ and 4-NMe₂ in the aryl ring as well as aliphatic isothiocyanates failed to afford the product.

Table 1 Optimization of reaction conditions for the synthesis 3b

Entry	Base (25 mol%)	Solvent	Conditions^a	Yield of 3b^b (%)
a All microwave reactions performed at 120 W, 100 °C and 1 bar pressure.b Isolated yield after purification.c These microwave reactions performed at 120 W and 1 bar pressure.
1	TEA	EtOH	Thermal, 3 h, reflux	82
2	TEA	EtOH	MW, 3 min	85
3	TEA	MeOH	MW, 3 min	78
4	TEA	DMF	MW, 4 min	71
5	TEA	CH3CN	MW, 4 min	63
6	TEA	THF	MW, 3 min	34
7	TEA	Water	MW, 4 min	56
8	TEA	—	MW, 3 min	86
9	DIPEA	—	MW, 3 min	81
10	DBU	—	MW, 3 min	69
11	DABCO	—	MW, 3 min	62
12	K2CO3	—	MW, 3 min	57
13	KF/Al2O3	—	MW, 3 min	78
14	—	—	MW, 3 min	88
15	—^c	—	MW, 3 min 110 °C	90
16	—^c	—	MW, 3 min 120 °C	89

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Table 2 Substrate scope of the two-component reaction leading to 3^a

Entry	Ar	Comp.	Time/min	Yield 3^b/%
a All microwave reactions performed at 120 W, 110 °C and 1 bar pressure.b Isolated yield after washing with cold ethanol.
1	4-FC6H4	3a	4	88
2	4-ClC6H4	3b	4	90
3	4-BrC6H4	3c	4	92
4	C6H5	3d	3	96
5	4-MeC6H4	3e	3	94
6	4-EtC6H4	3f	3	93
7	4-^iPrC6H4	3g	3	95
8	4-MeOC6H4	3h	3	92
9	3-FC6H4	3i	3	93
10	3-BrC6H4	3j	4	91
11	3-MeC6H4	3k	4	92
12	3-MeOC6H4	3l	3	94
13	2-MeOC6H4	3m	3	96

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The structures of 4-hydroxy-3-arylthiazolidine-2-thiones 3 were deduced from one- and two-dimensional NMR spectroscopic data as detailed for 3e as a representative example (vide ESI†). Finally, the structure of the product 3a was confirmed unambiguously by a single crystal X-ray crystallographic study²⁵ (Fig. 1).

Fig. 1 X-ray crystallographic structure for 3a.

This transformation is 100% atom-economic, as all atoms of the reactants are built-in into the structure of the product, when one mole of 1 and 0.5 mole of 2 are allowed to react. The synthetic efficiency of the reaction, as measured by the product of atom-economy and yield, is also quite high justifying this reaction as an atom efficient reaction.

We also performed the reaction of aryl isocyanates (1 mmol) 4 and 1,4-dithiane-2,5-diol (0.5 mmol) 2 under the same reaction conditions. This reaction furnished solely 3-phenylthiazol-2(3H)-one 5 in excellent yields, instead of the expected 4-hydroxy-3-phenylthiazolidin-2-one (Table 3). The accompanied easy dehydration in this case may be attributed to the acidity of the ring methylene hydrogens.

Table 3 Synthesis of 3-arylthiazol-2(3H)-ones 5^a

Entry	Ar	Comp.	Time/min	Yield 5^b/%
a All microwave reactions performed at 120 W, 110 °C and 1 bar pressure.b Isolated yield after washing with cold ethanol.
1	C6H5	5a	3	95
2	4-ClC6H4	5b	3	94
3	4-MeOC6H4	5c	3	92

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Further, we have also developed a rapid access to 3-arylthiazole-2(3H)-thione 6 in excellent yield from the reaction of 3 with 40% aq. H₂SO₄ (Table 4) under microwave irradiation in just 1 min – much quicker than the reported procedure.²⁶

Table 4 Synthesis of 3-arylthiazole-2(3H)-thiones 6

Entry	Ar	Comp.	Yield 6^a/%
a All microwave reactions performed at 120 W, 110 °C and 1 bar pressure.
1	C6H5	6a	98
2	4-FC6H4	6b	96
3	4-EtC6H4	6c	94
4	3-FC6H4	6d	95
5	2-MeOC6H4	6e	97

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The structures of 3-arylthiazole-2(3H)-thione 5 and 4-hydroxy-3-arylthiazolidin-2-one 6 have been deduced from their NMR spectroscopic data and ESI mass spectra (vide ESI†).

The tentative mechanism for this transformation is outlined in Scheme 2. The first step presumably proceeds through the initial formation of 2-mercaptoacetaldehyde 7 from 1,4-dithiane-2,5-diol 2 which undergoes thia-Michael addition to arylisothiocyanate/aryl isocyanate 1/4 leading to the formation of intermediate 8. Then this intermediate undergoes regioselective hemiaminalization affording product 3. In this case, another possible regioisomer 3′ was not obtained even in traces. When X = O in 10, subsequent elimination of water led to the product 5.

Scheme 2 Probable domino sequence leading to the formation of 3 and 5.

Conclusion

In summary, we have developed an operationally facile, expedient, carbon disulfide free eco-friendly domino reaction for the synthesis of 4-hydroxy-3-thiazolidine-2-thiones, 3-arylthiazol-2(3H)-one and 3-arylthiazole-2(3H)-thiones in good to excellent yields from simple and inexpensive starting materials which involve a C–S and a C–N bond formation in a one pot operation with excellent atom economy. This present protocol may be useful for organic and medicinal applications.

Experimental section

General information

Melting points were measured in open capillary tubes and are uncorrected. The microwave assisted reactions have been carried out in a Biotage Initiator instrument. The ¹H-NMR, ¹³C-NMR, DEPT, H,H-COSY, C,H-COSY and HMBC spectra were recorded on a Bruker (Avance) 300 MHz NMR instrument using TMS as internal standard and CDCl₃ as solvent. Standard Bruker software was used throughout. Chemical shifts are given in parts per million (δ-scale) and the coupling constants are given in Hertz. Silica gel-G plates (Merck) were used for TLC analysis with a mixture of petroleum ether (60–80 °C) and ethyl acetate as eluent. Elemental analyses were performed on a Perkin Elmer 2400 Series II Elemental CHN analyzer. Mass spectra were recorded in LCQ Fleet mass spectrometer, Thermo Fisher Instruments Limited, US. Electrospray ionisation mass spectrometry (ESI-MS) analysis was performed in the positive ion mode on a liquid chromatography ion trap.

General procedure for the synthesis of 4-hydroxy-3-arylthiazolidine-2-thiones, 3a–m

A vial containing a mixture of arylisothiocyanate (1 mmol) 1 and 1,4-dithiane-2,5-diol (0.5 mmol) 2 was placed in a microwave synthesizer. The vial was subjected to microwave irradiation programmed at 110 °C, 120 W and 1 bar pressure. After 3–4 min of irradiation, the mixture was cooled to room temperature. Then the crude reaction mixture was triturated with cold ethanol to give pure products.

3-(4-Fluorophenyl)-4-hydroxythiazolidine-2-thione 3a. Isolated as off white solid. Yield: 88%; mp = 166–167 °C; ¹H NMR (300 MHz, DMSO-d₆) δ_H: 3.20 (d, J = 12.0 Hz, 1H), 3.89 (dd, J = 6.3, 12.0 Hz, 1H), 5.87 (t, J = 7.05 Hz, 1H), 7.28–7.35 (m, 2H), 7.38–7.43 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C: 36.3, 91.9, 115.4 (d, ²J_C,F = 22.6 Hz), 130.0 (d, ³J_C,F = 8.8 Hz), 135.1, 160.9 (d, ¹J_C,F = 243.3 Hz), 196.9; anal. calcd for C₉H₈FNOS₂; C, 47.15; H, 3.52; N, 6.11%. Found: C, 47.10; H, 3.56; N, 6.19%. ESI-MS: m/z. Calcd: 229.00; found: 230.00 (M + 1).

3-(4-Chlorophenyl)-4-hydroxythiazolidine-2-thione 3b. Isolated as off white solid. Yield: 90%; mp = 153–154 °C; ¹H NMR (300 MHz, DMSO-d₆) δ_H: 3.20 (d, J = 11.7 Hz, 1H), 3.90 (dd, J = 6.6, 11.8 Hz, 1H), 5.90 (t, J = 6.0 Hz, 1H), 7.35–7.47 (m, 2H), 7.55 (d, J = 8.7 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C: 36.8, 92.2, 128.9, 130.0, 132.5, 138.1, 197.3; anal. calcd for C₉H₈ClNOS₂: C, 43.99; H, 3.28; N, 5.70%. Found: C, 44.08; H, 3.23; N, 5.73%. ESI-MS: m/z. Calcd: 244.97; found: 246.05 (M + 1).

3-(4-Bromophenyl)-4-hydroxythiazolidine-2-thione 3c. Isolated as off white solid. Yield: 92%; mp = 148–149 °C; ¹H NMR (300 MHz, CDCl₃) δ_H: 3.31 (dd, J = 1.5, 12.3 Hz, 1H), 3.63 (d, J = 9.3 Hz, 1H), 3.89 (dd, J = 6.0, 12.3 Hz, 1H), 5.79 (t, J = 5.7 Hz, 1H), 7.31–7.36 (m, 2H), 7.57–7.62 (m, 2H); ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆) δ_C: 36.5, 91.6, 121.1, 129.1, 131.4, 137.7, 197.4; anal. calcd for C₉H₈BrNOS₂; C, 37.25; H, 2.78; N, 4.83%. Found: C, 37.32; H, 2.89; N, 4.88%. ESI-MS: m/z. Calcd: 288.92; found: 287.94 (M − 1), 289.91 (M + 1).

4-Hydroxy-3-phenylthiazolidine-2-thione 3d. Isolated as off white solid. Yield: 96%; mp = 157–158 °C [168 °C];^{20 1}H NMR (300 MHz, DMSO-d₆) δ_H: 3.20 (dd, J = 2.1, 12.0 Hz, 1H), 3.91 (dd, J = 6.3, 12.0 Hz, 1H), 5.88–5.93 (m, 1H) 7.32–7.41 (m, 3H), 7.45–7.56 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C: 36.8, 92.4, 128.0, 128.1, 128.9, 139.3, 196.9; anal. calcd for C₉H₉NOS₂: C, 51.16; H, 4.29; N, 6.63%. Found: C, 51.24; H, 4.33; N, 6.68%. ESI-MS: m/z. Calcd: 211.01; found: 212.08 (M + 1).

4-Hydroxy-3-(p-tolyl)thiazolidine-2-thione 3e. Isolated as white solid; yield 94%; mp = 130–131 °C [143–44 °C];^{20 1}H NMR (300 MHz, CDCl₃) δ_H: 2.39 (s, 3H), 3.29 (dd, J = 12.3, 1.5 Hz, 1H), 3.63 (brs, 1H), 3.86 (dd, J = 12.1, 6.1 Hz, 1H), 5.78 (brs, 1H), 7.41–7.72 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 20.8, 36.7, 92.4, 127.9, 129.4, 136.7, 137.5, 196.8; anal. calcd for C₁₀H₁₁NOS₂: C, 53.31; H, 4.92; N, 6.22%. Found: C, 53.35; H, 4.99; N, 6.17%. ESI-MS: m/z. Calcd: 225.03; found: 226.03 (M + 1).

3-(4-Ethylphenyl)-4-hydroxythiazolidine-2-thione 3f. Isolated as white solid; yield: 93%; mp = 148–149 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆) δ_H: 1.25 (t, J = 7.6 Hz, 3H), 2.68 (q, J = 7.5 Hz, 2H), 3.28 (d, J = 12.0 Hz, 1H), 3.81 (dd, J = 6.3, 12.0 Hz, 1H), 5.79 (t, J = 6.6 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆) δ_C: 15.5, 27.9, 36.7, 92.4, 127.9, 128.2, 136.9, 143.6, 196.8; anal. calcd for C₁₁H₁₃NOS₂; C, 55.20; H, 5.47; N, 5.85%. Found: C, 55.14; H, 5.52; N, 5.76%. ESI-MS: m/z. Calcd: 239.04; found: 239.99 (M + 1).

4-Hydroxy-3-(4-isopropylphenyl)thiazolidine-2-thione 3g. Isolated as white solid; yield: 95%; mp = 186–187 °C; ¹H NMR (300 MHz, DMSO-d₆) δ_H: 1.21 (d, J = 7.2 Hz, 3H), 1.23 (d, J = 3.3 Hz, 3H), 2.88–2.95 (m, 1H), 3.17 (d, J = 12.0 Hz, 1H), 3.88 (ddd, J = 3.2, 6.5, 11.9 Hz, 1H), 5.83 (m, 1H), 7.27–7.34 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C: 23.8, 33.2, 36.7, 92.4, 126.8, 127.9, 136.9, 148.1, 196.8; anal. calcd for C₁₂H₁₅NOS₂; C, 56.88; H, 5.97; N, 5.53%. Found: C, 56.98; H, 6.02; N, 5.60%. ESI-MS: m/z. Calcd: 253.06; found: 254.04 (M + 1).

4-Hydroxy-3-(4-methoxyphenyl)thiazolidine-2-thione 3h. Isolated as white solid; yield: 92%; mp = 176–177 °C [162–63 °C];^{20 1}H NMR (300 MHz, CDCl₃ + DMSO-d₆) δ_H: 3.02 (m, 1H), 3.54–3.59 (m, 4H), 4.45 (brs, 1H), 5.53 (brs, 1H), 6.71–6.79 (m, 2H), 7.07–7.17 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C: 36.5, 55.4, 92.3, 114.1, 129.3, 131.9, 158.7, 196.9; anal. calcd for C₁₀H₁₁NO₂S₂; C, 49.77; H, 4.59; N, 5.80%. Found: C, 49.69; H, 4.64; N, 5.89%. ESI-MS: m/z. Calcd: 241.02; found: 241.98 (M + 1).

3-(3-Fluorophenyl)-4-hydroxythiazolidine-2-thione 3i. Isolated as white solid; yield: 93%; mp = 175–176 °C; ¹H NMR (300 MHz, DMSO-d₆) δ_H: 3.21 (dd, J = 7.2, 12.1 Hz, 1H), 3.89 (dd, J = 6.6, 12.0 Hz, 1H), 5.93–5.95 (m, 1H), 7.24–7.29 (m, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.48–7.55 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C: 36.9, 92.3, 114.9 (d, ²J_C,F = 20.0 Hz), 115.3 (d, ²J_C,F = 23.3 Hz), 124.4 (d, ⁴J_C,F = 2.8 Hz), 130.5 (d, ³J_C,F = 8.9 Hz), 140.7 (d, ³J_C,F = 10.2 Hz), 161.8 (d, ¹J_C,F = 242.8 Hz), 197.3; anal. calcd for C₉H₈FNOS₂: C, 47.15; H, 3.52; N, 6.11%. Found: C, 47.18; H, 3.48; N, 6.17%. ESI-MS: m/z. Calcd: 229.00; found: 230.00 (M + 1).

3-(3-Bromophenyl)-4-hydroxythiazolidine-2-thione 3j. Isolated as white solid; yield: 91%; mp = 124–125 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆) δ_H: 3.29–3.33 (m, 1H), 3.82 (d, J = 6.3, 12.0 Hz, 1H), 5.81 (t, J = 6.0 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.35–7.40 (m, 1H), 7.50–7.53 (m, 1H), 7.63 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C: 36.9, 92.3, 121.2, 127.5, 130.8, 130.9, 140.7, 197.4; anal. calcd for C₉H₈BrNOS₂; C, 37.25; H, 2.78; N, 4.83%. Found: C, 37.18; H, 2.89; N, 4.87%. ESI-MS: m/z. Calcd: 288.92; found: 289.92 (M + 1), 291.88 (M + 2).

4-Hydroxy-3-(m-tolyl)thiazolidine-2-thione 3k. Isolated as white solid; yield: 92%; mp = 151–152 °C; ¹H NMR (300 MHz, CDCl₃) δ_H: 2.39 (s, 3H), 3.31 (dd, J = 1.5, 12.4 Hz, 1H), 3.53 (brs, 1H), 3.88 (dd, J = 6.0, 12.3 Hz, 1H), 5.81 (d, J = 5.7 Hz, 1H), 7.20–7.26 (m, 3H), 7.34–7.39 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 21.3, 37.2, 92.2, 124.7, 128.1, 129.3, 129.6, 138.6, 139.6, 198.1; anal. calcd for C₁₀H₁₁NOS₂; C, 53.31; H, 4.92; N, 6.22%. Found: C, 53.40; H, 4.84; N, 6.28%. ESI-MS: m/z. Calcd: 225.03; found: 226.01 (M + 1).

4-Hydroxy-3-(3-methoxyphenyl)thiazolidine-2-thione 3l. Isolated as white solid; yield: 94%; mp = 128–129 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆) δ_H: 3.27–3.31 (m, 1H), 3.78–3.84 (m, 4H), 5.81 (brs, 1H), 6.84 (brs, 1H), 6.90–6.94 (m, 1H), 7.00–7.02 (m, 2H), 7.34–7.39 (m, 1H); ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆) δ_C: 36.8, 55.3, 92.4, 113.5, 113.8, 120.3, 129.6, 140.3, 159.5, 196.8; anal. calcd for C₁₀H₁₁NO₂S₂; C, 49.77; H, 4.59; N, 5.80%. Found: C, 49.71; H, 4.64; N, 5.72%. ESI-MS: m/z. Calcd: 241.02; found: 242.06 (M + 1).

4-Hydroxy-3-(2-methoxyphenyl)thiazolidine-2-thione 3m. Isolated as white solid; yield: 96%; mp = 79–80 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆) δ_H: 3.22 (dd, J = 2.2, 12.1 Hz, 1H), 3.79 (s, 3H), 3.86 (dd, J = 6.7, 12.4 Hz, 1H), 5.75 (brs, 1H), 7.01 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 36.3, 55.1, 90.0, 111.4, 120.0, 126.4, 129.2, 130.9, 196.9; anal. calcd for C₁₀H₁₁NO₂S₂; C, 49.77; H, 4.59; N, 5.80%. Found: C, 49.73; H, 4.55; N, 5.89%.

General procedure for the synthesis of 3-phenylthiazol-2(3H)-ones 5a–c

A vial containing a mixture of arylisocyanate (1 mmol) 4 and 1,4-dithiane-2,5-diol (0.5 mmol) 2 was placed in a Biotage microwave synthesizer. The vial was subjected to microwave irradiation programmed at 110 °C, 120 W and 1 bar pressure. After 3 min of irradiation, the mixture was cooled to room temperature. Then the crude reaction mixture was triturated with cold ethanol to give pure products 5a–c.

3-Phenylthiazol-2(3H)-one 5a. Isolated as off white. Yield: 95%; mp = 53–54 °C; ¹H NMR (300 MHz, CDCl₃) δ_H: 6.25 (d, J = 5.4 Hz, 1H), 6.82 (d, J = 5.4 Hz, 1H), 7.34–7.38 (m, 2H), 7.39–7.50 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 101.9, 124.3, 124.9, 127.6, 129.3, 136.7, 170.9; anal. calcd for C₉H₇NOS: C, 61.00; H, 3.98; N, 7.90%. Found: C, 61.08; H, 3.91; N, 7.94%.

3-(4-Chlorophenyl)thiazol-2(3H)-one 5b. Isolated as off white solid. Yield: 94%; mp = 62–63 °C; ¹H NMR (300 MHz, CDCl₃) δ_H: 6.26 (d, J = 5.4 Hz, 1H), 6.79 (d, J = 5.7 Hz, 1H), 7.38–7.50 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 102.4, 124.4, 125.4, 129.4, 133.3, 135.2, 170.7; anal. calcd for C₉H₆ClNOS: C, 51.07; H, 2.86; N, 6.62%. Found: C, 51.16; H, 2.92; N, 6.52%.

3-(4-Methoxyphenyl)thiazol-2(3H)-one 5c. Isolated as off white solid. Yield: 92%; mp = 55–56 °C; ¹H NMR (300 MHz, CDCl₃) δ_H: 3.83 (s, 3H), 6.21 (d, J = 5.4 Hz, 1H), 6.76 (d, J = 5.4 Hz, 1H), 6.95–6.99 (m, 2H), 7.33–7.37 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 55.4, 101.4, 114.5, 125.3, 125.8, 129.6, 158.8, 171.0; anal. calcd for C₁₀H₉NO₂S; C, 57.96; H, 4.38; N, 6.76%. Found: C, 57.92; H, 4.45; N, 6.84%. ESI-MS: m/z. Calcd: 207.04; found: 208.03 (M + 1).

General procedure for the synthesis of 3-phenylthiazole-2(3H)-thiones 6a–e

A vial containing a mixture of 4-hydroxy-3-arylthiazolidine-2-thione 3 (1 mmol) and 40% aq. H₂SO₄ was placed in a Biotage microwave synthesizer. The vial was subjected to microwave irradiation programmed at 100 °C, 120 W and 1 bar pressure. The vial was cooled and the mixture poured into water. Then mixture was extracted with DCM; organic phases were collected and dried over Na₂SO₄. Removal of the solvent furnished pure 3-phenylthiazole-2(3H)-thiones 6a–e as semisolids.

3-Phenylthiazole-2(3H)-thione 6a. Isolated as off white solid. Yield: 98%; mp = 73–74 °C; ¹H NMR (300 MHz, CDCl₃) δ_H: 6.68 (d, J = 4.5 Hz, 1H), 7.13 (d, J = 4.5 Hz, 1H), 7.44–7.75 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 111.2, 126.4, 129.2, 129.4, 132.5, 138.5, 188.7; anal. calcd for C₉H₇NS₂; C, 55.93; H, 3.65; N, 7.25%. Found: C, 56.01; H, 3.59; N, 7.28%. ESI-MS: m/z. Calcd: 193.00; found: 193.98 (M + 1).

3-(4-Fluorophenyl)thiazole-2(3H)-thione 6b. Isolated as off white solid. Yield: 96%; mp = 127–128 °C; ¹H NMR (300 MHz, CDCl₃) δ_H: 6.68 (d, J = 4.5 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 7.18–7.26 (m, 2H), 7.45–7.51 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 111.3, 116.5 (d, ²J_C,F = 23.0 Hz), 128.5 (d, ³J_C,F = 8.7 Hz), 132.4, 134.4, 162.4 (d, ¹J_C,F = 248.7 Hz), 188.9; anal. calcd for C₉H₆FNS₂; C, 51.17; H, 2.86; N, 6.63%. Found: C, 51.12; H, 2.95; N, 6.67%. ESI-MS: m/z. Calcd: 210.99; found: 211.96 (M + 1).

3-(4-Ethylphenyl)thiazole-2(3H)-thione 6c. Isolated as viscous brown liquid. Yield: 94%; ¹H NMR (300 MHz, CDCl₃) δ_H: 1.28 (t, J = 7.5 Hz, 3H), 2.72 (q, J = 7.6 Hz, 2H), 6.66 (d, J = 4.5 Hz, 1H), 7.11 (d, J = 4.5, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.38–7.41 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 15.1, 28.4, 111.1, 126.1, 128.8, 132.7, 136.0, 145.4, 188.5; anal. calcd for C₁₁H₁₁NS₂; C, 59.69; H, 5.01; N, 6.33%. Found: C, 59.79; H, 5.07; N, 6.26%. ESI-MS: m/z. Calcd: 221.03; found: 222.04 (M + 1).

3-(3-Fluorophenyl)thiazole-2(3H)-thione 6d. Isolated as off white solid. Yield: 95%; mp = 69–70 °C; ¹H NMR (300 MHz, CDCl₃) δ_H: 6.68 (d, J = 4.5 Hz, 1H), 7.12 (d, J = 4.5 Hz, 1H), 7.16–7.22 (m, 1H), 7.26–7.31 (m, 2H), 7.45–7.55 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 111.5, 114.4 (d, ²J_C,F = 24.2 Hz), 116.3 (d, ²J_C,F = 20.0 Hz), 122.2 (d, ⁴J_C,F = 3.3 Hz), 130.7 (d, ³J_C,F = 10.0 Hz), 132.1, 139.4 (d, ³J_C,F = 7.5 Hz), 162.5 (d, ¹J_C,F = 247.5 Hz), 188.6; anal. calcd for C₉H₆FNS₂; C, 51.17; H, 2.86; N, 6.63%. Found: C, 51.24; H, 2.97; N, 6.61%. ESI-MS: m/z. Calcd: 210.99; found: 211.96 (M + 1).

3-(2-Methoxyphenyl)thiazole-2(3H)-thione 6e. Isolated as off white solid. Yield: 97%; mp = 89–90 °C; ¹H NMR (300 MHz, CDCl₃) δ_H: 3.84 (s, 3H), 6.64 (d, J = 4.8 Hz, 1H), 7.02 (d, J = 4.8 Hz, 1H), 7.07–7.12 (m, 2H), 7.39–7.49 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C: 55.8, 110.4, 112.6, 120.7, 126.9, 128.9, 130.9, 132.8, 154.0, 189.2; anal. calcd for C₁₀H₉NOS₂: C, 53.79; H, 4.06; N, 6.27%. Found: C, 53.84; H, 4.03; N, 6.35%. ESI-MS: m/z. Calcd: 223.01; found: 223.95 (M + 1).

Acknowledgements

S. P. thanks DST-SERB New Delhi, for a Major Research Project (SR/S1/OC-50/2011) and University Grants Commission, New Delhi for the award of BSR Faculty Fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra. CCDC 1056825. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra19112b

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