Preparation of 2,3-Diarylthiazolidin-4-one Derivatives Using Barium Sulfate Nano-Powders

Barium sulfate is an abundantly available material with numerous applications,^1,2 and as a result there are several techniques for its preparation.^3–10 Even so, much work remains to be done on the evaluation of the catalytic properties of BaSO₄ in organic transformations. The present work concentrates on the preparation of BaSO₄ nano-powder and its use as an efficient catalyst in the synthesis of 2,3-diarylthiazolidin-4-ones. Derivatives containing thiazolidin-4-ones are of broad interest because of their diverse and beneficial biological activities, including anticancer,¹¹ anti-HIV,¹² antimalarial,¹³ tuberculostatic,¹⁴ antihistaminic,¹⁵ anticonvulsant,¹⁶ antibacterial,¹⁷ and antiarrhythmic¹⁸ properties; but surely, in light of the coronavirus pandemic, their significant antiviral characteristics make them of high current interest to the medical research community.^19–21 Their preparation is an important issue in synthetic organic chemistry, and among the existing methods, the cyclo-condensation reaction of aldehydes, amines and thioglycolic acid has been especially versatile.^22–32 In keeping with our interest in exploring synthetic methodologies for the production of heterocyclic compounds,^33–39 we now report the preparation of several thiazolidin-4-ones (Scheme 1, compounds T₁-T₁₁), using the cyclo-condensation reaction of aldehydes, amines and thioglycolic acid in the presence of BaSO₄ nano-powder as a catalyst.

Scheme 1. Synthesis of 2,3-diarylthiazolidin-4-one derivatives (T₁-T₁₁).

To search for the optimal conditions, the synthesis of 2-phenyl-3-p-tolylthiazolidin-4-one (Scheme 1, T9) from benzaldehyde, 4-methylaniline, and thioglycolic acid was selected as a model. This reaction was investigated in solvent-free conditions and in different solvents using a catalytic amount of barium sulfate nanoparticles (Table 1). We found that ethanol was the best solvent for the reaction. The maximum yield was obtained when 0.18 mmol of catalyst was used (Table 1, Entry 5). A further increase in the amount of BaSO₄ nano-powder had no significant impact on the product yield. Under the standard conditions, no reaction was observed in the absence of a catalyst. This shows that the catalyst is essential for the product formation (Table 1, Entry 13).

Table 1. Optimization of the reaction conditions in the synthesis of T₉.

Entry	Catalyst (mmol)	T (°C)	Solvent (5 mL)	Yield $\mathbf{\%}$
1	0.18	RT	n-hexane	–
2	0.18	RT	CH2Cl2	25
3	0.18	RT	Et2O	30
4	0.18	RT	EtOAc	51
5	0.18	RT	EtOH	87
6	0.18	RT	MeOH	81
7	0.18	RT	MeCN	75
8	0.18	RT	–	70
9	0.36	RT	EtOH	86
10	0.09	RT	EtOH	78
11	0.05	RT	EtOH	47
12	0.03	RT	EtOH	29
13	–	RT	EtOH	–

RT: room temperature; CH₂Cl₂: dichloromethane; Et₂O: diethyl ether; EtOH: ethanol; EtOAc: ethyl acetate; MeOH: methanol; MeCN: acetonitrile. Reactions were done on a 1 mmol scale.

We used our procedure for the synthesis of substituted 2,3-diarylthiazolidin-4-one derivatives (Table 2). This reaction proceeded smoothly, and the desired products were obtained in good yields (mean 72%). In general, aromatic aldehydes and aromatic amines were well tolerated.

Table 2. Synthesis of 2,3-diarylthiazolidin-4-one derivatives using BaSO₄ nano-powder as catalyst.

Entry	Chemical Structure	m.p. [Lit. m.p.]^ref (°C)	Time (min)	Yield (%)^a
T1		145-147*	120	77
T2		127-129*	130	60
T3		121-123*	70	85
T4		155-157*	100	72
T5		131-133*	180	83
T6		149-151*	180	65
T7		166-168*	180	55
T8		124-126*	120	60
T9		110-112 [110-112]^28,^37	100	87
T10		121-123 [120-122]^28,^37	80	80
T11		152-154 [151-152]^28,^37	120	71

^aIsolated yield. *Novel derivatives.

Aromatic aldehydes with electron-donating groups gave higher yields than those with electron-withdrawing groups. When an ortho-substituted aldehyde (Table 2, Entry T₂) was used, the corresponding product was obtained in good yield. Electron donating groups on the amine appear to facilitate the reactions, giving higher yields of products than the cases using halogen-substituted anilines (Table 2). The work-up procedure is very clear-cut; that is, the products were isolated and purified by simple filtration and recrystallization from n-hexane/ethyl acetate.

Next, ethylamine as an aliphatic amine and butyraldehyde and heptanal as aliphatic aldehydes were used to investigate the potential of BaSO₄ in promoting the reaction for aliphatic substrates. The desired products were formed in negligible yields, suggesting that BaSO₄ is not a suitable catalyst to catalyze this multi-component reaction for aliphatic amines and aliphatic aldehydes.

In order to estimate the efficiency and generality of this methodology, our results on the synthesis of 2,3-diphenylthiazolidin-4-one using BaSO₄ nano-powder as catalyst has been compared with those of the previously reported methods (Table 3).

Table 3. Comparison results of BaSO₄ with other catalysts reported in the literature.

Entry	Catalyst	Condition	^aYield (%)	Reference
1	Bi(SCH2COOH)3	Solvent-free; 70 °C; 2 h	75	^24
2	H2SO4	Toluene; 100 °C; 5 h	34	^25
3	P-TsOH	Toluene; 100 °C; 5 h	32	^25
4	MsOH	Toluene; 100 °C; 5 h	24	^25
5	HClO4-TiO2	Toluene; 100 °C; 5 h	48	^25
6	Acidic Al2O3	Toluene; 100 °C; 5 h	15	^25
8	TiO2	Toluene; 100 °C; 5 h	8	^25
8	Amberlite	Toluene; 100 °C; 5 h	36	^25
9	Zeolite type Y	Toluene; 100 °C; 5 h	41	^25
10	BaMoO4	EtOH; RT; 2 h	81	^33
11	BaSO4	EtOH; RT; 100 min	87	This study

^aIsolated yield; based on the preparation of 2,3-diphenylthiazolidin-4-one.

The present method is superior to the reported methods with respect to the reaction time and yield of the product. Our attention was then turned to the possibility of recycling the catalyst from the reaction media since the recovery and reuse of the catalyst are preferable for a green context. At the completion of the reaction, the reaction mixture was poured into chloroform and stirred for 5 min. The separated solid catalyst was filtered, dried and reused for subsequent reactions, with the preparation of T₉ as a model. The BaSO₄ nanoparticles still had good activity after 10 cycles (Figure 1).

Figure 1. Reusability of BaSO₄ nano-powder.

In conclusion, the nano-powder BaSO₄ prepared by a simple precipitation method was used as an efficient catalyst for the preparation of 2,3-diarylthiazolidin-4-one derivatives. Application of 0.18 equivalents of BaSO₄ provides good yields of products for the condensation reaction of aromatic aldehydes, aromatic amines, and thioglycolic acid under ambient conditions. We feel that the simplicity of the method system makes it suitable for further research and practical applications.

Experimental section

All reagents were purchased from Merck and Aldrich (Germany), and used without further purification. All yields refer to isolated products after purification. The NMR spectra were recorded on a Bruker Avance DPX 400 MHz instrument (Germany). The spectra were measured in DMSO-d₆ relative to TMS (0.00 ppm). Elemental analysis was performed on a Heraeus CHN-O-Rapid analyzer. TLC was performed on silica gel PolyGram SIL G/UV 254 plates to monitor reactions. The powder X-Ray diffraction patterns were measured with a D8 Avance, Bruker, AXS (Germany), diffractometer using Cu-K_α irradiation. FE-SEM was taken on a Hitachi S-4160 (Japan) photograph to examine the shape and size of BaSO₄ nanoparticles.

Preparation of triethylammonium hydrogen sulfate

Triethylammonium hydrogen sulfate was prepared and characterized according to a literature method as follows: Triethylamine (100 mmol) was added to sulfuric acid (100 mmol) drop wise at room temperature. Subsequently, the reaction mixture was stirred at 100 °C for 30 min. Then, to remove the traces of water, the mixture was placed in a vacuum at 80 °C until the weight of the residue remained constant.⁴⁰

Preparation of BaSO4 nano-powder

Triethylammonium hydrogen sulfate (10 mmol dissolved in 50 mL of EtOH) was added dropwise to an aqueous solution of BaCl₂ (10 mmol BaCl₂ in 250 mL of water), with vigorous stirring at room temperature. After complete addition, the resulting mixture was left for 30 min. The resulting precipitate was separated from the mother liquor by filtering and then washed with ethanol several times, then dried at 100 °C for 10 min. The obtained BaSO₄ nanoparticles were slightly ground for analysis, then characterized using the instrumentation described above. The characterization data were submitted for review and are available in the Supplementary Material or from the corresponding author upon request.

General procedure for synthesis of 2,3-diarylthiazolidin-4-one derivatives

To a mixture of thioglycolic acid (1 mmol), benzaldehyde (1 mmol) and aromatic amine (1 mmol) in ethanol (5 mL), BaSO₄ nano-powder (0.18 mmol) was added and the mixture was stirred for the appropriate time at room temperature, with progress of the reaction monitored by TLC. Upon completion, the solvent was evaporated, and the mixture was diluted in dichloromethane. The catalyst was isolated by simple filtration for re-use as described above, and the crude compounds were crystallized from n-hexane/ethyl acetate to afford the pure products (T₁-T₁₁) (Scheme 1, Table 2). Known compounds were identified by matching their melting points with values in the literature cited in Table 2.

2-(4-Chlorophenyl)-3-p-tolylthiazolidin-4-one (T₁)

White powder, m.p. 145-147 °C, ¹H NMR (400 MHz, DMSO-d₆): δ = 2.24 (s, 3H), 3.68 (d, J = 16.0 Hz, 1H), 3.93 (d, J = 16.0 Hz, 1H), 6.39 (s, 1H), 7.13-7.16 (dd, J = 8.0 Hz, J = 3.2 Hz, 2H), 7.43-7.46 (dd, J = 8.0 Hz, J = 2.8 Hz, 2H), 7.63-7.72 (m, 4H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): 20.8, 33.8, 68.2, 113.6, 129.3, 129.4, 129.7, 132.3, 135.5, 139.2, 144.6, 170.8 ppm.

Anal. Calcd for C₁₆H₁₄ClNOS: C, 63.26; H, 4.65; N, 4.61; S, 10.55. Found: C, 63.33; H, 4.71; N, 4.58; S, 10.46.

2-(2-Chlorophenyl)-3-p-tolylthiazolidin-4-one (T₂)

White powder, m.p. 121-123 °C, ¹H NMR (400 MHz, DMSO-d₆): δ = 2.26 (s, 3H), 3.78 (d, J = 16.0 Hz, 1H), 4.07 (d, J = 16.0 Hz, 1H), 6.13 (s, 1H), 7.08-7.28 (dd, J = 8.0 Hz, J = 2.8 Hz, 2H), 7.29-7.39 (m, 4H), 7.58 (d, J = 8.0 Hz, 1H), 7.70-7.74 (dd, J = 8.0 Hz, J = 2.8 Hz, 2H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): 20.9, 34.0, 68.3, 113.7, 127.5, 127.7, 128.6, 129.7, 130.4, 130.6, 132.4, 133.0, 152.5, 172.4 ppm.

Anal. Calcd for C₁₆H₁₄ClNOS: C, 63.26; H, 4.65; N, 4.61; S, 10.55. Found: C, 63.29; H, 4.68; N, 4.57; S, 10.48.

2-(4-Methoxyphenyl)-3-p-tolylthiazolidin-4-one (T₃)

White powder, m.p. 152-154 °C, ¹H NMR (400 MHz, DMSO-d₆): δ = 2.27 (s, 3H), 3.71 (d, J = 15.6 Hz, 1H), 3.84-3.89 (m, 4H), 5.94 (s, 1H), 6.90-6.93 (dd, J = 8.0 Hz, J = 2.8 Hz, 2H), 7.07-7.30 (m, 6H) ppm.

Anal. Calcd for C₁₇H₁₇NO₂S: C, 68.20; H, 5.72; N, 4.68; S, 10.71. Found: C, 68.29; H, 5.78; N, 4.71; S, 10.75.

2-(4-Hydroxyphenyl)-3-p-tolylthiazolidin-4-one (T₄)

White powder, m.p. 127-129 °C, ¹H-NMR (400 MHz, CDCl3): 2.27 (s, 3H), 3.71 (d, J = 12.4 Hz, 1H), 3.82 (d, J = 12.4 Hz, 1H), 5.14 (s, 1H), 6.70-7.14 (m, 6H), 7.73 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 20.6, 34.0, 52.3, 115.7, 120.8,129.7, 130.8, 148.7, 157.2,159.3, 160.7, 170.4 ppm.

Anal. Calcd for C₁₆H₁₅NO₂S: C, 67.34; H, 5.30; N, 4.91; S, 11.23. Found: C, 67.39; H, 5.36; N, 4.94; S, 11.17.

2,3-bis(4-Methoxyphenyl)thiazolidin-4-one (T₅)

White powder, m.p. 121-123 °C, ¹H NMR (400 MHz, DMSO-d₆): δ = 3.72-3.79 (m, 7H), 3.98 (d, J = 16.0 Hz, 1H), 6.15 (s, 1H), 6.77-6.80 (dd, J = 8.0 Hz, J = 2.8 Hz, 2H), 6.98 (d, J = 7.2 Hz, 2H), 7.08-7.10 (dd, J = 8.0 Hz, J = 2.4 Hz, 2H), 7.37 (d, J = 7.2 Hz, 2H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): 33.7, 55.0, 57.6, 68.2, 114.3, 123.4, 127.6, 139.1, 144.6, 156.9, 160.4, 170.9 ppm.

Anal. Calcd for C₁₇H₁₇NO₃S: C, 64.74; H, 5.43; N, 4.44; S, 10.17. Found: C, 64.78; H, 5.47; N, 4.39; S, 10.14.

2-(4-Chlorophenyl)-3-(4-methoxyphenyl)thiazolidin-4-one (T₆)

White powder, m.p. 155-157 °C, ¹H NMR (400 MHz, DMSO-d₆): δ = 3.78-3.81 (m, 4H), 4.01 (d, J = 16.0 Hz, 1H), 5.98 (s, 1H), 6.87-6.90 (dd, J = 7.6 Hz, J = 2.8 Hz, 2H), 7.12-7.15 (dd, J = 7.6 Hz, J = 2.4 Hz, 2H), 7.32-7.34 (dd, J = 7.6 Hz, J = 2.8 Hz, 2H), 7.46-7.48 (dd, J = 8.0 Hz, J = 2.8 Hz, 2H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): 33.9, 55.1, 68.2, 114.4, 123.5, 129.4, 129.5, 135.6, 139.2, 144.7, 156.9, 170.9 ppm.

Anal. Calcd for C₁₆H₁₄ClNO₂S: C, 60.09; H, 4.41; N, 4.38; S, 10.02. Found: C, 60.16; H, 4.48; N, 4.32; S, 9.96.

2-(4-Nitrophenyl)-3-(4-methoxyphenyl)thiazolidin-4-one (T₇)

White powder, m.p. 149-151 °C, ¹H NMR (400 MHz, DMSO-d₆): δ = 3.77-3.85 (m, 4H), 3.99 (d, J = 16.0 Hz, 1H), 6.39 (s, 1H), 6.79-6.82 (dd, J = 8.0 Hz, J = 2.4 Hz, 2H), 7.13-7.16 (dd, J = 8.4 Hz, J = 2.8 Hz, 2H), 7.50-7.52 (dd, J = 7.6 Hz, J = 2.4 Hz, 2H), 8.14-8.17 (dd, J = 7.6 Hz, J = 2.4 Hz, 2H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): 33.8, 55.1, 68.2, 114.3, 123.4 (2C), 127.6, 139.1, 144.6, 147.9, 156.9, 170.9 ppm.

Anal. Calcd for C₁₆H₁₄N₂O₄S: C, 58.17; H, 4.27; N, 8.48; S, 9.70. Found: C, 58.21; H, 4.30; N, 8.46; S, 9.64.

2-Phenyl-3-(4-chlorophenyl)thiazolidin-4-one (T₈)

White powder, m.p. 166-168 °C, ¹H NMR (400 MHz, DMSO-d₆): δ = 3.85 (d, J = 15.6 Hz, 1H), 4.11 (d, J = 15.6 Hz, 1H), 6.31 (s, 1H), 7.30-7.59 (m, 7H), 7.97 (t, J = 5.2 Hz, 2H) ppm.

Anal. Calcd for C₁₅H₁₂ClNOS: C, 62.17; H, 4.17; N, 4.83; S, 11.06. Found: C, 62.25; H, 4.23; N, 4.86; S, 11.09.

Acknowledgments

We thank the Research Council of Najafabad Branch, Islamic Azad University, for partial support of this research. Financial assistance from the Shiraz University of Medical Sciences by way of grant number 23670 is also gratefully acknowledged.