5-[2-(4-Chlorophenyl)-2-oxoethyl]-3-(4-hydroxyphenyl)-2-thioxo-1,3-thiazolidin-4-one

Abstract

Rhodanine derivatives, as a subtype of thiazolidin-4-ones, represent an important class of heterocyclic compound known for their broad spectrum of biological activities and practical applications. In this short note, the synthesis of a new compound, 5-[2-(4-chlorophenyl)-2-oxoethyl]-3-(4-hydroxyphenyl)-2-thioxo-1,3-thiazolidin-4-one, is described. The target molecule was synthesized via a thia-Michael addition followed by cyclocondensation. Its structure was confirmed by ¹H and ¹³C NMR spectroscopy and further supported by 2D NMR studies.

1. Introduction

In recent years, heterocyclic compounds have attracted considerable attention due to their remarkable structural diversity and broad spectrum of biological activities. Among these, rhodanine derivatives stand out as a particularly important subclass of thiazolidin-4-ones, well known for their promising pharmacological potential and versatile synthetic applications [1,2,3]. Their chemical scaffold enables the design of molecules with diverse biological properties, making them valuable candidates for the development of new antimicrobial [4,5], antiviral [6,7], anticancer [8,9], and anti-inflammatory [10,11] agents. Beyond their therapeutic significance, rhodanine-based compounds are also widely used as intermediates in organic synthesis and as key building blocks for advanced materials, dyes, and sensors [12,13].

Motivated by the ongoing search for new bioactive molecules, this short note describes the synthesis of a novel 5-[2-(4-chlorophenyl)-2-oxoethyl]-3-(4-hydroxyphenyl)-2-thioxo-1,3-thiazolidin-4-one, which may serve as a promising candidate for further biological studies.

2. Results and Discussion

The target, compound 3, was obtained through two-step synthesis (Scheme 1) [14]. In the first step, 4-aminophenol (1) was reacted with carbon disulfide in the presence of triethylamine, leading to the formation of triethylammonium (4-hydroxyphenyl)dithiocarbamate (2). In the second step, compound 2 underwent a thia-Michael addition with 3-(4-chlorobenzoyl)acrylic acid, followed by cyclocondensation of the resulting intermediate, to yield the target compound, 5-[2-(4-chlorophenyl)-2-oxoethyl]-3-(4-hydroxyphenyl)-2-thioxo-1,3-thiazolidin-4-one (3).

The structure of the target, compound 3, was elucidated through elemental analysis, FT-IR, and ¹H and ¹³C NMR spectroscopy, and supported by 2D NMR experiments (COSY, NOESY, HSQC, and HMBC), which were instrumental in assigning key signals.

The chemical shifts in proton signals derived from para-substituted phenyl moieties were presented as two doublets at 6.89 and 7.08 ppm for the 4-hydroxyphenyl fragment, and 7.64 and 8.01 ppm for the 4-chlorophenyl substituent with coupling constants (J) 8.8 and 8.7 Hz, respectively. Furthermore, compound 3 contains diastereotopic protons of the methylene group. This fragment is presented in ¹H NMR as an ABX spin system (CH^AH^BCH^X), which appears as three doublets of doublets at 4.01, 4.18, and 4.96 ppm. The values of coupling constants were 3.5, 8.4, and 19.0 Hz for J_AB, J_AX, and J_BX, respectively. The high value of J_BX agreed with the data from Takahashi (“carbonyl effect”) for the structurally related 2-thioxo-4-oxothiazolidine-5-acetic acid [15].

The ¹³C NMR spectrum of compound 3 confirmed the presence of all carbon atoms in the molecule. It exhibited a characteristic signal for the C=S group at 204.2 ppm. The signals of the two C=O groups were observed at 176.8 ppm for the carbonyl of the thiazolidine ring and at 196.5 ppm for the carbonyl of the 4-chlorobenzoyl moiety. The signals from the aliphatic fragment of the molecule appeared at 41.1 ppm (CH₂) and 46.5 ppm (CH). All aromatic carbons were observed in the range of 116.2–158.5 ppm. The HMBC experiment shown in Figure 1 presented long-range correlations between protons and carbon atoms (¹³C).

The detailed data from the ¹H and ¹³C NMR, DEPT-135, and 2D NMR experiments (COSY, NOESY, HSQC, and HMBC) are presented in the Materials and Methods Section and the Supplementary Materials (Figures S1–S7).

The IR spectral analysis of compound 3 confirms two distinct carbonyl stretching vibrations at 1731 and 1668 cm⁻¹, corresponding to the carbonyl groups in the thiazolidine ring and next to the 4-chlorophenyl moiety. Also observed was an absorption band at 1157 cm⁻¹, corresponding to the C=S group. The detailed FT-IR absorption bands are presented in the Supplementary Materials (Figure S8).

3. Materials and Methods

3.1. General

All commercial reagents and solvents were purchased from Merck Co. (Darmstadt, Germany) or Fisher Scientific (Waltham, MA, USA) and used without further purification. The melting point was determined using an Electrothermal Standard 120 VAC apparatus (Cole-Parmer, Wertheim, Germany) and was uncorrected. The ¹H NMR and ¹³C NMR spectra and DEPT-135 and 2D NMR experiments were recorded by a Bruker Avance DPX 600 (Billerica, MA, USA) using DMSO-d₆ as solvent and TMS as an internal standard. Chemical shifts were expressed as δ (ppm). Multiplicities are reported, using the standard abbreviations, as follows: singlet (s), doublet (d), doublet of doublets (dd). The FT-IR spectrum was recorded with a Nicolet 6700 spectrometer (Thermo Scientific, Philadelphia, PA, USA). Elemental analysis was performed with an AMZ 851 CHX analyser (PG, Gdansk, Poland) and the results were within ±0.4% of the theoretical value.

3.2. Synthesis of Triethylammonium (4-hydroxyphenyl)dithiocarbamate (2)

The synthesis of triethylammonium (4-hydroxyphenyl)dithiocarbamate (compound 2) was performed according to a previously described method [16,17]. The physicochemical data were consistent with those reported in the patents [16,17].

3.3. Synthesis of 5-[2-(4-Chlorophenyl)-2-oxoethyl]-3-(4-hydroxyphenyl)-2-thioxo-1,3-thiazolidin-4-one (3)

To a solution of 0.005 mol (1.43 g) of triethylammonium (4-hydroxyphenyl)dithiocarbamate in 10 mL of ethanol, a solution of 0.005 mol (1.05 g) of 3-(4-chlorobenzoyl)acrylic acid in ethanol (10 mL) was added. The reaction mixture was stirred at room temperature for 30 min. Then, the reaction mixture was acidified with 3 mL of concentrated HCl. The product was precipitated by pouring the mixture into 100 mL of water. The resulting precipitate was filtered and recrystallized from methanol.

Yield 74%, m.p. = 200–201 °C. FT-IR (ν, cm⁻¹): 1731, 1668 (C=O), 1589 (C=C), 1348 (C-N), 1212 (C_ar-OH), 1157 (C=S), 806 (C-S).

¹H NMR (600 MHz, DMSO-d₆) δ (ppm): 4.01 dd (1H, CH-CH₂, J = 8.4, 19.0 Hz); 4.18 dd (1H, CH-CH₂, J = 3.5, 19.0 Hz); 4.96 dd (1H, CH-CH₂, J = 3.5, 8.4 Hz); 6.89 d, 7.08 d (4H, 4-OH-C₆H₄, J = 8.8 Hz); 7.64 d, 8.01 d (4H, 4-Cl-C₆H₄, J = 8.7 Hz); 9.85 s (1H, OH). ¹³C NMR (150 MHz, DMSO-d₆) δ (ppm): 41.1 (CH₂), 46.5 (CH), 116.2 (2C_ar.), 127.1 (C_ar.-N), 129.5 (2C_ar.), 130.1 (2C_ar.), 130.6 (2C_ar.), 134.6 (C_ar.-CO), 139.4 (C_ar.-Cl), 158.5 (C_ar.-OH), 176.8 (C=O, thiazolidine), 196.5 (C=O), 204.2 (C=S). Anal. calc. for C₁₇H₁₂ClNO₃S₂ (377.865) (%): C 54.04, H 3.20, N 3.71. Found: C 54.07, H 3.17, N 3.65.

4. Conclusions

As a result of the current research, a new rhodanine derivative 3, namely, 5-[2-(4-chlorophenyl)-2-oxoethyl]-3-(4-hydroxyphenyl)-2-thioxo-1,3-thiazolidin-4-one, has been synthesized. The compound was obtained at a good yield via a thia-Michael addition reaction followed by intramolecular cyclocondensation, starting from triethylammonium (4-hydroxyphenyl)dithiocarbamate.