A method for preparing ultrafast metal-free and solvent-free disulfide bond-containing compounds

Abstract

The application discloses a kind of ultrafast metal-free and solvent-free preparation method for preparing symmetric and asymmetric disulfide, which comprises the following steps: at room temperature, raw material R-SH, R'-SH and oxidant and base are added to reaction bottle, shake rapidly for 10-30 seconds, and R-S-S-R' is prepared after the reaction product is purified;Wherein R in R-SH is aliphatic or aromatic group, R' in R'-SH is aliphatic or aromatic group;R in R-SH and R' in R'-SH are same or different;The aromatic group has substituent or no substituent, and the aliphatic is straight chain or has branch;The oxidant is chloroform, and the base is N, N-diisopropylethylamine (DIPEA).The method is simple in operation, high in yield (60-99%), ultrafast in reaction kinetics, greatly improves production efficiency, wide in applicability, avoids the use of organic reaction solvent, raw material is cheap and easy to obtain, and does not contain residual metal and other sticky contaminants from reagent and ligand, provides a safer and more effective method for the synthesis and production of symmetric and asymmetric disulfide-containing compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and particularly relates to an ultrafast method for preparing metal-free and solvent-free disulfide-bonded compounds. Background Technology

[0002] Disulfides play a crucial role in organic synthesis, natural products, and pharmaceuticals. Some valuable disulfide-containing compounds include:

[0003]

[0004] Furthermore, disulfide bonds are readily cleaved via intracellular thiol redox mechanisms, making them excellent linkers for drug delivery and release in vivo. Marine-derived disulfide and polysulfide-containing metabolites, as important natural products, often exhibit favorable biological activities, such as antibiotics, antitumor agents, and enzyme inhibitors, including acetylhydroxy acid synthase (AHAS) inhibitors and anticancer drugs. Therefore, disulfides have been actively and extensively studied in recent years as potential bioactive drugs. In biological systems, disulfide bond formation is crucial for the folding of many polypeptides and proteins, and also influences the formation of protein molecular stereostructure. Due to the widespread importance of organic disulfides, the search for efficient, mild, and inexpensive methods for SS bond formation (i.e., disulfide synthesis) has become an important area of ​​modern research. Over the past few decades, chemists have made numerous efforts in the synthesis of symmetric and asymmetric disulfides.

[0005] (1) Misra et al. reported a thiol / phenol oxidative coupling reaction promoted by concentrated nitric acid (65%) as an oxidant to generate the corresponding symmetrical disulfides. The reaction was carried out at 0 °C and was completed in 30 minutes to two hours. This method has the advantages of simple operation and low cost, but it is only applicable to some aryl thiols and a very few alkyl thiols, and the substrate range is limited (16 examples). Moreover, this method only reports the synthesis of symmetrical disulfides. In addition, the reaction uses concentrated nitric acid as a reagent, which generates a large amount of strongly oxidizing and strongly acidic waste liquid, which will bring environmental protection pressure. (See reference 1: AKMisra and G.Agnihotri, Nitric Acid Mediated Oxidative Transformation of Thiols to Disulfides, Synth. Commun., 2004, 34(6): 1079-1085.), and its reaction equation is:

[0006]

[0007] (2) In 2006, Professors Hosseinpoor and Golchoubian studied a novel catalyst, the Mn(III)Schiff base complex, which, under the action of urea peroxide (UHP) oxidant, oxidizes thiophenols to generate the corresponding symmetrical disulfides. The reaction was carried out at 0°C and concluded within 5 to 30 minutes. The yield was high, between 90% and 97%. The catalyst demonstrated good stability and reusability, being able to be recycled four times without losing activity; the UV and IR spectra of the recovered catalyst showed no significant changes. However, this method only reported thiophenol substrates, a limited range (8 examples), and the product was only a symmetrical disulfide. Furthermore, the use of a manganese catalyst poses a risk of toxic metal residues in the product and potential environmental pollution. (See reference 2: F. Hosseinpoor and H. Golchoubian, Mild and highly efficient transformation of thiols to symmetrical disulfides using urea-hydrogen peroxide catalyzed by a Mn(III)-salen complex, Catal. Lett., 2006, 111, 165-168.). The reaction equation is:

[0008]

[0009] (3) In 2010, Garcia et al. used Fe(BTC) (BTC: 1,3,5-benzoate) to catalyze an oxidative coupling reaction to convert thiols / phenols into symmetrical disulfides, with yields between 60% and 90%. In this reaction, Fe(BTC) can be reused, and O2 is used as the oxidant. This reaction introduces a metal catalyst, and the preparation process of this catalyst is complicated, increasing the difficulty of the reaction. The product is only a symmetrical disulfide. The large-scale use of metallic iron may cause environmental pollution. (See reference 3: A. Dhakshinamoorthy, M. Alvaro and H. Garcia, Aerobic oxidation of thiols todisulfides using iron metal-organic frameworks as solid redox catalysts, Chem. Commun., 2010, 46(35), 6476-6478.), and its reaction equation is:

[0010]

[0011] (4) Professor Wu Lizhu et al. reported the conversion of various thiols into corresponding symmetrical disulfides and molecular H2 under the co-catalysis of cadmium selenide quantum dots (CdSe QDs) and nickel ion salts. Since the reaction proceeds at a mild room temperature without the addition of other oxidants, and the catalyst can be recycled multiple times, this method can be used to link disulfide bonds in biological proteins and to form disulfide bonds in other systems sensitive to specific oxidants. The drawbacks are the use of ultraviolet light and toxic materials (Cd, Se, Ni, etc.), which is not safe, and the product is only a symmetrical disulfide. (See reference 4: XB.Li, ZJ.Li, YJ.Gao, et al., Mechanistic Insights into the Interface-Directed Transformation of Thiols into Disulfides and Molecular Hydrogen by Visible-Light Irradiation of Quantum Dots, Angew. Chem. Int. Ed. 2014, 53, 2085-2089.), the reaction equation is:

[0012]

[0013] (5) Sheriff Shah and colleagues developed a method for synthesizing disulfides using copper hydroxyphosphate (CHP)Cu2(OH)PO4 as a Vis / NIR active photocatalyst. This method requires no activators or oxidants and is suitable for synthesizing disulfides from various thiols / phenols. The catalyst can efficiently synthesize disulfides under both visible and near-infrared light sources. Vis photocatalysis can achieve complete thiol conversion within two hours with a high yield. Near-infrared light often requires a longer reaction time (approximately 12 hours), resulting in a lower disulfide yield. This method is only reported for the synthesis of symmetrical disulfides. The extensive use of catalysts containing copper and phosphorus may lead to environmental pollution. (See reference 5: SSShah, S. Karthik and NDPSingh, Vis / NIR light driven mild and clean synthesis of disulfides in the presence of Cu2(OH)PO4 under aerobic conditions, RSC Adv., 2015, 5: 45416-45419.), the reaction equation is:

[0014]

[0015] (6) Witt and colleagues prepared functionalized asymmetric disulfides by reacting disulfides with various thiols in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). The developed method can also prepare asymmetric disulfides with additional hydroxyl, carboxyl, or amino functional groups. The simplicity and good yield of this method make it one of the most attractive methods for preparing functionalized asymmetric disulfides, especially disulfate phosphate derivatives with wide synthetic applications. (See reference 6: M. Musiejuk, T. Klucznik, J. Rachon, DDQ-mediated synthesis of functionalized unsymmetrical disulfanes, RSC Adv. 2015, 5(40): 31347-31351.), and the reaction equation is:

[0016]

[0017] (7) Wu et al. reported a transition metal-free disulfide exchange reaction. This reaction uses the strong base potassium tert-butoxide (t-BuOK) in tetrahydrofuran as a catalyst to synthesize the corresponding asymmetric disulfides through the exchange between two symmetrical disulfides or the exchange reaction between thiols and disulfides. The reaction requires a high temperature of 100°C. Aryl thiols and aliphatic thiols are oxidatively coupled to form asymmetric disulfides. This method achieves a yield of up to 90%. The use of non-metallic base catalysts is more environmentally friendly, inexpensive, and readily available than transition metal catalysts. The reaction does not require reflux and can be performed simply by heating, making the operation simpler. However, the addition of the base slows down the reaction rate, extending the reaction time to 8 hours. Furthermore, the substrate range for this reaction is limited, with only 7 examples currently known. Additionally, this reaction uses the water-sensitive strong base potassium tert-butoxide. (See reference 7: Y-1.Xu, Xn.Shi and Lp.Wu, tBuOK-triggered bond formation reactions, RSC Adv., 2019, 9: 24025-24029.), the reaction equation is:

[0018]

[0019] (8) In 2016, Yang and colleagues used trichloroisocyanuric acid (TCCA) as an oxidant to construct asymmetric disulfides under mild conditions. This method yielded asymmetric aromatic-aromatic and aromatic-aliphatic disulfides (A). Good yields were also obtained under slightly modified conditions for constructing more challenging aliphatic-aliphatic disulfides (B). The reaction is applicable to both aryl-alkyl thiols and aliphatic-aliphatic thiols, achieving a broad substrate range (22 examples). Furthermore, the reaction completes thiol oxidative coupling within 5 minutes, making it rapid and efficient, providing a convenient method for the synthesis of asymmetric disulfides. (See reference 8: F. Yang, W. Wang, K. Li, et al., Efficient one-pot construction of unsymmetrical disulfide bonds with TCCA, Tetrahedron Lett. 2017, 58(3): 218-222.), and its reaction equation is:

[0020]

[0021] (9) Xu and colleagues used TEMPO as a visible light photocatalyst and O2 as an oxidant to oxidize thiols to synthesize asymmetric disulfides under 460 nm blue light irradiation. This reaction only showed good results for the heterocoupling of tert-butylthiol, thus severely limiting the substrate range. (See reference 9: H. Xu, YF. Zhang, XJ. Lang, TEMPO visible light photocatalysis: The selective aerobic oxidation of thiols to disulfides, ChinChem Lett, 2020, 31(06): 1520-1524.), and the reaction equation is:

[0022]

[0023] (10) The Kokotos group reported the synthesis of asymmetric disulfides using phenylglyoxylic acid as a photoinitiator. This method was successfully applied to the oxidation of aryl and alkyl thiols to symmetric and asymmetric disulfides. The use of transition metal complexes, organic dyes, and thermal initiators was avoided, and the phenylglyoxylic acid catalyst loading was low (1 mol%). However, the yield of asymmetric disulfides hovered between 30-50%, with only one example achieving a yield of 90%. Furthermore, the substrate scope was limited, confined to reactions between aryl and alkyl groups, failing to form asymmetric diaryl sulfides. Therefore, this method still needs improvement in substrate versatility to enable more applications related to organisms. (See reference 10: S. Nikoleta and KG Christoforos, Photochemical metal-free aerobic oxidation of thiols to disulfides, Green Chem., 2021, 23(1): 546-551.), and the reaction equation is:

[0024]

[0025] Currently, there are many methods for preparing symmetrical disulfides via thiol oxidative coupling reactions, but methods for preparing asymmetric disulfides are extremely limited. Furthermore, many synthetic methods still rely on expensive and toxic metal complexes and hazardous halide reagents; the use of large amounts of strong oxidants and strong bases is unsuitable for sensitive groups and generates large amounts of oxidizing and alkaline waste, causing severe environmental pressure; the use of large amounts of organic solvents leads to serious environmental pollution; and the limited substrate range for asymmetric disulfides severely restricts the application of these reactions. Therefore, in the research of bioactive small molecules, developing a low-cost, simple, and mild conversion method for synthesizing disulfides is highly desirable. Methods for preparing asymmetric disulfides are particularly important. Summary of the Invention

[0026] The purpose of this invention is to provide an ultrafast, metal-free, and solvent-free method for achieving efficient homocoupling and crosscoupling of thiols to prepare symmetric and asymmetric disulfides. This aims to overcome the shortcomings of existing technologies described in the background section.

[0027] To achieve the above objectives, the present invention is implemented through the following technical solutions.

[0028] A method for preparing an ultrafast, metal-free, and solvent-free disulfide-bonded compound includes the following steps: At room temperature, raw materials R-SH and R′-SH, along with an oxidant and a base, are added to a reaction flask and rapidly shaken for 10-30 seconds. The reaction product is then purified to obtain RSSR′. Wherein, R in R-SH is an aliphatic or aromatic group, and R′ in R′-SH is an aliphatic or aromatic group; the R in R-SH may be the same as or different from the R′ in R′-SH; the aromatic group may or may not have substituents, and the aliphatic group may be straight-chain or branched; the oxidant is trichlorobromomethane, and the base is one of sodium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, triethylamine, pyridine, N,N-diisopropylethylamine, DBU, or 4-dimethylaminopyridine.

[0029] Preferably, the molar volume ratio of the raw materials R-SH, R′-SH to the oxidant and the base is 0.8 mmol: 0.1–4.0 mmol: 0.1–4.0 mmol: 0.1–4.0 mmol.

[0030] Preferably, the purification specifically involves: directly separating and enriching the reaction solution using silica gel column chromatography to obtain compounds containing disulfide bonds.

[0031] Preferably, R-SH and R′-SH are any one of sec-butanethiol, tert-butanethiol, cyclohexanethiol, n-octanethiol, phenylethylthiol, 2-mercaptoethanol, ethyl 2-mercaptopropionate, p-methoxybenzylthiol, p-tert-butylbenzylthiol, benzylthiol, o-chlorobenzylthiol, p-chlorobenzylthiol, isooctylthiol, 2-methyl-3-butanethiol, o-hydroxybenzylthiophenol, p-hydroxybenzylthiophenol, o-methoxybenzylthiophenol, o-chlorobenzylthiophenol, p-chlorobenzylthiophenol, o-bromobenzylthiophenol, m-bromobenzylthiophenol, p-bromobenzylthiophenol, (tert-butyloxycarbonyl)-L-cysteine ​​methyl ester, and cysteine.

[0032] To overcome the shortcomings and deficiencies of existing technologies, this invention provides an ultrafast, metal-free, and catalyst-free method for preparing disulfide-bonded compounds. In this method, at room temperature and in air, using R-SH and R′-SH as raw materials, disulfide bonds are generated by the oxidation of thiols through the synergistic action of the oxidant trichlorobromomethane and the base DIPEA. The chemical reaction equation for this synthesis process is as follows:

[0033]

[0034] Based on this, the reaction product can be purified to obtain a compound containing disulfide bonds.

[0035] Compared to the shortcomings and deficiencies of existing technologies, this invention has the following advantages: 1) It is the first successful development of BrCCl3 and DIPEA-promoted, ultrafast, catalyst-free, and metal oxidation-free thiol cross-coupling; 2) This method is economical in terms of reaction time and has ultrafast reaction kinetics, which is beneficial to improving the production efficiency of disulfide products; 3) This method synthesizes symmetric and asymmetric disulfides with a wide substrate range and high yields (up to 98%); 4) This method provides a safer way to prepare disulfide compounds, free from residual metals and other sticky contaminants from reagents and ligands; 5) The successful cross-coupling of cysteine ​​derivatives with various types of thiols will encourage us to explore more biocompatible methods to manipulate bioconjugations on biomolecules such as antibodies, peptides, and proteins. Attached Figure Description

[0036] Figure 1 This is the 1H NMR spectrum of the coupling reaction product from Example 1;

[0037] Figure 2 This is the 1H NMR spectrum of the coupling reaction product from Example 2;

[0038] Figure 3 This is the 1H NMR spectrum of the coupling reaction product in Example 3;

[0039] Figure 4 This is the 1H NMR spectrum of the coupling reaction product in Example 4;

[0040] Figure 5 This is the 1H NMR spectrum of the coupling reaction product from Example 5;

[0041] Figure 6 This is the 1H NMR spectrum of the coupling reaction product from Example 6;

[0042] Figure 7 This is the 1H NMR spectrum of the coupling reaction product from Example 7;

[0043] Figure 8 This is the 1H NMR spectrum of the coupling reaction product from Example 8;

[0044] Figure 9 This is the 1H NMR spectrum of the coupling reaction product from Example 9;

[0045] Figure 10 This is the 1H NMR spectrum of the coupling reaction product from Example 10;

[0046] Figure 11 This is the 1H NMR spectrum of the coupling reaction product from Example 11;

[0047] Figure 12 This is the 1H NMR spectrum of the coupling reaction product from Example 12;

[0048] Figure 13 This is the 1H NMR spectrum of the coupling reaction product in Example 13;

[0049] Figure 14 This is the 1H NMR spectrum of the coupling reaction product from Example 14;

[0050] Figure 15 This is the 1H NMR spectrum of the coupling reaction product from Example 15;

[0051] Figure 16 This is the 1H NMR spectrum of the coupling reaction product from Example 16;

[0052] Figure 17 This is the 1H NMR spectrum of the coupling reaction product from Example 17;

[0053] Figure 18 This is the 1H NMR spectrum of the coupling reaction product from Example 18;

[0054] Figure 19 This is the 1H NMR spectrum of the coupling reaction product from Example 19;

[0055] Figure 20 This is the 1H NMR spectrum of the coupling reaction product from Example 20;

[0056] Figure 21 This is the 1H NMR spectrum of the coupling reaction product from Example 21;

[0057] Figure 22 This is the 1H NMR spectrum of the coupling reaction product from Example 22. Detailed Implementation

[0058] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. It is impossible to exhaustively describe all possible implementations here. All technical solutions obtained through equivalent substitution or transformation fall within the protection scope of this invention.

[0059] Example 1

[0060] At room temperature in air, the reaction mixture of p-methoxythiophenol (0.8 mmol), sec-butanethiol (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was rapidly shaken for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to obtain a colorless oily substance: 59.5 mg, yield: 67%. The NMR spectrum analysis of the reaction product is shown below. Figure 1 As shown.

[0061] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.48 (d, J=8.8Hz, 2H), 6.85 (d, J=8.8Hz, 2H), 3.80 (s, 3H ), 2.87-2.78 (m, 1H), 1.77-1.45 (m, 2H), 1.28 (d, J=6.8Hz, 3H), 0.93 (t, J=7.4Hz, 3H).

[0062] Example 2

[0063] At room temperature in air, the reaction mixture of p-methylthiophenol (0.8 mmol), tert-butyritin (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to obtain a colorless oily substance: 92.4 mg, yield: 68%. The NMR spectrum analysis of the reaction product is as follows: Figure 2 As shown.

[0064] The characterization data of this product are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.45 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 2.32 (s, 3H), 1.31 (s, 9H).

[0065] Example 3

[0066] At room temperature, o-hydroxythiophenol (0.8 mmol), cyclohexanethiol (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) were added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After TLC monitoring confirmed complete reaction, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a yellow oily substance: 101.8 mg, yield: 98%. The NMR spectrum analysis of the reaction product is shown below. Figure 3 As shown.

[0067] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.50 (dd, J=7.8, 1.7Hz, 1H), 7.30-7.26 (m, 1H), 6.98 (dd, J=8.2, 1.3Hz, 1H), 6.88 (td, J=7.4 , 1.3Hz, 1H), 6.44 (s, 1H), 2.86-2.81 (m, 1H), 2.07-2.03 (m, , 2H), 1.79-1.75 (m, 2H), 1.63-1.59 (m, 1H), 1.40-1.26 (m, 5H).

[0068] Example 4

[0069] At room temperature, o-methoxythiophenol (0.8 mmol), n-octylthiol (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) were added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After TLC monitoring confirmed complete reaction, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to obtain a colorless oily substance: 53.0 mg, yield: 93%. The NMR spectrum analysis of the reaction product is as follows: Figure 4 As shown.

[0070] The characterization data of this product are as follows: 1H NMR (400MHz, Chloroform-d) δ7.71 (dd, J=7.7, 1.6Hz, 1H), 7.21 (td, J=7.6, 1.6Hz, 1H), 7.00 (td, J=7.5, 1.1Hz, 1H), 6.85 (dd, J=8.1, 1.0Hz, 1H), 3.89 (s, 3H), 2.72 (t, J=7.3Hz, 2H), 1.71-1.64 (m, 2H), 1.38-1.25 (m, 10H), 0.88 (t, J=6.8Hz, 3H).

[0071] Example 5

[0072] At room temperature in air, the reaction mixture of p-methoxythiophenol (0.8 mmol), phenylethyl mercaptan (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to obtain a colorless oily substance: 61.0 mg, yield: 56%. The NMR spectrum analysis of the reaction product is as follows: Figure 5 As shown.

[0073] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.52 (d, J=8.8Hz, 2H), 7.31 (t, J=7.0Hz, 2H), 7.24-7.17 (m, 3H), 6.89 (d, J=8.9Hz, 2H), 3.82 (s, 3H), 3.00 (s, 4H).

[0074] Example 6

[0075] At room temperature, the reaction mixture of m-bromothiophenol (0.8 mmol), 2-mercaptoethanol (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a yellow oily substance: 82.1 mg, yield: 80%. The NMR spectrum analysis of the reaction product is as follows: Figure 6 As shown.

[0076] The characterization data of this product are as follows: 1H NMR (400MHz, Chloroform-d) δ7.70 (t, J=1.8Hz, 1H), 7.46-7.43 (m, 1H), 7.36-7.33 (m, 1H), 7.18 (t, J=7.9Hz, 1H), 3.85 (t, J=5.8Hz, 2H), 2.89 (t, J=5.9Hz, 2H), 2.05 (s, 1H).

[0077] Example 7

[0078] At room temperature in air, the reaction mixture of m-chlorothiophenol (0.8 mmol), ethyl 3-mercaptopropionate (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a pale yellow oily substance: 84.7 mg, yield: 80%. The NMR spectrum analysis of the reaction product is as follows: Figure 7 As shown.

[0079] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.53 (s, 1H), 7.37 (d, J=7.7Hz, 1H), 7.27-7.18 (m, 2H), 4. 14 (q, J=7.1Hz, 2H), 2.97 (t, J=7.1Hz, 2H), 2.71 (t, J=7.2Hz, 2H), 1.25 (t, J=7.2Hz, 3H).

[0080] Example 8

[0081] At room temperature in air, the reaction mixture of p-methylthiophenol (0.8 mmol), p-hydroxythiophenol (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a yellow oily substance: 34.0 mg, yield: 64%. The NMR spectrum analysis of the reaction product is shown below. Figure 8 As shown.

[0082] The characterization data of this product are as follows: 1H NMR (400MHz, Chloroform-d) δ7.39 (t, J=8.1Hz, 4H), 7.13 (d, J=7.9Hz, 2H), 6.76 (d, J=8.8Hz, 2H), 5.35 (s, 1H), 2.34 (s, 3H).

[0083] Example 9

[0084] At room temperature in air, the reaction mixture of p-tert-butylbenzyl thiol (0.8 mmol), p-hydroxybenzyl thiophenol (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a yellow oily substance: 79.5 mg, yield: 69%. The NMR spectrum analysis of the reaction product is shown below. Figure 9 As shown.

[0085] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.31 (t, J=8.0Hz, 4H), 7.22 (d, J=8.3Hz, 2H), 6.73 (d, J=8.6Hz, 2H), 4.99 (s, 1H), 3.94 (s, 2H), 1.31 (s, 9H).

[0086] Example 10

[0087] At room temperature in air, the reaction mixture of benzyl mercaptan (0.8 mmol), 2-mercaptoethanol (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a yellow oily substance: 55.7 mg, yield: 71%. The NMR spectrum analysis of the reaction product is as follows: Figure 10 As shown.

[0088] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.34-7.26 (m, 5H), 3.91 (s, 2H), 3.72 (t, J=5.8Hz, 2H), 2.52 (t, J=5.8Hz, 2H), 2.06 (s, 1H).

[0089] Example 11

[0090] At room temperature in air, the reaction mixture of cyclohexanethiol (0.8 mmol), ethyl 3-mercaptopropionate (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a yellow oily substance: 66.8 mg, yield: 69%. The NMR spectrum analysis of the reaction product is as follows: Figure 11 As shown.

[0091] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ4.14 (q, J=7.2Hz, 2H), 2.88 (t, J=7.3Hz, 2H), 2.75-2.6 7(m, 3H), 2.03-1.99(m, 2H), 1.78-1.75(m, 2H), 1.62-1.58(m, 1H), 1.39-1.21(m, 8H).

[0092] Example 12

[0093] At room temperature in air, the reaction mixture of o-chlorothiophenol (0.8 mmol), (tert-butyloxycarbonyl)-L-cysteine ​​methyl ester (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to obtain a colorless oily substance: 98.5 mg, yield: 67%. The NMR spectrum analysis of the reaction product is shown below. Figure 12 As shown.

[0094] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.74 (dd, J=8.0, 1.5Hz, 1H), 7.34-7.28 (m, 2H), 7.17 (td, J=7.6, 1. 5Hz, 1H), 5.41 (d, J=7.7Hz, 1H), 4.62-4.57 (m, 1H), 3.73 (s, 3H), 3.26-3.13 (m, 2H), 1.43 (s, 9H).

[0095] Example 13

[0096] At room temperature in air, the reaction mixture of p-tert-butylbenzyl mercaptan (0.8 mmol), (tert-butyloxycarbonyl)-L-cysteine ​​methyl ester (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a colorless oily substance: 125.8 mg, yield: 77%. The NMR spectrum analysis of the reaction product is shown below. Figure 13 As shown.

[0097] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.34 (d, J=8.2Hz, 2H), 7.25 (d, J=8.4Hz, 2H), 5.29 (d, J=7.7Hz, 1 H), 4.52-4.48 (m, 1H), 3.89 (s, 2H), 3.72 (s, 3H), 2.90-2.76 (m, 2H), 1.45 (s, 9H), 1.31 (s, 9H).

[0098] Example 14

[0099] At room temperature in air, the reaction mixture of 3-methylbutane-2-thiol (0.8 mmol), (tert-butyloxycarbonyl)-L-cysteine ​​methyl ester (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a pale yellow oil: 130.9 mg, yield: 88%. The NMR spectrum analysis of the reaction product is as follows: Figure 14 As shown.

[0100] The characterization data of this product are as follows: 1H NMR (400MHz, Chloroform-d) δ5.39-5.37(m, 1H), 4.58-4.57(m, 1H), 3.74(s, 3H), 3.14-3.03(m, 2H), 2.81-2.74 (m, 1H), 1.97-1.87 (m, 1H), 1.42 (s, 9H), 1.23-1.20 (m, 3H), 0.96 (d, J=6.8Hz, 3H), 0.91 (dd, J=6.8, 1.9Hz, 3H).

[0101] Example 15

[0102] At room temperature in air, the reaction mixture of cyclohexanethiol (0.8 mmol), (tert-butyloxycarbonyl)-L-cysteine ​​methyl ester (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a yellow oily substance: 135.8 mg, yield: 97%. The NMR spectrum analysis of the reaction product is as follows: Figure 15 As shown.

[0103] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ5.36-5.35 (m, 1H), 4.61-4.57 (m, 1H), 3.76 (s, 3H), 3.17-3.07 (m, 2H), 2.7 8-2.71 (m, 1H), 2.02-1.96 (m, 2H), 1.79-1.76 (m, 2H), 1.63-1.60 (m, 2H), 1.45 (s, 9H), 1.35-1.23 (m, 5H).

[0104] Example 16

[0105] At room temperature in air, the reaction mixture of isooctyl mercaptan (0.8 mmol), (tert-butyloxycarbonyl)-L-cysteine ​​methyl ester (0.4 mmol), BrCCl3 (1.0 equiv., 0.8 mmol, 158.6 mg), and DIPEA (1.0 equiv., 0.8 mmol, 103.9 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a yellow oily substance: 125.0 mg, yield: 85%. The NMR spectrum analysis of the reaction product is as follows: Figure 16 As shown.

[0106] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ5.38-5.36 (m, 1H), 4.62-4.58 (m, 1H), 3.75 (s, 3H), 3.15-3.05 (m, 2H), 2.70 (d, J= 6.4Hz, 2H), 1.60-1.52 (m, 1H), 1.43 (s, 9H), 1.40-1.23 (m, 8H), 0.87 (t, J=6.72Hz, 3H), 0.85 (t, J=7.56Hz, 3H).

[0107] Example 17

[0108] At room temperature, the reaction mixture of thiophenol (0.4 mmol), BrCCl3 (1.0 equiv., 0.4 mmol, 79.3 mg), and DIPEA (1.0 equiv., 0.4 mmol, 52.0 mg) was added sequentially to a 5 mL sample vial. The mixture was rapidly shaken for 10–30 seconds. After TLC monitoring confirmed complete reaction, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a white solid: 26.4 mg, yield: 91%. The NMR spectrum analysis of the reaction product is shown below. Figure 17 As shown.

[0109] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.54-7.50 (m, 4H), 7.34-7.29 (m, 4H), 7.26-7.22 (m, 2H).

[0110] Example 18

[0111] At room temperature in air, the reaction mixture of m-methylthiophenol (0.4 mmol), BrCCl3 (1.0 equiv., 0.4 mmol, 79.3 mg), and DIPEA (1.0 equiv., 0.4 mmol, 52.0 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to obtain a colorless oily substance: 46.6 mg, yield: 95%. The NMR spectrum analysis of the reaction product is as follows: Figure 18 As shown.

[0112] The characterization data of this product are as follows: 1H NMR (400MHz, Chloroform-d) δ 7.34-7.32 (m, 4H), 7.21 (t, J = 7.6Hz, 2H), 7.06-7.04 (m, 2H), 2.34 (s, 6H).

[0113] Example 19

[0114] At room temperature in air, the reaction mixture of benzyl mercaptan (0.4 mmol), BrCCl3 (1.0 equiv., 0.4 mmol, 79.3 mg), and DIPEA (1.0 equiv., 0.4 mmol, 52.0 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a white solid: 34.5 mg, yield: 99%. The NMR spectrum analysis of the reaction product is as follows: Figure 19 As shown.

[0115] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.37-7.26 (m, 10H), 3.62 (s, 4H).

[0116] Example 20

[0117] At room temperature in air, the reaction mixture of phenylethyl mercaptan (0.4 mmol), BrCCl3 (1.0 equiv., 0.4 mmol, 79.3 mg), and DIPEA (1.0 equiv., 0.4 mmol, 52.0 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to give a colorless oily substance: 48.8 mg, yield: 91%. The NMR spectrum analysis of the reaction product is as follows: Figure 20 As shown.

[0118] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.33 (t, J=7.0Hz, 4H), 7.27-7.22 (m, 6H), 3.05-3.00 (m, 4H), 2.98-2.94 (m, 4H).

[0119] Example 21

[0120] At room temperature in air, the reaction mixture of 2-mercaptothiol (0.4 mmol), BrCCl3 (1.0 equiv., 0.4 mmol, 79.3 mg), and DIPEA (1.0 equiv., 0.4 mmol, 52.0 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to obtain a colorless oily substance: 55.9 mg, yield: 97%. The NMR spectrum analysis of the reaction product is as follows: Figure 21 As shown.

[0121] The characterization data of this product are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 3.89 (t, J = 5.8 Hz, 4H), 2.87 (t, J = 5.8 Hz, 4H), 2.79 (s, 2H).

[0122] Example 22

[0123] At room temperature, the reaction mixture of cyclohexanethiol (0.4 mmol), BrCCl3 (1.0 equiv., 0.4 mmol, 79.3 mg), and DIPEA (1.0 equiv., 0.4 mmol, 52.0 mg) was added sequentially to a 5 mL sample vial. The mixture was shaken rapidly for 10–30 seconds. After TLC monitoring confirmed complete reaction, the reaction solution was directly separated by silica gel column chromatography (eluent: petroleum ether) to obtain a colorless oily substance: 43.6 mg, yield: 97%. The NMR spectrum analysis of the reaction product is shown below. Figure 22 As shown.

[0124] The characterization data of this product are as follows: 1 H NMR (400MHz, Chloroform-d) δ2.70-2.64(m, 2H), 2.06-2.02(m, 4H), 1.79-1.76(m, 4H), 1.62-1.58(m, 2H), 1.33-1.21(m, 10H).

[0125] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a metal-free and solvent-free disulfide-bonded compound, characterized in that, This method The process includes the following steps: at room temperature, a thiol or thiophenol is added to a reaction flask along with trichlorobromomethane and a base, and the mixture is shaken rapidly for 10-30 seconds; the reaction product is purified to obtain a disulfide-bonded compound; wherein, when one type of thiol or thiophenol is used, a symmetrical disulfide-bonded compound is obtained; when two types of thiol or thiophenol are used, an asymmetrical disulfide-bonded compound is obtained; the base is any one of sodium carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, triethylamine, pyridine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 4-methylaminopyridine.

2. The method for preparing a metal-free and solvent-free disulfide-bonded compound according to claim 1, characterized in that, When the thiol or thiophenol is one type, the molar ratio of the thiol or thiophenol, trichlorobromomethane, and the base is 0.8 mmol: 0.1–4.0 mmol: 0.1–4.0 mmol; when the thiol or thiophenol is two types, the molar ratio of the first thiol or thiophenol, the second thiol or thiophenol, trichlorobromomethane, and the base is 0.8 mmol: 0.1–4.0 mmol: 0.1–4.0 mmol: 0.1–4.0 mmol.

3. The method for preparing a metal-free and solvent-free disulfide-bonded compound according to claim 1, characterized in that, The purification step includes: directly separating and enriching the reaction solution using silica gel column chromatography to obtain compounds containing disulfide bonds.

4. The method for preparing a metal-free and solvent-free disulfide-bonded compound according to claim 1, characterized in that, The thiol or thiophenol is any one or two of the following: sec-butanethiol, tert-butanethiol, cyclohexanethiol, n-octanethiol, phenylethylthiol, 2-mercaptoethanol, ethyl 2-mercaptopropionate, p-methoxybenzylthiol, p-tert-butylbenzylthiol, benzylthiol, o-chlorobenzylthiol, m-chlorobenzylthiol, isooctylthiol, 2-methyl-3-butanethiol, o-hydroxybenzylthiophenol, p-hydroxybenzylthiophenol, o-methoxybenzylthiophenol, o-chlorobenzylthiophenol, p-chlorobenzylthiophenol, o-bromobenzylthiophenol, m-bromobenzylthiophenol, p-bromobenzylthiophenol, (tert-butyloxycarbonyl)-L-cysteine ​​methyl ester, and cysteine.

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