Disulfide transfer reagents and their synthesis and application

Abstract

The present invention discloses a disulfide transfer reagent and its synthesis and application. The reagent has the following molecular formula: #imgabs0# wherein R 1 R is independently selected from methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, substituted heteroaryl, benzyl; 2 R is independently selected from methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heteroaryl, substituted heteroaryl; 3 The phenyl group is independently selected from phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, substituted heteroaryl, and substituted C1-C20 alkyl. The present invention provides a novel disulfide transfer reagent, which can be used to synthesize asymmetric disulfide compounds in a relatively simple manner.

Description

Technical Field

[0001] The invention relates to the field of organic synthetic chemistry, and in particular to a preparation method of a novel disulfide transfer reagent and application thereof in the synthesis of asymmetric disulfide compounds. Background Art

[0002] Organic disulfides have unique stability, reactivity, and physiological activity, which makes them widely used in many fields, such as food chemistry, medicinal chemistry, natural product chemistry and material chemistry (CS Jiang, WE G Müller, HC YW Guo, Chem. Rev. 2012, 112, 2179). In addition, disulfide bonds can also be used as bridging chemical bonds to increase the stability of the three-dimensional structure of proteins, which is of great significance to the folding and function of proteins and has a profound impact on life sciences (Z. Cheng, J. Zhang, D. Ballou, C. Williams, Chem. Rev. 2011, 111, 5768). Therefore, the exploration of asymmetric disulfide synthesis methods is very important. Traditional methods rely on the construction of sulfur-sulfur bonds to synthesize asymmetric disulfide compounds, usually requiring two thiol precursors, which are activated by oxidation of thiols and then attacked by another thiol molecule nucleophilically to obtain the final product. Traditional disulfide ligation methods still have certain limitations: sulfur-containing starting materials are difficult to obtain; oxidation produces self-coupling byproducts. In recent years, the synthesis of asymmetric disulfides by constructing carbon-linked disulfide bonds (C-SSR) has begun to attract widespread attention. Specifically, nucleophilic disulfide, electrophilic disulfide, transition metal-catalyzed disulfide, and free radical disulfide are used to synthesize asymmetric disulfide compounds. On the other hand, olefin difunctionalization based on free radical processes is also very common. Disulfide ester reagents (ArSO2-SSR) can be reduced by a single electron with a photosensitive catalyst to produce sulfonyl radicals, which add to olefins, and the generated alkyl radicals are captured by sulfonyl disulfide reagents to obtain polysulfide compounds. Summary of the invention

[0003] In view of the defects of the prior art, the present invention provides a disulfide transfer reagent, a synthesis method, and application thereof in the synthesis of asymmetric disulfide compounds.

[0004] A disulfide transfer reagent having the following molecular formula:

[0005]

[0006] Where R 1R is independently selected from methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, substituted heteroaryl, benzyl; 2 R is independently selected from methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heteroaryl, substituted heteroaryl; 3 Independently selected from phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, substituted heteroaryl, and substituted C1-C20 alkyl.

[0007] A method for synthesizing a disulfide transfer reagent comprises the following steps: adding a disulfide ester reagent, a photocatalyst and an additive into an organic solvent, adding olefins, and reacting under light conditions to obtain the disulfide transfer reagent.

[0008] A method for synthesizing an asymmetric disulfide compound using a disulfide transfer reagent comprises the following steps: adding an alkaline additive to the disulfide transfer reagent to generate a nucleophilic disulfide anion (R 2 SSˉ), then adding an alkyl halide, a Michael acceptor or an epoxy compound, and then adding an organic solvent to react to obtain the asymmetric disulfide compound.

[0009] The beneficial effects of the present invention are as follows: the present invention provides a novel disulfide transfer reagent, and uses the same to obtain an asymmetric disulfide compound, including using the novel disulfide transfer reagent to perform a nucleophilic substitution reaction with a halogenated alkane or a quasi-halogenated alkane, nucleophilically attacking an epoxy compound to cause ring opening, or performing a nucleophilic addition reaction with a Michael acceptor, thereby synthesizing an asymmetric disulfide compound in a relatively simple manner. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 is a schematic diagram of the synthesis process in Example 2;

[0011] Figure 2 is a schematic diagram of the synthesis process in Example 3;

[0012] Figure 3-1 to Figure 3-20 NMR diagrams of the relevant compounds in various experimental examples of the present invention. DETAILED DESCRIPTION

[0013] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below in conjunction with the accompanying drawings, so that the above-mentioned and other objects, features and advantages of the present invention will be clearer. The same reference numerals in all the drawings indicate the same parts. The drawings are not deliberately drawn to scale, and the focus is on illustrating the subject matter of the present invention.

[0014] General Description

[0015] The abbreviations used in the examples have the following meanings: Me is methyl, Ph is phenyl, TMS is trimethylsilyl, Boc is tert-butyloxycarbonyl, Bn is benzyl, i Pr is isopropyl, t Bu is tert-butyl. MeCN is acetonitrile, DCM is dichloromethane. TLC is thin layer chromatography, NMR is nuclear magnetic resonance, and HRMS is high resolution mass spectrometry.

[0016] The anhydrous and oxygen-free experimental conditions involved in the present invention are all performed in accordance with the Schlenk technical standards. The solvents used are purified and dried by standard methods before use, and the compounds used are commercially available or synthesized according to existing literature methods, and purified before use (according to the Purification of Laboratory Chemicals Handbook). In particular, the preparation method of the disulfide ester reagent is referenced (K. Gong, YL Zhou, XF Jiang, Green Chem. 2021, 23, 9865).

[0017] Embodiment 1

[0018] This example focuses on the structure of a novel disulfide transfer reagent, which has the following molecular formula:

[0019]

[0020] Where R 1 independently selected from methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, substituted heteroaryl, benzyl, the substituent on the substituted phenyl is a C1-C20 hydrocarbon group, alkoxy, alkylthio, silicon, boron, ester group, amide, cyano, trifluoromethyl, aldehyde group, nitro, phenyl or halogen atom, and the number of substituents is 1-5, the heteroaryl is furyl, thienyl or pyridyl, the substituent on the substituted heteroaryl is a C1-C20 hydrocarbon group, alkoxy, alkylthio, silicon, boron, ester group, amide, cyano, trifluoromethyl, aldehyde group, nitro, phenyl or halogen atom, and the number of substituents is 1-4.

[0021] Where R 2independently selected from methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heteroaryl, substituted heteroaryl, the substituent on the substituted phenyl is a C1-C20 hydrocarbon group, alkoxy, alkylthio, silicon, boron, ester, amide, cyano, trifluoromethyl, aldehyde, nitro, phenyl or halogen atom, the number of substituents is 1-5, the substituent on the substituted benzyl is C1-C20 The substituents are 1 to 5 hydrocarbon groups, alkoxy groups, alkylthio groups, silicon groups, boron groups, ester groups, amide groups, cyano groups, trifluoromethyl groups, aldehyde groups, nitro groups, phenyl groups or halogen atoms; the number of substituents is 1 to 5; the heteroaryl group is furyl group, thienyl group, pyridyl group, benzothienyl group, benzofuranyl group, indolyl group; the substituents of the substituted heteroaryl group are C1 to C20 hydrocarbon groups, alkoxy groups, alkylthio groups, silicon groups, boron groups, ester groups, amide groups, cyano groups, trifluoromethyl groups, aldehyde groups, nitro groups, phenyl groups or halogen atoms; the number of substituents is 1 to 4.

[0022] Where R 3 Independently selected from phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, substituted heteroaryl, and substituted C1-C20 alkyl, the substituent on the substituted phenyl is a C1-C20 hydrocarbon group, alkoxy, alkylthio, silicon, boron, ester, amide, cyano, trifluoromethyl, aldehyde, nitro, phenyl or halogen atom, the number of substituents is 1-5, the heteroaryl is furyl, thienyl, pyridyl, benzothienyl, benzofuranyl, indolyl, the substituent on the substituted heteroaryl is a C1-C20 hydrocarbon group, alkoxy, alkylthio, silicon, boron, ester, amide, cyano, trifluoromethyl, aldehyde, nitro, phenyl or halogen atom, the number of substituents is 1-4, the substituent on the substituted C1-C20 alkyl is phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, substituted heteroaryl.

[0023] The molecular formula of the novel disulfide transfer reagent includes the following structure:

[0024]

[0025] Embodiment 2

[0026] This example focuses on the synthesis of a novel disulfide transfer reagent. Figure 1 As shown, specifically, the following steps are included: a disulfide ester reagent, a photocatalyst and an additive are added to a 10 mL Schlenk tube, the reaction tube is replaced with a nitrogen atmosphere, and then 2 mL of dry organic solvent is added, and the corresponding olefin is added, and the reaction is carried out at room temperature for 12 hours under light conditions, and the target compound is synthesized through the process of atom transfer radical addition, and the reaction is completed by TLC monitoring. The solvent is removed by a rotary evaporator, and the target compound is separated by silica gel column chromatography.

[0027] Among them, the additives are LiHCO3, Li2CO3, Li3PO4, LiH2PO4, Li2HPO4, LiHSO4, Li2SO4, LiHC2O4, Li2C2O4, CH3COOLi, HCOOLi, LiOH, NaHCO3, Na2CO3, Na3PO4, NaH2PO4, Na2HPO4, NaHSO4, Na2SO4, NaHC2O4, Na2C2O4, CH3COONa, HCOONa, NaOH, KHCO3, K2CO3, K3PO4 , KH2PO4, K2HPO4, KHSO4, K2SO4, KHC2O4, K2C2O4, CH3COOK, HCOOK, KOH, NH4HCO3, (NH4)2CO3, (NH4)3PO4, (NH4)H2PO4, (NH4)2HPO4, NH4HSO4, (NH4)2SO4, NH4HC2O4, (NH4)2C2O4, CH3COONH4, HCOONH4, ammonia water, triethylamine, diisopropylamine, trimethylamine, piperidine, pyridine or a mixed additive thereof.

[0028] The photocatalyst is any of the following:

[0029]

[0030] Wherein, the substituent on the olefin is a C1-C20 hydrocarbon group, alkoxy group, alkylthio group, silicon group, boron group, ester group, amide group, cyano group, trifluoromethyl group, aldehyde group, phenyl group, substituted phenyl group, 1-naphthyl group, 2-naphthyl group, heteroaryl group or benzyl group; the substituent on the substituted phenyl group is a C1-C20 hydrocarbon group, alkoxy group, alkylthio group, silicon group, boron group, ester group, amide group, cyano group, trifluoromethyl group, aldehyde group, nitro group, phenyl group, halogen atom or the like; the number of substituents is 1 to 5; the heteroaryl group is furyl group, thienyl group or pyridyl group.

[0031] The light source is a light source of 254nm to 800nm; the organic solvent is one or a combination of dimethyl sulfoxide, DMF, DMA, benzene, toluene, xylene, methanol, anisole, 1,2-dichloroethane, dichloromethane, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, tert-butanol, ethanol, isopropanol, methanol, and water; and the reaction temperature is -50 to 150°C.

[0032] Embodiment 3

[0033] This example focuses on the synthesis method of asymmetric disulfide compounds prepared by using a novel disulfide transfer reagent. The synthesis process is as follows: Figure 2As shown, specifically, the following steps are included: a novel disulfide transfer reagent and an additive are added to a 10 mL Schlenk tube, the reaction tube is replaced with a nitrogen atmosphere, and then the corresponding alkyl halide or Michael acceptor or epoxy compound is added, and then 1 mL of dry organic solvent is added, and the reaction is carried out at room temperature for 12 hours, and the reaction is completed by TLC monitoring. The solvent is removed by a rotary evaporator, and the target compound is separated by silica gel column chromatography.

[0034] The application of new disulfide transfer reagents in the synthesis of asymmetric disulfide compounds is to generate nucleophilic disulfide anions (R 2 SSˉ), undergo nucleophilic substitution reaction with halogenated alkanes and quasi-halogenated alkanes, nucleophilically attack epoxy compounds to cause ring opening, or undergo nucleophilic addition reaction with Michael acceptors to synthesize asymmetric disulfide compounds.

[0035] Among them, the additives are LiHCO3, Li2CO3, Li3PO4, LiH2PO4, Li2HPO4, LiHSO4, Li2SO4, LiHC2O4, Li2C2O4, CH3COOLi, HCOOLi, LiOH, NaHCO3, Na2CO3, Na3PO4, NaH2PO4, Na2HPO4, NaHSO4, Na2SO4, NaHC2O4, Na2C2O4, CH3COONa, HCOONa, NaOH, KHCO3, K2CO3, K3PO4 , KH2PO4, K2HPO4, KHSO4, K2SO4, KHC2O4, K2C2O4, CH3COOK, HCOOK, KOH, NH4HCO3, (NH4)2CO3, (NH4)3PO4, (NH4)H2PO4, (NH4)2HPO4, NH4HSO4, (NH4)2SO4, NH4HC2O4, (NH4)2C2O4, CH3COONH4, HCOONH4, ammonia water, triethylamine, diisopropylamine, trimethylamine, piperidine, pyridine or a mixed additive thereof.

[0036] Among them, the organic solvent is one or a combination of dimethyl sulfoxide, DMF, DMA, benzene, toluene, xylene, methanol, anisole, 1,2-dichloroethane, dichloromethane, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, tert-butanol, ethanol, isopropanol, methanol, and water.

[0037] Wherein, the reaction temperature is -20~150℃.

[0038] Experimental Example 1

[0039]

[0040] This experiment mainly takes compound 2-1 as an example for detailed explanation.

[0041] Add disulfide ester 1-1 (55.3 mg, 0.200 mmol), photocatalyst 4-CzIPN (7.9 mg, 10 μmol) and NaHCO3 (16.8 mg, 0.200 mmol) to a 10 mL Schlenk tube, and replace the reaction tube with a nitrogen atmosphere. Then add 2 mL of dry acetonitrile and styrene (41.6 mg, 0.400 mmol), react at room temperature for 12 hours under blue light irradiation, and monitor the completion of the reaction by TLC. Remove the solvent with a rotary evaporator, and separate the white solid 2-1 (62.4 mg, 0.164 mmol) by silica gel column chromatography, with a yield of 82%. The new disulfide transfer reagent is very stable and hardly decomposes when stored in a -18 ° C refrigerator for one year. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.49 (d, J = 8.28Hz, 2H), 7.21–7.15 (m, 3H), 7.13–7.10 (m, 4H), 4.29 (dd, J 1 =2.84Hz,J 2 =11.44Hz,1H),4.08(dd,J 1 =2.88Hz,J 2 =14.52Hz,1H),3.75(dd,J 1 =11.48Hz,J 2 =14.52Hz,1H),2.35(s,3H),1.30(s,9H); 13 CNMR (101MHz, CDCl3, 300K): δ (ppm) = 144.3, 136.4, 136.3, 129.5, 128.7, 128.3, 128.1,128.0,60.0,49.6,48.9,30.0,21.5; HRMS(ESI)m / z=403.0831calcd.for C 19 H 24 NaO2S3[M+Na] + ,found:403.0836.

[0042] Experimental Example 2

[0043]

[0044] The specific operation of the synthesis of compound 2-2 refers to compound 2-1. Compound 2-2 is a white solid with a yield of 70%. 1HNMR (400MHz, CDCl3, 300K): δ (ppm) = 7.49 (d, J = 7.96Hz, 2H), 7.14 (d, J = 7.92Hz, 2 H),7.03(d,J=8.44Hz,2H),6.70(d,J=8.44Hz,2H),4.28–4.25(m,1H),4.07(dd,J 1 =2.32Hz,J 2 =14.48Hz,1H),3.75(s,3H),3.71(dd,J 1 =11.88Hz,J 2 =14.20Hz,1H),2.36(s,3H),1.30(s,9H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 159.5, 144.2, 136.4, 129.4, 129.2, 128.1, 1 27.9,114.1,59.9,55.2,48.8,29.9,21.4; HRMS(ESI)m / z=428.1382,calcd.forC 20 H 30 NO3S3[M+NH4] + ,found:428.1382.

[0045] Experimental Example 3

[0046]

[0047] The specific operation of the synthesis of compound 2-3 refers to compound 2-1. Compound 2-3 is a yellow solid with a yield of 55%. 1 HNMR (400MHz, CDCl3, 300K): δ (ppm) = 7.84 (d, J = 8.08Hz, 2H), 7.49 (d, J = 8.04Hz, 2H), 7.17 (d, J = 8.12Hz, 2H), 7.12 (d, J = 7.92Hz, 2H), 4.32 (dd, J 1 =2.24Hz,J 2 =11.24Hz,1H),4.06(dd,J 1 =2.52Hz,J 2 =14.56Hz,1H),3.91(s,3H),3.75(dd,J 1 =11.56Hz,J 2 =14.24Hz,1H),2.34(s,3H),1.30(s,9H); 13C NMR (101MHz, CDCl3, 300K): δ (ppm) = 166.4, 144.6, 141.6, 136.0, 129.9, 129.8, 129.6, 128.1,127.9,59.7,52.1,49.3,49.0,29.9,21.4; HRMS(ESI)m / z=461.0885,calcd.for C 21 H 26 NaO4S3[M+Na] + ,found:461.0890.

[0048] Experimental Example 4

[0049]

[0050] The specific operation of the synthesis of compound 2-4 refers to compound 2-1. Compound 2-4 is a white solid with a yield of 95%. 1 HNMR (400MHz, CDCl3, 300K): δ (ppm) = 7.52 (d, J = 8.24Hz, 2H), 7.18 (d, J = 8.12Hz, 2H), 7.06 (d, J = 8.68Hz, 2H), 6.69 (d, J = 8.68Hz,2H),4.40(d,J=7.12Hz,1H),3.76(s,3H),3.61–3.54(m,1H),2.39(s,3H),1.62(d,J=7.12Hz,3H),1.27(s,9H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 158.9, 144.0, 135.9, 131.5, 129.7, 129.4, 128.5 ,113.7,66.0,57.2,55.1,48.4,30.0,21.5,11.8; HRMS(ESI)m / z=447.1093calcd.for C 21 H 28 NaO3S3[M+Na] + ,found:447.1103.

[0051] Experimental Example 5

[0052]

[0053] The specific operation of the synthesis of compound 2-5 refers to compound 2-1. Compound 2-5 is a white solid with a yield of 53%. 1HNMR (400MHz, CDCl3, 300K): δ (ppm) = 7.58 (d, J = 8.16Hz, 2H), 7.19 (d, J = 8.08Hz ,2H),7.16(d,J=5.00Hz,1H),6.86–6.85(m,1H),6.82–6.80(m,1H),4.61(dd,J 1 =2.64Hz,J 2 =11.28Hz,1H),4.11(dd,J 1 =2.76Hz,J 2 =14.52Hz,1H),3.69(dd,J 1 =11.32Hz,J 2 =14.48Hz,1H),2.38(s,3H),1.30(s,9H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 144.4, 139.5, 136.2, 129.5, 127.9, 127.0, 126.9,126.0,61.2,49.1,44.6,29.9,21.5; HRMS(ESI)m / z=409.0395calcd.for C 17 H 22 NaO2S4[M+Na] + ,found:409.0399.

[0054] Experimental Example 6

[0055]

[0056] The specific operation of the synthesis of compound 2-6 refers to compound 2-1. Compound 2-6 is a white solid with a yield of 44%. 1 HNMR (400MHz, CDCl3, 300K): δ (ppm) = 7.50 (d, J = 8.28Hz, 2H), 7.41–7.39 (m, 1H), 7.19–7.13 (m, 3H), 6.91 (d, J = 7.96Hz, 2H), 6.49 (s, 1H), 4.51 (dd, J 1 =4.20Hz,J 2 =10.36Hz,1H),4.04–3.93(m,2H),2.09(s,3H),1.31(s,9H); 13C NMR (101MHz, CDCl3, 300K): δ (ppm) = 154.5, 151.0, 144.5, 135.5, 129.1, 127.7, 127.7, 124.5, 1 22.8,120.9,111.0,106.8,57.7,49.0,43.6,29.9,21.3; HRMS(ESI)m / z=443.0780,calcd.for C 21 H 24 NaO3S3[M+Na] + ,found:443.0786.

[0057] Experimental Example 7

[0058]

[0059] The specific operation of the synthesis of compound 2-7 refers to compound 2-1. Compound 2-7 is a white solid with a yield of 95%. 1 HNMR (400MHz, CDCl3, 300K): δ (ppm) = 8.35 (d, J = 4.56Hz, 1H), 7.59–7.55 (m, 3H), 7.21–7.15 (m,3H),7.11–7.08(m,1H),4.41–4.34(m,2H),3.95–3.88(m,1H),2.36(s,3H),1.29(s,9H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 155.8, 149.7, 144.2, 136.5, 136.3, 129.5, 128. 0,124.2,122.7,58.6,51.2,48.7,29.9,21.5; HRMS(ESI)m / z=382.0964,calcd.forC 18 H 24 NO2S3[M+H] + ,found:382.0961.

[0060] Experimental Example 8

[0061]

[0062] The specific operation of the synthesis of compound 2-8 refers to compound 2-1. Compound 2-8 is a white solid with a yield of 54%. 1 HNMR (400MHz, CDCl3, 300K): δ (ppm) = 7.52 (d, J = 8.28Hz, 2H), 7.19–7.17 (m, 3H), 7.15–7.13 (m, 4H), 4.27 (dd, J1 =3.24Hz,J 2 =11.00Hz,1H),4.04(dd,J 1 =3.28Hz,J 2 =14.52Hz,1H),3.78(dd,J 1 =11.00Hz,J 2 =14.52Hz,1H),2.46–2.41(m,1H),2.36(s,3H),1.92–1.86(m,2H),1.73–1.72(m,2H),1.59–1.57(m,1H),1.25–1.17(m,5H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 144.3, 136.7, 136.3, 129.5, 128.5, 128.1, 128.1, 128. 0,59.7,49.5,48.8,32.7,32.5,25.9,25.9,25.4,21.5; HRMS(ESI)m / z=429.0987calcd.for C 21 H 26 NaO2S3[M+Na] + ,found:429.0981.

[0063] Experimental Example 9

[0064]

[0065] The specific operation of the synthesis of compound 2-9 refers to compound 2-1. Compound 2-9 is a white solid with a yield of 75%. 1 HNMR (400MHz, CDCl3, 300K): δ (ppm) = 7.44–7.42 (m, 2H), 7.34–7.32 (m, 3H), 7.23–7.21 (m, 2H), 7.17–7.15 (m, 3H) ),7.12–7.10(m,2H),6.99–6.97(m,2H),3.95–3.92(m,1H),3.86–3.82(m,1H),3.68–3.60(m,3H),2.36(s,3H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 144.3, 136.6, 136.5, 136.4, 129.5, 129.5, 128.7, 128. 5,128.2,128.1,127.9,127.7,59.7,47.9,43.1,21.5; HRMS(ESI)m / z=437.0674calcd.for C22 H 22 NaO2S3[M+Na] + ,found:437.0680.

[0066] Experimental Example 10

[0067]

[0068] The specific operation of the synthesis of compound 2-10 refers to compound 2-1. Compound 2-10 is a white solid with a yield of 72%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.48 (d, J = 8.24Hz, 2H), 7.30–7.26 (m, 2H), 7.19–7.16 (m, 6H), 7.09–7.06 (m, 4H), 4.28 (dd, J 1 =2.88Hz,J 2 =11.40Hz,1H),4.08(dd,J 1 =2.92Hz,J 2 =14.56Hz,1H),3.77(dd,J 1 =11.40Hz,J 2 =14.52Hz,1H),2.68–2.61(m,2H),2.32(s,3H),1.93–1.77(m,2H),1.33(s,3H),1.31(s,3H); 13 CNMR (101MHz, CDCl3, 300K): δ (ppm) = 144.3, 141.8, 136.3, 136.2, 129.5, 128.6, 128.4, 128.3, 128.2, 12 8.0,127.9,125.8,60.1,52.0,49.7,43.4,31.1,28.1,27.3,21.4; HRMS(ESI)m / z=493.1300calcd.forC 26 H 30 NaO2S3[M+Na] + ,found:493.1299.

[0069] Experimental Example 11

[0070]

[0071] The specific operation of the synthesis of compound 2-11 refers to compound 2-1. Compound 2-11 is a white solid with a yield of 69%. 1H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.53–7.51 (m, 2H), 7.20–7.18 (m, 3H), 7.12–7.10 (m, 2H), 6.78–6.76 (m, 2H), 4.30 (dd, J 1 =2.88Hz,J 2 =11.44Hz,1H),4.07(dd,J 1 =2.92Hz,J 2 =14.52Hz,1H),3.81(s,3H),3.75(dd,J 1 =11.48Hz,J 2 =14.52Hz,1H),1.31(s,9H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 163.4, 136.5, 130.8, 130.1, 128.7, 128.3, 128.0,114.1,60.0,55.6,49.7,48.9,30.0; HRMS(ESI)m / z=419.0780calcd.for C 19 H 24 NaO3S3[M+Na] + ,found:419.0778.

[0072] Experimental Example 12

[0073]

[0074] The specific operation of the synthesis of compound 2-12 refers to compound 2-1. Compound 2-12 is a white solid with a yield of 61%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.59–7.55 (m, 2H), 7.20–7.15 (m, 3H), 7.09–7.07 (m, 2H), 6.98–6.93 (m, 2H), 4.32 (dd, J 1 =2.92Hz,J 2 =11.60Hz,1H),4.12(dd,J 1 =2.96Hz,J 2 =14.64Hz,1H),3.77(dd,J 1 =11.60Hz,J 2 =14.68Hz,1H),1.33(s,9H); 13C NMR (101MHz, CDCl3, 300K): δ (ppm) = 165.4 (d, J = 257.28Hz, 1C), 136.1, 135.3 (d, J = 3.26Hz, 1C), 130.7 (d, J = 9.62H z,1C),128.8,128.4,128.0,116.0(d,J=22.89Hz,1C),60.0,49.6,49.0,30.0; HRMS(ESI)m / z=407.0580calcd.for C 18 H 21 FNaO2S3[M+Na] + ,found:407.0575.

[0075] Experimental Example 13

[0076]

[0077] A new disulfide transfer reagent 2-1 (45.6 mg, 0.120 mmol) and NaHCO3 (8.4 mg, 0.10 mmol) were added to a 10 mL schlenk tube, the reaction tube was replaced with a nitrogen atmosphere, and then 3-phenylchloropropane (15.5 mg, 0.100 mmol) was added, and then 1 mL of dry dichloromethane was added, and the reaction was reacted at room temperature for 12 hours. The reaction was monitored by TLC to complete. The solvent was removed by rotary evaporator, and the colorless oil 3-1 (14.4 mg, 0.0600 mmol) was separated by silica gel column chromatography, with a yield of 60%. 1 HNMR (400MHz, CDCl3, 300K): δ (ppm) = 7.29–7.25 (m, 2H), 7.19–7.16 (m, 3H), 2.73–2.68 (m, 4H), 2.03–1.96 (m, 2H), 1.31 (s, 9H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 141.4, 128.5, 128.3, 125.9, 47.7, 39.8, 34.4, 30.6, 29.9; HRMS (EI) m / z = 226.0850calcd for C12H18S2[M] + ,found:226.0845.

[0078] Experimental Example 14

[0079]

[0080] The specific operation of the synthesis of compound 3-2 refers to compound 3-1. Compound 3-2 is a colorless liquid with a yield of 93%. 1HNMR (400MHz, CDCl3, 300K): δ (ppm) = 3.64 (t, J = 6.56Hz, 2H), 2.71 (t, J = 7.38H z,2H),1.71–1.64(m,2H),1.61–1.54(m,2H),1.42–1.38(m,5H),1.33(s,9H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 62.8, 47.7, 40.8, 32.6, 29.9, 29.2, 28.3, 25.3; HRMS (EI) m / z = 222.1112calcd for C10H22OS2[M] + ,found:222.1109.

[0081] Experimental Example 15

[0082]

[0083] The specific operation of the synthesis of compound 3-3 refers to compound 3-1. Compound 3-3 is a colorless oil with a yield of 86%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 3.31–3.25 (m, 1H), 1.98–1.92 (m, 2H), 1.76–1.64 (m, 4H), 1.58–1.55 (m, 2H), 1.33 (s, 9H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 51.1, 47.5, 33.1, 30.1, 24.6; HRMS (ESI) m / z = 213.0742calcd.for C9H 18 NaS2[M+Na] + ,found:213.0749.

[0084] Experimental Example 16

[0085]

[0086] The specific operation of the synthesis of compound 3-4 refers to compound 3-1. Compound 3-4 is a colorless oil with a yield of 40%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 4.01–3.96 (m, 2H), 3.43–3.37 (m, 2H), 2.93–2.86 (m, 1H), 2.03–2.00 (m, 2H), 1.63–1.56 (m, 2H), 1.33 (s, 9H); 13C NMR (101MHz, CDCl3, 300K): δ (ppm) = 67.3, 47.5, 46.7, 32.8, 30.0; HRMS (EI) m / z = 206.0799calcd for C9H 18 OS2[M] + ,found:206.0792.

[0087] Experimental Example 17

[0088]

[0089] The specific operation of the synthesis of compound 3-5 refers to compound 3-1. Compound 3-5 is a colorless oil with a yield of 65%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.39–7.37 (m, 2H), 7.33–7.29 (m, 2H), 7.23–7.22 (m, 1H), 6.49 (d, J = 15.64Hz, 1H), 6.27 – 6.20 (m, 1H), 2.53 (d, J = 7.60 Hz, 2H), 1.35 (s, 9H); 13 C NMR (101 MHz, CDCl3, 300 K): δ (ppm)=136.7,133.5,128.5,127.6,126.4,124.7,47.8,43.7,30.0; HRMS(ESI)m / z=261.0742calcd.for C 13 H 18 NaS2[M+Na] + ,found:261.0746.

[0090] Experimental Example 18

[0091]

[0092] The specific operation of the synthesis of compound 3-6 refers to compound 3-1. Compound 3-6 is a colorless oil with a yield of 60%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.62 (d, J = 8.28Hz, 1H), 7.40 (d, J = 8.20Hz, 1H), 3.91 (s, 2H), 1.33 (s, 9H); 13CNMR (101MHz, CDCl3, 300K): δ (ppm) = 143.1, 132.3, 129.9, 118.7, 111.1, 48.3, 44.7, 30.0; HRMS (ESI) m / z = 260.0538calcd.for C 12 H 15 NNaS2[M+Na] + ,found:260.0548.

[0093] Experimental Example 19

[0094]

[0095] The specific operation of the synthesis of compound 3-7 refers to compound 3-1. Compound 3-7 is a colorless oil with a yield of 53%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.45–7.42 (m, 2H), 7.31–7.28 (m, 3H), 3.83 (q, J = 6.96Hz, 1H), 1.63 (d, J = 6.92Hz, 3H) 1.37 (s, 9H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 131.7, 128.2, 128.2, 123.0, 89.5, 84.8, 48.0, 37.7, 30.1, 21.6; HRMS (ESI) m / z = 273.0742calcd.for C 14 H 18 NaS2[M+Na] + ,found:273.0742.

[0096] Experimental Example 20

[0097]

[0098] The specific operation of the synthesis of compound 3-8 refers to compound 3-1. Compound 3-8 is a colorless oil with a yield of 90%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 3.49–3.43 (m, 1H), 2.77 (br, 1H), 2.62–2.5 5(m,1H),2.16–2.06(m,2H),1.75–1.71(m,2H),1.35(s,9H),1.30–1.25(m,4H); 13C NMR (101MHz, CDCl3, 300K): δ (ppm) = 74.0, 59.1, 47.5, 34.1, 31.8, 30.0, 26.0, 24.2; HRMS (ESI) m / z = 243.0848calcd.for C 10 H 20 NaOS2[M+Na] + ,found:243.0851.

[0099] Experimental Example 21

[0100]

[0101] The specific operation of the synthesis of compound 3-9 refers to compound 3-1. Compound 3-9 is a colorless oil with a yield of 96%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 2.70 (t, J = 7.28Hz, 4H), 1.70–1.63 (m, 4H), 1.42–1.38 (m, 4H), 1.33 (s, 18H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 47.7, 40.7, 29.9, 29.1, 28.1; HRMS (ESI) m / z = 349.1123calcd.for C 14 H 30 NaS4[M+Na] + ,found:349.1124.

[0102] Experimental Example 22

[0103]

[0104] The specific operation of the synthesis of compound 3-10 refers to compound 3-1. Compound 3-10 is a colorless oil with a yield of 84%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.30–7.26 (m, 2H), 7.21–7.16 (m, 3H), 2.87–2.80 (m, 1H), 2.79–2.68(m,2H),2.06–1.97(m,1H),1.85–1.76(m,1H),1.33(d,J=6.80Hz,3H),1.29(s,9H); 13C NMR (101MHz, CDCl3, 300K): δ (ppm) = 141.6, 128.4, 128.3, 125.8, 47.4, 46.3, 37.9, 33.1, 30.0, 20.4; HRMS (ESI) m / z = 255.1236calcd.for C 14 H 23 S2[M+H] + ,found:255.1236.

[0105] Experimental Example 23

[0106]

[0107] The specific operation of the synthesis of compound 3-11 refers to compound 3-1. Compound 3-11 is a colorless oil with a yield of 85%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.29–7.25 (m, 2H), 6.96–6.90 (m, 3H), 4.20 (t, J = 6.96Hz, 2H), 3.04 (t, J = 6.96Hz, 2H), 1.35 (s, 9H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 158.4, 129.4, 120.9, 114.6, 66.4, 47.9, 38.9, 29.8; HRMS (EI) m / z = 352.1311calcd.for C 21 H 20 O5[M] + ,found:352.1309.

[0108] Experimental Example 24

[0109]

[0110] The specific operation of the synthesis of compound 3-12 refers to compound 3-1. Compound 3-12 is a colorless oil with a yield of 70%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.31–7.25 (m, 2H), 6.97–6.91 (m, 3H), 4.23 (t, J = 6.80Hz, 2H), 2.76 (t, J = 6.80Hz,2H),2.78–2.71(m,1H),2.05–2.02(m,2H),1.79–1.76(m,2H),1.63–1.59(m,1H),1.37–1.24(m,5H); 13C NMR (101MHz, CDCl3, 300K): δ (ppm) = 158.3, 129.5, 121.0, 114.6, 66.2, 49.6, 38.3, 32.7, 26.0, 25.6; HRMS (ESI) m / z = 291.0848calcd.for C 14 H 20 NaOS2[M+Na] + ,found:291.0858.

[0111] Experimental Example 25

[0112]

[0113] The specific operation of the synthesis of compound 3-13 refers to compound 3-1. Compound 3-13 is a colorless oil with a yield of 70%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.32–7.25 (m, 7H), 6.97–6.93 (m, 1H), 6. 88–6.86(m,2H),4.08(t,J=6.64Hz,2H),3.91(s,2H),2.76(t,J=6.64Hz,2H); 13 C NMR (101MHz, CDCl3, 300K): δ (ppm) = 158.3, 137.2, 129.5, 129.3, 128.6, 127.5, 121.1, 114.6, 66.0, 43.7, 37.2; HRMS (EI) m / z = 299.0535calcd.for C 15 H 16 NaOS2[M] + ,found:299.0545.

[0114] Experimental Example 26

[0115]

[0116] The specific operation of the synthesis of compound 3-14 refers to compound 3-1. Compound 3-14 is a colorless oil with a yield of 97%. 1 H NMR (400MHz, CDCl3, 300K): δ (ppm) = 7.99 (d, J = 7.40Hz, 2H), 7.60–7.56 (m, 1H), 7.50–7.46(m,2H),3.40(t,J=7.32Hz,2H),3.07(t,J=7.16Hz,2H),1.35(s,9H); 13C NMR (101MHz, CDCl3, 300K): δ (ppm) = 198.3, 136.5, 133.3, 128.6, 128.1, 48.1, 38.6, 34.3, 30.0; HRMS (EI) m / z = 226.0486calcd for C 11 H 14 OS2[M] + ,found:226.0488.

[0117] Many specific details are described in the above description to facilitate a full understanding of the present invention. However, the above description is only a preferred embodiment of the present invention. The present invention can be implemented in many other ways different from those described herein, so the present invention is not limited to the specific implementation disclosed above. At the same time, any person familiar with the art can make many possible changes and modifications to the technical solution of the present invention using the methods and technical contents disclosed above without departing from the scope of the technical solution of the present invention, or modify it into an equivalent embodiment of equivalent changes. Any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the scope of protection of the technical solution of the present invention.

Claims

1. A disulfide transfer reagent, characterized in that The reagent has the following molecular formula: Among them, the R 1 The substituents on the substituted phenyl are C1-C20 hydrocarbon groups, alkoxy groups, alkylthio groups, silicon groups, boron groups, ester groups, amide groups, cyano groups, trifluoromethyl groups, aldehyde groups, nitro groups, phenyl groups or halogen atoms, and the number of substituents is 1-5; the heteroaryl group is furanyl, thienyl or pyridyl; the substituents on the substituted heteroaryl group are C1-C20 hydrocarbon groups, alkoxy groups, alkylthio groups, silicon groups, boron groups, ester groups, amide groups, cyano groups, trifluoromethyl groups, aldehyde groups, nitro groups, phenyl groups or halogen atoms, and the number of substituents is 1-4; The R 2 The substituents on the substituted phenyl are C1-C20 hydrocarbon groups, alkoxy groups, alkylthio groups, silicon groups, boron groups, ester groups, amide groups, cyano groups, trifluoromethyl groups, aldehyde groups, nitro groups, phenyl groups or halogen atoms, and the number of substituents is 1-5. The substituents on the substituted benzyl groups are C1-C20 hydrocarbon groups, alkoxy groups, alkylthio groups, silicon groups, boron groups, ester groups, amide groups, cyano groups, trifluoromethyl groups, aldehyde groups, nitro groups, phenyl groups or halogen atoms, and the number of substituents is 1-5. The heteroaryl groups are furyl groups, thienyl groups, pyridyl groups, benzothienyl groups, benzofuranyl groups, indolyl groups. The substituents on the substituted heteroaryl groups are C1-C20 hydrocarbon groups, alkoxy groups, alkylthio groups, silicon groups, boron groups, ester groups, amide groups, cyano groups, trifluoromethyl groups, aldehyde groups, nitro groups, phenyl groups or halogen atoms, and the number of substituents is 1-4. The R 3 The substituents on the substituted phenyl are C1-C20 hydrocarbon groups, alkoxy groups, alkylthio groups, silicon groups, boron groups, ester groups, amide groups, cyano groups, trifluoromethyl groups, aldehyde groups, nitro groups, phenyl groups or halogen atoms, and the number of substituents is 1-5. The heteroaryl group is furyl, thienyl, pyridyl, benzothienyl, benzofuranyl, indolyl. The substituents on the substituted heteroaryl group are C1-C20 hydrocarbon groups, alkoxy groups, alkylthio groups, silicon groups, boron groups, ester groups, amide groups, cyano groups, trifluoromethyl groups, aldehyde groups, nitro groups, phenyl groups or halogen atoms, and the number of substituents is 1-4. The substituents on the substituted C1-C20 alkyl groups are phenyl groups, substituted phenyl groups, 1-naphthyl groups, 2-naphthyl groups, heteroaryl groups, and substituted heteroaryl groups.

2. The disulfide transfer reagent according to claim 1, characterized in that The disulfide transfer reagent comprises:

3. A method for synthesizing an asymmetric disulfide compound using the disulfide transfer reagent according to any one of claims 1 to 2, characterized in that: The following steps are involved: Adding a basic additive to the disulfide transfer reagent generates a nucleophilic disulfide anion (R 2 SSˉ), then adding an alkyl halide, a Michael acceptor or an epoxy compound, and then adding an organic solvent to react to obtain the asymmetric disulfide compound; Wherein, the alkaline additive is LiHCO3, Li2CO3, Li3PO4, LiH2PO4, Li2HPO4, LiHSO4, Li2SO4, LiHC2O4, Li2C2O4, CH3COOLi, HCOOLi, LiOH, NaHCO3, Na2CO3, Na3PO4, NaH2PO4, Na2HPO4, NaHSO4, Na2SO4, NaHC2O4, Na2C2O4, CH3COONa, HCOONa, NaOH, KHCO3, K2CO3, K3P O4, KH2PO4, K2HPO4, KHSO4, K2SO4, KHC2O4, K2C2O4, CH3COOK, HCOOK, KOH, NH4HCO3, (NH4)2CO3, (NH4)3PO4, (NH4)H2PO4, (NH4)2HPO4, NH4HSO4, (NH4)2SO4, NH4HC2O4, (NH4)2C2O4, CH3COONH4, HCOONH4, ammonia water, triethylamine, diisopropylamine, trimethylamine, piperidine, pyridine or a mixture of several of them; Wherein, the alkyl halide includes any one of alkyl chloride, alkyl bromide, alkyl iodide, and alkyl triflate; The epoxy compound has the following molecular formula: Where R 5 is independently selected from phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, substituted heteroaryl, and substituted C1-C20 alkyl, R 6 independently selected from phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, substituted heteroaryl, and substituted C1-C20 alkyl; The Michael receptor has the following molecular formula: Where R 7 The electron-withdrawing substituent is any one of nitro, carbonyl, ester, carboxyl, sulfonyl, phosphonyl, cyano and their corresponding substituents.

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