Method for synthesizing eight-membered sulfur-bridged dithiacyclophane derivative under catalysis of copper

Abstract

(1), (2) and (3)

Description

Technical Field

[0001] This invention belongs to the field of fine chemical organic synthesis technology, specifically relating to a method for copper-catalyzed synthesis of octetrate sulfur-bridged disulfide heterocyclic derivatives. Background Technology

[0002] Currently, strategies for constructing eight-membered sulfur-bridged disulfide heterocyclic structures mainly rely on intramolecular cyclization or multi-step reaction sequences of prefunctionalized substrates. For example, eight-membered disulfide rings can be constructed through nucleophilic substitution of thiols with halides, but this method is typically cumbersome and difficult to control in terms of regio and stereoselectivity. Furthermore, electrochemical oxidation or strong oxidants have been reported to treat dithiol precursors to generate disulfide bonds, but these methods also suffer from operational complexity, high equipment requirements, and limited functional group compatibility. Therefore, developing a novel method that is economical, operates under mild conditions, has good functional group tolerance, and can directly construct eight-membered sulfur-bridged ring structures from readily available raw materials has significant scientific value and practical application needs.

[0003] Sulfur-containing heterocyclic compounds, especially those with medium-sized sulfur-bridged structures, play a crucial role in medicinal chemistry, materials science, and supramolecular chemistry. For example, Deanxit is a compound anti-anxiety drug suitable for neurasthenia, chronic fatigue syndrome, anxiety and depression, and nervous headaches; Chlorprothixene is a prescription antipsychotic drug used for schizophrenia, menopausal depression, and anxiety neurosis accompanied by anxiety or depression; Aureothricin was first obtained from Streptomyces and has relatively broad-spectrum antibacterial activity, inhibiting the adhesion of human umbilical vein endothelial cells (HUVECs) to hydrin; Asparagusic acid is a sulfur-containing odorant in asparagus plants that can inhibit fungal growth and repel pests and diseases, and has strong nematicidal activity, thus preventing damage to body tissues by parasitic nematodes; (R)-(+)-Lipoic Acid is a dextrorotatory sulfur-containing vitamin drug clinically used to treat chronic hepatitis, cirrhosis, lupus erythematosus, and as an adjunct treatment for diabetes, neurological diseases, and immune system diseases. Therefore, exploring different methods to synthesize diverse sulfur-bridged heterocyclic compounds is a hot topic in organic synthesis research, with broad prospects and significant importance.

[0004] Summary of the Invention

[0005] The purpose of this invention is to provide a copper-catalyzed method for synthesizing octetral sulfur-bridged dithiocyclic bismuth derivatives. This method is simple to operate, uses readily available reagents, has mild reaction conditions, and yields high product yields.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for the copper-catalyzed synthesis of an octetary sulfur-bridged disulfide heterocyclic derivative, wherein in an organic solvent system, o-bromobenzylthioamide compound as shown in formula (1) and potassium ethyl xanthate as shown in formula (2) are used as raw materials, and copper salt is used as a catalyst, alkali and ligand are added, and the reaction is stirred at 70°C. The reaction is monitored by TLC until the reaction is complete, and the reaction solution is treated to obtain the octetary sulfur-bridged disulfide heterocyclic derivative shown in formula (3); The organic solvent is one of dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, and toluene. The copper salt is one of cuprous iodide, cuprous bromide, cuprous oxide, and copper oxide; The alkali is one of potassium carbonate, cesium carbonate, sodium carbonate, and sodium bicarbonate; The ligand is one of L-proline, triphenylphosphine, and o-phenanthroline; The molar ratio between the o-bromobenzylthioamide compound and potassium ethyl xanthate is 2:1; Among them, R 1 It is one of -Cl, -Me, or -H; R 2 It is one of -i-Pr, -Me, or -H; R 3 It is one of -Me or -H.

[0007] Preferably, the copper salt is cuprous iodide, the base is potassium carbonate, and the ligand is L-proline.

[0008] Preferably, the amount of the copper salt is 10 mol% of the o-bromobenzylthioamide compound shown in formula (1), the amount of the ligand is 20 mol% of the o-bromobenzylthioamide compound shown in formula (1), and the amount of the base is 100 mol% of the o-bromobenzylthioamide compound shown in formula (1).

[0009] Preferably, the organic solvent is dimethyl sulfoxide.

[0010] Preferably, the amount of the organic solvent used is 5 mL / mmol of the o-bromobenzylthioamide compound represented by formula (1).

[0011] Preferably, the developing solvent used for TLC tracking reaction is petroleum ether: ethyl acetate = 10: 1, V / V.

[0012] Further, the post-treatment method of the reaction solution is as follows: after the reaction is completed, the reaction is quenched with water, extracted with ethyl acetate, then the organic phase is backwashed with water, dried with anhydrous sodium sulfate, distilled under reduced pressure, and then separated by silica gel column chromatography. The eluent is distilled under reduced pressure and dried to obtain the octagonal sulfur-bridged disulfide heterocyclic derivative shown in formula (3).

[0013] Preferably, the eluent for the silica gel column chromatography is petroleum ether: ethyl acetate = 10: 1, V / V.

[0014] Compared with the prior art, the present invention has the following beneficial effects: This invention uses copper salts as catalysts and o-bromobenzylthioamide compounds and potassium ethyl xanthate as raw materials to synthesize octyl-sulfur-bridged disulfide heterocyclic piracene derivatives via a Ullmann coupling one-pot method. This invention is simple to operate, uses readily available reagents, employs mild reaction conditions, has a green and environmentally friendly reaction system, and produces easily separable and purified products with high yields. It is suitable for synthesizing various highly functionalized octyl-sulfur-bridged disulfide heterocyclic piracene derivatives, and is particularly suitable for large-scale industrial production, enabling the efficient and high-yield production of high-purity octyl-sulfur-bridged disulfide heterocyclic piracene derivatives. Attached Figure Description

[0015] Figure 1 For octetrate-bridged disulfide heterocyclic derivative 3a 1 H-NMR nuclear magnetic resonance spectrum; Figure 2 For octetrate-bridged disulfide heterocyclic derivative 3a 13 C-NMR nuclear magnetic resonance spectrum; Figure 3 For octylsulfide-bridged disulfide heterocyclic derivative 3b 1 H-NMR nuclear magnetic resonance spectrum; Figure 4 For octylsulfide-bridged disulfide heterocyclic derivative 3b 13 C-NMR nuclear magnetic resonance spectrum; Figure 5 3c is an octetrally sulfur-bridged disulfide heterocyclic derivative. 1 H-NMR nuclear magnetic resonance spectrum; Figure 6 3c is an octetrally sulfur-bridged disulfide heterocyclic derivative. 13 C-NMR nuclear magnetic resonance spectrum; Figure 7 For 3d octetrate sulfur-bridged disulfide heterocyclic derivatives 1 H-NMR nuclear magnetic resonance spectrum; Figure 8 For 3d octetrate sulfur-bridged disulfide heterocyclic derivatives 13 C-NMR nuclear magnetic resonance spectrum; Figure 9 3e is an octyl sulfur-bridged disulfide heterocyclic derivative. 1 H-NMR nuclear magnetic resonance spectrum; Figure 10 3e is an octyl sulfur-bridged disulfide heterocyclic derivative. 13 C-NMR nuclear magnetic resonance spectrum; Figure 11 3f is an octetrating sulfur-bridged disulfide heterocyclic derivative. 1 H-NMR nuclear magnetic resonance spectrum; Figure 12 3f is an octetrating sulfur-bridged disulfide heterocyclic derivative. 13 C-NMR nuclear magnetic resonance spectrum. Detailed Implementation

[0016] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0017] Example 1: Preparation of octa-sulfur-bridged disulfide heterocyclic derivative 3a N-(3-chlorophenyl)-2-bromobenzylthionamide 1a (0.292 g, 1.0 mmol), cuprous iodide (0.019 g, 10% mmol), L-proline (0.023 g, 20% mmol), potassium carbonate (0.138 g, 100% mmol), and potassium ethyl xanthate 2a (0.080 g, 0.5 mmol) were added to a 25 mL Shrek flask equipped with a magnetic stirrer and then transferred to a dry reaction flask with a high-vacuum valve. After three purgings under vacuum with argon, dimethyl sulfoxide (5.0 mL) was injected into the mixture. The mixture was stirred thoroughly and then placed in a 70°C oil bath with continued stirring. TLC (developing solvent: V) was performed. 石油醚 V 乙酸乙酯 = 10:1) The reaction ended when the substrate disappeared. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (3 × 10 mL), and the organic phases were combined. The organic phase was then backwashed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a viscous solid. Finally, the solid was subjected to silica gel column chromatography (eluent: V). 石油醚 V 乙酸乙酯 = 10 : 1) to obtain a white solid, which was confirmed by NMR and MS to be an octetary sulfur-bridged disulfide heterocyclic compound 3a, with a yield of 82%.

[0018] Hydrogen and carbon spectra are as follows Figure 1 and Figure 2 As shown, the spectral analysis data is 3a: White solid; 1H NMR (400 MHz, Chloroform-d): 7.68-7.66 (m, 2H), 7.47~7.35 (m, 6H), 7.32~7.28 (m, 2H), 7.18~7.16 (m, 2H), 6.54 (s, 2H), 6.50 (d, J= 8.0 Hz, 2H) ( Figure 1 ); 13C NMR (101 MHz, CHLOROFORM-D): 159.6, 149.8, 141.7, 134.7, 134.3, 134.0, 131.3, 130.7, 129.9, 128.9, 125.0, 120.6, 118.7 Figure 2 );HRMS (ESI-TOF, m / z): calcd for [M + H] + ,491.0205; found, 491.0216. Example 2: Replacing 1a in Example 1 with 1b, and keeping all other conditions the same as in Example 1, yields a 75% success rate.

[0019] Hydrogen and carbon spectra are as follows Figure 3 and Figure 4 As shown, spectral analysis data 3b: White solid; 1 H NMR (400 MHz, Chloroform-d): 7.64-7.63 (m, 2H), 7.41~7.29 (m, 6H), 7.15~7.13 (m, 4H), 6.55 (s, 2H), 6.53 (s, 2H), 2.38 (s, 6H) ( Figure 3 ); 13C NMR (101 MHz, CHLOROFORM-D): 158.4, 146.3, 142.4, 134.7, 134.4, 133.7, 130.8, 130.7, 129.1, 128.7, 120.7, 120.3, 21.0 Figure 4 ); HRMS (ESI-TOF, m / z): calcd for [M + H] + ,451.1297; found, 451.1305. Example 3: Replacing 1a in Example 1 with 1c, and keeping all other conditions the same as in Example 1, yields a return of 81%.

[0020] Hydrogen and carbon spectra are as follows Figure 5 and Figure 6 As shown, the spectral analysis data is 3c: White solid; 1 H NMR (400 MHz, Chloroform-d): 7.64-7.62 (m, 2H), 7.40~7.33 (m, 6H), 7.20~7.18 (m, 4H), 6.55~6.54 (m, 4H), 2.97~2.90 (m, 2H), 1.30(s, 6H), 1.28 (s, 6H) ( Figure 5 ); 13C NMR (101 MHz, CHLOROFORM-D): 158.4, 146.7, 145.6, 142.3, 134.4, 133.7, 133.9, 130.8, 128.7, 126.4, 120.6, 33.6, 24.1 Figure 6 ); HRMS (ESI-TOF, m / z): calcd for [M + H] + ,507.1923; found, 507.1931. Example 4: Replacing 1a in Example 1 with 1d, and keeping all other conditions the same as in Example 1, yields a return of 73%.

[0021] Hydrogen and carbon spectra are as follows Figure 7 and Figure 8 As shown, the spectral analysis data is in 3D: White solid; 1 H NMR (400 MHz, Chloroform-d): 7.68-7.66 (m, 2H), 7.45~7.39 (m, 6H), 7.15~7.11 (m, 4H), 7.08~7.43 (m, 2H), 6.48~6.46 (m, 2H), 1.79(s, 6H) ( Figure 7 ); 13C NMR (101 MHz, CHLOROFORM-D): 158.3, 147.9, 142.5, 134.5, 134.1, 130.8, 130.7, 130.3, 128.9, 128.1, 125.9, 124.9, 119.5, 17.6 Figure 8 ); HRMS(ESI-TOF, m / z): calcd for [M + H] + ,451.1297; found,. 451.1303 Example 5: Replacing 1a in Example 1 with 1e, and keeping all other conditions the same as in Example 1, yields a return of 80%.

[0022] Hydrogen and carbon spectra are as follows Figure 9 and Figure 10 As shown, the spectral analysis data 3e: White solid; 1 H NMR (400 MHz, Chloroform-d): 7.64-7.62 (m, 2H), 7.40~7.24 (m, 6H), 7.10~7.08 (m, 2H), 6.42 (s, 2H), 6.39~6.37 (m, 2H), 2.28 (s,6H), 2.26 (s, 6H) ( Figure 9 ); 13C NMR (101 MHz, CHLOROFORM-D): 158.2, 146.7, 142.4, 136.7, 134.4, 133.7, 133.1, 130.7, 129.6, 128.6, 121.7, 118.0, 19.8, 19.3 Figure 10 ); HRMS (ESI-TOF, m / z): calcd for [M + H] + ,479.1610; found, 479.1623. Example 6: Replacing 1a in Example 1 with 1f, and keeping all other conditions the same as in Example 1, yields a return of 71%.

[0023] Hydrogen and carbon spectra are as follows Figure 11 and Figure 12 As shown, the spectral analysis data 3f: White solid; 1 H NMR (400 MHz, Chloroform-d): 7.65-7.63 (m, 2H), 7.42~7.25 (m, 6H), 6.81 (s, 2H), 6.22 (s, 4H), 2.32 (s, 12H)( Figure 11 ); 13C NMR (101MHz, CHLOROFORM-D): 158.2, 148.8, 142.4, 138.1, 134.4, 133.7, 130.7, 128.5,126.4, 118.0, 21.3( Figure 12 ); HRMS (ESI-TOF, m / z): calcd for [M + H] + , 479.1610;found, 479.1619。

Claims

1. A method for the copper-catalyzed synthesis of octa- thiaspirothiophene derivatives, characterized in that, An o-bromobenzylthioamide compound shown in formula (1) and potassium ethyl xanthate shown in formula (2) are used as raw materials, a copper metal salt is used as a catalyst, a base and a ligand are added, and the reaction is stirred at 70 DEG C, and the reaction is tracked by TLC until the reaction is complete, and the eight-membered sulfur-bridged dithiacyclophane derivative shown in formula (3) is obtained after the reaction liquid is treated; The organic solvent is one of dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide and toluene. The copper metal salt is one of cuprous iodide, cuprous bromide, cuprous oxide and copper oxide. The base is one of potassium carbonate, cesium carbonate, sodium carbonate and sodium bicarbonate. The ligand is one of L-proline, triphenylphosphine and o-phenanthroline. The molar ratio between the o-bromobenzylthioamide compound and potassium ethyl xanthate is 2:

1. wherein R 1 is one of -Cl, -Me, -H; R 2 is one of -i-Pr, -Me, -H; R 3 is one of -Me, -H.

2. The process for the copper catalyzed synthesis of octathiabicyclononane derivatives according to claim 1, characterized in that, The copper metal salt is cuprous iodide, the base is potassium carbonate, and the ligand is L-proline.

3. The method for the copper catalyzed synthesis of octathiabicyclo[4.4.0]decane derivatives according to claim 1 or 2, characterized in that, The amount of the copper metal salt is 10 mol% of the o-bromobenzylthioamide compound shown in formula (1), the amount of the ligand is 20 mol% of the o-bromobenzylthioamide compound shown in formula (1), and the amount of the base is 100 mol% of the o-bromobenzylthioamide compound shown in formula (1).

4. The method for the copper catalyzed synthesis of octathiabicyclo[4.2.2]deca-2,4,6,8- tetraene derivatives according to claim 1 or 2, characterized in that, The organic solvent is dimethyl sulfoxide.

5. The method for the copper catalyzed synthesis of octathiabicyclo[4.2.2]deca-2,4,6,8- tetraene derivatives according to claim 1 or 2, characterized in that, The amount of the organic solvent is 5 mL / mmol of the o-bromobenzylthioamide compound shown in formula (1).

6. The method for the copper catalyzed synthesis of octathiabicyclo[4.2.2]deca-2,4,6,7,9-pentaene derivatives according to claim 1 or 2, characterized in that, The developing agent used for tracking the reaction by TLC is petroleum ether: ethyl acetate = 10:1, V / V.

7. The method for the copper catalyzed synthesis of octathiabicyclo[4.2.2]deca-2,4,6,7,9-pentaene derivatives according to claim 1 or 2, characterized in that, The reaction liquid treatment method is as follows: after the reaction is completed, the reaction is quenched with water, extracted with ethyl acetate, and then the organic phase is backwashed with water, dried with anhydrous sodium sulfate, distilled under reduced pressure, and then separated by silica gel column chromatography, and the obtained eluent is distilled under reduced pressure and dried to obtain the eight-membered sulfur-bridged dithiacyclophane derivative shown in formula (3).

8. The method for copper-catalyzed synthesis of an octetral sulfur-bridged disulfide heterocyclic derivative according to claim 7, characterized in that, The eluent of the silica gel column chromatography is petroleum ether: ethyl acetate = 10:1, V / V.

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