A method for synthesizing acyl disulfide compounds via solvent-free rearrangement reaction

Abstract

The invention discloses a method for synthesizing acyl disulfide compounds by solvent-free rearrangement reaction. In a reaction system, a thiol compound, N-thioalkynylphthalimide, and a phenyl sulfoxide compound are used as raw materials, and substitution and rearrangement reactions occur under the action of a catalyst to obtain an acyl disulfide compound. The invention adopts a solvent-free green synthesis process and develops a method for efficiently preparing acyl disulfide compounds by [3,3]-rearrangement.

Description

Technical Field

[0001] The invention relates to a method for synthesizing acyl disulfide compounds by an acid-catalyzed solvent-free rearrangement reaction, and belongs to the field of organic compound preparation. Background Art

[0002] In the chemical and pharmaceutical industries, reducing the use of solvents and the generation of by-products is the core of current green chemical processes, so the development of solvent-free chemical reactions is of great research significance.

[0003] Disulfide bonds are important structural scaffolds in the fields of life science, materials science and pharmaceuticals. It is reported that disulfide structures are widely present in biologically active natural products and drug molecules, such as disulfiram, a drug molecule for alcohol withdrawal, Varacins A, a biologically active molecule with anti-tumor effects in natural products, immunosuppressant gliotoxin, and Dimeric lissoclinotoxin D, a natural antibacterial active molecule, all contain disulfide structures. The presence of these disulfide bonds is of great significance for maintaining drug activity and biological structural stability. It is particularly worth mentioning that according to literature reports (Synthesis, 2001, 1035), acyl disulfide compounds have unique biological activities in medicine or physiology, and some of them have been shown to significantly inhibit the growth of bacteria or fungi; in addition, monoacyl disulfide compounds can be used as mediators for the formation of peptide bonds between unprotected peptide segments. However, there are still few reports on monoacyl disulfide compounds, and acyl disulfide compounds are mainly synthesized by nucleophilic substitution reaction of potassium thioacetate (ACIE.2016, 55, 14121).

[0004] Summary of the invention

[0005] The present invention uses an acid-catalyzed solvent-free reaction with thiol and N-thioalkynylphthalimide as substrates, generates alkynyl disulfide in situ, and then undergoes a [3,3]-sigma rearrangement with sulfoxide to obtain a series of acyl disulfide compounds. The reaction is carried out under very mild reaction conditions and produces a reversible disulfide bond with excellent functional group tolerance. The disulfide bond formed by the sulfur reagent and the thiol group is more convenient and practical. In addition, the obtained acyl disulfide compound can also undergo further functional transformation, such as undergoing a hydrolysis reaction to generate a corresponding product, etc., which lays a good foundation for the realization of molecular multifunctionality.

[0006] The present invention provides a method for synthesizing acyl disulfide compounds by solvent-free rearrangement reaction. In a reaction system, thiol compounds, N-thioalkynylphthalimide and phenyl sulfoxide compounds are used as raw materials, and substitution and rearrangement reactions occur under the action of a catalyst to obtain acyl disulfide compounds.

[0007] The structural formula of N-thioalkynylphthalimide is:

[0008]

[0009] In the above formula, R 1 is one of an alkyl group, an aryl group, and a silicon group;

[0010] The structural formula of thiol compounds is:

[0011] HS-R 2

[0012] In the above formula, R 2 It is one of a chain alkyl group, a cyclic alkyl group, a (substituted) aryl group, an ester group, and a glucose derivative.

[0013] The structural formula of phenyl sulfoxide compounds is:

[0014]

[0015] In the above formula, R is an alkyl group or an aryl group.

[0016] The reaction process of the present invention is shown in the following reaction formula:

[0017]

[0018] In this reaction formula, R 1 is one of alkyl, aryl and silicon; R 2 It is one of a chain alkyl group, a cyclic alkyl group, a (substituted) aryl group, an ester group, and a glucose derivative; R is one of an alkyl group or an aryl group.

[0019] In the above method, the molar ratio of N-alkynylthiophthalimide I, thiol compound II, and phenyl sulfoxide compound is 1:1.2-5.0:1.5-10.0, preferably, the molar ratio of N-alkynylthiophthalimide, thiol compound, and phenyl sulfoxide compound is 1:1.2:2.5.

[0020] In the above method, the reaction temperature is 0-100°C, preferably, the reaction temperature is 30°C.

[0021] The catalyst used in the above method is not limited to one or more of trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, trifluoroacetic acid, trifluoromethanesulfonic anhydride, and bistrifluoromethanesulfonyl imide. Preferably, the catalyst in the reaction is trimethylsilyl trifluoromethanesulfonate. The amount of the catalyst used is 1-30mol% of the amount of the substrate, preferably, the amount of the catalyst is 10mol% of the amount of the substrate.

[0022] The above synthesis method selects to carry out the reaction under solvent-free conditions.

[0023] The basic reaction principle of the present invention is as follows: under the action of a catalyst, the carbonyl group of phthalimide is activated by a proton, and phthalimide leaves as a leaving group to release an alkynyl sulfide cation with higher activity, which is captured by a thiol group in a reaction system to obtain an alkynyl disulfide, and the proton released in the reaction system reacts with the alkynyl disulfide to form an alkene carbon cation, which is then captured by an oxygen anion of an aryl sulfoxide, and a final acyl disulfide compound is obtained through a Claisen rearrangement.

[0024]

[0025] Beneficial effects of the present invention:

[0026] The present invention adopts a solvent-free green synthesis process and develops a method for efficiently preparing acyl disulfide by [3,3]-rearrangement. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The figure is a diagram of the preparation process of acyl disulfide compounds in the prior art.

[0028] Figure 2 The figure is a diagram of the preparation process of the acyl disulfide compound of the present invention. DETAILED DESCRIPTION

[0029] In conjunction with the following specific examples, the present invention is further described in detail, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, the changes and advantages that can be thought of by those skilled in the art are included in the present invention. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention has no special restrictions. The data given in the following examples include specific operations and reaction conditions and products. The product purity is identified by nuclear magnetic resonance.

[0030] Example 1

[0031] Synthesis of compound IIIa

[0032]

[0033] In a 10 mL reaction bottle, add cyclohexyl mercaptan (20.9 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), diphenyl sulfoxide (121.4 mg, 0.6 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), stir at 40 ° C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 52.0mg (82%); TLC, Rf=0.20 (PE:EtOAc=49:1); 1H NMR (CDCl3, 400MHz): δ7.41(t,J=8.0Hz,2H),7.35-7.27(m,2H),7.26-7.22(m,3H),7.21-7.17(m,2H),4.75(t,J=8.0Hz,1H),2.69-2 13C NMR (CDCl3, 100MHz): δ199.6,140.1,136.7,134.9,134.4,131.0,129.6,129.1,128.8,128. 5,128.3,127.0,126.5,55.3,49.6,33.6,32.5,29.5,25.9,25.4,22.4,13.8; HRMS(ESI)m / z calcd.for C 24 H 30 OS3[M+Na] + :453.1351,found:453.1351.

[0034] Example 2

[0035] Synthesis of compound IIIb

[0036]

[0037] In a 10 mL reaction bottle, add adamantanethiol (126.2 mg, 0.75 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), diphenyl sulfoxide (242.7 mg, 1.2 mmol), trimethylsilyl trifluoromethanesulfonate (6 μL, 20 mol%), and 2 mL of dichloromethane. Stir at 30°C for 20 hours, concentrate the reaction solution, and purify it by flash column chromatography to obtain a yellow liquid. Yield: 51.1 mg (71%); TLC, R f=0.20 (PE:EtOAc=49:1); 1 H NMR (CDCl3, 400MHz): δ7.425 (dd, J=12.0, 8.0Hz, 2H), 7.33-7.28 (m, 2H), 7.27-7.18 (m, 5H), 4.80 (t, J=8.0Hz, 1H),2.16-2.10(m,1H),2.00(s,3H),1.72(s,7H),1.66-1.54(m,7H),1.29-1.12(m,4H),0.81(t,J=8.0Hz,1H); 13 C NMR(CDCl3,100MHz):199.6,140.2,136.7,134.8,134.5,129.6,129.1,128.7,128. 4,128.2,126.5,55.3,50.6,42.2,35.9,33.5,29.8,29.5,22.4,13.8; HRMS(ESI)m / z calcd.for C 28 H 34 OS3[M+Na] + :505.1664,found:505.1657.

[0038] Example 3

[0039] Synthesis of compound IIIc

[0040]

[0041] In a 10 mL reaction bottle, add mercaptopropionate (23.4 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), diphenyl sulfoxide (75.9 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), stir at 40°C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 17.3 mg (24%); TLC, R f =0.20 (PE:EtOAc=49:1); 1H NMR (CDCl3, 400MHz): δ7.44(d,J=8.0Hz,1H),7.40(d,J=8.0Hz,1H),7.33(t,J=8.0Hz,1H),7.27-7.24(m,3H),7.23-7.19(m,3H),4.72(t,J=8.0H z,1H),4.16-4.11(m,2H),2.86-2.83(m,2H),2.55-2.52(m,2H),2.17-2 .08(m,1H),1.77-1.68(m,1H),1.25(t,J=8.0Hz,7H),0.82-0.79(m,3H); 13 C NMR (CDCl3, 100MHz): δ198.6,171.3,139.8,136.6,135.0,134.4,129.5,129.2,128.9,128.6 ,128.4,126.6,60.8,55.5,33.9,33.4,29.7,29.5,22.4,14.2,13.8; HRMS(ESI)m / zcalcd.for C 23 H 28 O3S3[M+Na] + :471.1093,found:471.1094.

[0042] Example 4

[0043] Synthesis of compound IIId

[0044]

[0045] In a 10 mL reaction bottle, add 1-mercaptoglucose (65.5 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), diphenyl sulfoxide (75.9 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (6 μL, 20 mol%), stir at 50 ° C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 41.5 mg (41%); TLC, R f =0.20 (PE:EtOAc=4:1); 1HNMR (CDCl3, 400MHz): δ7.37 (d, J = 8.0Hz, 1H), 7.33-7.27 (m, 2H), 7.24-7.15 (m, 6H), 5.13- 5.06(m,1H),4.97-4.88(m,2H),4.66-4.62(m,1H),4.28(dd,J=28.0,12.0Hz,1H),4.17-4.0 4(m,1H),3.97-3.93(m,1H),3.58-3.47(m,1H),2.05(d,J=4.0Hz,3H),2.00(d,J=4.0Hz,3H ),1.94-1.93(d,J=4.0Hz,6H),1.73-1.59(m,2H),1.21-1.16(m,4H),0.74(t,J=8.0Hz,3H); 13 C NMR (CDCl3, 100MHz): δ196.4,170.6,170.1,169.5,169.3,139.5,136.5,134.9,134.8,129.7,129.2,128.8,128.7,1 28.6,126.7,87.2,87.0,76.1,73.7,69.6,67.8,61.9,55.6,33.2,29.3,26.9,22.4,20.7,20.5,13.8; HRMS(ESI)m / z calcd.for C 32 H 38 NaO 10 S3[M+Na] + :701.1519,found:701.1518.

[0046] Example 5

[0047] Synthesis of compound IIIe

[0048]

[0049] In a 10 mL reaction bottle, add p-methylthiophenol (22.4 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), diphenyl sulfoxide (75.9 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), stir at 0°C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 39.3 mg (60%); TLC, R f =0.20 (PE:EtOAc=49:1); 1H NMR (CDCl3, 400MHz): δ7.32 (m, 2H), 7.25-7.20 (m, 3H), 7.18-7.10 (m, 6H), 6.96 (d, J = 8.0Hz, 2H), 4.65 (t, J =4.0Hz,1H),2.22(s,3H),2.10-2.01(m,1H),1.70-1.60(m,1H),1.22-1.00(m,4H),0.72(t,J=4.0Hz,3H); 13 C NMR (CDCl3, 100MHz): δ198.1,139.7,138.3,136.5,134.8,134.7,132.5,130.7,129.7,129.7,1 29.2,128.7,128.6,128.4,126.6,55.3,33.5,29.5,22.4,21.1,13.8; HRMS(ESI)m / zcalcd.for C 25 H 26 OS3[M+Na] + :461.1038,found:461.1032.

[0050] Example 6

[0051] Synthesis of compound IIIf

[0052]

[0053] In a 10 mL reaction bottle, add 2-naphthalenethiol (28.8 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), diphenyl sulfoxide (273.1 mg, 1.35 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), stir at 0°C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 47.5 mg (67%); TLC, R f =0.20 (PE:EtOAc=49:1); 1H NMR (CDCl3, 400MHz): δ7.88 (d, J = 2.0Hz, 1H), 7.82 (t, J = 4.0Hz, 3H), 7.76-7.71 (m, 2H), 7.52-7.44 (m, 6H), 7.36 (t, J = 8.0Hz, 1H), 7.32-7.29 (m, 1 H),7.27-7.26(m,3H),7.23-7.20(m,1H),4.84(t,J=8.0Hz,1H),2.25-2 .16(m,1H),1.84-1.74(m,1H),1.34-1.23(m,4H),0.84(t,J=8.0Hz,3H); 13 CNMR (CDCl3, 100MHz): δ197.7,139.5,136.4,134.8,134.7,133.3,133.0,132.6,129.7,129.2,128.8,12 8.8,128.7,128.6,128.5,127.7,127.5,127.0,126.6,126.5,55.4,33.4,29.5,22.4,13.8; HRMS(ESI)m / z calcd.for C 28 H 26 OS3[M+H] + :475.1219,found:475.1216.

[0054] Example 7

[0055] Synthesis of compound IIIg

[0056]

[0057] In a 10 mL reaction bottle, add benzyl mercaptan (22.4 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), diphenyl sulfoxide (273.1 mg, 1.35 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), and 1 mL of methanol. Stir at 100 ° C for 20 hours, concentrate the reaction solution, and purify it by flash column chromatography to obtain a yellow liquid. Yield: 39.9 mg (61%); TLC, R f =0.20 (PE:EtOAc=49:1); 1H NMR (CDCl3, 400MHz): δ7.36 (d, J=8.0Hz, 1H), 7.31-7.23 (m, 2H), 7.19-7.14 (m, 6H), 7.12-7.07 (m, 5H), 4.63 (t, J=8.0H z,1H),3.71(dd,J=17.2,12.0Hz,2H),2.06-1.92(m,1H),1.66-1.57(m,1H),1.21-1.16(m,4H),0.74(t,J=4.0Hz,3H); 13 C NMR (CDCl3, 100MHz): δ198.4,139.9,136.6,136.1,134.9,134.5,129.6,129.4,129.2,12 8.8,128.5,128.4,128.3,127.6,126.5,55.3,42.4,33.5,29.4,22.4,13.8; HRMS(ESI)m / z calcd.for C 25 H 26 OS3[M+H] + :439.1219,found:439.1226.

[0058] Example 8

[0059] Synthesis of compound IIIh

[0060]

[0061] In a 10 mL reaction bottle, add cyclohexyl mercaptan (20.9 mg, 0.18 mmol), N-1-tert-butylethynylthiophthalimide (38.9 mg, 0.15 mmol), diphenyl sulfoxide (151.8 mg, 0.76 mmol), trimethylsilyl trifluoromethanesulfonate (6 μL, 20 mol%), stir at 30 ° C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 45.6 mg (71%); TLC, R f =0.20 (PE:EtOAc=49:1); 1 H NMR (CDCl3, 400MHz): δ7.61 (d, J=8.0Hz, 1H), 7.40 (dd, J=7.6, 1.6Hz, 1H), 7.27-7.26 (m, 5H), 7.24-7.22 (m, 1H),7.21-7.20(m,1H),4.95(s,1H),2.71-2.64(m,2H),1.90-1.84(m,2H),1.29-1.17(m,6H),1.08(s,9H); 13C NMR (CDCl3, 100MHz): δ198.4,136.9,136.7,136.5,134.7,130.1,130.1,129.1,128 .2,127.4,126.6,63.3,49.5,36.9,32.4,28.1,25.9,25.4; HRMS(ESI)m / zcalcd.for C 24 H 30 OS3[M+Na] + :453.1351,found:453.1345.

[0062] Example 9

[0063] Synthesis of compound IIIi

[0064]

[0065] In a 10 mL reaction bottle, add cyclohexyl mercaptan (20.9 mg, 0.18 mmol), N-triisopropylsilylethynylthiophthalimide (53.9 mg, 0.15 mmol), diphenyl sulfoxide (75.9 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), stir at 30°C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 31.6 mg (40%); TLC, R f =0.20 (PE:EtOAc=49:1); 1 H NMR (CDCl3, 400MHz): δ7.77(d,J=8.0Hz,1H),7.41(d,J=8.0Hz,1H),7.32-7.26(m,3H),7.24-7.21(m,2H 13C NMR (CDCl3, 100MHz): δ196.78,138.24,136.79,135.07,133.35,131.68,131.52,130.99,130.40,129.60,129.34,12 9.15,129.11,128.27,127.20,126.40,49.14,48.65,32.56,32.50,25.93,25.46,18.80,18.70,12.11.HRMS(ESI)m / z calcd.forC 29 H 42 OS3Si[M+Na]+ :553.2059,found:553.2047.

[0066] Example 10

[0067] Synthesis of compound IIIj

[0068]

[0069] In a 10 mL reaction bottle, add cyclohexyl mercaptan (20.9 mg, 0.18 mmol), N-phenylethynylthiophthalimide (41.9 mg, 0.15 mmol), diphenyl sulfoxide (75.9 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), stir at 30°C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 45.1 mg (67%); TLC, R f =0.20 (PE:EtOAc=49:1); 1 H NMR (CDCl3, 400MHz): δ7.43 (dd, J=7.6, 1.6Hz, 1H), 7.34-7.27 (m, 6H), 7.24-7.21 (m, 4H), 7.20-7.1 5(m,3H),6.11(s,1H),2.71-2.64(m,1H),1.93-1.89(m,2H),1.74-1.70(m,2H),1.29-1.22(m,6H); 13 C NMR(CDCl3,100MHz): δ198.3,163.3,140.0,135.0,130.1,129.4129.2,128.8,128 .7,128.6,127.6,126.6,119.6,113.1,60.6,49.7,32.6,25.9,25.5; HRMS(ESI)m / z calcd.for C 26 H 26 NaOS3[M+Na] + :473.1038,found:473.1030.

[0070] Embodiment 11

[0071] Synthesis of compound IIIk

[0072]

[0073] In a 10 mL reaction bottle, add cyclohexyl mercaptan (20.9 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), phenylbenzyl sulfoxide (81 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), 1 mL of ethyl acetate, stir at 30 ° C for 20 hours, concentrate the reaction solution, and purify by flash column chromatography to obtain a yellow liquid. Yield: 51.3 mg (77%); TLC, R f =0.20 (PE:EtOAc=49:1); 1 H NMR (CDCl3, 400MHz): δ7.39(dd,J=7.6,1.6Hz,1H),7.31-7.23(m,6H),7.22-7.18(m,2H),4.76(t,J=7.2Hz,3H),4.11(s,2H),2.71- 2.65(m,1H),2.15-2.06(m,1H),1.92-1.86(m,2H),1.74-1.70(m,2H),1.63-1.54(m,2H),1.32-1.12(m,9H),0.85(t,J=8.0Hz,3H); 13 C NMR (CDCl3, 100MHz): δ199.5,139.3,137.2,135.6,132.6,128.9,128.5,128.0,127.8, 127.6,127.3,55.2,49.5,40.5,33.5,32.4,29.5,25.9,25.4,22.5,13.9; HRMS(ESI)m / z calcd.for C 25 H 32 OS3[M+Na] + :467.1507,found:467.1500.

[0074] Example 12

[0075] Synthesis of compound IIIl

[0076]

[0077] In a 10 mL reaction bottle, cyclohexyl mercaptan (20.9 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), 4,4'-dimethylbenzene sulfoxide (86.4 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), dimethyl sulfoxide 1 mL were added, stirred at 30 ° C for 20 hours, then saturated NaCl aqueous solution was added, the product was extracted with EtOAc (3x10 mL), the combined organic layer was dried with anhydrous Na2SO4, filtered, and the solvent was removed under vacuum, and the crude product was purified by flash column chromatography to obtain a yellow liquid. Yield: 44.5 mg (65%); TLC, R f =0.20 (PE:EtOAc=49:1); 1 H NMR (CDCl3, 400MHz): δ7.31 (dd, J = 8.0Hz, 1H), 7.17 (s, 1H), 7.14-7.11 (m, 2H), 7.07-7.05 (m, 2H), 7.04-7.01 (m, 1H), 4.74 (t, J = 4.0Hz, 1H), 2.71-2.63(m,1H),2.31(d,J=8.0Hz,6H),2.14-2.05(m,1H),1.92-1.8 6(m,1H),1.74-1.56(m,4H),1.26-1.23(m,9H),0.81(t,J=6.8Hz,3H); 13 C NMR (CDCl3, 100MHz): δ199.7,139.9,138.8,136.4,134.8,133.5,131.4,129.9,129.7,129 .1,128.9,55.2,49.5,33.7,32.5,29.6,26.0,25.4,22.5,21.2,21.0,13.8; HRMS(ESI)m / z calcd.for C 26 H 34 OS3[M+Na] + :481.1664,found:481.1655.

[0078] Example 13

[0079] Synthesis of compound IIIm

[0080]

[0081] In a 10 mL reaction bottle, add cyclohexyl mercaptan (20.9 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), dibenzothiophene 5-oxide (75 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (9 μL, 30 mol%), stir at 50 ° C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 48.7 mg (76%); TLC, R f =0.20 (PE:EtOAc=49:1); 1 H NMR (CDCl3, 400MHz): δ8.17-8.15 (m, 1H), 8.10 (dd, J = 7.6, 1.6Hz, 1H), 7.90- 7.87(m,1H),7.50-7.45(m,4H),4.24(t,J=4.0Hz,1H),2.68-2.61(m,1H),2. 33-2.23(m,1H),2.10-2.01(m,1H),1.89-1.80(m,2H),1.72-1.64(m,2H),1. 57-1.49(m,3H),1.43-1.30(m,3H),1.28-1.08(m,4H),0.86(t,J=8.0Hz,3H); 13 C NMR (CDCl3, 100MHz): δ198.9,139.9,138.8,136.1,136.0,132.3,127.0,125.5,125.2,124. 6,122.8,121.8,120.9,57.9,49.6,32.6,32.4,29.5,25.8,25.4,22.5,13.8; HRMS(ESI)m / z calcd.for C 24 H 28 OS3[M+Na] + :451.1194,found:451.1193.

[0082] Embodiment 14

[0083] Synthesis of Compound IIIn

[0084]

[0085] In a 10 mL reaction bottle, add cyclohexyl mercaptan (20.9 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), phenylethyl sulfoxide (57.8 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), stir at 30°C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 13.6 mg (24%); TLC, R f =0.20 (PE:EtOAc=49:1); 1 H NMR (CDCl3, 400MHz): δ7.43-7.41(m,1H),7.32-7.29(m,1H),7.25-7.17(m,2H),4.74(t,J=8.0Hz,1H),2.96(q,J=8.0Hz,2H),2.79-2.65(m,2 H),2.20-2.10(m,1H),2.00-1.96(m,1H),1.92-1.87(m,2H),1.82-1.6 6(m,5H),1.34-1.30(m,3H),1.27-1.19(m,6H),0.86(t,J=8.0Hz,3H); 13 C NMR (CDCl3, 100MHz): δ199.6,138.4,136.3,130.7,128.0,127.9,126.8,55. 0,49.5,33.4,32.4,29.5,29.0,25.9,25.5,22.5,14.4,13.9; HRMS(ESI)m / z calcd.for C 20 H 30 OS3[M+Na] + :383.1532,found:383.1526.

[0086] Embodiment 15

[0087] Synthesis of compound IIIo

[0088]

[0089] In a 10 mL reaction bottle, add cyclohexyl mercaptan (20.9 mg, 0.18 mmol), N-phenylethynylthiophthalimide (41.9 mg, 0.15 mmol), methyl phenyl sulfoxide (52.6 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), stir at 30 ° C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 31.4 mg (54%); TLC, Rf =0.20 (PE:EtOAc=49:1); 1 H NMR (CDCl3, 400MHz): δ7.37-7.27(m,7H),7.24-7.21(m,1H),7.17-7.13(m,1H),5.99(s,1H) ),2.74-2.67(m,1H),2.45(s,3H),1.97-1.92(m,2H),1.77-1.72(m,2H),1.35-1.14(m,6H); 13 C NMR (CDCl3, 100MHz): δ198.5,138.0,136.8,136.5,129.3,129.1,128.7,12 8.3,127.8,127.7,125.7,60.1,49.6,32.5,25.9,25.5,17.1; HRMS(ESI)m / z calcd.for C 21 H 24 OS3[M+Na] + :411.0881,found:411.0877.

[0090] Example 16

[0091] Synthesis of compound IIIp

[0092]

[0093] In a 10 mL reaction bottle, add cyclohexyl mercaptan (20.9 mg, 0.18 mmol), N-1-hexynylthiophthalimide (38.9 mg, 0.15 mmol), phenyl trifluoromethyl sulfoxide (72.8 mg, 0.38 mmol), trimethylsilyl trifluoromethanesulfonate (3 μL, 10 mol%), stir at 30°C for 20 hours, and purify the crude product of the reaction solution by flash column chromatography to obtain a yellow liquid. Yield: 25.2 mg (40%); TLC, R f =0.20 (PE:EtOAc=49:1); 1 H NMR (CDCl3, 400MHz): δ7.75 (d, 1H), 7.53-7.47 (m, 2H), 7.36-7.31 (m, 1H), 4.86 (t, J = 8.0Hz, 1H), 2.72-2.65 (m, 1H), 2 .25-2.16(m,1H),1.99-1.91(m,2H),1.79-1.68(m,4H),1.34-1.29(m,5H),1.24-1.20(m,4H),0.87(t,J=4.0Hz,3H); 13C NMR (CDCl3, 100MHz): δ199.2, 143.3, 138.2, 131.9, 129.3 (q, J = 309Hz), 128.6 (d, J =58Hz),124.28,55.5,49.6,42.4,33.9,32.5,31.1,29.7,25.9,25.2,22.5,13.8; 19 F(376MHz,CDCl3)δ-42.1.HRMS(ESI)m / z calcd.for C 19 H 26 F3OS3[M+H] + :423.1092,found:423.1094.

[0094] Embodiment 17

[0095] Synthesis of compound IIIq

[0096]

[0097] In a 10 mL reaction bottle, add cyclohexyl 2-(2-(phenylthio)phenyl)hexane (dithioperoxy acid salt) (64.5 mg, 0.15 mmol), sodium hydroxide 1M aqueous solution (0.75 mL, 0.75 mmol), tetrahydrofuran 1 mL, stir at 60 ° C for 2 hours, concentrate the reaction solution, and obtain a light yellow liquid by column chromatography. Yield: 34.5 mg (77%); TLC, R f =0.20 (PE:EtOAc=3:1); 1 H NMR (CDCl3, 400MHz): δ7.45-7.41(m,2H),7.32(t,J=8.0Hz,1H),7.26-7.15(m,6H),4.41(t,J =8.0Hz,1H),2.08-2.00(m,1H),1.74-1.64(m,1H),1.31-1.08(m,5H),0.81(t,J=8.0Hz,3H); 13 C NMR (CDCl3, 100MHz): δ179.9,141.2,136.8,134.8,134.1,129.4,129.0,128.7,128.1,128.0,126.4,47.7,32.9,29.6,22.4,13.8; HRMS(ESI)m / zcalcd.for C 18 H 19 O2S[MH] + :299.1111,found:299.1113.

[0098] Embodiment 18

[0099] Synthesis of compound IIIr

[0100]

[0101] In a 10mL reaction bottle, add cyclohexyl 2-(2-(phenylthio)phenyl)hexane (dithioperoxy acid salt) (64.5mg, 0.15mmol), ammonium acetate (17.3mg, 0.23mmol), dimethyl sulfoxide 1mL, stir at 120°C for 2 hours, then add saturated NaCl aqueous solution, extract the product with EtOAc (3x10mL), dry the combined organic layer with anhydrous Na2SO4, filter, and remove the solvent under vacuum. The crude product is purified by flash column chromatography to obtain a light yellow solid. Yield: 33.1mg (74%); time: 2h; light yellow solid; TLC, R f =0.20 (PE:EtOAc=4:1); 1 H NMR (CDCl3, 400MHz): δ7.49(d,J=8.0Hz,1H),7.39(d,J=8.0Hz,1H),7.29(t,J=8.0Hz,1H),7.22-7.09(m,6H),5.29(d,J=76.0Hz ,2H),4.06(t,J=8.0Hz,1H),2.07-1.98(m,1H),1.62-1.53(m,1H),1.20-1.12(m,3H),1.06-0.94(m,1H),0.74(t,J=8.0Hz,3H); 13 C NMR(CDCl3,100MHz): δ175.5,142.7,

[0102] 137.0,135.1,132.7,129.4,129.3,129.0,128.3,127.9,126.5,48.1,32.8,29.7,22.5,13.9; HRMS

[0103] (ESI) m / z calcd.for C 18 H 21 NOS[M+Na] + :322.1236,found:322.1234.

Claims

1. A method for synthesizing acyl disulfide compounds by solvent-free rearrangement reaction, characterized in that: In the reaction system, a thiol compound, N-thioalkynylphthalimide and a phenyl sulfoxide compound are used as raw materials, and substitution and rearrangement reactions occur under the action of a catalyst to obtain an acyl disulfide compound; The structural formula of the N-thioalkynylphthalimide is: In the above formula, R 1 is one of an alkyl group, an aryl group, and a silicon group; The structural formula of thiol compounds is: HS--R2 In the above formula, R 2 It is one of a chain alkyl group, a cyclic alkyl group, an aryl group or a substituted aryl group, an ester group, and a 2,3,4,6-tetraacetoxyglucose group; The structural formula of phenyl sulfoxide compounds is: In the above formula, R is one of an alkyl group or an aryl group; The structural formula of acyl disulfide compounds is: The catalyst used includes one or more of trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, trifluoroacetic acid, trifluoromethanesulfonic anhydride, and bistrifluoromethanesulfonimide.

2. The method for synthesizing acyl disulfide compounds by solvent-free rearrangement reaction according to claim 1, characterized in that: The molar ratio of N-alkynylthiophthalimide, thiol compound and phenyl sulfoxide compound is 1:1.2-5.0:1.5-10.

0.

3. The method for synthesizing acyl disulfide compounds by solvent-free rearrangement reaction according to claim 2, characterized in that: The molar ratio of N-alkynylthiophthalimide, the sulfhydryl compound and the phenyl sulfoxide compound is 1:1.2:2.

5.

4. The method for synthesizing acyl disulfide compounds by solvent-free rearrangement reaction according to claim 1, characterized in that: The reaction temperature is 0-100°C.

5. The method for synthesizing acyl disulfide compounds by solvent-free rearrangement reaction according to claim 1, characterized in that: The amount of the catalyst used is 1-30 mol% of the amount of the substrate mercapto compound.

6. The method for synthesizing acyl disulfide compounds by solvent-free rearrangement reaction according to claim 5, characterized in that: The amount of catalyst used was 10 mol% of the amount of substrate used.

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