5,5′-(Piperazine-1,4-diyl)bis(4-chloro-3H-1,2-dithiol-3-one)

Abstract

Conjugates of 3H-1,2-dithiol-3-ones with various biologically active compounds are intensively investigated. Although many derivatives of this class have been described in the literature, the compounds containing two dithiole cycles have been explored much less. In this communication, it was shown that the reaction of 4,5-dichloro-3H-1,2-dithiol-3-one with piperazine can selectively lead to the mono-product, 4-chloro-5-piperazin-1-yl-3H-1,2-dithiol-3-one and bis-product, 5,5′-(piperazine-1,4-diyl)bis(4-chloro-3H-1,2-dithiol-3-one). The structure of the synthesized compounds was established by elemental analysis, high resolution mass-spectrometry, ¹H, ¹³C NMR and IR spectroscopy, and mass-spectrometry.

1. Introduction

Among 1,2-dithioles, 3H-1,2-dithiole-3-thiones have been widely studied [1,2,3] as compounds that endogenously produce hydrogen sulfide (H₂S), the third gaseous signaling molecule [4]. It is known that 1,2-dithiole-3-thiones can extrude sulfur and convert to 1,2-dithiol-3-ones, which are also characterized by many types of biological actions, particularly cancer prevention [5,6,7], amongst other activities [8,9]. In some cases, keto-analogues showed an activity comparable to the effects of the corresponding thione derivatives. Thus, the keto-analogue of the active ingredient of the cancer-preventive drug oltipraz, 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one (Figure 1), increased the activity of the detoxifying cytoprotective enzyme DT-diaphorase in HT29 intestinal adenocarcinoma cells by 2.8 times compared to the control, while this factor for oltipraz itself was only 2.6 times [10].

Among dithiolones, the readily available 4,5-dichloro-3H-1,2-dithiol-3-one 1 [11] can be considered an attractive starting material for many biologically active molecules due to the easy reactivity of the 5-chlorine atom in 5-chloro-3H-1,2-dithiol-3-ones [12,13,14]. Piperazine is a remarkable scaffold in the generation of diverse pharmacological agents [15]. We have suggested that the combination of the piperazine scaffold together with one or with two 3H-1,2-dithiol-3-one cores can provide novel biologically important compounds. Herein, we report the reaction of 4,5-dichloro-3H-1,2-dithiol-3-one 1 with piperazine with the selective formation of 4-chloro-5-piperazin-1-yl-3H-1,2-dithiol-3-one 2 and 5,5′-(piperazine-1,4-diyl)bis(4-chloro-3H-1,2-dithiol-3-one) 3.

2. Results and Discussion

The treatment of 4,5-dichloro-3H-1,2-dithiol-3-one 1 with an excess of piperazine in methanol at room temperature led to a mono-product 2 with a high yield (Scheme 1,

Table 1. Reaction of 4,5-dichloro-3H-1,2-dithiol-3-one 1 with piperazine.

Entry	Solvent	Piperazine (equiv)	Et3N (equiv)	Temperature, °C	Time, h	Yield, %
						2	3
1	MeOH	2	0	25	0.5	85	0
2	MeOH	1.5	0	65	1	71	15
3	MeOH	0.5	2	25	6	33	51
4	MeOH	0.5	2	65	2	0	89
5	MeCN	0.5	2	81	1	0	86

, Entry 1). At the same time, carrying out the reaction at a higher temperature with a slightly smaller (1.5 eqv) excess of piperazine gave a mixture of 4-chloro-5-piperazin-1-yl-3H-1,2-dithiol-3-one 2 and 5,5′-(piperazine-1,4-diyl)bis(4-chloro-3H-1,2-dithiol-3-one) 3 (Entry 2). For the selective formation of bis-product 3, we decided to use a base (triethylamine) to bind the released hydrogen chloride. However, conducting the reaction in methanol at room temperature also resulted in a mixture of mono- 2 and bis-product 3 (Entry 3). The refluxing of a similar reaction mixture led to the selective formation of bis-product 3 with a high yield (Entry 4). The use of acetonitrile as a solvent instead of methanol, although it reduced the reaction time, did not increase the yield of the final product 3 (Entry 5). A separate experiment has shown that the treatment of mono-product 2 with dichlorodithiol 1 in the presence of triethylamine led to bis-product 3.

The structure of 5,5′-(piperazine-1,4-diyl)bis(4-chloro-3H-1,2-dithiol-3-one) 3 and 4-chloro-5-piperazin-1-yl-3H-1,2-dithiol-3-one 2 was fully confirmed by elemental analysis, high resolution mass-spectrometry, ¹H, ¹³C NMR and IR spectroscopy, and mass-spectrometry.

In conclusion, the selective synthesis of 5-piperazinyl derivatives of 1,2-dithiol-3-one 2 and 3 was developed by the reaction of 4,5-dichloro-3H-1,2-dithiol-3-one 1 with piperazine. The compounds obtained may have useful pharmacological properties.

3. Materials and Methods

4,5-Dichloro-1,2-dithiol-3-one 1 was prepared according to the published method [12]. The solvents and reagents were purchased from commercial sources and used as received. Elemental analysis was performed on a 2400 Elemental Analyzer (Perkin ElmerInc., Waltham, MA, USA). The melting point was determined on a Kofler hot-stage apparatus and is uncorrected. The ¹H and ¹³C NMR spectra were taken with a Bruker AM-300 machine (Bruker AXS Handheld Inc., Kennewick, WA, USA) (at frequencies of 300 and 75 MHz) with TMS as the standard. The MS spectrum (EI, 70 eV) was obtained with a Finnigan MAT INCOS 50 instrument (Hazlet, NJ, USA). The IR spectrum was measured with a Bruker “Alpha-T” instrument in a KBr pellet. The high-resolution MS spectrum was measured on a Bruker micrOTOF II instrument (Bruker Daltonik Gmbh, Bremen, Germany) using electrospray ionization (ESI).

Synthesis of 4-chloro-5-piperazin-1-yl-3H-1,2-dithiol-3-one 2 (Supplementary Materials, Figures S1–S5).

A solution of 4,5-dichloro-1,2-dithiol-3-one 1 (94 mg, 0.5 mmol) in MeOH (5 mL) was added to a solution of piperazine (86 mg, 1 mmol) in MeOH (10 mL). The reaction mixture was stirred for 30 min at room temperature. The solvent was distilled, and the residue was treated with water (10 mL) and extracted with CH₂Cl₂ (2 × 20 mL). Combined organic extracts were washed with brine and dried with MgSO₄. The solvent was removed, and the residue was treated with water, filtered, washed with water (5 mL) and dried. Yield 98 mg (83%), yellow solid, mp. 90–92 °C. IR spectrum (KBr), ν, cm⁻¹: 3448 (C-H), 3342 (N-H), 2956 and 2824 (C-H), 1631 (C=O), 1532, 1442 (CH₂), 1327, 1258, 1198, 1027 (C-Cl), 814, 778, 648, 517. ¹H-NMR (DMSO-d₆, ppm): δ 2.86 (4H, m), 3.61 (4H, m). ¹³C-NMR (DMSO-d₆, ppm): 45.4 (2 C-H), 51.1 (2 C-H), 98.5 (C-Cl), 168.7 (C-N), 183.2 (C=O). MS (EI, 70 Ev), m/z (I, %): 238 (M + 2, 15), 236 (M+, 45), 201 (100), 194 (20), 172 (10), 137 (25), 91 (15), 87 (20), 64 (45), 56 (82), 42 (30). HRMS (ESI-TOF): calcd for C₇H₁₀ClN₂OS₂ [M + H]⁺ 236.9921; found m/z 236.9918; calcd for C₇H₉ClN₂NaOS₂ [M + Na]⁺ 258.9741, found m/z 258.9737.

Synthesis of 5,5′-(piperazine-1,4-diyl)bis(4-chloro-3H-1,2-dithiol-3-one) 3 (Supplementary Materials, Figures S6–S10).

• From 4,5-dichloro-1,2-dithiol-3-one 1

Triethylamine (0.28 mL, 2 mmol) and piperazine (43 mg, 0.5 mmol) were added to a solution of 4,5-dichloro-1,2-dithiol-3-one 1 (187 mg, 1 mmol) in MeOH (15 mL), and the reaction mixture was refluxed for 2 h. The residue was treated with water (10 mL), filtered, washed with 2M solution HCl (3 mL), brine (3 mL) and dried. Yield 172 mg (89%), dark yellow solid, mp. 78–80 °C. IR spectrum (KBr), ν, cm⁻¹: 3467, 2925 and 2852 (all C-H), 1648 (C=O), 1528, 1438 (CH₂), 1376, 1281, 1197, 1006 (C-Cl), 822, 775, 477. ¹H-NMR (DMSO-d₆, ppm): δ 3.91 (8H, br s). ¹³C-NMR (DMSO-d₆, ppm): 48.6 (4 C-H), 98.8 (C-Cl), 167.9 (C-N), 182.8 (C=O). MS (EI, 70 Ev), m/z (I, %): 388 (M + 2, 10), 386 (M+, 15), 351 (5), 256 (10), 201 (10), 128 (15), 96 (15), 64 (100), 32 (45). HRMS (ESI-TOF): calcd for C₁₀H₉Cl₂N₂O₂S₄ [M + H]⁺ 386.8920; found m/z 386.8918; calcd for C₁₀H₈Cl₂N₂NaO₂S₄ [M + Na]⁺ 408.8737, found m/z 408.8738.

b.

From 4-chloro-5-piperazin-1-yl-3H-1,2-dithiol-3-one 2

Triethylamine (0.28 mL, 2 mmol) was added to a solution of 4,5-dichloro-1,2-dithiol-3-one 1 (187 mg, 1 mmol) and 4-chloro-5-piperazin-1-yl-3H-1,2-dithiol-3-one 2 (118 mg, 1 mmol) in MeOH (15 mL), and the reaction mixture was refluxed for 2 h. The residue was treated with water (10 mL), filtered, washed with 2M solution HCl (3 mL), brine (3 mL) and dried. Yield 328 mg (85%).