阅读说明：本技术 一种芳环上含冠醚或硫杂冠醚结构的分子中芳香甲硫基转化为二硫键的方法 (Method for converting aromatic methylthio in molecule containing crown ether or thia crown ether structure on aromatic ring into disulfide bond ) 是由 孔建飞 李明梅 蒋立英 童珊珊 张立虎 石云 于 2019-10-08 设计创作，主要内容包括：本发明公开一种芳环上含冠醚或硫杂冠醚结构的分子中芳香甲硫基转化为二硫键的方法,该方法包括：在第一有机溶剂存在下,将式Ⅰ所示化合物和间氯过氧苯甲酸湿固体进行接触反应,过滤得到滤液；将滤液与三氟乙酸进行接触反应,然后加热去除第一有机溶剂、水和过量的三氟乙酸,冷却后加入氨-氯化铵缓冲溶液,搅拌混合,过滤得到固体；在第一有机溶剂和任选的第二有机溶剂的存在下,将固体与氧化剂进行氧化反应,得到式Ⅱ化合物；其中,R为吡啶基或三联砒啶基,X为氧原子或硫原子。本发明的方法可以连续进行,无需对中间产物进行分离提纯,关键环节使用微波反应,经验证有效提高了反应效率,并避免柱层析操作,总体产率大于40％。<Image he="154" wi="700" file="DDA0002225502790000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a method for converting aromatic methylthio in molecules containing crown ether or thia crown ether structures on aromatic rings into disulfide bonds, which comprises the following steps: in the presence of a first organic solvent, carrying out contact reaction on a compound shown as a formula I and wet m-chloroperoxybenzoic acid solid, and filtering to obtain a filtrate; carrying out contact reaction on the filtrate and trifluoroacetic acid, then heating to remove the first organic solvent, water and excessive trifluoroacetic acid, cooling, adding ammonia-ammonium chloride buffer solution, stirring and mixing, and filtering to obtain a solid; carrying out oxidation reaction on the solid and an oxidant in the presence of a first organic solvent and an optional second organic solvent to obtain a compound shown in a formula II; wherein R is pyridyl or terpyridyl, and X is oxygen atom or sulfur atom. The method can be continuously carried out, the intermediate product does not need to be separated and purified, the microwave reaction is used in a key link, the reaction efficiency is effectively improved through verification, the column chromatography operation is avoided, and the total yield is more than 40%.)

1. A method for converting an aromatic methylthio group in a molecule having a crown ether or thiacrown ether structure in an aromatic ring into a disulfide bond, comprising:

(1) in the presence of a first organic solvent, carrying out contact reaction on a compound shown as a formula I and wet m-chloroperoxybenzoic acid solid, and filtering to obtain a filtrate;

(2) carrying out contact reaction on the filtrate and trifluoroacetic acid, then heating to remove the first organic solvent, water and excessive trifluoroacetic acid, cooling, adding an ammonia-ammonium chloride buffer solution, stirring and mixing, and filtering to obtain a solid;

(3) carrying out oxidation reaction on the solid and an oxidant in the presence of the first organic solvent and an optional second organic solvent to obtain a compound shown as a formula II;

wherein R is pyridyl or terpyridyl, and X is oxygen atom or sulfur atom.

2. The process of claim 1, wherein in step (1), the first organic solvent is dichloromethane.

3. The method according to claim 1, wherein in the step (2), the contact reaction is carried out by adding the trifluoroacetic acid into the filtrate and carrying out a microwave reaction in a microwave reactor.

4. The method as claimed in claim 1, wherein the power of the microwave reactor is 150-300W, and the microwave frequency is 2200-2500 MHz.

5. The method according to claim 1, wherein in the step (2), the temperature of the contact reaction is 45-55 ℃ and the reaction time is 5-30 min.

6. The method according to claim 1, wherein, in the step (2), the cooling is to 0 to-2 ℃; the pH value of the ammonia-ammonium chloride buffer solution is 8-10.

7. The method according to claim 1, wherein in the step (3), the oxidant is hydrogen peroxide or air.

8. The method according to claim 1, wherein the temperature of the oxidation reaction in step (3) is 40-50 ℃.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for converting aromatic methylthio into disulfide bond in molecules containing crown ether or thia-crown ether structures on aromatic rings.

Background

In the field of biochemistry, disulfide bonds are chemical bonds that link different peptide chains or different portions of the same peptide chain. It is formed by sulfur-containing amino acid, is a relatively stable covalent bond, can stabilize the spatial structure of a peptide chain, and plays an important role in the formation of the three-dimensional structure of a protein molecule [ Zhao Xinhuai. Scientific press 2009 ]. Thus, the formation and opening of disulfide bonds plays a key role in understanding the higher order structure of protein molecules and in achieving the regulation of certain important biological functions.

In the chemical related field, the construction of disulfide bond also has wide application value. For example, in the direction of synthesizing the medicament, preparing an intermediate containing a disulfide bond, and further producing medicaments such as desmopressin, oxytocin, terlipressin, somatostatin, calcitonin, efaction peptide and the like; in the electrochemical direction, the gold or glassy carbon electrode modified by disulfide bonds can form various modified electrodes which are highly ordered and thermodynamically stable, and show great advantages in the aspects of electrochemical sensing, catalysis and the like [ C.K.Cheng, C.H.Lin, H.C.Wu, Nanoscale Research Letters,2016,11,117 ]; in the polymer direction, the self-repairing polymer material based on disulfide bonds has made remarkable research progress in recent years [ xu xing wang, shengwei, liu jiali, guangdong chemical industry, 2017,44(11),124 ]; in addition, designing a molecular switch containing a disulfide bond and adjusting energy transfer between molecules or within molecules, electron transfer, and the like by redox reaction is also a leading direction of research which is currently attracting attention.

Crown ethers, on the other hand, have been reported since 1965 as an important class of macrocyclic compounds (and thiacrown ethers) that have shown irreplaceable effects in the fields of host-guest recognition, sol-gel, phase transfer catalysis, etc. due to their unique structural morphology and properties, such as selective complexation with alkali metal ions, etc. The crown ether structure and the disulfide bond are combined to form a novel molecular structural unit, and the novel molecular structural unit brings huge potential application values in the aspects of novel molecular switches, molecular recognition, interface catalysis and the like.

Due to the instability of sulfhydryl, it is often converted into methylthio for protection during synthesis and storage, and oxidized into disulfide bond by appropriate method during use. Methods for converting methylthio groups into disulfide bonds are reported in the literature, but are almost limited to cases where aromatic rings carry common activating groups such as alkyl or aromatic groups, such as the reaction of alkylthiophenes with corresponding azide compounds, and a mixed product containing disulfide bonds and monosulfur bonds can be obtained, and the method is applicable to structures without other substituents on benzene rings [ H.Takeuchi, T.yanase, K.Itou, J.chem.Soc.chem.Commun.,1992,916 ]; for 4-methylthiophenylpyridine, heating with sodium tert-butylmercaptide in freshly distilled DMF to 170 ℃ for 48h, sealing and reacting to obtain a corresponding sulfhydryl compound, and oxidizing to form a disulfide bond [ M.A. Bartucci, P.M. Wierzbicki, C.Gwengo, Tetrahedron Letters,2010,51,6839 ]; lithiation at a low temperature of 77K, followed by reaction with dimethyl disulfide, can produce a disulfide compound of a specific structure [ j.p. dunne, m.bockmeye, m.ticket, eur.j. incorg.chem., 2003,458 ]; some organic sulfides can be removed by heating for 10-40h under the Catalysis of K10 montmorillonite, so that disulfide compounds containing aromatic structures can be formed, but the reaction is difficult when passivation groups such as nitro, carboxyl and the like exist on a benzene ring [ K.P.Naicker, A.Lalitha, K.Pitchumani, Catalysis Letters,1998,56,237 ]. For example, few reports are reported in the literature that can be retrieved at present for the conversion of methylthio groups to disulfide bonds in molecules containing crown ether structures.

Disclosure of Invention

The object of the present invention is to provide a method applicable to the conversion of a methylthio group having a crown ether or thiacrown ether structure into a disulfide bond, so that a methylthio group on an aromatic ring having a crown ether or thiacrown ether structure can be converted into a disulfide bond.

In order to achieve the above object, the present invention provides a method for converting an aromatic methylthio group in a molecule having a crown ether or thiacrown ether structure on an aromatic ring into a disulfide bond, the method comprising:

(1) in the presence of a first organic solvent, carrying out contact reaction on a compound shown as a formula I and wet m-chloroperoxybenzoic acid solid, and filtering to obtain a filtrate;

(2) carrying out contact reaction on the filtrate and trifluoroacetic acid, then heating to remove the first organic solvent, water and excessive trifluoroacetic acid, cooling, adding an ammonia-ammonium chloride buffer solution, stirring and mixing, and filtering to obtain a solid;

(3) carrying out oxidation reaction on the solid and an oxidant in the presence of the first organic solvent and an optional second organic solvent to obtain a compound shown as a formula II;

wherein R is pyridyl or terpyridyl, and X is oxygen atom or sulfur atom.

The technical scheme of the invention has the following advantages:

the method can be continuously carried out, the intermediate product does not need to be separated and purified, the microwave reaction is used in the key link, the reaction efficiency is effectively improved through verification, the column chromatography operation is avoided, the method is suitable for the condition that the aromatic ring of the methylthio group contains the passivating groups such as crown ether, pyridyl and the like, the reaction condition is mild, the total time is only 2-5 hours, and the total yield is more than 40%. From the comparison of the nuclear magnetic spectra of the starting material and the product, the methylthio signal at δ ═ 2.07 completely disappeared after the reaction, confirming that the reaction was complete.

Additional features and advantages of the invention will be set forth in the detailed description which follows.

Detailed Description

Preferred embodiments of the present invention will be described in more detail below. While the following describes preferred embodiments of the present invention, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

The invention provides a method for converting aromatic methylthio in a molecule containing crown ether or thiacrown ether structure on an aromatic ring into a disulfide bond, which comprises the following steps:

(1) in the presence of a first organic solvent, carrying out contact reaction on a compound shown as a formula I and wet m-chloroperoxybenzoic acid solid, and filtering to obtain a filtrate;

(2) carrying out contact reaction on the filtrate and trifluoroacetic acid, then heating to remove the first organic solvent, water and excessive trifluoroacetic acid, cooling, adding an ammonia-ammonium chloride buffer solution, stirring and mixing, and filtering to obtain a solid;

(3) carrying out oxidation reaction on the solid and an oxidant in the presence of the first organic solvent and an optional second organic solvent to obtain a compound shown as a formula II;

wherein R is pyridyl or terpyridyl, and X is oxygen atom or sulfur atom.

The formation of disulfide bonds from methylthio belongs to conventional reactions, and has various reaction paths, but for the condition that crown ether or thia crown ether groups exist on an aromatic ring where methylthio is located, the molecular activity is low, so that most methods can not carry out the reaction through practical verification; however, the inventors of the present application have found, through research, a method for converting an aromatic methylthio group in a molecule having a crown ether or thiacrown ether structure in an aromatic ring into a disulfide bond; the method adopts m-chloroperoxybenzoic acid-trifluoroacetic acid (microwave) to continuously treat reactants so as to realize the conversion of a methyl sulfide group to a sulfhydryl group and oxidize the reactants under mild conditions to form a disulfide bond. The method can be continuously carried out, the intermediate product does not need to be separated and purified, the microwave reaction is used in the key link, the reaction efficiency is effectively improved through verification, the column chromatography operation is avoided, the method is suitable for the condition that the aromatic ring of the methylthio group contains the passivating groups such as crown ether, pyridyl and the like, the reaction condition is mild, the total time is only 2-5 hours, and the total yield is more than 40%. From the comparison of the nuclear magnetic spectra of the starting material and the product, the methylthio signal at δ ═ 2.07 completely disappeared after the reaction, confirming that the reaction was complete.

The method is characterized in that aiming at the condition that crown ether or thia crown ether exists on a benzene ring where methylthio is located, a strong oxidant (m-chloroperoxybenzoic acid) is used for oxidizing the methylthio into methyl sulfoxide, the product is not required to be separated and purified, only filtrate is directly subjected to microwave reaction with trifluoroacetic acid for 5-30min, the solvent and excessive acid are removed and then mixed with ammonia-ammonium chloride buffer solution, the mixture is filtered to obtain solid containing sulfhydryl, and finally the solid is oxidized in air or treated by an oxidant (such as hydrogen peroxide and the like) to obtain a target product. The total reaction time is 2-5h, and the yield after recrystallization is over 40 percent.

In the present invention, the wet meta-chloroperoxybenzoic acid solid is commercially available; because the pure m-chloroperoxybenzoic acid is unstable and easy to explode, the general commercially available product is the wet m-chloroperoxybenzoic acid solid, and the mass concentration of the m-chloroperoxybenzoic acid in the wet m-chloroperoxybenzoic acid solid used in the invention is 50-55%. In the present invention, in the step (2), the removal of water in the first organic solvent, water and excess trifluoroacetic acid by heating is conducted by using m-chloroperoxybenzoic acid wet solid.

According to the present invention, preferably, in step (1), the first organic solvent is dichloromethane.

In the present invention, the molar ratio of the compound represented by the formula I to m-chloroperoxybenzoic acid is preferably 1: 2.

According to the present invention, preferably, in the step (2), the contact reaction is to add the trifluoroacetic acid to the filtrate, and the microwave reaction is performed in a microwave reactor.

According to the invention, the power of the microwave reactor is preferably 150-300W, and the microwave frequency is 2200-2500 MHz.

According to the present invention, preferably, in the step (2), the temperature of the contact reaction is 45 to 55 ℃ and the reaction time is 5 to 30 min.

According to the present invention, preferably, in the step (2), the cooling is to 0 to-2 ℃; the pH value of the ammonia-ammonium chloride buffer solution is 8-10.

According to the present invention, preferably, in step (3), the oxidant is hydrogen peroxide or air.

In the invention, when the oxidant is air, only one organic solvent, namely the first organic solvent is used in the step (3), and the first organic solvent is dichloromethane; when the oxidant is hydrogen peroxide, two organic solvents, namely a first organic solvent and a second organic solvent, are used in the step (3), and the second organic solvent is methanol and is used for diluting the hydrogen peroxide.

In the invention, the mass concentration of the hydrogen peroxide is preferably 20-40%.

According to the present invention, preferably, in the step (3), the temperature of the oxidation reaction is 40 to 50 ℃.

The invention is further illustrated by the following examples: