Asymmetric polysulfide compound and its synthesis method and use

文档序号：126920 发布日期：2021-10-22 浏览：82次中文

阅读说明：本技术 非对称多硫类化合物及其合成方法和应用 (Asymmetric polysulfide compound and its synthesis method and use ) 是由姜雪峰薛佳晖于 2020-04-21 设计创作，主要内容包括：本发明公开了一种式(1)、式(2)、式(3)和式(4)所示的非对称多硫类化合物及其合成方法,所述方法分别以式(6)、式(7)、式(8)和式(9)所示的化合物与二硫试剂(5)为反应原料,在催化剂的作用下,反应得到所述非对称多硫类化合物。本发明反应条件温和,原料廉价易得,反应操作简单、产率较高；反应底物容易制备；本发明的反应可以用于构建新型的多硫化合物。本发明还提出了所述非对称多硫类化合物在小分子药物偶联物和多肽物偶联物中的应用。(The invention discloses asymmetric polysulfide compounds shown in a formula (1), a formula (2), a formula (3) and a formula (4) and a synthesis method thereof, wherein the asymmetric polysulfide compounds are obtained by reacting compounds shown in a formula (6), a formula (7), a formula (8) and a formula (9) with a disulfide reagent (5) as reaction raw materials under the action of a catalyst. The method has the advantages of mild reaction conditions, cheap and easily-obtained raw materials, simple reaction operation and higher yield; the reaction substrate is easy to prepare; the reaction of the present invention can be used to construct novel polysulfide compounds. The invention also provides application of the asymmetric polysulfide compound in small molecule drug conjugates and polypeptide conjugate.)

1. An asymmetric polysulfide compound having a structural formula represented by the following formulae (1), (2), (3), (4):

wherein Ar is¹Selected from phenyl, substituted phenyl, heterocyclic;

RX is selected from alkylamino, arylamino, amino acid ester, sulfonamide, alkylmercapto, arylmercapto, and benzylthiol;

Ar²selected from aryl, vitamin E, heterocyclic aryl;

R¹selected from alkyl, amino acid derivatives, sulfonamides, aryl;

R²selected from alkyl, penicillamine;

R³selected from alkyl, aryl, thioglycoside, amino acid and polypeptide.

2. The asymmetric polysulfide compound of claim 1, wherein Ar is Ar¹Selected from phenyl, chloro, bromo, fluoro, acetyl, ethoxyacyl, 3, 4-dimethylene substituted phenyl, estrone, phenylalanine ester, thiaA thiophene; RX is selected from methyl, tert-butyl substituted anilino, 1-methylbenzylamine, amino acid ester, sulfonamides, straight-chain amino, 2-mercaptopyrimidine, methoxy substituted benzylthiol, 2-hydroxyethyl, adamantyl, tert-butyl, n-dodecyl and 1-triethoxysilyl n-propyl; ar (Ar)²Selected from 1,3, 5-trimethoxybenzene, vitamin E, methyl substitution, methoxy substitution, chlorine substitution, methoxy methyl indole, pyrrole; r¹Selected from cyano, bromo, chloro, vinyl, phenyl, methyl, tert-butyl substituted phenyl, amino acid derivatives, sulfonamides, octadecyl; r²Selected from adamantane, tert-butyl, n-propyl, 1-triethoxysilyl-n-propyl mercaptan, penicillamine; r³Selected from 2-mercaptopyrimidine, pyrazine-2-ethyl, allyl mercaptan, thioglycoside, cysteine and polypeptide.

3. The asymmetric polysulfides of claim 1 or 2, wherein said asymmetric disufides comprise:

4. a synthetic method of asymmetric polysulfide compounds is characterized in that a disulfide reagent shown in a formula (5), aryl boric acid shown in a formula (7) and organic amine or mercaptan shown in a formula (8) are used as reaction raw materials, and the reaction raw materials are reacted in an organic solvent under the action of a catalyst and a ligand to obtain the asymmetric polysulfide compounds shown in a formula (1), wherein the reaction process is shown in a reaction formula (a);

wherein Ar is¹Selected from phenyl, chloro-substituted, bromo-substituted, fluoro-substituted, acetyl-substituted, ethoxyacyl-substituted, 3, 4-dimethylene-substituted phenyl, estrone, phenylalanine ester, thiophene;

RX is selected from methyl, tert-butyl substituted anilino, 1-methylbenzylamine, amino acid ester, sulfonamides, straight-chain amino, 2-mercaptopyrimidine, methoxy substituted benzylmercaptan, 2-hydroxyethyl, adamantyl, tert-butyl, n-dodecyl and 1-triethoxysilyl n-propyl.

5. A synthetic method of asymmetric polysulfide compounds is characterized in that a disulfide reagent shown in a formula (5), aryl boric acid shown in a formula (7) and aromatic hydrocarbon reaction raw materials shown in a formula (9) react in an organic solvent under the action of a catalyst and a ligand to obtain the asymmetric polysulfide compounds shown in a formula (2), and the reaction process is shown in a reaction formula (b);

wherein Ar is¹Selected from phenyl, chloro, bromo, fluoro, acetyl and ethoxyacylSubstituted 3, 4-dimethylene substituted phenyl, estrone, phenylalanine ester and thiophene;

Ar²selected from 1,3, 5-trimethoxybenzene, vitamin E, methyl substitution, methoxy substitution, chlorine substitution, methoxy methyl indole and pyrrole.

6. The synthesis process of asymmetric polysulfide compound features that the disulfide reagent in the formula (5) and the organic amine R in the formula (10) are used¹NH₂The other molecule of organic amine or mercaptan RXH shown in the formula (8) is used as a reaction raw material and reacts in an organic solvent under the action of a catalyst and alkali to obtain the asymmetric polysulfide compound shown in the formula (3), and the reaction process is shown in a reaction formula (c);

wherein R is¹Selected from cyano, bromo, chloro, vinyl, phenyl, methyl, tert-butyl substituted phenyl, amino acid derivatives, sulfonamides, octadecyl;

7. A method for synthesizing asymmetric polysulfide compound is characterized in that a disulfide reagent shown as a formula (6) and a mercaptan R shown as a formula (11)²SH, another molecule of thiol R of formula (12)³SH is a reaction raw material, and is reacted in an organic solvent under the action of a catalyst to obtain an asymmetric polysulfide compound shown as a formula (4), wherein the reaction process is shown as a reaction formula (d);

wherein R is²Selected from adamantane, tert-butyl, n-propyl, 1-triethoxysilyl-n-propyl mercaptan, penicillamine;

R³selected from 2-mercaptopyrimidine, pyrazine-2-ethyl, allyl mercaptan, thioglycoside, cysteine and polypeptide.

8. The method of claim 4, wherein the molar ratio of arylboronic acid of formula (7) to dithiol reagent of formula (5) is from 1.0:2.0 to 2.0: 1.0; the molar ratio of the organic amine or mercaptan RXH shown in the formula (8) to the compound shown in the formula (5) is 1.0:2.0-2.0: 1.0.

9. The method of synthesis according to claim 4, wherein the catalyst is CuI, CuCl, Cu (MeCN)₄BF₄，Cu(MeCN)₄BF₆One or more of the above; and/or the molar amount of the catalyst is 5-10 mol% of the compound shown in the formula (5); and/or the ligand is one or more of 2,2 ' -bipyridyl, 4 ' -dimethyl-2, 2 ' -bipyridyl, 1, 10-phenanthroline and 4, 7-diphenyl-1, 10-phenanthroline; and/or the molar amount of the ligand is 10-20 mol% of the compound shown in the formula (5).

10. The synthesis method according to claim 4, wherein when a base is added, the base is one or more of lithium carbonate, sodium carbonate and potassium carbonate, and the amount of the base is 1 to 2 equivalents of the disulfide reagent represented by formula (5); and/or the organic solvent is one or more of dichloromethane, tetrahydrofuran and toluene; and/or, the reaction is carried out at 0-40 ℃; and/or the reaction time is 10-28 hours.

11. The method of claim 5, wherein the molar ratio of arylboronic acid of formula (7) to dithiol reagent of formula (5) is from 1.0:2.0 to 2.0: 1.0; the molar ratio of the aromatic hydrocarbon shown in the formula (9) to the disulfide reagent shown in the formula (5) is 1.0:2.0-2.0: 1.0.

12. The method of synthesis according to claim 5, wherein the catalyst is CuI, CuCl, Cu (MeCN)₄BF₄，Cu(MeCN)₄BF₆One or more of the above; and/or the molar amount of the catalyst is 10-20 mol% of the disulfide reagent shown in the formula (5); and/or the ligand is one or more of 2,2 ' -bipyridyl, 4 ' -dimethyl-2, 2 ' -bipyridyl, 1, 10-phenanthroline and 4, 7-diphenyl-1, 10-phenanthroline; and/or the molar amount of the ligand is 10 mol% -20 mol% of the disulfide reagent shown in the formula (5).

13. The synthesis method according to claim 5, wherein when a base is added, the base is one or more of lithium carbonate, sodium carbonate and potassium carbonate, and the amount of the base is 1 to 2 equivalents of the disulfide reagent represented by formula (5); the organic solvent is one or more of dichloromethane, tetrahydrofuran and toluene; and/or, the reaction is carried out at 0-40 ℃; and/or the reaction time is 10-28 hours.

14. The method of claim 6, wherein the organic amine R of formula (10)¹NH₂The molar ratio of the disulfide reagent to the starting material represented by the formula (5) is 1.05 to 1.0: 1.2-1.0; the molar ratio of the other molecule of organic amine or mercaptan RXH shown in the formula (8) to the initial raw material of the disulfide reagent shown in the formula (5) is (1.0-1.2): 1.0.

15. The synthesis of claim 6, wherein the catalyst is tris-pentafluorophenyl boron; and/or the equivalent weight of the catalyst is 1-5 mol% of the disulfide reagent shown in the formula (5); and/or, the base is lithium carbonate; and/or the equivalent of the base is 1-2 equivalents of the disulfide reagent shown in the formula (5).

16. The synthetic method of claim 6 wherein the organic solvent is one or more of dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetone, and acetonitrile; and/or, the reaction is carried out at 0-25 ℃; and/or the reaction time is 4-20 hours.

17. The synthesis process according to claim 7, wherein the organothiol R of formula (11)²The molar ratio of SH to the disulfide reagent represented by the formula (6) is 1.05-1.0: 1.2-1.0; another thiol R represented by the formula (12)³The molar ratio of SH to the disulfide reagent represented by the formula (6) is (1.0-1.2): 1.0.

18. The synthesis of claim 7, wherein the catalyst is tris-pentafluorophenyl boron; the equivalent weight of the catalyst is 1-5 mol% of the disulfide reagent shown in the formula (5); and/or the organic solvent is one or more of dichloromethane, tetrahydrofuran and methanol; and/or, the reaction is carried out at-78 ℃ to 25 ℃; and/or the reaction time is 1-5.

19. Use of an asymmetric polysulfide compound of any one of claims 1 to 3 as or for the preparation of small molecule drug conjugates and polypeptide conjugate.

Technical Field

The invention belongs to the technical field of organic compound process application, and particularly relates to an asymmetric polysulfide compound and a synthetic method and application thereof.

Background

Asymmetric polysulfide compounds are widely present in natural products, drugs and organisms, and therefore, the synthesis method of asymmetric polysulfide compounds has been widely concerned. Scientists have now devised a variety of over-sulfurizing methods, but the existing preparation methods all have a common disadvantage in that they require a multi-step synthesis through a special step for each reagent, the synthesis route is long, and the time and reagents are consumed. Although there are many reports on the synthesis method of asymmetric polysulfide compound, no good reagent has been found so far, and molecules on both sides of sulfur-sulfur bond can be randomly connected to obtain novel asymmetric polysulfide compound.

Therefore, it is important to find a versatile, efficient, environmentally friendly, mild and economically feasible over-vulcanization process.

Disclosure of Invention

The invention overcomes the limitation of traditional synthesis of asymmetric polysulfide compound, uses bilateral disulfide reagent with two sides capable of leaving, the reaction has strong compatibility, and six different asymmetric polysulfide compounds can be obtained by connecting different nucleophilic reagents of carbon, sulfur and nitrogen. In view of the above, the present invention provides a reaction method for preparing an asymmetric polysulfide compound by using a metallic copper catalyst, by using an organoboronic acid compound, a bilateral disulfide reagent and an organic amine or a thiol, or by using an organoboronic acid compound, a bilateral disulfide reagent and an aromatic hydrocarbon, or by using an organic amine, a bilateral disulfide reagent and another thiol or an organic amine, or by using a thiol, a bilateral disulfide reagent and another thiol.

The invention provides an asymmetric polysulfide compound, the structural formula of which is shown in formulas (1), (2), (3) and (4):

wherein Ar is¹Selected from phenyl, substituted phenyl, heterocyclic;

RX is selected from alkylamino, arylamino, amino acid ester, sulfonamide, alkylmercapto, arylmercapto, and benzylthiol;

Ar²selected from aryl, vitamin E, heterocyclic aryl;

R¹selected from alkyl, amino acid derivatives, sulfonamides, aryl;

R²selected from alkyl, penicillamine;

R³selected from alkyl, aryl, thioglycoside, amino acid and polypeptide.

Preferably, Ar¹Selected from phenyl, chloro-substituted, bromo-substituted, fluoro-substituted, acetyl-substituted, ethoxyacyl-substituted, 3, 4-dimethylene-substituted phenyl, estrone, phenylalanine ester, thiophene;

RX is selected from methyl, tert-butyl substituted anilino, 1-methylbenzylamine, amino acid ester, sulfonamides, straight-chain amino, 2-mercaptopyrimidine, methoxy substituted benzylthiol, 2-hydroxyethyl, adamantyl, tert-butyl, n-dodecyl and 1-triethoxysilyl n-propyl;

Ar²selected from 1,3, 5-trimethoxybenzene, vitamin E, methyl-substituted, methoxy-substituted, chloro-substituted, methoxymethyl-substituted indoles, pyrroles;

R¹selected from cyano, bromo, chloro, vinyl, phenyl, methyl, tert-butyl substituted phenyl, amino acid derivatives, sulfonamides, octadecyl;

R²selected from adamantane, tert-butyl, n-propyl, 1-triethoxysilyl-n-propyl mercaptan, penicillamine;

R³selected from 2-mercaptopyrimidine, pyrazine-2-ethyl, allyl mercaptan, thioglycoside, cysteine and polypeptide.

Further, the asymmetric polysulfide compounds represented by the formulae (1) to (4) of the present invention include:

the invention also provides a preparation method of the asymmetric polysulfide compound, which comprises the steps of taking a disulfide reagent shown in a formula (5), aryl boric acid shown in a formula (7) and organic amine shown in a formula (8) or mercaptan RXH as reaction raw materials, reacting in an organic solvent under the action of a catalyst and a ligand and with or without adding alkali to obtain the asymmetric polysulfide compound shown in a formula (1), wherein the reaction process is shown in a reaction formula (a);

wherein Ar is¹Selected from phenyl, substituted phenyl, heterocyclic;

RX is selected from alkylamino, arylamino, alkylmercapto and arylmercapto.

Preferably, Ar¹Selected from phenyl, chloro, bromo, fluoro, acetyl, ethoxyacyl, 3, 4-dimethylene substituted phenyl, estrone, phenylalanine ester, thiaA thiophene;

In the present invention, the molar ratio of the arylboronic acid (organoboronic acid) represented by the formula (7) to the disulfide reagent represented by the formula (5) is 1.0:2.0 to 2.0: 1.0; preferably, the molar ratio of the two amounts is 1.5: 1.0.

In the invention, the molar ratio of the organic amine or mercaptan RXH shown in the formula (8) to the compound shown in the formula (5) is 1.0:2.0-2.0: 1.0; preferably, the molar ratio of the two amounts is 1.2: 1.0.

In the present invention, the catalyst is CuI, CuCl, Cu (MeCN)₄BF₄，Cu(MeCN)₄BF₆One or more of the following; preferably, the catalyst is Cu (MeCN)₄BF₆。

In the invention, the molar amount of the catalyst is 5-10 mol% of the disulfide reagent shown in the formula (5); preferably, the molar amount of the catalyst is 10 mol% based on the disulfide agent represented by the formula (5).

In the invention, the ligand is one or more of 2,2 ' -bipyridyl, 4 ' -dimethyl-2, 2 ' -bipyridyl, 1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline and the like; preferably, it is 2, 2' -bipyridine.

In the invention, the molar amount of the ligand is 10-20 mol% of the disulfide reagent shown in the raw material formula (5); preferably, the ligand is used in a molar amount of 20 mol% based on the disulfide reagent represented by the formula (5).

In the present invention, preferably, no base is added. When the base is added, the base is one or more of lithium carbonate, sodium carbonate, potassium carbonate and the like.

In the invention, the dosage of the alkali is 1-2 equivalents of the disulfide reagent shown in the formula (5); preferably, the amount of the base used is 1 equivalent to that of the disulfide reagent represented by the formula (5) as a starting material.

In the invention, the organic solvent is one or more of dichloromethane, tetrahydrofuran, toluene and the like; preferably, the organic solvent is dichloromethane or toluene.

In the invention, the reaction temperature is 0-40 ℃; preferably, it is 25 ℃.

In the invention, the reaction time is 10-28 hours; preferably, it is 28 hours.

In the present invention, the reaction is carried out in a nitrogen atmosphere.

The invention also provides a preparation method of the asymmetric polysulfide compound, which comprises the steps of taking the disulfide reagent shown in the formula (5), the arylboronic acid shown in the formula (7) and the aromatic hydrocarbon shown in the formula (9) as reaction raw materials, reacting in an organic solvent under the action of a catalyst and a ligand and with or without adding alkali to obtain the asymmetric disulfide compound shown in the formula (2), wherein the reaction process is shown in the reaction formula (b);

wherein Ar is¹Selected from phenyl, substituted phenyl, heterocyclic;

Ar²selected from aryl, heterocyclic aryl.

Ar²selected from 1,3, 5-trimethoxybenzene, vitamin E, methyl substitution, methoxy substitution, chlorine substitution, methoxy methyl indole and pyrrole.

In the invention, the molar ratio of the aromatic hydrocarbon shown in the formula (9) to the disulfide reagent shown in the formula (5) is 1.0:2.0-2.0: 1.0; preferably, the molar ratio of the two amounts is 1.2: 1.0.

In the present invention, the catalyst is CuI, CuCl, Cu (MeCN)₄BF₄，Cu(MeCN)₄BF₆One or more of the above; preferably, the catalyst is Cu (MeCN)₄BF₆。

In the invention, the molar amount of the catalyst is 5-10 mol% of the disulfide reagent shown in the formula (5); preferably, the molar amount of the catalyst is 10 mol% of the disulfide reagent shown in the raw material formula (5);

in the invention, the ligand is one or more of 2,2 ' -bipyridyl, 4 ' -dimethyl-2, 2 ' -bipyridyl, 1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline and the like; preferably, the ligand is 2, 2' -bipyridine.

In the present invention, preferably, no base is added. When the base is added, the base is one or more of lithium carbonate, sodium carbonate, potassium carbonate and the like.

In the invention, the organic solvent is one or more of dichloromethane, tetrahydrofuran, toluene and the like; preferably, the organic solvent is dichloromethane or toluene.

In the invention, the reaction temperature is 0-40 ℃; preferably, it is 25 ℃.

In the invention, the reaction time is 10-28 hours; preferably, it is 28 hours.

In the present invention, the reaction is carried out in a nitrogen atmosphere.

The invention also provides a preparation method of the asymmetric polysulfide compound, which is a disulfide reagent shown as a formula (5) and organic amine R shown as a formula (10)¹NH₂Another molecule of organic amine or mercaptan RXH shown in the formula (8) is used as a reaction raw material,under the action of a catalyst and alkali, in an organic solvent, reacting to obtain an asymmetric polysulfide compound shown as a formula (3), wherein the reaction process is shown as a reaction formula (c);

wherein R is¹Selected from alkyl, aryl;

RX is selected from alkylamino, arylamino, alkylmercapto and arylmercapto.

Preferably, R¹Selected from cyano, bromo, chloro, vinyl, phenyl, methyl, tert-butyl substituted phenyl, amino acid derivatives, sulfonamides, octadecyl;

In the present invention, the organic amine R represented by the formula (10)¹NH₂The molar ratio of the disulfide reagent to the starting material represented by the formula (5) is 1.05 to 1.0: 1.2-1.0; preferably, it is 1.05: 1.0.

In the invention, the molar ratio of the other molecule of organic amine or mercaptan RXH shown in the formula (8) to the initial raw material disulfide reagent shown in the formula (5) is (1.0-1.2): 1.0; preferably, it is 1.2: 1.0.

In the present invention, the catalyst is tris-pentafluorophenyl boron.

In the invention, the equivalent weight of the catalyst is 1-5 mol% of the disulfide reagent shown in the formula (5); preferably, the catalyst equivalent is 2 mol% of the disulfide reagent represented by formula (5).

In the invention, the alkali is lithium carbonate.

In the present invention, the equivalent of the base is 1 to 2 equivalents of the disulfide reagent represented by formula (5); preferably 1 equivalent.

In the invention, the organic solvent is one or more of dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile and the like; preferably, the organic solvent is 1, 4-dioxane.

In the invention, the reaction temperature is 0-25 ℃; preferably, it is 25 ℃.

In the invention, the reaction time is 4-20 hours; preferably, it is 14 hours.

In the present invention, the reaction is carried out in an air atmosphere.

The invention also provides a preparation method of the asymmetric polysulfide compound, which is a disulfide reagent shown as a formula (6) and an organic mercaptan R shown as a formula (11)²SH, another molecule of thiol R of formula (12)³SH is a reaction raw material, and is reacted in an organic solvent under the action of a catalyst to obtain an asymmetric polysulfide compound (tetrasulfide compound) shown as a formula (4), wherein the reaction process is shown as a reaction formula (d);

wherein R is²Selected from alkyl groups;

R³selected from alkyl and aryl.

Preferably, R²Selected from adamantane, tert-butyl, n-propyl, 1-triethoxysilyl-n-propyl mercaptan, penicillamine;

R³selected from 2-mercaptopyrimidine, pyrazine-2-ethyl, allyl mercaptan, thioglycoside, cysteine and polypeptide.

In the present invention, the organic thiol R represented by the formula (11)²The mol ratio of SH to the disulfide reagent shown in the formula (6) as the starting material is 1.05-1.0: 1.2-1.0; preferably, it is 1.2: 1.0.

In the present invention, another thiol R represented by the above formula (12)³The molar ratio of SH to the disulfide reagent represented by the formula (6) as the starting material is (1.0-1.2): 1.0; preferably, it is 1.2: 1.0.

In the present invention, the catalyst is tris-pentafluorophenyl boron.

In the invention, the organic solvent is one or more of dichloromethane, tetrahydrofuran, methanol and the like; preferably, the organic solvent is methanol.

In the invention, the reaction temperature is-78-25 ℃; preferably, it is-78 ℃.

In the invention, the reaction time is 1-5; preferably, it is 4.5 hours.

In the present invention, the reaction is carried out in an air atmosphere.

In the present invention, the selective control of the reaction is influenced by the ring tension of the cyclic disulfide reagent.

In one embodiment, as shown in reaction formula (a), the synthesis reaction of the present invention is to add a disulfide reagent (5) (U mmol), an organic boronic acid (7) (V mmol), a catalyst (W mmol), a ligand (X mmol), a base (Y mmol), an organic solvent (P mL) to a reaction flask a, and the reaction system is stirred at 25 ℃ under an air atmosphere; after the disulfide reagent (5) was consumed, RXH (8) (Z mmol) was added and stirred for 4 hours; after the reaction is finished, adding silica gel for spin drying, and separating by column chromatography to obtain the target product.

In another embodiment, as shown in reaction formula (b), the synthesis reaction of the present invention is to add a disulfide reagent (5) (U mmol), an organic boronic acid (7) (V mmol), a catalyst (W mmol), a ligand (X mmol), a base (Y mmol), an organic solvent (P mL) to a reaction flask a, and the reaction system is stirred at 25 ℃ under an air atmosphere; after the disulfide reagent (5) is consumed, adding arene (9) (Z mmol), and stirring for 4 hours; after the reaction is finished, adding silica gel for spin drying, and separating by column chromatography to obtain the target product.

In another embodiment, as shown in reaction formula (c), the synthesis reaction of the present invention is to add a disulfide reagent (5) (X mmol), an organic amine (10) (Y mmol), a catalyst (Z mmol), an organic solvent (P mL) to a reaction flask A, and the reaction system is stirred at 25 ℃ for 4 hours; after the disulfide reagent (5) is consumed, adding RXH (8) (U mmol) and base (V mmol), and stirring for 10 hours; after the reaction is finished, adding silica gel for spin drying, and separating by column chromatography to obtain the target product.

In another embodiment, as shown in reaction formula (d), the synthesis reaction of the present invention is performed by adding the disulfide reagent (6) (X mmol), the organic thiol (11) (Y mmol), and the organic solvent (P mL) to the reaction flask A, stirring the reaction system at-78 deg.C for 0.5 hours, and adding R³SH (12) (U mmol), catalyst (V mmol), stirred for 4 hours; after the reaction is finished, adding silica gel for spin drying, and separating by column chromatography to obtain the target product.

The invention also provides the asymmetric polysulfide compounds shown in the formulas (1), (2), (3) and (4) prepared by the synthesis method.

The invention also provides application of the asymmetric polysulfide compound shown in the formulas (1), (2), (3) and (4) in serving as or preparing a small molecule drug conjugate and a polypeptide conjugate.

The optimum conditions of the asymmetric polysulfide compound shown in formula (1) prepared by the synthetic method are shown in the following, wherein the yield of the reaction formula (a) is 75% or more.

Wherein Ar is¹Selected from phenyl, chloro-substituted, bromo-substituted, fluoro-substituted, acetyl-substituted, ethoxyacyl-substituted, 3, 4-dimethylene-substituted phenyl, estrone, phenylalanine ester, thiophene;

The optimal conditions of the asymmetric polysulfide compound shown in the formula (2) prepared by the synthetic method are shown as follows, wherein the yield of the reaction formula (b) is 70% or more.

Ar²selected from 1,3, 5-trimethoxybenzene, vitamin E, methyl substitution, methoxy substitution, chlorine substitution, methoxy methyl indole and pyrrole.

The optimal conditions of the asymmetric polysulfide compound shown in the formula (3) prepared by the synthetic method are shown as follows, wherein the yield of the reaction formula (c) is 88% or more.

Wherein R is¹Selected from cyano, bromo, chloro, vinyl, phenyl, methyl, tert-butyl substituted phenyl, amino acid derivatives, sulfonamides, octadecyl;

RX is selected from adamantane, tert-butyl, n-propyl, 1-triethoxysilyl-n-propyl mercaptan, penicillamine; r³Selected from 2-mercaptopyrimidine, pyrazine-2-ethyl, allyl mercaptan, thioglycoside, cysteine and polypeptide.

The optimal conditions of the symmetric diheterodisulfide compound shown in the formula (3) prepared by the synthetic method are shown as follows, wherein the yield of the reaction formula (d) is 98% or more.

Wherein R is²Selected from adamantane, tert-butyl, n-propyl, 1-triethoxysilyl-n-propyl mercaptan, penicillamine;

R³selected from 2-mercaptopyrimidine, pyrazine-2-ethyl, allyl mercaptan, thioglycoside, cysteine and polypeptide.

The invention has the following advantages: the raw materials are cheap and easy to obtain, reaction substrates are easy to prepare, reaction operation is simple, reaction is efficient, the yield is high, the yield of examples 28, 42, 43, 45, 46, 49, 52 and 53 is over 80 percent, and an over-sulfurizing reagent is simple and stable to prepare and has no pungent smell; the reaction conditions are mild. The bilateral disulfide reagent and dichotomous mercaptan or amine react to obtain an asymmetric diheterodisulfide compound, or boric acid is coupled and then reacts with mercaptan, amine and aromatic hydrocarbon to obtain a polysulfide compound.

Detailed Description

The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited. The data given in the examples below include specific operating and reaction conditions and products. The purity of the product was identified by nuclear magnetism.

The synthesis reaction of the asymmetric disulfide compound comprises the following steps:

according to the reaction formula (a), the synthetic reaction of the invention is that a disulfide reagent (5), organic boric acid (7), a catalyst, a ligand and an organic solvent are added into a reaction bottle, and the reaction system is stirred for 24 hours at 25 ℃ under the air atmosphere; after the disulfide reagent (5) was consumed, RXH (8) (Z mmol) was added and stirred for 4 hours; adding silica gel, spin-drying, and separating by column chromatography to obtain the target product.

According to the reaction formula (b), the synthetic reaction of the invention is that a disulfide reagent (5), organic boric acid (7), a catalyst, a ligand and an organic solvent are added into a reaction bottle, and the reaction system is stirred for 24 hours at 25 ℃ under the air atmosphere; after the disulfide reagent (5) is consumed, adding arene (9) (Z mmol), and stirring for 4 hours; adding silica gel, spin-drying, and separating by column chromatography to obtain the target product.

According to the reaction formula (c), the synthetic reaction of the invention is that a disulfide reagent (5), organic amine (10), a catalyst, alkali and an organic solvent are added into a reaction bottle, and the reaction system is stirred for 4 hours at 25 ℃ under the air atmosphere; after the disulfide reagent (5) is consumed, RXH (8) is added, the stirring is carried out for 10 hours, silica gel is added for spin-drying, and the target product is obtained by column chromatography separation.

According to the reaction formula (d), the synthetic reaction of the invention is that a disulfide reagent (5), an organic mercaptan (11), a catalyst and an organic solvent are added into a reaction bottle, and the reaction system is stirred for 0.5 hour at-78 ℃ under the air atmosphere; adding R³SH (12), stirring for 4 hours, adding silica gel, spin-drying, and separating by column chromatography to obtain the target product.

The asymmetric polysulfide compounds shown in table 1 are all products synthesized by the method of the present invention, and no publication has been found yet.

TABLE 1 novel asymmetric disulfides of the invention

Example 1

Synthesis of compound 1 a:

phenylboronic acid (18.3mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), and reacted for 10 hours with replacement of nitrogen. 4-toluidine (12.8mg,0.12mmol,1.2equiv) was added, reacted for 8 hours, the solvent was removed, and column chromatography was performed to give colorless liquid 1a (17.3mg, 70%).¹H NMR(400MHz,DMSO-d₆)δ8.10(s,1H),7.51(d,J＝7.5Hz,2H),7.32(dd,J＝10.2,4.1Hz,2H),7.26(dd,J＝7.7,5.3Hz,1H),6.95(d,J＝7.8Hz,2H),6.87(d,J＝7.8Hz,2H),2.14(s,3H).¹³C NMR(100MHz,DMSO-d₆)δ143.42,137.82,130.26,130.06,129.94,129.63,128.15,116.76,20.65.IR(film)3340,2972,2920,1612,1508,1475,1438,1373,1226,1022,812,740,688.HRMS(EI)Calcd for C₁₃H₁₃NS₂247.0489,found 247.0492.

Example 2

Synthesis of compound 1 b:

to the reaction tube was added 4-chlorobenzeneboronic acid (23.4mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), and reacted for 10 hours with replacement of nitrogen. 4-Tert-butylaniline (17.9mg,0.12mmol,1.2equiv) was added, reacted for 8 hours, the solvent was removed, and column chromatography was performed to give colorless liquid 1b (23.6mg, 73%).¹H NMR(400MHz,CDCl₃)δ7.32(d,J＝8.5Hz,2H),7.20–7.11(m,4H),6.83(d,J＝8.7Hz,2H),5.19(s,1H),1.21(s,9H).¹³C NMR(100MHz,CDCl₃)δ145.11,141.97,136.02,134.11,132.58,129.12,126.07,116.87,34.20,31.50.IR(film)3350,2963,1608,1510,1473,1267,1234,1184,1092,1013,899,818,742,553.HRMS(EI)Calcd for C₁₆H₁₈ClNS₂323.0569,found 323.0564.

Example 3

Synthesis of compound 1 c:

phenylboronic acid (18.3mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), and reacted for 10 hours with replacement of nitrogen. 2, 2-diphenylethan-1-amine (23.7mg,0.12mmol,1.2equiv) was added, reacted for 8 hours, the solvent was removed, and column chromatography was performed to give colorless liquid 1c (25.3mg, 75%).¹HNMR(400MHz,DMSO-d₆)δ7.62–7.58(m,2H),7.39–7.33(m,2H),7.31–7.13(m,11H),5.34(t,J＝4.7Hz,1H),4.24(t,J＝7.8Hz,1H),3.49(dd,J＝7.7,4.8Hz,2H).¹³C NMR(100MHz,CDCl₃)δ141.93,138.21,129.94,129.17,128.76,128.18,127.48,126.82,55.62,50.64.IR(film)3315,3059,2922,2852,1739,1579,1492,1450,1438,1066,1024,1024,1001,739,698.HRMS(EI)Calcd for C₂₀H₁₉NS₂337.0959,found 337.0955.

Example 4

Synthesis of compound 1 d:

to the reaction tube was added 4-trifluoromethylphenylboronic acid (28.5mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), and reacted for 10 hours with replacement of nitrogen. 3-phenyl-1-propylamine (16.2mg,0.12mmol,1.2equiv) was added, reacted for 8 hours, the solvent was removed, and column chromatography was performed to give colorless liquid 1d (23.3mg, 68%).¹H NMR(400MHz,CDCl₃)δ7.59(d,J＝8.1Hz,2H),7.48(d,J＝8.2Hz,2H),7.16(d,J＝7.4Hz,2H),7.09(t,J＝6.9Hz,1H),7.02(d,J＝7.4Hz,2H),3.02(s,1H),2.86(dd,J＝12.8,6.3Hz,2H),2.51(t,J＝7.6Hz,2H),1.79–1.67(m,2H).¹⁹F NMR(282MHz,CDCl₃)δ-62.41.¹³C NMR(100MHz,CDCl₃)δ143.14,141.43,128.97(q,²J_C-F＝32.7Hz),128.44,128.39,128.31,126.00,125.85(q,³J_C-F＝3.8Hz),124.09(q,¹J_C-F＝271.9Hz),50.45,33.05,30.70.IR(film)3350,2926,2856,1602,1494,1454,1400,1323,1165,1122,1105,1080,1061,1012,830,698.HRMS(EI)Calcd for C₁₆H₁₆F₃NS₂343.0676,found343.0681.

Example 5

Synthesis of compound 1 e:

to the reaction tube was added 4-bromobenzeneboronic acid (30.0mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), and reacted for 10 hours with replacement of nitrogen. 1-Phenylethylamine (14.5mg,0.12mmol,1.2equiv) was added thereto, reacted for 8 hours, the solvent was removed, and column chromatography was performed to give colorless liquid 1e (28.2mg, 83%).¹H NMR(400MHz,CDCl₃)δ7.30(q,J＝8.5Hz,4H),7.25–7.20(m,2H),7.20–7.15(m,1H),7.11(d,J＝7.4Hz,2H),4.11(q,J＝6.5Hz,1H),3.36(s,1H),1.30(d,J＝6.6Hz,3H).¹³C NMR(100MHz,CDCl₃)δ143.24,137.26,132.06,131.05,128.57,127.65,127.04,121.25,57.95,22.68.IR(film)3317,3028,2974,2924,2868,1602,1493,1470,1452,1384,1369,1340,1307,1078,1007,812,760,698,640.HRMS(EI)Calcd for C₁₄H₁₄BrNS₂338.9751,found338.9748.

Example 6

Synthesis of compound 1 f:

to the reaction tube was added 4-bromobenzeneboronic acid (30.0mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), and reacted for 10 hours with replacement of nitrogen. L-Tryptophan methyl ester (14.5mg,0.12mmol,1.2equiv) was added, the reaction was carried out for 8 hours, the solvent was removed, and column chromatography was carried out to give colorless liquid 1f (29.3mg, 67%).¹H NMR(400MHz,CDCl₃)δ7.96(s,1H),7.50(d,J＝7.9Hz,1H),7.28–7.22(m,3H),7.14(t,J＝7.5Hz,1H),7.09–7.03(m,3H),6.90(d,J＝1.8Hz,1H),4.00(dt,J＝7.5,5.2Hz,1H),3.63(d,J＝5.0Hz,1H),3.59(s,3H),3.21(dd,J＝14.6,5.2Hz,1H),3.03(dd,J＝14.6,7.7Hz,1H).¹³C NMR(100MHz,CDCl₃)δ173.41,136.75,136.23,132.03,131.73,127.24,123.09,122.38,121.76,119.76,118.75,111.25,110.21,63.22,52.36,28.80.IR(film)3414,2976,2949,1734,1470,1456,1437,1340,1211,1093,1006,814,742.HRMS(EI)Calcd for C₁₈H₁₇BrN₂O₂S₂435.9915,found 435.9908.

Example 7

Synthesis of Compound 1 g:

to the reaction tube was added a boric acid derivative of N- (t-butoxycarbonyl) phenylalanine methyl ester (48.4mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 48 hours, removal of the solvent, addition of L-tryptophan methyl ester (14.5mg,0.12mmol,1.2equiv) and toluene (1mL), reaction for 8 hours, removal of the solvent, column chromatography to give 1g (19.0mg, 34%) of a yellow liquid.¹H NMR(400MHz,CDCl₃)δ8.30(s,1H),7.53(d,J＝7.7Hz,1H),7.30(d,J＝7.9Hz,1H),7.15(t,J＝7.5Hz,1H),7.10–7.05(m,1H),7.01(d,J＝6.2Hz,2H),6.86(d,J＝7.2Hz,2H),6.78(s,1H),4.93(d,J＝7.4Hz,1H),4.52(s,1H),4.05(dd,J＝14.0,6.9Hz,1H),3.68(s,3H),3.65–3.61(m,3H),3.52(s,1H),3.27(dd,J＝20.1,7.0Hz,1H),3.05–2.96(m,2H),2.89(dd,J＝13.8,6.5Hz,1H),1.38(s,9H).¹³C NMR(100MHz,CDCl₃)δ173.30,172.30,155.21,136.43,135.71,135.54,130.16,129.87,127.12,123.23,122.25,119.59,118.78,111.35,109.93,80.40,62.23,54.46,52.42,52.33,37.94,28.78,28.34.IR(film)3416,2972,2926,1736,1697,1491,1437,1365,1213,1165,1101,1051,1016,881,742.HRMS(ESI)Calcd for C₂₇H₃₄N₃O₆S₂(M+H⁺)560.1884,found 560.1882.

Example 8

Synthesis of compound 1 h:

phenylboronic acid (18.3mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, removal of solvent, addition of sulfadimidine (33.4mg,0.12mmol,1.2equiv) and toluene (1mL), reaction for 24 hours, removal of solvent, column chromatography to give a pale yellow solid for 1h (27.6mg, 66%).¹H NMR(400MHz,CDCl₃)δ7.86(d,J＝8.7Hz,2H),7.44–7.40(m,2H),7.24–7.19(m,3H),6.91(d,J＝8.8Hz,2H),6.55(s,1H),5.79(s,1H),2.29(s,6H).¹³C NMR(100MHz,CDCl₃)δ168.36,156.27,149.40,136.72,131.55,131.25,130.61,129.23,128.52,115.53,114.97,23.64,23.62.IR(film)3343,2956,2922,1595,1552,1490,1439,1153,1084,679,584.HRMS(ESI)Calcd for C₁₈H₁₉N₄O₂S₃(M+H⁺)419.0665,found 419.0661.

Example 9

Synthesis of compound 1 i:

phenylboronic acid (18.3mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of 2-mercaptopyrimidine (13.4mg,0.12mmol,1.2equiv) to the solution, reaction for 2 hours, removal of the solvent, column chromatography to give 1i (18.9mg, 75%) as a white solid.¹H NMR(400MHz,CDCl₃)δ8.50(d,J＝4.8Hz,2H),7.58–7.54(m,2H),7.28–7.22(m,3H),7.00(t,J＝4.8Hz,1H).¹³C NMR(100MHz,CDCl₃)δ170.25,157.86,136.08,131.24,129.08,128.68,118.17.IR(film)3190,1658,1554,1379,1168,742,686.HRMS(EI)Calcd for C₁₀H₈N₂S₃251.9850,found251.9849.

Example 10

Synthesis of compound 1 j:

to the reaction tube was added 4-chlorobenzeneboronic acid (23.4mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of 2-mercaptoethanol (9.4mg,0.12mmol,1.2equiv) to the solution, reaction for 2 hours, removal of the solvent, column chromatography to give 1j (16.4mg, 65%) as a yellow liquid.¹H NMR(400MHz,CDCl₃)δ7.49–7.45(m,2H),7.31–7.25(m,2H),3.84(t,J＝5.8Hz,2H),2.97(t,J＝5.8Hz,2H),1.90(s,1H).¹³C NMR(100MHz,CDCl₃)δ134.95,134.85,131.79,129.43,59.86,41.68.IR(film)3354,2922,2872,1641,1570,1472,1387,1089,1043,1010,814.742.HRMS(EI)Calcd for C₈H₉ClOS₃251.9504,found 251.9503.

Example 11

Synthesis of compound 1 k:

to the reaction tube was added 4-acetylphenylboronic acid (24.5mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 24 hours, filtration, addition of 4-methoxybenzenethiol (18.5mg,0.12mmol,1.2equiv) to the solution, reaction for 2 hours, removal of the solvent, column chromatography to give 1k (21.2mg, 63%) as a colorless liquid.¹H NMR(400MHz,CDCl₃)δ7.84(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.12(d,J＝8.6Hz,2H),6.77(d,J＝8.6Hz,2H),3.99(s,2H),3.72(s,3H),2.51(s,3H).¹³C NMR(100MHz,CDCl₃)δ197.06,159.33,143.17,136.05,130.61,128.88,128.32,127.79,114.14,55.29,42.97,26.55.IR(film)3001,2955,1680,1585,1462,1392,1248,1086,956,820,617,588.HRMS(EI)Calcd for C₁₆H₁₆O₂S₃336.0312,found 336.0316.

Example 12

Synthesis of Compound 1 l:

phenylboronic acid (18.3mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of N- (phthaloyl) cysteine methyl ester (31.8mg,0.12mmol,1.2equiv) to the solution, reaction for 6 hours, removal of the solvent, column chromatography to give 1l (32.4mg, 80%) of yellow liquid.¹H NMR(400MHz,CDCl₃)δ7.79(dd,J＝5.5,3.0Hz,2H),7.67(dd,J＝5.4,3.1Hz,2H),7.50(dd,J＝7.9,1.4Hz,2H),7.28–7.18(m,3H),5.19(dd,J＝10.7,4.7Hz,1H),3.66(s,3H),3.65–3.46(m,2H).¹³C NMR(100MHz,CDCl₃)δ168.36,167.37,136.40,134.34,131.78,130.57,129.22,128.43,123.72,53.08,51.00,36.86.IR(film)3068,1745,1713,1467,1437,1385,1240,1172,1068,914,866,788,688.HRMS(ESI)Calcd for C₁₈H₁₆NO₄S₃(M+H⁺)406.0236,found 406.0231.

Example 13

Synthesis of compound 1 m:

to the reaction tube was added 4-acetylphenylboronic acid (24.5mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), displace nitrogen, react for 24 hours, filter, add adamantane thiol (20.2mg,0.12mmol,1.2equiv) to the solution, react for 6 hours, remove the solvent, column chromatographically obtain a pale yellow solid 1m (18.2mg, 52%).¹H NMR(400MHz,CDCl₃)δ7.89–7.82(m,2H),7.60–7.53(m,2H),2.52(s,3H),2.02(s,3H),1.84(d,J＝2.5Hz,6H),1.67–1.55(m,6H).¹³C NMR(100MHz,CDCl₃)δ197.16,143.76,135.73,128.86,127.88,51.25,42.52,36.01,29.89,26.61.IR(film)2905,2848,1684,1587,1392,1259,1089,1051,883,819,617.HRMS(EI)Calcd for C₁₈H₂₂OS₃350.0833,found 350.0835.

Example 14

Synthesis of compound 1 o:

to the reaction tube was added 4-ethoxycarbonylphenylboronic acid (29.1mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane: (1mL), the nitrogen gas was replaced, reaction was carried out for 24 hours, filtration was carried out, dodecanethiol (24.2mg,0.12mmol,1.2equiv) was added to the solution, reaction was carried out for 2 hours, the solvent was removed, and column chromatography was carried out to give 1o (24.9mg, 60%) as a pale yellow solid.¹H NMR(400MHz,CDCl₃)δ7.96–7.91(m,2H),7.58–7.54(m,2H),4.31(q,J＝7.1Hz,2H),2.85–2.71(m,2H),1.68–1.56(m,2H),1.32(t,J＝7.1Hz,3H),1.29–1.24(m,2H),1.18(s,16H),0.81(t,J＝6.8Hz,3H).¹³C NMR(100MHz,CDCl₃)δ166.02,142.89,130.09,129.48,128.11,61.10,39.18,31.93,29.65,29.63,29.57,29.47,29.35,29.14,28.90,28.46,22.70,14.33,14.12.IR(film)2922,2853,1718,1591,1564,1487,1396,1269,1103,846,758,688.HRMS(EI)Calcd for C₂₁H₃₄O₂S₃414.1721,found 414.1723.

Example 15

Synthesis of compound 1 p:

estrone-derived boric acid (44.7mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reacted for 48 hours, filtered, added to the solution 3- (triethoxysilyl) 1-propanethiol (28.6mg,0.12mmol,1.2equiv), reacted for 4 hours, the solvent was removed, and column chromatography gave 1p (28.6mg, 34%) as a pale yellow solid.¹H NMR(400MHz,CDCl₃)δ7.32(d,J＝8.1Hz,1H),7.27(s,1H),7.21(s,1H),3.75(q,J＝7.0Hz,6H),2.88–2.79(m,4H),2.44(dd,J＝18.7,8.7Hz,1H),2.35(dd,J＝12.9,4.6Hz,1H),2.24(dd,J＝20.7,10.6Hz,1H),2.09(dd,J＝18.5,9.3Hz,1H),2.04–1.88(m,3H),1.84–1.73(m,2H),1.61–1.31(m,10H),1.16(t,J＝7.0Hz,9H),0.84(s,3H),0.68–0.62(m,2H).¹³C NMR(100MHz,CDCl₃)δ140.31,137.65,133.92,130.90,127.89,126.23,58.45,50.52,47.94,44.36,41.75,38.00,35.84,31.57,29.70,29.30,26.35,25.66,22.42,21.59,18.33,13.84,9.62.IR(film)3030,2945,1741,1639,1375,1124,1072,921,866,557.HRMS(ESI)Calcd for C₂₇H₄₂O₄S₃SiNa(M+Na⁺)577.1907,found 577.1902.

Example 16

Synthesis of compound 2 a:

phenylboronic acid (18.3mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of 1,3, 5-trimethoxybenzene (20.1mg,0.12mmol,1.2equiv) and B (C) to the solution₆F₅)₃(0.5mg,0.001mmol,1 mol%) was reacted for 2 hours, the solvent was removed, and column chromatography was performed to give colorless liquid 2a (17.3mg, 56%).¹H NMR(400MHz,CDCl₃)δ7.56–7.51(m,2H),7.24–7.17(m,2H),7.11(t,J＝7.3Hz,1H),6.00(s,2H),3.73(s,3H),3.65(s,6H).¹³C NMR(100MHz,CDCl₃)δ163.11,162.28,138.80,128.98,128.37,126.56,104.57,91.02,55.94,55.39.IR(film)2940,2837,1580,1466,1410,1337,1227,1159,1088,812,740.HRMS(EI)Calcd for C₁₅H₁₆O₃S₂308.0541,found 308.0537.

Example 17

Synthesis of compound 2 b:

phenylboronic acid (18.3mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of delta-tocopherol (48.2mg,0.12mmol,1.2equiv) and B (C) to the solution₆F₅)₃(0.5mg,0.001mmol,1 mol%), reaction for 2 hours, removal of the solvent, column chromatography to give 2b (21.1mg, 37%) as a colorless liquid.¹H NMR(400MHz,CDCl₃)δ7.43(d,J＝6.5Hz,2H),7.29–7.20(m,3H),6.57(s,1H),5.74(s,1H),2.62–2.43(m,2H),2.07(s,3H),1.64–1.53(m,2H),1.50–1.14(m,15H),1.10(s,3H),1.09–0.94(m,6H),0.82–0.74(m,12H).¹³C NMR(100MHz,CDCl₃)δ150.40,146.07,137.09,133.07,131.87,129.24,129.18,124.01,116.52,115.00,75.16,39.75,39.39,37.49,37.48,37.45,37.31,32.82,32.70,31.29,27.99,24.81,24.47,23.82,22.72,22.63,21.99,20.95,19.76,19.66,16.57.IR(film)2951,2924,1460,1377,1221,1151,1076,1038,744.HRMS(EI)Calcd for C₃₃H₅₀O₂S₂542.3252,found 542.3248.

Example 18

Synthesis of compound 2 c:

phenylboronic acid (18.3mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of 5-methoxyindole (17.6mg,0.12mmol,1.2equiv) and B (C) to the solution₆F₅)₃(0.5mg,0.001mmol,1 mol%) was reacted for 2 hours, the solvent was removed, and column chromatography was performed to give colorless liquid 2c (21.8mg, 76%).¹H NMR(400MHz,CDCl₃)δ8.09(s,1H),7.53–7.46(m,1H),7.26–7.21(m,1H),7.19–7.15(m,1H),7.12(d,J＝8.8Hz,1H),6.87(d,J＝2.2Hz,1H),6.77(dd,J＝8.8,2.4Hz,1H),3.62(s,1H).¹³C NMR(100MHz,CDCl₃)δ155.22,138.77,131.05,130.65,130.17,129.19,128.91,127.45,113.94,112.40,108.08,100.93,55.63.IR(film)3416,2829,1622,1581,1436,1286,1207,1168,920,802,742,690.HRMS(EI)Calcd for C₁₅H₁₃NOS₂ 287.0439,found 287.0434.

Example 19

Synthesis of compound 2 d:

phenylboronic acid (18.3mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of N- (methoxymethyl) indole (19.3mg,0.12mmol,1.2equiv) and B (C)₆F₅)₃(0.5mg,0.001mmol,1 mol%) was reacted for 2 hours, the solvent was removed, and column chromatography was performed to give colorless liquid 2d (14.4mg, 48%).¹H NMR(400MHz,CDCl₃)δ7.56(d,J＝7.9Hz,1H),7.45(d,J＝7.7Hz,2H),7.39(d,J＝8.1Hz,1H),7.27–7.17(m,5H),7.15–7.09(m,1H),5.29(s,2H),3.11(s,3H).¹³C NMR(100MHz,CDCl₃)δ138.23,136.82,133.47,130.33,129.51,128.88,127.57,123.35,121.46,120.09,110.43,108.13,77.65,56.05.IR(film)3053,2949,1502,1458,1335,1234,1153,1111,1086,972,743,688.HRMS(EI)Calcd for C₁₆H₁₅NOS₂301.0595,found 301.0590.

Example 20

Synthesis of compound 2 e:

phenylboronic acid (18.3mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of N-methylindole (15.7mg,0.12mmol,1.2equiv) and B (C) to the solution₆F₅)₃(0.5mg,0.001mmol,1 mol%) was reacted for 2 hours, the solvent was removed, and column chromatography was performed to give colorless liquid 2e (13.0mg, 48%).¹H NMR(400MHz,CDCl₃)δ7.52(d,J＝7.9Hz,1H),7.49–7.45(m,2H),7.26–7.20(m,3H),7.20–7.15(m,2H),7.11(s,1H),7.10–7.06(m,1H),3.65(s,3H).¹³C NMR(100MHz,CDCl₃)δ138.56,137.31,134.52,129.92,129.20,128.87,127.34,122.71,120.69,119.91,109.69,106.18,33.09.IR(film)2976,1580,1475,1458,1332,1242,1051,881,741,688.HRMS(EI)Calcd for C₁₅H₁₃NS₂271.0489,found 271.0490.

Example 21

Synthesis of compound 2 f:

to the reaction tube was added 4-chlorobenzeneboronic acid (23.4mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of N-methyl-6-chloroindole (19.8mg,0.12mmol,1.2equiv) and B (C) to the solution₆F₅)₃(0.5mg,0.001mmol,1 mol%) was reacted for 2 hours, the solvent was removed, and column chromatography was performed to give 2f (22.1mg, 65%) as a white solid.¹HNMR(400MHz,CDCl₃)δ7.39–7.36(m,2H),7.35–7.33(m,1H),7.21(d,J＝1.7Hz,1H),7.20(d,J＝1.9Hz,1H),7.18(dd,J＝4.4,1.6Hz,1H),7.07(s,1H),7.05(dd,J＝8.5,1.7Hz,1H),3.62(s,3H).¹³C NMR(100MHz,CDCl₃)δ137.71,136.87,135.06,133.73,131.57,129.07,129.02,127.62,121.54,120.78,109.92,106.42,33.25.IR(film)2933,1606,1504,1472,1460,1418,1387,1327,1232,1090,1065,1011,974,806,642,598.HRMS(EI)Calcd for C₁₅H₁₁Cl₂NS₂338.9710,found 338.9713.

Example 22

Synthesis of Compound 2 g:

adding 2-thia to the reaction tubePhenylboronic acid (19.2mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of N-methylindole (15.7mg,0.12mmol,1.2equiv) and B (C) to the solution₆F₅)₃(0.5mg,0.001mmol,1 mol%) was reacted for 2 hours, the solvent was removed, and column chromatography was performed to give 2g (15.5mg, 56%) of a colorless liquid.¹HNMR(400MHz,CDCl₃)δ7.56(d,J＝7.9Hz,1H),7.36(dd,J＝5.3,1.1Hz,1H),7.27(d,J＝8.1Hz,1H),7.24–7.19(m,1H),7.15–7.11(m,1H),7.11–7.08(m,1H),6.96(dd,J＝3.5,1.2Hz,1H),6.88(dd,J＝5.3,3.6Hz,1H),3.72(s,3H).¹³C NMR(100MHz,CDCl₃)δ137.60,137.43,135.31,134.71,131.29,129.31,127.56,122.80,120.77,119.87,109.69,106.15,33.18.IR(film)3107,2816,1626,1504,1333,1242,1215,1144,1113,848,742,706.HRMS(EI)Calcd for C₁₃H₁₁NS₃277.0054,found 277.0059.

Example 23

Synthesis of compound 2 h:

to the reaction tube was added 3, 4-methylenephenylboronic acid (24.9mg,0.15mmol,1.5equiv), 5(27.6mg,0.10mmol,1equiv), Cu (MeCN)₄PF₆(3.7mg,0.01mmol,10 mol%), 2, 2' -bipyridine (3.1mg,0.02mmol,20 mol%) and redistilled dichloromethane (1mL), with replacement of nitrogen, reaction for 10 hours, filtration, addition of N-methylindole (15.7mg,0.12mmol,1.2equiv) and B (C) to the solution₆F₅)₃(0.5mg,0.001mmol,1 mol%) was reacted for 2 hours, the solvent was removed, and column chromatography was performed to give a yellow liquid for 2 hours (14.6mg, 55%).¹HNMR(400MHz,CDCl₃)δ6.93–6.89(m,1H),6.84–6.79(m,1H),6.76(s,1H),6.67–6.63(m,1H),6.29–6.24(m,1H),6.04–5.99(m,1H),5.93–5.88(m,2H),3.54(s,3H).¹³C NMR(100MHz,CDCl₃)δ148.54,147.99,129.45,127.29,127.07,121.95,119.71,113.12,108.49,108.42,101.50,34.31.IR(film)3003,2889,1716,1475,1363,1290,1039,933,806,731,612.HRMS(ESI)Calcd for C₁₂H₁₂NO₂S₂(M+H⁺)266.0304,found 266.0302.

Example 24

Synthesis of compound 3 a:

to the reaction tube were added 4-cyanoaniline (11.8mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(1.0mg, 0.002mmol, 2 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then benzylamine (12.8mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 12 hours, the solvent was removed and column chromatography gave 3a white solid (20.3mg, 71%).¹H NMR(400MHz,Acetone-d₆)δ7.61(d,J＝8.7Hz,2H),7.33(d,J＝4.0Hz,4H),7.29(dt,J＝9.4,4.8Hz,1H),7.23(d,J＝8.8Hz,2H),4.64(t,J＝5.0Hz,1H),4.19(d,J＝5.3Hz,2H),2.10(s,1H).¹³C NMR(100MHz,Acetone-d₆)δ151.25,138.79,133.34,128.49,128.33,127.31,119.23,116.03,102.28,54.98.IR(film)3361,2974,2926,2222,1383,1335,1093,1053,883,804,574.HRMS(EI)Calcd for C₁₄H₁₃N₃S₂287.0551,found287.0549.

Example 25

Synthesis of compound 3 b:

to the reaction tube were added 4-bromoaniline (17.2mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then benzylamine (12.8mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, and stirred at room temperatureStirring for 12 h, solvent removed and column chromatography gave 3b (26.6mg, 78%) as a white solid.¹H NMR(400MHz,CDCl₃)δ7.25(dt,J＝11.8,4.9Hz,5H),7.19(d,J＝7.8Hz,2H),6.79(d,J＝8.5Hz,2H),4.77(s,1H),3.99(d,J＝3.3Hz,2H),3.07(s,1H).¹³C NMR(100MHz,CDCl₃)δ145.44,138.47,132.06,128.66,128.45,127.76,117.99,113.29,55.81.IR(film)3360,3294,1585,1481,1435,1365,1276,1228,1113,1001,887,812,748,696,632,578.HRMS(EI)Calcd for C₁₃H₁₃BrN₂S₂339.9704,found339.9709.

Example 26

Synthesis of compound 3 c:

4-chloroaniline (12.7mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, and then cyclohexylamine (11.9mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave colorless liquid 3c (21.6mg, 75%).¹HNMR(400MHz,CDCl₃)δ7.12(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),5.01(s,1H),2.80(s,1H),2.73–2.63(m,1H),1.79(d,J＝11.7Hz,2H),1.61(dd,J＝8.5,4.5Hz,2H),1.15–0.93(m,6H).¹³C NMR(100MHz,CDCl₃)δ145.28,129.12,125.92,117.55,57.67,32.56,25.85,24.38.IR(film)3329,2935,2856,1774,1595,1489,1448,1276,1232,825,739.HRMS(EI)Calcd for C₁₂H₁₇ClN₂S₂288.0522,found 288.0525.

Example 27

Synthesis of compound 3 d:

adding into a reaction tubeAdding 4-vinylaniline (11.9mg,0.1 mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then 3, 4-dimethoxybenzylamine (11.9mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 12 hours, the solvent was removed and column chromatography gave 3d (19.1mg, 55%) as a white solid.¹H NMR(400MHz,CDCl₃)δ7.24(dd,J＝17.5,7.4Hz,2H),6.92(dd,J＝16.7,8.3Hz,2H),6.81–6.66(m,3H),6.64–6.49(m,1H),5.54(t,J＝17.3Hz,1H),5.13–4.89(m,1H),3.93(d,J＝17.4Hz,1H),4.01–3.41(m,2H),3.80(dd,J＝16.8,7.5Hz,6H),3.01(s,1H).¹³C NMR(100MHz,DMSO-d₆)δ148.99,148.39,147.35,136.83,131.73,129.52,127.44,120.91,116.26,112.58,111.99,111.34,55.96,55.81,54.89.IR(film)3200,3055,2835,1604,1508,1325,1269,1238,1139,1026,738.HRMS(ESI)Calcd for C₁₇H₂₀N₂O₂S₂(M+H⁺)349.1039,found 349.1037.

Example 28

Synthesis of compound 3 e:

4-chloroaniline (12.7mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then 2, 2-diphenylethan-1-amine (23.6mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave bright yellow liquid 3e (34.7mg, 90%).¹H NMR(400MHz,CDCl₃)δ7.23(t,J＝7.5Hz,4H),7.15(d,J＝6.7Hz,2H),7.09(d,J＝7.7Hz,4H),7.06(d,J＝8.6Hz,2H),6.77(d,J＝8.4Hz,2H),4.82(s,1H),4.11(t,J＝7.6Hz,1H),3.45–3.34(m,2H),2.70(s,1H).¹³C NMR(100MHz,CDCl₃)δ144.85,141.98,129.20,128.81,128.06,126.88,126.08,117.69,56.77,51.14.IR(film)3358,3061,2924,2852,1593,1487,1275,1230,889,823,738,702.HRMS(EI)Calcd for C₂₀H₁₉ClN₂S₂386.0678,found 386.0681.

Example 29

Synthesis of compound 3 f:

to the reaction tube were added 4-aminobiphenyl (16.9mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then diallylamine (11.6mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 12 hours, the solvent was removed and column chromatography gave bright yellow liquid 3f (22.0mg, 67%).¹H NMR(400MHz,CDCl₃)δ7.50–7.40(m,4H),7.36–7.28(m,2H),7.24–7.17(m,1H),6.99–6.92(m,2H),5.87–5.64(m,2H),5.10–4.94(m,4H),4.83(s,1H),3.38–3.34(m,4H).¹³C NMR(100MHz,CDCl₃)δ145.89,140.81,134.86,134.04,128.78,127.88,126.69,126.62,118.08,116.74,60.28.IR(film)3373,3030,2920,1714,1606,1516,1485,1361,1282,1265,1224,991,925,889,833,761,698.HRMS(EI)Calcd for C₁₈H₂₀N₂S₂328.1068,found 328.1070.

Example 30

Synthesis of Compound 3 g:

4-chloroaniline (12.7mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) was stirred at room temperature for 4 hours, then tryptamine (19.2mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0 mmol) were addedequiv), stirred at room temperature for 12 hours, the solvent removed, and column chromatography gave 3g (25.2mg, 72%) of a bright yellow liquid.¹H NMR(400MHz,CDCl₃)δ7.91(s,1H),7.57(t,J＝7.2Hz,1H),7.33(t,J＝6.7Hz,1H),7.23–7.15(m,1H),7.10(dd,J＝14.6,7.3Hz,1H),6.94–6.83(m,3H),6.72–6.63(m,2H),4.70(s,1H),3.20(s,3H),2.99–2.84(m,3H),2.76(s,1H).¹³C NMR(100MHz,CDCl₃)δ144.75,136.49,129.03,127.19,125.72,122.45,122.38,119.65,118.83,117.32,112.75,111.47,51.22,25.60.IR(film)3314,3061,2924,2868,1593,1487,1275,1230,889,823,739.702.HRMS(ESI)Calcd for C₁₆H₁₆ClN₃S₂(M+H⁺)350.0547,found 350.0546.

Example 31

Synthesis of compound 3 h:

4-Methylaniline (10.7mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then 2-aminomethylpyridine (13.0mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave a brown liquid for 3 hours (20.2mg, 73%).¹H NMR(400MHz,DMSO-d₆)δ8.48(d,J＝4.2Hz,1H),7.72(td,J＝7.7,1.8Hz,1H),7.54(s,1H),7.33(d,J＝7.8Hz,1H),7.27–7.21(m,1H),7.00(d,J＝8.3Hz,2H),6.90(d,J＝8.4Hz,2H),5.14(t,J＝5.5Hz,1H),4.13(d,J＝5.5Hz,2H),2.18(s,3H).¹³C NMR(100MHz,DMSO-d₆)δ159.03,149.31,144.81,137.04,129.87,129.00,122.75,122.67,116.42,56.80,20.64.IR(film)2920,2848,1714,1633,1508,1431,1361,1093,763,723.HRMS(ESI)Calcd for C₁₃H₁₆N₃S₂(M+H⁺)278.0780,found 278.0782.

Example 32

Synthesis of compound 3 i:

3-Cyanoaniline (11.8mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(1.0mg, 0.002mmol, 2 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 12 hours, then L-phenylalanine tert-butyl ester (26.5mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave 3i (23.2mg, 58%) as a colorless liquid.¹H NMR(300MHz,CDCl₃)δ7.22(ddd,J＝11.2,4.9,2.3Hz,5H),7.14–7.06(m,4H),5.37(s,1H),3.66(dt,J＝8.5,6.9Hz,1H),3.56(d,J＝8.6Hz,1H),2.89(d,J＝6.7Hz,2H),1.38(s,9H).¹³C NMR(100MHz,CDCl₃)δ169.39,141.60,131.64,125.23,124.73,123.69,122.22,119.71,116.18,114.62,114.15,108.34,77.84,61.89,34.73,23.18.IR(film)3348,3030,2980,2229,1726,1598,1583,1495,1456,1392,1369,1269,1151,740,702.HRMS(ESI)Calcd for C₂₀H₂₃N₃O₂S₂(M+Na⁺)424.1124,found424.1119.

Example 33

Synthesis of compound 3 j:

4-Tert-butylaniline (14.9mg,0.1 mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(0.5mg, 0.005mmol, 1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then L-tryptophan methyl ester (26.1mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave 3j (28.3mg, 66%) as a pale yellow solid.¹H NMR(400MHz,CDCl₃)δ7.98(s,1H),7.55(d,J＝7.8Hz,1H),7.28(d,J＝8.1Hz,1H),7.12(dd,J＝8.6,2.3Hz,3H),7.06(t,J＝7.4Hz,1H),6.92(d,J＝2.1Hz,1H),6.72(d,J＝8.6Hz,2H),4.62(s,1H),3.97(dd,J＝13.2,6.4Hz,1H),3.65(s,3H),3.45(d,J＝6.4Hz,1H),3.11(ddd,J＝22.3,14.6,6.6Hz,2H),1.19(s,9H).¹³C NMR(100MHz,CDCl₃)δ175.00,143.99,142.67,136.21,127.21,126.02,123.34,122.37,119.75,118.76,116.10,111.40,110.39,63.69,52.53,52.49,34.11,31.51,28.86.IR(film)3495,3290,2926,1728,1510,1282,1093,1053,881,827,742,643.HRMS(ESI)Calcd for C₂₂H₂₈N₃O₂S₂(M+H⁺)430.1617,found 430.1616.

Example 34

Synthesis of compound 3 k:

to the reaction tube were added (R) -4- (2-aminophenyl) -1- (benzenesulfonyl) -2, 3-dihydro-1H-pyrrole-2-carboxylic acid tert-butyl ester (40.0mg,0.1 mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(2.5mg, 0.005mmol, 5 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 12 hours, then 2, 2-diphenylethan-1-amine (23.6mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave 3k (40.9mg, 62%) as a brown foamy solid.¹H NMR(400MHz,CDCl₃)δ7.78(d,J＝6.8Hz,2H),7.54(dd,J＝8.4,6.2Hz,1H),7.47(t,J＝7.2Hz,2H),7.17(ddd,J＝20.3,14.0,7.0Hz,8H),7.05(d,J＝6.7Hz,4H),6.81(d,J＝7.5Hz,1H),6.75(t,J＝7.2Hz,1H),6.53(s,1H),5.22(s,1H),4.21(t,J＝7.6Hz,1H),4.06(t,J＝6.9Hz,1H),3.30(s,2H),2.90–2.73(m,2H),2.69(t,J＝4.8Hz,1H),1.44(s,9H).¹³C NMR(100MHz,CDCl₃)δ169.75,143.94,142.06,141.99,136.65,133.51,129.41,128.72,128.36,128.03,127.92,127.58,126.78,122.74,121.27,120.72,117.30,82.75,61.12,56.80,51.07,38.06,27.98.IR(film)3489,3001,1633,1446,1373,1168,1149,1089,1041,754,721.HRMS(ESI)Calcd for C₃₅H₃₇N₃O₄S₃(M+H⁺)660.2019,found 660.2010.

Example 35

Synthesis of compound 3 l:

tryptophan methyl ester (21.8mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(1.0mg, 0.002mmol, 2 mol%) and redistilled acetonitrile (0.5mL) were stirred at room temperature for 12 hours, then octadecylamine (32.3mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave 3l (19.3mg, 35%) of a pale yellow solid.¹H NMR(400MHz,CDCl₃)δ7.99(s,1H),7.56–7.49(m,1H),7.31–7.23(m,1H),7.12(dd,J＝13.4,6.6Hz,1H),7.05(dd,J＝13.3,6.6Hz,1H),6.99(s,1H),3.96–3.89(m,1H),3.63(d,J＝5.3Hz,3H),3.40(t,J＝5.7Hz,1H),3.23–3.01(m,2H),2.76(s,1H),2.70(s,1H),2.51(s,1H),1.38–1.30(m,2H),1.17(s,30H),0.84–0.77(m,3H).¹³C NMR(100MHz,CDCl₃)δ175.38,136.13,127.35,123.02,122.29,119.69,118.74,111.25,110.66,64.04,52.45,50.37,31.96,29.74,29.66,29.61,29.56,29.46,29.40,29.03,26.96,22.73,14.16.IR(film)3072,3061,1512,1404,1269,742,704.HRMS(ESI)Calcd for C₃₀H₅₁N₃O₂S₂(M+H⁺)550.3495,found 550.3498.

Example 36

Synthesis of compound 3 m:

sulfadimidine (27.8mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(2.5mg, 0.005mmol, 5 mol%) and redistilled 1, 4-dioxane (0.25mL) was stirred at room temperature for 24 hours, then octadecylamine (32.3mg,0.12mmol, 1) was added.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv), stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave 3m (24.4mg, 40%) of a white solid.¹H NMR(400MHz,DMSO-d₆)δ8.36(s,1H),7.84(d,J＝8.5Hz,2H),7.05(d,J＝8.5Hz,2H),6.75(s,1H),4.88(s,1H),2.79(d,J＝5.1Hz,2H),2.25(s,6H),1.38–1.32(m,3H),1.23(s,30H),0.85(t,J＝6.0Hz,3H).¹³C NMR(100MHz,DMSO-d₆)δ167.79,156.95,151.55,130.75,130.29,114.64,112.29,51.07,31.78,29.52,29.40,29.28,29.19,28.88,26.74,23.51,22.57,14.40.IR(film)3091,3012,1716,1688,1421,1220,1091,992,708,686.HRMS(ESI)Calcd for C₃₀H₅₁N₅O₂S₃(M+H⁺)610.3278,found 610.3274.

Example 37

Synthesis of compound 3 n:

tryptophan methyl ester (21.8mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(2.5mg, 0.005mmol, 5 mol%) and redistilled acetonitrile (0.5mL) were stirred at room temperature for 12 hours, then L-phenylalanine methyl ester (21.5mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave 3n (19.3mg, 42%) as a pale yellow solid.¹H NMR(400MHz,CDCl₃)δ7.98(s,1H),7.52(d,J＝7.7Hz,1H),7.25(d,J＝7.7Hz,1H),7.20–7.16(m,3H),7.15–7.09(m,2H),7.07–7.02(m,2H),6.94(s,1H),3.85(dd,J＝13.6,6.5Hz,1H),3.70–3.63(m,1H),3.59(s,3H),3.57(s,3H),3.49(d,J＝6.8Hz,1H),3.38(d,J＝6.8Hz,1H),3.09(ddd,J＝21.9,14.7,6.5Hz,2H),2.84(ddd,J＝21.1,13.8,6.7Hz,2H).¹³C NMR(100MHz,CDCl₃)δ175.25,175.01,136.58,136.13,129.27,128.43,127.41,126.87,122.99,122.16,119.55,118.76,111.24,110.62,64.78,63.80,52.47,52.39,39.28,29.14.IR(film)3055,2953,1734,1494,1456,1435,1340,1267,1203,1097,742,702.HRMS(ESI)Calcd for C₂₂H₂₅N₃O₄S₂(M+H⁺)460.1359,found 460.1353.

Example 38

Synthesis of compound 3 o:

tryptophan methyl ester (21.8mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(2.5mg, 0.005mmol, 5 mol%) and redistilled acetonitrile (0.5mL) were stirred at room temperature for 12 hours, then L-valine methyl ester (15.7mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave 3o (22.2mg, 54%) as a white solid.¹H NMR(400MHz,CDCl₃)δ8.03(s,1H),7.55(d,J＝7.8Hz,1H),7.27(d,J＝8.0Hz,1H),7.11(t,J＝7.5Hz,1H),7.05(t,J＝7.4Hz,1H),6.99(s,1H),3.95(dd,J＝13.3,6.6Hz,1H),3.63(d,J＝2.6Hz,6H),3.37(d,J＝9.3Hz,1H),3.12(ddd,J＝22.1,14.6,6.6Hz,1H),2.97(s,1H),1.77(td,J＝13.4,6.7Hz,1H),1.64(s,1H),0.78(t,J＝6.5Hz,6H).¹³C NMR(100MHz,CDCl₃)δ175.91,175.42,136.21,127.39,123.10,122.15,119.54,118.81,111.22,110.67,70.50,63.66,52.46,52.26,32.03,29.30,18.98,18.24.IR(film)3055,1746,1467,1269,1189,1022,740,704.HRMS(ESI)Calcd for C₁₈H₂₅N₃O₄S₂(M+H⁺)412.1359,found 412.1351.

Example 39

Synthesis of compound 3 p:

sulfadimidine (27.8mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(2.5mg, 0.005mmol, 5 mol%) and redistilled 1, 4-dioxane (0.25mL) was stirred at room temperature for 24 hours, thenThen tert-butoxycarbonyl-L-isoleucyl-L-lysine methyl ester (44.8mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave 3p (46.4mg, 65%) as a white solid.¹H NMR(400MHz,CDCl₃)δ7.89(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),6.76(d,J＝7.4Hz,1H),6.52(s,1H),6.28(s,1H),5.28(d,J＝8.9Hz,1H),4.51(dd,J＝13.0,7.8Hz,1H),4.02(t,J＝7.6Hz,1H),3.65(s,3H),3.02(brs,1H),2.83(t,J＝6.1Hz,2H),2.27(s,6H),1.84–1.68(m,2H),1.63–1.54(m,1H),1.51–1.40(m,3H),1.35(s,9H),1.29–1.17(m,2H),1.15–1.01(m,2H),0.89(d,J＝6.7Hz,3H),0.83(t,J＝7.3Hz,3H).¹³C NMR(100MHz,CDCl₃)δ172.51,172.13,168.16,156.34,156.02,151.06,130.50,114.91,114.59,113.27,80.07,59.19,52.42,52.09,51.04,37.31,31.80,28.69,28.33,24.76,23.56,22.52,15.50,11.27.IR(film)3433,3275,2941,1741,1689,1593,1346,1244,1207,1155,1080,866.HRMS(ESI)Calcd for C₃₀H₄₇N₇O₇S₃(M+H⁺)714.2772,found 714.2764.

Example 40

Synthesis of compound 3 q:

sulfamethoxazole (25.3mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(2.5mg, 0.005mmol, 5 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 24 hours, then t-butyloxycarbonyl-L-phenylalanyl-L-leucyl-L-lysine (62.4mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave 3q (37.6mg, 45%) of a white solid.¹H NMR(400MHz,CDCl₃)δ7.63(d,J＝8.7Hz,2H),7.19–7.10(m,5H),7.03(s,2H),6.91(d,J＝7.7Hz,2H),6.20(s,1H),6.12(d,J＝3.9Hz,1H),5.09(d,J＝7.0Hz,1H),4.55–4.41(m,2H),4.32(s,1H),3.66(s,3H),3.09(s,1H),2.95–2.65(m,4H),2.26(s,3H),1.82–1.70(m,1H),1.58–1.49(m,3H),1.46–1.34(m,3H),1.26(s,9H),1.22–1.14(m,3H),0.83–0.76(m,6H).¹³C NMR(100MHz,CDCl₃)δ172.48,172.24,172.20,170.47,158.30,155.49,151.40,136.53,130.24,129.36,128.62,128.52,126.87,115.63,95.84,80.28,55.55,52.43,52.19,52.05,51.77,40.78,37.92,31.72,28.97,28.21,24.51,22.69,22.08,12.65.IR(film)3406,3313,3219,2976,1382,1093,1055,883,688.HRMS(ESI)Calcd for C₃₇H₅₃N₇O₉S₃Na(M+Na⁺)858.2959,found 858.2952.

EXAMPLE 41

Synthesis of compound 3 r:

sulfadimidine (27.8mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(2.5mg, 0.005mmol, 5 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 24 hours, then cinacalcet (42.9mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 12 hours, the solvent was removed, and column chromatography gave 3r (51.6mg, 74%) as a yellow solid.¹HNMR(400MHz,CDCl₃)δ7.94(d,J＝8.1Hz,2H),7.90(d,J＝8.3Hz,1H),7.74(d,J＝8.1Hz,1H),7.64(d,J＝7.9Hz,1H),7.40(dt,J＝14.7,7.0Hz,3H),7.33–7.22(m,3H),7.10(t,J＝7.6Hz,1H),7.02(s,1H),6.82(d,J＝8.0Hz,3H),6.42(s,1H),5.34(s,1H),4.66(br,1H),2.72–2.50(m,2H),2.32–2.25(m,2H),2.22(s,6H),2.08–1.95(m,2H),1.49(br,3H).¹⁹F NMR(376MHz,CDCl₃)δ-62.42.¹³C NMR(101MHz,CDCl₃)δ168.28,156.32,150.78,142.63,138.19,133.99,131.57,131.39,130.75,130.63,130.36(q,²J_CF＝31.8Hz),128.94,128.63,128.27,126.29,125.74,125.23,124.73(q,³J_CF＝3.6Hz),124.48,124.25(q,¹J_CF＝272.5Hz),123.54,122.56(q,³J_CF＝3.8Hz),114.63,63.17,52.02,32.18,29.75,28.68,23.50.IR(film)3319,3055,1593,1552,1438,1153,1074,972,868,736,671,582.HRMS(ESI)Calcd for C₃₄H₃₅F₃N₅O₂S₃(M+H⁺)698.1899,found 698.1881.

Example 42

Synthesis of compound 3 s:

4-chloroaniline (12.7mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then 1-adamantanethiol (20.1mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3s (33.3mg, 93%) as a white solid.¹H NMR(400MHz,CD₃CN)δ7.23–7.10(m,2H),7.07–6.97(m,2H),6.61(s,1H),1.97(s,3H),1.77(d,J＝2.6Hz,6H),1.60(q,J＝12.4Hz,6H).¹³C NMR(100MHz,CD₃CN)δ144.89,129.56,126.16,118.54,117.85,50.30,43.11,36.17,30.50.IR(film)2906,1591,1487,1228,1093,891,819,659.HRMS(EI)Calcd for C₁₆H₂₀ClNS₃357.0446,found 357.0437.

Example 43

Synthesis of compound 3 t:

to the reaction tube were added 4-bromoaniline (17.2mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then 1-adamantanethiol (20.1mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3t (39.4mg, 98%) of a white solid。¹H NMR(400MHz,Acetone-d₆)δ7.50(s,1H),7.28(d,J＝8.8Hz,2H),7.04(d,J＝8.8Hz,2H),1.93(s,3H),1.74(s,6H),1.56(q,J＝12.3Hz,6H).¹³C NMR(100MHz,Acetone-d₆)δ145.10,131.87,118.43,112.73,49.58,42.62,35.78,29.94.IR(film)3360,2903,2849,1587,1483,1296,1273,1228,1037,1003,895,818,684.HRMS(EI)Calcd for C₁₆H₂₀BrNS₃400.9941,found 400.9945.

Example 44

Synthesis of compound 3 u:

4-Tert-butylaniline (14.9mg,0.1 mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then 1-adamantanethiol (20.1mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3u (28.5mg, 75%) as a white solid.¹HNMR(400MHz,Acetone-d₆)δ7.24(s,1H),7.20–7.16(m,2H),7.03–6.98(m,2H),1.95–1.89(m,3H),1.74(d,J＝2.7Hz,6H),1.55(q,J＝12.3Hz,6H),1.16(s,9H).¹³C NMR(100MHz,Acetone-d₆)δ143.78,142.93,125.80,116.27,49.38,42.64,35.79,33.76,30.96,29.93.IR(film)3344,2960,2903,2848,1510,1450,1296,1284,1234,1184,1039,904,825.HRMS(EI)Calcd for C₂₀H₂₉NS₃379.1462,found 379.1464.

Example 45

Synthesis of compound 3 v:

to the reaction tube were added 4-cyanoaniline (11.8mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 12 hours, then 1-adamantanethiol (20.1mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3v (28.5mg, 86%) as a white solid.¹H NMR(400MHz,Acetone-d₆)δ8.02(s,1H),7.58–7.48(m,2H),7.27–7.19(m,2H),1.94(s,3H),1.75(d,J＝2.6Hz,6H),1.56(q,J＝12.3Hz,6H).¹³C NMR(100MHz,Acetone-d₆)δ150.02,133.42,118.94,116.70,103.48,49.84,42.56,35.70,29.91.IR(film)3361,2904,2212,1624,1448,1309,1170,1045,831,738,688.HRMS(EI)Calcd for C₁₇H₂₀N₂S₃348.0789,found 348.0788.

Example 46

Synthesis of compound 3 w:

2-Phenylaniline (11.8mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 12 hours, then 1-adamantanethiol (20.1mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3w (28.5mg, 86%) of a white solid.¹HNMR(400MHz,Acetone-d₆)δ7.50(d,J＝8.2Hz,1H),7.39–7.30(m,2H),7.29–7.18(m,4H),7.01(d,J＝7.5Hz,1H),6.89(t,J＝7.4Hz,1H),6.34(s,1H),1.90(s,3H),1.68(s,6H),1.54(q,J＝12.3Hz,6H).¹³C NMR(100MHz,Acetone-d₆)δ141.77,138.37,131.32,130.48,129.25,128.98,128.44,127.60,121.55,116.62,49.54,42.55,35.75,29.89.IR(film)3379,2903,2848,1499,1477,1296,1261,1207,1039,896,750.HRMS(EI)Calcd for C₂₂H₂₅NS₃399.1149,found 399.1151.

Example 47

Synthesis of compound 3 x:

3-fluoroaniline (11.1mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 12 hours, then 1-adamantanethiol (20.1mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 8 hours, the solvent was removed and column chromatography gave 3X (26.2mg, 77%) as bright yellow liquid.¹H NMR(400MHz,Acetone-d₆)δ7.61(s,1H),7.14(dd,J＝15.0,7.7Hz,1H),6.93–6.82(m,2H),6.53(ddd,J＝8.6,2.6,1.2Hz,1H),1.94(s,3H),1.75(d,J＝2.7Hz,6H),1.57(q,J＝12.3Hz,6H).¹⁹F NMR(376MHz,Acetone-d₆)δ-113.77.¹³C NMR(100MHz,Acetone-d₆)δ163.69(d,¹J_CF＝242.5Hz),147.94(d,³J_CF＝10.2Hz),130.58(d,³J_CF＝9.8Hz),112.49(d,⁴J_CF＝2.5Hz),107.35(d,²J_CF＝21.6Hz),103.21(d,²J_CF＝26.0Hz),49.60,42.59,35.74,29.92.IR(film)3199,2905,1612,1487,1273,1165,1139,1001,968,765,681.HRMS(EI)Calcd for C₁₆H₂₀FNS₃341.0742,found 341.0744.

Example 48

Synthesis of compound 3 y:

to the reaction tube were added 3, 5-difluoroaniline (12.9mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 12 hours, then 1-adamantanethiol (20.1mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added at room temperatureStirring for 8 h, removal of solvent and column chromatography gave 3y (25.1mg, 70%) as a bright yellow liquid.¹H NMR(400MHz,Acetone-d₆)δ7.85(s,1H),6.76–6.61(m,2H),6.39(ddd,J＝9.2,5.7,2.3Hz,1H),1.95(s,3H),1.76(d,J＝2.7Hz,6H),1.58(q,J＝12.4Hz,6H).¹⁹F NMR(282MHz,Acetone-d₆)δ-105.54,-105.57.¹³C NMR(100MHz,Acetone-d₆)δ163.81(dd,¹J_CF＝244.3,³J_CF＝15.4Hz),149.25(t,³J_CF＝12.7Hz),99.41(d,²J_CF＝29.2Hz),95.69(t,²J_CF＝26.4Hz),49.79,42.57,35.71,29.92.IR(film)3362,2904,2849,1620,1597,1485,1467,1342,1296,1139,1112,1016,993,827,671.HRMS(EI)Calcd for C₁₆H₁₉F₂NS₃359.0648,found 359.0649.

Example 49

Synthesis of compound 3 z:

4-chloroaniline (12.7mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then 4-toluene thiol (14.9mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3z (28.8mg, 92%) as a yellow solid.¹H NMR(400MHz,Acetone-d₆)δ7.54(s,1H),7.25(d,J＝8.2Hz,2H),7.12–7.04(m,2H),7.04–6.95(m,4H),2.18(s,3H).¹³C NMR(100MHz,Acetone-d₆)δ145.17,139.01,134.23,130.59,130.41,129.63,126.41,118.76,20.91.IR(film)3354,2918,2852,1591,1487,1435,1276,1224,1170,1090,817,800.HRMS(EI)Calcd for C₁₃H₁₂ClNS₃312.9820,found 312.9821.

Example 50

Synthesis of compound 3 aa:

4-chloroaniline (12.7mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then 2-bromobenzenethiol (22.7mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3aa (29.2mg, 77%) as a colorless liquid.¹H NMR(400MHz,Acetone-d₆)δ7.68(s,1H),7.48(dd,J＝13.5,7.9Hz,2H),7.12(dd,J＝14.3,6.6Hz,2H),7.08–7.01(m,4H).¹³C NMR(100MHz,Acetone-d₆)δ145.09,138.00,133.81,129.87,129.53,129.25,129.14,126.84,122.17,118.90.IR(film)3414,2953,2922,2851,1651,1462,1377,1080,746,543.HRMS(EI)Calcd for C₁₂H₉BrClNS₃376.8769,found 376.8772.

Example 51

Synthesis of compound 3 ab:

4-chloroaniline (12.7mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then 2-mercaptopyrimidine (13.4mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3ab (19.9mg, 66%) as a white solid.¹HNMR(300MHz,Acetone-d₆)δ8.58(d,J＝4.8Hz,2H),7.72(s,1H),7.26(t,J＝4.8Hz,1H),7.22–7.13(m,4H).¹³C NMR(100MHz,Acetone-d₆)δ169.78,157.97,144.86,128.78,125.61,118.58,118.11.IR(film)2976,1593,1553,1487,1377,1169,1092,903,824,770742,629.HRMS(EI)Calcd for C₁₀H₈ClN₃S₃300.9569,found 300.9572.

Example 52

Synthesis of compound 3 ac:

aniline (9.3mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then n-dodecyl mercaptan (24.2mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3ac (29.0mg, 81%) as a bright yellow liquid.¹H NMR(300MHz,CD₃CN)δ7.30(dd,J＝8.5,7.4Hz,2H),7.16(dd,J＝8.6,1.0Hz,2H),6.96(t,J＝7.3Hz,1H),6.59(s,1H),2.81–2.62(m,2H),1.63(dt,J＝14.7,7.2Hz,2H),1.30(s,18H),0.91(t,J＝6.7Hz,3H).¹³C NMR(100MHz,CD₃CN)δ146.11,129.80,122.05,117.20,40.03,32.26,29.96,29.87,29.77,29.69,29.36,29.35,28.64,23.01,14.01.IR(film)3352,2976,2924,2852,1598,1492,1468,1282,1229,1093,1051,885,750,690.HRMS(EI)Calcd for C₁₈H₃₁NS₃357.1619,found 357.1622.

Example 53

Synthesis of compound 3 ad:

4-chloroaniline (12.7mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) was stirred at room temperature for 4 hours, then N- (phthaloyl) cysteine (33.5mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave bright yellow liquid 3ad(37.5mg,80％)。¹H NMR(400MHz,Acetone-d₆)δ7.78(s,4H),7.58(s,1H),7.11(d,J＝8.8Hz,2H),7.06–7.02(m,2H),5.05(dd,J＝10.2,5.1Hz,1H),4.05(q,J＝7.1Hz,2H),3.51(qd,J＝14.5,7.6Hz,2H),1.05(t,J＝7.1Hz,3H).¹³C NMR(100MHz,Acetone-d₆)δ167.57,167.15,144.40,134.86,131.59,129.05,125.72,123.51,118.04,61.94,51.36,38.07,13.49.IR(film)3329,2980,1776,1745,1715,1489,1387,1232,1094,1022,875,824,721.HRMS(EI)Calcd for C₁₉H₁₇ClN₂O₄S₃468.0039,found 468.0037.

Example 54

Synthesis of compound 3 ae:

4-chloroaniline (12.7mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) was added to the reaction tube₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then furyl-2-methanethiol (13.7mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3ae (20.3mg, 67%) as a colorless liquid.¹HNMR(400MHz,Acetone-d₆)δ7.47(s,1H),7.39(dd,J＝1.8,0.8Hz,1H),7.20–7.14(m,2H),7.11–7.05(m,2H),6.23(dd,J＝3.2,1.9Hz,1H),6.10(dd,J＝3.2,0.6Hz,1H),3.92(s,2H).¹³C NMR(100MHz,Acetone-d₆)δ149.74,144.78,142.97,129.03,125.58,118.00,110.64,109.28,35.92.IR(film)3354,1593,1487,1436,1274,1228,1172,1149,1091,1010,935,822738.HRMS(EI)Calcd for C₁₁H₁₀ClNOS₃302.9613,found 302.9616.

Example 55

Synthesis of compound 3 af:

Example 56

Synthesis of Compound 3 ag:

to the reaction tube were added (R) -4- (2-aminophenyl) -1- (benzenesulfonyl) -2, 3-dihydro-1H-pyrrole-2-carboxylic acid tert-butyl ester (40.0mg,0.1 mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(2.5mg, 0.005mmol, 5 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 12 hours, then dodecanethiol (24.2mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3ag (27.9mg, 42%) as a brown solid.¹HNMR(400MHz,Acetone-d₆)δ7.83–7.79(m,2H),7.63(t,J＝7.3Hz,1H),7.57(t,J＝7.4Hz,2H),7.32(t,J＝6.3Hz,1H),7.14(t,J＝7.7Hz,1H),6.98(d,J＝7.6Hz,1H),6.82(t,J＝7.6Hz,1H),6.63–6.56(m,1H),6.44(s,1H),4.23(dd,J＝10.9,7.3Hz,1H),3.05(ddd,J＝16.0,11.0,1.9Hz,1H),2.78(ddd,J＝16.2,7.3,1.7Hz,1H),2.55–2.50(m,2H),1.50–1.41(m,2H),1.39(s,9H),1.15(s,18H),0.75(t,J＝6.6Hz,3H).¹³C NMR(100MHz,Acetone-d₆)δ169.52,142.97,136.90,133.56,129.52,129.08,128.41,128.03,128.00,127.64,124.00,122.17,120.50,118.58,81.54,61.37,39.36,37.75,31.77,29.50,29.43,28.67,28.18,27.26,22.47,13.53.IR(film)2953,2924,2852,1736,1487,1446,1367,1309,1171,1092,752,721,690,605,572.HRMS(ESI)Calcd for C₃₃H₄₉N₂O₄S₄(M+H⁺)665.2570,found 665.2551.

Example 57

Synthesis of compound 3 ah:

to the reaction tube were added methyl (tert-butyloxycarbonyl) -L-isoleucine-D-lysine (37.3mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(1.0mg, 0.002mmol, 2 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then dodecanethiol (24.2mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3ah (24.2mg, 40%) as a white solid.¹H NMR(400MHz,CDCl₃)δ6.35(d,J＝7.5Hz,1H),4.98(d,J＝8.3Hz,1H),4.53(td,J＝7.7,5.4Hz,1H),3.93–3.85(m,1H),3.68(s,3H),3.24(t,J＝5.1Hz,1H),2.95(dd,J＝12.5,6.6Hz,2H),2.03(s,3H),1.87–1.76(m,8H),1.72(s,1H),1.67–1.58(m,6H),1.51(dt,J＝14.2,7.2Hz,2H),1.38(s,9H),1.35–1.28(m,2H),1.27–1.17(m,2H),0.89–0.83(m,6H).IR(film)3319,2970,2910,2854,1743,1658,1520,1452,1369,1292,1246,1167,1088,1045,977,877.¹³C NMR(100MHz,CDCl₃)δ172.55,171.39,155.76,79.99,59.33,52.43,51.97,50.27,49.85,42.66,37.13,36.09,32.15,29.87,28.56,28.34,24.79,22.51,15.53,11.43.IR(film)3319,2970,2910,2854,1743,1658,1452,1369,1292,1246,1209,1087,1045,877.HRMS(ESI)Calcd for C₂₈H₅₀N₃O₅S₃(M+H⁺)604.2907,found 604.2902.

Example 58

Synthesis of compound 3 aj:

to the reaction tube were added tryptamine (16.0mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C)₆F₅)₃(0.5mg,0.001mmol,1 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then adamantanethiol (20.1mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3aj (20.3mg, 52%) as a colorless liquid.¹H NMR(400MHz,Acetone-d₆)δ9.89(s,1H),7.48(d,J＝7.8Hz,1H),7.24(d,J＝8.0Hz,1H),7.05(d,J＝1.8Hz,1H),6.96(t,J＝7.5Hz,1H),6.89(t,J＝7.4Hz,1H),4.42(s,1H),3.25(td,J＝7.3,5.5Hz,2H),2.94(t,J＝7.4Hz,2H),1.94–1.88(m,3H),1.73(d,J＝2.3Hz,6H),1.61–1.48(m,6H).¹³C NMR(100MHz,Acetone-d₆)δ136.85,127.67,122.59,121.24,118.56,118.37,112.37,111.30,51.85,49.11,42.62,35.84,29.87,25.18.IR(film)3410,2903,2849,1456,1340,1298,1078,1039,740,582.HRMS(ESI)Calcd for C₂₀H₂₇N₂S₃(M+H⁺)391.1331,found 391.1328.

Example 59

Synthesis of compound 3 ak:

sulfanilamide (21.4mg, 0.1mmol,1.0equiv), 3ak (29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(2.5mg, 0.001mmol, 5 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 24 hours, then dodecanethiol (24.2mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 8 hours,the solvent was removed and column chromatography gave 3ak (33.0mg, 69%) as a white solid.¹HNMR(400MHz,CDCl₃)δ8.84(s,1H),7.87(d,J＝8.8Hz,2H),7.14(d,J＝8.8Hz,2H),5.99(s,1H),2.75(t,J＝7.3Hz,2H),2.00(s,3H),1.62(dt,J＝14.8,7.3Hz,2H),1.32–1.25(m,2H),1.19(s,16H),0.81(t,J＝6.8Hz,3H).¹³C NMR(100MHz,Acetone-d₆)δ173.21,162.01,155.40,137.51,135.80,120.54,119.51,71.95,44.71,36.97,34.70,34.69,34.63,34.51,34.13,33.99,33.31,27.97,27.67,18.73.IR(film)3244,2922,2850,1697,1589,1450,1232,1151,910,736,680.HRMS(ESI)Calcd for C₂₀H₃₅N₂O₃S₄(M+H⁺)479.1525,found 479.1517.

Example 60

Synthesis of compound 3 al:

sulfasoxazole (25.3mg, 0.1mmol,1.0equiv), 3al (29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(2.5mg, 0.001mmol, 5 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 24 hours, then 1-adamantylthiol (20.1mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added and stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3al (31.4mg, 65%) as a white solid.¹HNMR(400MHz,Acetone-d₆)δ9.72(s,1H),8.01(s,1H),7.84–7.55(m,2H),7.37–7.10(m,2H),6.10(s,1H),2.19(s,3H),1.93–1.90(m,3H),1.73(s,6H),1.54(dd,J＝25.4,12.1Hz,6H).¹³C NMR(100MHz,Acetone-d₆)δ170.38,157.91,150.42,131.37,128.88,128.77,116.09,95.34,49.85,42.55,35.69,29.89,11.55.IR(film)3053,2949,1591,1275,1157,1072,1008,862,742,702,586.HRMS(ESI)Calcd for C₂₀H₂₆N₃O₃S₄(M+H⁺)484.0852,found 484.0854.

Example 61

Synthesis of Compound 3 am:

octadecylamine (26.9mg, 0.1mmol,1.0equiv), 5(29.0mg, 0.105mmol, 1.05equiv), B (C) were added to the reaction tube₆F₅)₃(1.0mg, 0.002mmol, 2 mol%) and redistilled 1, 4-dioxane (0.25mL) were stirred at room temperature for 4 hours, then dodecanethiol (24.2mg,0.12mmol,1.2equiv) and lithium carbonate (7.4mg,0.1mmol,1.0equiv) were added, stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3am (18.7mg, 35%) as a white solid.¹H NMR(400MHz,CDCl₃)δ3.15(s,1H),2.95(dd,J＝11.5,6.6Hz,2H),2.78(t,J＝7.3Hz,2H),1.64(dt,J＝14.8,7.3Hz,2H),1.53–1.44(m,2H),1.37–1.29(m,4H),1.19(s,44H),0.81(t,J＝6.6Hz,6H).¹³C NMR(100MHz,CDCl₃)δ50.94,39.24,31.94,29.72,29.68,29.65,29.62,29.58,29.53,29.41,29.38,29.37,29.34,29.22,29.11,28.54,26.91,22.71,14.13.IR(film)2953,2916,2847,1462,1402,1371,1296,1242,1061,1022,723,633.HRMS(EI)Calcd for C₃₀H₆₃NS₃533.4123,found 533.4133.

Example 62

Synthesis of compound 3 an:

to the reaction tube were added H-Ala-Phe-Lys-OMe (75.6mg,0.2mmol,1.0equiv), 5(55.2mg,0.2mmol,1.0equiv) and dichloromethane (20mL), followed by B (C)₆F₅)₃(5.1mg, 0.01mmol, 5 mol%) was stirred at room temperature for 8 hours, the solvent was removed, and column chromatography was performed to give 3an (22.0mg, 25%) as a white solid.¹H NMR(400MHz,CD₃OD)δ7.26(d,J＝4.4Hz,4H),7.22–7.16(m,1H),4.73(dd,J＝9.2,6.4Hz,1H),4.52(dd,J＝7.0,3.9Hz,1H),3.94(q,J＝6.9Hz,1H),3.70(s,3H),3.17(dd,J＝14.0,6.4Hz,1H),2.98(ddd,J＝13.6,9.4,6.3Hz,2H),2.80(dt,J＝13.6,4.5Hz,1H),1.88–1.70(m,2H),1.53(ddd,J＝14.1,10.8,5.7Hz,2H),1.31–1.26(m,6H),1.11(d,J＝6.9Hz,3H).¹³C NMR(100MHz,CD₃OD)δ175.95,171.99,170.90,137.21,128.88,128.04,126.28,58.37,53.62,53.29,51.66,51.41,34.74,30.56,28.92,21.33,18.51.IR(film)3325,2976,2916,1732,1649,1528,1452,1383,1290,1184,1091,1051,885,808,740.HRMS(ESI)Calcd for C₁₉H₂₉N₄O₄S₂(M+H⁺)441.1625,found 441.1622.

Example 63

Synthesis of compound 3 ao:

to the reaction tube were added H-Ala-Phe-Trp-Lys-OMe (112.9mg,0.2mmol,1.0equiv), 5(55.2mg,0.2mmol,1.0equiv) and dichloromethane (20mL), followed by addition of B (C)₆F₅)₃(5.1mg, 0.01mmol, 5 mol%) was stirred at room temperature for 8 hours, the solvent was removed, and column chromatography gave 3ao (28.8mg, 23%) as a white solid.¹HNMR(400MHz,CD₃OD)δ7.57(t,J＝7.9Hz,2H),7.39(td,J＝7.6,1.3Hz,1H),7.33(t,J＝7.4Hz,2H),7.29(dd,J＝11.5,4.8Hz,2H),7.25–7.19(m,3H),7.13–7.10(m,2H),7.09(dd,J＝7.9,0.8Hz,1H),7.01(t,J＝7.5Hz,1H),6.96(s,1H),4.64(t,J＝6.7Hz,1H),4.52–4.45(m,2H),4.30(s,2H),3.65(dd,J＝9.4,4.5Hz,1H),3.62(s,3H),3.36(dd,J＝14.4,6.6Hz,1H),3.20(dd,J＝14.5,7.0Hz,1H),3.12(dd,J＝14.2,4.4Hz,1H),2.84(dd,J＝14.1,9.9Hz,1H),2.76–2.64(m,1H),1.78(ddd,J＝11.1,7.9,3.9Hz,1H),1.65–1.54(m,1H),1.51–1.40(m,2H),1.29(s,2H),1.00(d,J＝7.0Hz,3H).¹³C NMR(100MHz,CD₃OD)δ176.54,172.38,172.09,171.79,139.22,138.83,136.63,129.22,128.93,128.35,127.43,126.67,123.76,121.11,118.49,118.32,111.02,109.09,61.41,55.32,54.41,51.37,51.30,50.01,36.77,30.10,27.00,26.44,22.48,18.09.IR(film)3373,2978,2887,1689,1554,1390,1333,1092,1051,883,795,739.HRMS(ESI)Calcd for C₃₀H₃₉N₆O₅S₂(M+H⁺)627.2418,found 627.2420.

Example 64

Synthesis of compound 4 a:

to a solution of 6(24.0mg,0.12mmol,1.2equiv) in methanol (1mL) was added dropwise a solution of adamantanethiol (16.8mg,0.1mmol) in methanol (1mL) at-78 deg.C, reacted for 0.5 hour, the methanol was removed, and 2-mercaptopyrimidine (12.3mg,0.11mmol,1.1equiv), B (C), and₆F₅)₃(0.5mg,0.001mmol,1 mol%) and dichloromethane (1mL) for four hours, the solvent was removed and column chromatography gave 4a as a white solid (23.9mg, 70%).¹H NMR(400MHz,CDCl₃)δ8.60(d,J＝4.8Hz,2H),7.07(t,J＝4.8Hz,1H),2.04(s,3H),1.91–1.81(m,6H),1.68–1.57(m,6H).¹³C NMR(100MHz,CDCl₃)δ170.35,158.00,118.29,51.06,42.79,36.00,29.95.IR(film)2904,2848,1556,1377,1296,1167,769,742.HRMS(EI)Calcd for C₁₄H₁₈N₂S₄342.0353,found 342.0357.

Example 65

Synthesis of compound 4 b:

to a solution of 6(24.0mg,0.12mmol,1.2equiv) in methanol (1mL) at-78 deg.C was added dropwise a solution of adamantanethiol (16.8mg,0.1mmol) in methanol (1mL) to react for 0.5 h, the methanol was removed, and 2-pyrazinylethylthiol (15.4mg,0.11mmol,1.1equiv), B (C), was added₆F₅)₃(0.5mg,0.001mmol,1 mol%) and dichloromethane (1mL) were reacted for four hours, the solvent was removed, and column chromatography gave colorless liquid 4b (18.5mg, 50%).¹H NMR(400MHz,CDCl₃)δ8.46(s,2H),8.37(s,1H),3.39–3.18(m,4H),2.04(s,3H),1.85(s,6H),1.68–1.56(m,6H).¹³C NMR(100MHz,CDCl₃)δ155.02,145.09,144.27,142.76,51.13,42.77,37.70,36.02,34.69,29.94.IR(film)2972,1468,1377,1340,1097,1055,887,622.HRMS(ESI)Calcd for C₁₆H₂₃N₂S₄(M+H⁺)371.0739,found 371.0734.

Example 66

Synthesis of compound 4 c:

to a solution of 6(24.0mg,0.12mmol,1.2equiv) in methanol (1mL) was added dropwise a solution of tert-butylmercaptan (9.0mg,0.1mmol) in methanol (1mL) at-78 deg.C, reacted for 0.5 hour, the methanol was removed, and 2-mercaptopyrimidine (12.3mg,0.11mmol,1.1equiv), B (C), and₆F₅)₃(0.5mg,0.001mmol,1 mol%) and dichloromethane (1mL) for four hours, the solvent was removed and column chromatography gave 4c as a white solid (17.2mg, 65%).¹H NMR(400MHz,CDCl₃)δ8.59(d,J＝4.8Hz,2H),7.07(t,J＝4.8Hz,1H),1.35(s,9H).¹³C NMR(100MHz,CDCl₃)δ170.27,157.99,118.31,49.39,30.22.IR(film)2982,1641,1070,899,796,680,565.HRMS(ESI)Calcd for C₈H₁₃N₂S₄(M+H⁺)264.9956,found 264.9954.

Example 67

Synthesis of compound 4 d:

to a solution of 6(24.0mg,0.12mmol,1.2equiv) in methanol (1mL) at-78 deg.C, a solution of methyl acetylpenicillamine (20.5mg,0.1mmol) in methanol (1mL) was added dropwise, the reaction was carried out for 0.5 hour, the methanol was removed, and methyl acetylcysteine (19.5mg,0.11mmol,1.1equiv), B (C)₆F₅)₃(1.0mg,0.001mmol,2 mol%) and dichloromethane (1mL) for four hours, the solvent was removed and column chromatography gave 4d as a white solid (23.5mg, 53%).¹H NMR(400MHz,CDCl₃)δ6.52(dd,J＝15.2,8.0Hz,2H),4.88(dd,J＝12.4,5.3Hz,1H),4.73(d,J＝8.7Hz,1H),3.72(s,3H),3.69(s,3H),3.40(ddd,J＝42.6,14.3,5.3Hz,2H),2.01(s,3H),2.01(s,3H),1.42(s,3H),1.38(s,3H).¹³C NMR(100MHz,CDCl₃)δ170.67,170.44,170.16,170.13,58.90,53.64,52.89,52.38,52.00,40.98,26.30,24.99,23.14,23.07.IR(film)3294,2949,1740,1645,1529,1435,1371,1215,1126,1032,982,659,584.HRMS(ESI)Calcd for C₁₄H₂₅N₂O₆S₄(M+H⁺)445.0590,found 445.0595.

Example 68

Synthesis of compound 4 e:

to a solution of 6(24.0mg,0.12mmol,1.2equiv) in methanol (1mL) was added dropwise a solution of adamantanethiol (16.8mg,0.1mmol) in methanol (1mL) at-78 deg.C, reacted for 0.5 hour, the methanol was removed, and acetylcysteine methyl ester (19.5mg,0.11mmol,1.1equiv), B (C), and₆F₅)₃(1.0mg,0.001mmol,2 mol%) and dichloromethane (1mL) for four hours, the solvent was removed and column chromatography gave 4e as a white solid (21.2mg, 52%).¹H NMR(400MHz,CDCl₃)δ6.33(d,J＝7.1Hz,1H),4.89(dt,J＝7.6,5.0Hz,1H),3.72(s,3H),3.45(dd,J＝14.2,4.6Hz,1H),3.37(dd,J＝14.2,5.4Hz,1H),2.05(s,3H),2.00(s,3H),1.85(d,J＝2.3Hz,6H),1.70–1.58(m,7H).¹³C NMR(100MHz,CDCl₃)δ170.73,169.83,52.84,51.78,51.25,42.75,41.32,35.98,29.94,23.18.IR(film)3279,2904,1745,1657,1537,1450,1371,1296,1171,1038,976,684,588.HRMS(EI)Calcd for C₁₆H₂₅NO₃S₄407.0717,found 407.0713.

Example 69

Synthesis of compound 4 f:

to a solution of 6(24.0mg,0.12mmol,1.2equiv) in methanol (1mL) at-78 deg.C, a solution of adamantanethiol (16.8mg,0.1mmol) in methanol (1mL) was added dropwise, the reaction was carried out for 0.5 hour, the methanol was removed, and the tripeptide (51.8mg,0.11 mmo) was addedl,1.1equiv)，B(C₆F₅)₃(1.0mg,0.001mmol,2 mol%) and dichloromethane (1mL) were reacted for four hours, the solvent was removed, and column chromatography gave 4f (28.2mg, 40%) as a white solid.¹H NMR(400MHz,CDCl₃)δ7.69(d,J＝7.6Hz,2H),7.53(t,J＝6.6Hz,2H),7.33(t,J＝7.5Hz,2H),7.24(t,J＝7.2Hz,2H),7.07(s,1H),6.89(s,1H),5.83(dd,J＝33.6,5.8Hz,1H),4.50(s,1H),4.37(d,J＝6.0Hz,2H),4.16(t,J＝6.7Hz,1H),4.06–3.85(m,4H),3.62(s,3H),3.29(dd,J＝33.9,6.6Hz,2H),2.02(s,3H),1.84(s,6H),1.61(s,6H).¹³C NMR(100MHz,CDCl₃)δ170.58,170.40,170.09,168.79,143.65,141.33,127.82,127.13,125.11,120.05,67.51,52.38,51.38,47.15,43.19,42.85,42.69,42.54,41.12,36.00,29.87.IR(film)3572,2972,2881,1456,1419,1379,1327,1275,1088,1045,879.HRMS(ESI)Calcd for C₃₃H₄₀N₃O₆S₄(M+H⁺)702.1794,found 702.1793.

Example 70

Synthesis of Compound 4 g:

to a solution of 6(24.0mg,0.12mmol,1.2equiv) in methanol (1mL) at-78 deg.C, a solution of adamantanethiol (16.8mg,0.1mmol) in methanol (1mL) was added dropwise, the reaction was carried out for 0.5 hour, the methanol was removed, and glucosinolates (40.0mg,0.11mmol,1.1equiv), B (C), and₆F₅)₃(1.0mg,0.001mmol,2 mol%) and dichloromethane (1mL) were reacted for four hours, the solvent was removed, and column chromatography gave 4g (33.8mg, 57%) of a white solid.¹H NMR(400MHz,CDCl₃)δ5.27–5.04(m,3H),4.73(d,J＝9.5Hz,1H),4.23(dd,J＝12.4,4.7Hz,1H),4.13(dd,J＝12.4,2.2Hz,1H),3.73(ddd,J＝9.9,4.5,2.3Hz,1H),2.06(s,3H),2.03(s,3H),1.98(s,3H),1.97(s,3H),1.95(s,3H),1.85(d,J＝2.3Hz,6H),1.69–1.59(m,6H).¹³C NMR(100MHz,CDCl₃)δ170.64,170.17,169.32,169.19,88.22,76.29,73.89,69.70,68.05,61.99,51.14,42.75,35.99,29.93,20.79,20.77,20.68,20.67,20.57,20.56.IR(film)2906,2851,1747,1452,1365,1298,1211,1035,912,737,684,598.HRMS(ESI)Calcd for C₂₄H₃₄O₉S₄Na(M+Na⁺)617.0978,found 617.0970.

Example 71

Synthesis of compound 4 h:

to a solution of 6(24.0mg,0.12mmol,1.2equiv) in methanol (1mL) was added dropwise a solution of 3-triethoxysilylpropanethiol (23.8mg,0.1mmol) in methanol (1mL) at-78 deg.C, reacted for 0.5 hour, the methanol was removed, and 2-mercaptoethanol (8.6mg,0.11mmol,1.1equiv), B (C), was added₆F₅)₃(0.5mg,0.001mmol,1 mol%) and dichloromethane (1mL) for four hours, the solvent was removed and column chromatography gave a colorless liquid for 4h (16.2mg, 43%).¹HNMR(400MHz,CDCl₃)δ3.91(t,J＝5.8Hz,2H),3.76(q,J＝7.0Hz,6H),3.05(t,J＝5.8Hz,2H),2.92(t,J＝7.2Hz,2H),1.84(dt,J＝15.6,7.7Hz,2H),1.17(t,J＝7.0Hz,9H),0.73–0.66(m,2H).¹³C NMR(100MHz,CDCl₃)δ60.17,58.50,42.23,41.96,22.67,18.32,9.60.IR(film)3379,2980,1637,1089,1047,879,682,669.IR(film)3523,2980,1637,1089,1047,879,721,682,669.HRMS(ESI)Calcd for C₁₁H₂₆O₄S₄SiNa(M+H⁺)401.0375,found 401.0373.

Example 72

Synthesis of compound 4 i:

to a solution of 6(24.0mg,0.12mmol,1.2equiv) in methanol (1mL) was added dropwise a solution of n-propanethiol (7.6mg,0.1mmol) in methanol (1mL) at-78 deg.C, reacted for 0.5 hour, the methanol was removed, and allylmercaptan (8.1mg,0.11mmol,1.1equiv), B (C), and₆F₅)₃(1.0mg,0.001mmol,2 mol%) and dichloromethane (1mL) were reacted for four hours, the solvent was removed, and column chromatography gave 4i (10.2mg, 48%) as a white solid.¹H NMR(400MHz,CDCl₃)δ5.83(ddt,J＝17.2,9.9,7.3Hz,1H),5.18(dd,J＝21.3,5.5Hz,2H),3.52(d,J＝7.3Hz,2H),2.86(t,J＝7.2Hz,2H),1.80–1.66(m,2H),0.96(t,J＝7.3Hz,3H).¹³C NMR(100MHz,CDCl₃)δ132.57,119.50,42.11,41.41,22.38,13.10.IR(film)3082,2961,2928,2871,1634,1454,1377,1288,1074,1034,984,918,858,781,719,578.HRMS(EI)Calcd for C₆H₁₂S₄211.9822,found 211.9824.

The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.

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