CN110698496A - A method for converting aromatic methylthio group into disulfide bond in molecule containing crown ether or thiacrown ether structure on aromatic ring - Google Patents

Abstract

The invention discloses a method for converting an aromatic methylthio group into a disulfide bond in a molecule containing a crown ether or thiacrown ether structure on an aromatic ring. The method comprises: in the presence of a first organic solvent, compound the compound represented by formula I Carry out contact reaction with m-chloroperoxybenzoic acid wet solid, filter to obtain filtrate; carry out contact reaction with filtrate and trifluoroacetic acid, then remove the first organic solvent, water and excessive trifluoroacetic acid by heating, add ammonia-chlorination after cooling ammonium buffer solution, stirring and mixing, filtering to obtain solid; in the presence of the first organic solvent and optional second organic solvent, the solid is oxidized with an oxidant to obtain a compound of formula II; wherein, R is pyridyl or arsenic In the pyridyl group, X is an oxygen atom or a sulfur atom. The method of the invention can be carried out continuously without separating and purifying intermediate products, and the key link uses microwave reaction, which has been verified to effectively improve the reaction efficiency, avoid column chromatography operation, and the overall yield is greater than 40%.

Description

A kind of in-molecular aromatic methylthio conversion containing crown ether or thia crown ether structure on aromatic ring method for disulfide bonds

technical field

The invention belongs to the technical field of organic synthesis, and more particularly relates to a method for converting an aromatic methylthio group into a disulfide bond in a molecule containing a crown ether or thiacrown ether structure on an aromatic ring.

Background technique

In the field of biochemistry, disulfide bonds are chemical bonds that connect different peptide chains or different parts of the same peptide chain. It is formed by sulfur-containing amino acids and is a relatively stable covalent bond, which can stabilize the spatial structure of the peptide chain and play an important role in the formation of the three-dimensional structure of protein molecules [Zhao Xinhuai. Food Protein-Structure, Properties and Functions: Science Press, 2009]. Therefore, the formation and opening of disulfide bonds play a key role in understanding the higher-order structure of protein molecules and realizing the regulation of some important biological functions.

In chemical-related fields, the construction of disulfide bonds also has extensive application value. For example, in the direction of synthetic drugs, the preparation of intermediates containing disulfide bonds, and further production of desmopressin, oxytocin, teripressin, somatostatin, calcitonin, ephitide and other drugs; Modification of gold or glassy carbon electrodes with disulfide bonds can form a variety of highly ordered and thermodynamically stable modified electrodes, showing great advantages in electrochemical sensing and catalysis [C.K.Cheng, C.H.Lin, H.C.Wu, Nanoscale Research Letters, 2016, 11, 117.]; In the direction of polymers, self-healing polymer materials based on disulfide bonds have made significant research progress in recent years [Xu Xingwang, Shen Wei, Liu Jiali. Guangdong Chemical Industry, 2017, 44(11), 124.]; In addition, designing molecular switches containing disulfide bonds to regulate intermolecular or intramolecular energy transfer, electron transfer, etc. through redox reactions is also an attractive frontier research direction.

On the other hand, since crown ethers were reported in 1965, as an important class of macrocyclic compounds (and thiacrown ethers), due to their unique structural forms and properties, such as selective complexation with alkali metal ions, etc. It has shown irreplaceable roles in the fields of host-guest recognition, sol-gel, and phase transfer catalysis. Combining the structure of crown ethers with the construction of disulfide bonds may form novel molecular structural units and bring great potential application value in novel molecular switches, molecular recognition, and interface catalysis.

Due to the instability of the sulfhydryl group, it is often converted into a methylthio group for protection during synthesis and storage, and then oxidized to a disulfide bond by an appropriate method during use. There are many reports on the method of converting a methylthio group into a disulfide bond, but almost all of them are limited to the case where the aromatic ring has a common activating group such as an alkyl group or an aryl group, such as alkyl phenyl sulfide and the corresponding stack. Nitrogen compounds can be reacted to obtain mixed products containing disulfide bonds and monosulfide bonds, which are suitable for structures without other substituents on the benzene ring [H.Takeuchi,T.Yanase,K.Itou,J.Chem.Soc.Chem. Commun., 1992, 916.]; For 4-methylthiophenylpyridine, heat it with sodium tert-butyl mercaptan in freshly distilled DMF to 170°C for 48h tube-sealing reaction to obtain the corresponding sulfhydryl compound, and then carry out Oxidation can form disulfide bonds [M.A.Bartucci, P.M.Wierzbicki, C.Gwengo, Tetrahedron Letters, 2010, 51, 6839.]; lithiation at a low temperature of 77K, and then react with dimethyl disulfide to prepare disulfides of specific structures Sulfur compounds [J.P.Dunne, M.Bockmeyer, M.Tacke, Eur.J.Inorg.Chem., 2003, 458.]; when heated for 10-40h under the catalysis of K10 montmorillonite, some organic sulfides can be removed Alkyl group, thus forming disulfide compounds containing aromatic structures, but it is difficult to react when there are passivation groups such as nitro and carboxyl groups on the benzene ring [K.P.Naicker, A.Lalitha, K.Pitchumani, Catalysis Letters, 1998 , 56, 237.]. For example, the method of converting methylthio groups into disulfide bonds in molecules containing crown ether structures is rarely reported in the literature that can be retrieved at present.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a method that is applicable to the conversion of methylthio groups containing crown ether or thiacrown ether structures into disulfide bonds, so that methylthio groups on aromatic rings containing crown ether or thiacrown ether structures are can be converted into disulfide bonds.

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

(1) in the presence of the first organic solvent, the compound shown in formula I and the wet solid of m-chloroperoxybenzoic acid are carried out contact reaction, and the filtrate is obtained by filtration;

(2) the filtrate is contacted with trifluoroacetic acid, then heated to remove the first organic solvent, water and excessive trifluoroacetic acid, after cooling, add ammonia-ammonium chloride buffer solution, stir and mix, filter to obtain solid ;

(3) in the presence of the first organic solvent and the optional second organic solvent, the solid is subjected to an oxidation reaction with an oxidant to obtain a compound represented by formula II;

Wherein, R is a pyridyl group or a tripyridine group, and X is an oxygen atom or a sulfur atom.

The technical scheme of the present invention has the following advantages:

The method of the invention can be carried out continuously without the need to separate and purify the intermediate products. The microwave reaction is used in the key link. It has been verified that the reaction efficiency is effectively improved, and the column chromatography operation is avoided. In the case of passivation groups such as , pyridyl, etc., the reaction conditions are relatively mild, the total time is only 2-5 hours, and the overall yield is greater than 40%. From the comparison of the NMR spectra of the starting material and the product, the methylthio signal at δ=2.07 disappeared completely after the reaction, which confirmed that the reaction was completed.

Other features and advantages of the present invention will be described in detail in the detailed description that follows.

Detailed ways

Preferred embodiments of the present invention will be described in more detail below. While the preferred embodiments of the present invention are described below, 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 present invention to those skilled in the art.

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

(1) in the presence of the first organic solvent, the compound shown in formula I and the wet solid of m-chloroperoxybenzoic acid are carried out contact reaction, and the filtrate is obtained by filtration;

(2) the filtrate is contacted with trifluoroacetic acid, then heated to remove the first organic solvent, water and excessive trifluoroacetic acid, after cooling, add ammonia-ammonium chloride buffer solution, stir and mix, filter to obtain solid ;

(3) in the presence of the first organic solvent and the optional second organic solvent, the solid is subjected to an oxidation reaction with an oxidant to obtain a compound represented by formula II;

Wherein, R is a pyridyl group or a tripyridine group, and X is an oxygen atom or a sulfur atom.

The formation of disulfide bonds from methylthio groups is a conventional reaction, and there are various reaction paths. However, for the case where there are crown ether or thia crown ether groups on the aromatic ring where the methylthio group is located, due to the low molecular activity, it has been verified by practice. Most of the methods cannot make the reaction proceed; however, the inventor of the present application, through research, has found a method for converting an aromatic methylthio group into a disulfide bond in a molecule containing a crown ether or thiacrown ether structure on an aromatic ring; The method of the invention adopts m-chloroperoxybenzoic acid-trifluoroacetic acid (microwave) to continuously treat the reactants to realize the conversion of methylthio group to sulfhydryl group, and oxidize to form disulfide bond under mild conditions. The method of the invention can be carried out continuously without the need to separate and purify the intermediate products. The microwave reaction is used in the key link. It has been verified that the reaction efficiency is effectively improved, and the column chromatography operation is avoided. In the case of passivation groups such as , pyridyl, etc., the reaction conditions are relatively mild, the total time is only 2-5 hours, and the overall yield is greater than 40%. From the comparison of the NMR spectra of the starting material and the product, the methylthio signal at δ=2.07 disappeared completely after the reaction, which confirmed that the reaction was completed.

The method of the present invention, as shown in the above formula a, the main point is to use a strong oxidant (m-chloroperoxybenzoic acid) to oxidize the methylthio group first to the situation that there is a crown ether or a thia crown ether on the benzene ring where the methylthio group is located It is a methyl sulfoxide group, and the product does not need to be separated and purified. Only the filtrate is directly subjected to microwave reaction with trifluoroacetic acid for 5-30 minutes, the solvent and excess acid are removed, and then mixed with ammonia-ammonium chloride buffer solution. The solid is finally oxidized in the air or treated with an oxidant (such as hydrogen peroxide, etc.) to obtain the target product. The overall reaction time is 2-5h, and the yield after recrystallization is over 40%.

In the present invention, the wet solid of m-chloroperoxybenzoic acid is obtained commercially; because the pure product of m-chloroperoxybenzoic acid is unstable and easy to explode, the generally commercially obtained product is the wet solid of m-chloroperoxybenzoic acid. The mass concentration of the used meta-chloroperoxybenzoic acid wet solid meta-chloroperoxybenzoic acid is 50-55%. In the present invention, in step (2), heating to remove the water in the first organic solvent, water and excess trifluoroacetic acid is introduced from the wet solids of m-chloroperoxybenzoic acid.

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 step (2), the contact reaction is to add the trifluoroacetic acid to the filtrate, and perform a microwave reaction in a microwave reactor.

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

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

According to the present invention, preferably, in step (2), the cooling is cooling to 0 to -2° C.; the pH 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 present invention, when the oxidant is air, only one organic solvent is used in step (3), namely the first organic solvent, and the first organic solvent is dichloromethane; when the oxidant is hydrogen peroxide, in step (3) Two organic solvents are used, namely a first organic solvent and a second organic solvent, and the second organic solvent is methanol for diluting hydrogen peroxide.

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

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

The present invention is further illustrated below by embodiment:

Example 1

Preparation of starting material (compound shown in formula I, R is pyridyl, X is O) (12): as shown in formula b, 300 ml of freshly distilled N,N-dimethylform was added to a 500 ml three-necked round-bottomed flask 4-bromo-2,6-dimethylphenol (1) (30 g, 150 mmol) was added, cooled to 0° C. with an ice-water bath, and sodium hydride (60%, 8.3 g was added 5 times under nitrogen protection) , 200 mmol), kept at 0 °C for 1 h, added dimethylaminothiocarbonyl chloride (22 g, 180 mmol), heated to 100 °C and reacted for 8 h, the reaction mixture was cooled to room temperature and poured into 300 ml of ice water, and the resulting brown solid was filtered out, recrystallized 3 times in ethanol to obtain compound (2) 32.2 g, yield 75%; put compound (2) (20 g, 70 mmol) in a 250 ml single-necked flask, add 50 ml of diphenyl ether, heat under reflux for 4 h, The diphenyl ether was evaporated under reduced pressure, and the residue was subjected to column chromatography on a silica gel column (the mobile phase was a mixed solvent of petroleum ether:dichloromethane=5:1) to obtain 11 g of compound (3) in a yield of 55%; Compound (3) (10g, 35mmol) was added to a 250ml two-necked flask, 60ml of methanol was added, sodium hydroxide (3.6g, 90mmol) was added, heated to reflux for 5h, cooled to room temperature, and iodomethane (5.3ml, 87mmol) was added, The reaction was kept at room temperature for 8h, 150ml of deionized water was added, extracted with dichloromethane (60ml×3), and the compound (4) was obtained by distillation under reduced pressure as a pale yellow oil 7.07g, with a yield of 94%; the compound (4) ( 10g, 43.5mmol) was dissolved in 120ml of benzoin and placed in a 250ml double-necked flask, N-bromosuccinimide (21g, 109mmol) was added, 0.3g of azobisisobutyronitrile was added as a catalyst, and under nitrogen protection and The reaction was refluxed for 5 hours under light conditions, then cooled to room temperature, filtered, the filtrate was washed with an aqueous solution of sodium thiosulfate, the organic phase was spin-dried, and recrystallized in ethanol to obtain compound (5) as a white solid 6.6 g, yield 38% ; The metal sodium (1.5g, 65mmol) was cut into pieces and added to 100ml of diethylene glycol, heated at 40°C for 1h to completely dissolve the sodium, added compound (5) (5g, 13mmol), heated to 100°C and reacted for 8h, cooled After reaching room temperature, 200 ml of deionized water was added, and extracted with dichloromethane (150 ml × 3). The combined organic phases were washed 8 times with water, and the compound (6) was obtained by column chromatography (silica gel as the stationary phase and ethyl acetate as the mobile phase). ) was light yellow oil 5.12g, yield 96%; sodium hydride (0.16g, 6.8mmol) was placed in a 250ml three-necked flask, 100ml of freshly steamed tetrahydrofuran was added, compound (5) (0.9g, 2.28mmol) and Compound (6) (1.0 g, 2.28 mmol) was dissolved in 10 ml of freshly distilled tetrahydrofuran and separated into two dropping funnels. Under nitrogen protection, ( 5) The tetrahydrofuran solution of (6) was added dropwise to the three-necked flask simultaneously at the same speed, heated to reflux, reacted for 8 h, cooled to room temperature and then rotated to dry the solvent, and the solvent was dried by column chromatography (silica gel was the stationary phase and ethyl acetate was the mobile phase) ) to obtain compound (8) as a white solid 0.55g, with a yield of 36%; compound (8) (0.5g, 0.75mmol) was placed in a 100ml two-necked flask, 50ml of freshly steamed tetrahydrofuran was added, cooled to -78 ° C, nitrogen protection Add n-butyllithium (0.9M n-hexane solution, 1.8ml, 1.65mmol), add tri-tert-butylboronic acid (0.41ml, 1.51mmol) after 0.5h, continue to react at -78°C for 6h, add hydrochloric acid (2M , 2.6ml, 5.25mmol), reacted at room temperature for 8h, added 20ml of deionized water, and extracted with dichloromethane (4x 60ml), the organic phases were combined and then extracted with sodium hydroxide solution (2M, 4x2ml), to the combined after 2M hydrochloric acid was added dropwise to the sodium hydroxide solution, and the white precipitate that appeared was filtered, washed with water, and dried to obtain compound (10) 0.29 g, yield 60%; compound (10) (66 mg, 0.11 mmol) and 4-bromopyridinium salt The acid salt (62mg, 0.32mmol) was placed in a 25ml two-necked flask, potassium carbonate aqueous solution (150mg dissolved in 1ml water), 0.5ml ethanol, and 15ml freshly distilled toluene was added, 20mg tetrakis(triphenylphosphine) was added under nitrogen protection ) palladium catalyst, heated to reflux for 10h, cooled to room temperature and extracted with toluene (2×10ml), the combined organic phases were washed with water, spin-dried, and recrystallized in dichloromethane to obtain the starting material (12) as a white solid 54mg , the yield is 63%. ¹ H NMR (CDCl ₃ ): δ 2.03 (s, 6H, -SCH ₃ ), 3.78 (s, 16H, O-CH ₂ CH ₂ -O), 4.81 (s, 8H, Ph-CH ₂ -O) , 7.42 (d, J=6.0 Hz, 4H, py), 7.68 (s, 4H, -Ph), 8.59 (d, J=6.2 Hz, 4H, py).

The starting material (the compound represented by formula I, R is pyridyl, X is O) 2.4 g (3.64 mmol) was dissolved in 150 ml of dichloromethane, cooled to 0 °C with an ice-water bath, and m-chloroperoxide was added three times within 15 min. Oxybenzoic acid wet solid (the mass concentration of m-chloroperoxybenzoic acid is 50-55%) 2.44g (7.30mmol, this molar mass is calculated according to the mass concentration of m-chloroperoxybenzoic acid is 52.5%), warming up to Stir at 28°C for 30 min and filter to obtain a filtrate.

Add 20 ml of trifluoroacetic acid to the filtrate, place it in an XH-MC-1 microwave reactor, set a power of 300W, and conduct microwave reaction at 50°C and a frequency of 2450MHz for 30min. Dichloromethane, water and excess trifluoroacetic acid were evaporated under reduced pressure, placed in an ice-water bath and cooled to 0°C, added with pH=10, 30 ml of ammonia-ammonium chloride buffer solution with a concentration of 2M, stirred for 10 min, and filtered to obtain a solid .

The solid was dissolved in 80 ml of dichloromethane. Dissolve 0.6 ml of hydrogen peroxide (30% by mass) in 10 ml of methanol, add the above solution dropwise, stir at 45° C. for 1 h, spin dry, and wash the obtained solid with ethanol. Recrystallization in a dichloromethane-ethanol mixed solution gave 1.07 g of the target product (the compound represented by formula II, where R is a pyridyl group, and X is O) with a yield of 46.2%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 3.75-3.86 (m, 16H, O-CH ₂ CH ₂ -O), 4.88 (m, 8H, Ph-CH ₂ -O), 7.57 (d, J=6.1 Hz, 4H, py), 7.76 (s, 4H, -Ph), 8.64 (d, J=5.2 Hz, 4H, py). Mass spectrum: 634 (M+H ⁺ ). Elemental Analysis: Calculated C 64.53%, H 5.73%, N 4.43%, Measured C 64.15%, H 5.33%, N 4.41%.

Example 2

Preparation of starting material (compound represented by formula I, R is pyridyl, X is S) (13): as shown in formula b, the preparation steps to compound (5) are the same as in the aforementioned preparation of starting material (12) ; The metal sodium (1.5g, 65mmol) was cut into pieces and added to 100ml of thiodiethylene thiol, heated at 40°C for 1h to completely dissolve the sodium, added compound (5) (5g, 13mmol), heated to 100°C to react 10h, cooled to room temperature, added 200ml of deionized water, extracted with dichloromethane (150ml×3), the combined organic phase was washed 8 times with water, and obtained by column chromatography (silica gel as the stationary phase and ethyl acetate as the mobile phase) Compound (7) is light yellow oil 6.11g, yield 94%; put sodium hydride (0.16g, 6.8mmol) in a 250ml three-necked flask, add 100ml of freshly steamed tetrahydrofuran, compound (5) (0.74g, 1.87 mmol) and compound (7) (1.0 g, 1.87 mmol) were each dissolved in 10 ml of freshly distilled tetrahydrofuran and separated into two dropping funnels. The speed was added dropwise into the three-necked flask at the same time, heated to reflux, reacted for 10h, cooled to room temperature, and then spin-dried the solvent, through column chromatography (silica gel as the stationary phase, ethyl acetate as the mobile phase) to obtain compound (9) as a white solid 0.54g, Yield 38%; compound (9) (0.57g, 0.75mmol) was placed in a 100ml two-necked flask, 50ml of freshly distilled tetrahydrofuran was added, cooled to -78°C, and n-butyllithium (0.9M of n-hexane was added under nitrogen protection) solution, 1.8ml, 1.65mmol), added tri-tert-butylboronic acid (0.41ml, 1.51mmol) after 0.5h, continued to react at -78°C for 5h, added hydrochloric acid (2M, 2.6ml, 5.25mmol), and reacted at room temperature for 8h, 20ml of deionized water was added and extracted with dichloromethane (4x 60ml), the organic phases were combined and extracted with sodium hydroxide solution (2M, 4x2ml), 2M hydrochloric acid was added dropwise to the combined sodium hydroxide solution, The resulting pale yellow precipitate was filtered, washed with water, and dried to obtain compound (11) 0.33 g, yield 64%; compound (11) (83 mg, 0.12 mmol) and 4-bromopyridine hydrochloride (62 mg, 0.32 mmol) were placed in 25 ml In the two-necked flask, add potassium carbonate aqueous solution (150mg dissolved in 1ml water), 0.5ml ethanol, and 15ml freshly distilled toluene, add 20mg tetrakis(triphenylphosphine) palladium catalyst under nitrogen protection, heat under reflux for 10h, and cool to room temperature After extraction with toluene (2×10 ml), the combined organic phases were washed with water, spin-dried, and recrystallized in dichloromethane to obtain the starting material (13) as a pale yellow solid 60 mg with a yield of 61%. ¹ H NMR (CDCl ₃ ): δ 2.01 (s, 6H, -SCH ₃ ), 2.80 (s, 16H, S-CH ₂ CH ₂ -S), 3.84 (s, 8H, Ph-CH ₂ -S) , 7.40 (d, J=6.0 Hz, 4H, py), 7.69 (s, 4H, -Ph), 8.61 (d, J=6.2 Hz, 4H, py).

The starting material (the compound represented by formula I, R is pyridyl, X is S) 70 mg (0.092 mmol) was dissolved in 6 ml of dichloromethane, cooled to 0 °C with an ice-water bath, and m-chloroperoxygen was added in three portions within 15 min. Benzoic acid wet solid (the mass concentration of m-chloroperoxybenzoic acid is 50-55%) 62mg (0.185mmol, this molar mass is calculated according to the mass concentration of m-chloroperoxybenzoic acid is 52.5%), be warming up to 28 ℃ Stir for 30 min and filter to obtain a filtrate.

Add 2ml of trifluoroacetic acid to the filtrate, place it in the XH-MC-1 type microwave reactor, and place a conical flask containing 50ml of water as a microwave absorber, set the power to 150W, and microwave at 50°C and a frequency of 2450MHz. The reaction was carried out for 5 minutes. Dichloromethane, water and excess trifluoroacetic acid were evaporated under reduced pressure, placed in an ice-water bath and cooled to 0°C, added with pH=10, 5ml of ammonia-ammonium chloride buffer solution with a concentration of 2M, stirred for 10min, and filtered to obtain a solid .

The solid was dissolved in 10 ml of dichloromethane, refluxed in air at 45° C. for 4 h, the organic phase was spin-dried, and washed with ethanol. Then, it was recrystallized in a dichloromethane-ethanol mixed solution to obtain 33 mg of the target product (the compound represented by formula II, where R is pyridyl, and X is S) with a yield of 48.5%. ¹ H NMR (600 MHz, CDCl ₃ ) δ 2.76-2.85 (m, 16H, S-CH ₂ CH ₂ -S), 3.90 (m, 8H, Ph-CH ₂ -S), 7.55 (d, J=6.1 Hz, 4H, py), 7.77 (s, 4H, -Ph), 8.62 (d, J=5.2 Hz, 4H, py). Mass spectrum: 730 (M+H ⁺ ). Elemental Analysis: Calculated C 56.00%, H 4.98%, N 3.84%, Measured C 55.69%, H 4.93%, N 3.82%.

Example 3

Preparation of starting material (compound represented by formula I, R is terpyridyl, X is O) (14): as shown in formula b, the preparation step of compound (10) is the same as the above-mentioned preparation of starting material (12) The same; compound (10) (66mg, 0.11mmol) and 4-bromoterpyridine (100mg, 0.33mmol) were placed in a 25ml two-necked flask, potassium carbonate aqueous solution (150mg dissolved in 1ml water), 0.5ml ethanol, and 15ml fresh The evaporated toluene was added with 20 mg of tetrakis(triphenylphosphine) palladium catalyst under the protection of nitrogen, heated to reflux for 10 h, cooled to room temperature and extracted with toluene (2 × 10 ml), the combined organic phases were washed with water and then spin-dried, and the mixture was heated to room temperature. Recrystallization from methyl chloride gave the starting material (14) as a white solid, 64 mg, in 60% yield. ¹ H NMR (CDCl ₃ ): δ 2.07 (s, 6H, -SCH ₃ ), 3.79 (s, 16H, O-CH ₂ CH ₂ -O), 4.85 (s, 8H, Ph-CH ₂ -O) ,7.31(t,J=4.8Hz,4H,tpy),7.80(dt,J1 ₌ 5.5Hz, _J2 =1.6Hz,4H,tpy),7.90(s,4H,-Ph),8.56-8.58( d, J=6.4Hz, 4H, tpy), 8.63 (s, 4H, tpy), 8.68-8.70 (d, J=4.8 Hz, 4H, tpy).

The starting material (the compound represented by formula I, R is terpyridyl, X is O) 0.48 g (0.49 mmol) was dissolved in 50 ml of dichloromethane, cooled to 0 °C with an ice-water bath, and m-chlorine was added in three portions within 15 min. Peroxybenzoic acid wet solid (the mass concentration of m-chloroperoxybenzoic acid is 50-55%) 0.34g (1mmol, this molar mass is calculated according to the mass concentration of m-chloroperoxybenzoic acid is 52.5%), warming up to Stir at 28°C for 30 min and filter to obtain a filtrate.

Add 10ml of trifluoroacetic acid to the filtrate, place it in the XH-MC-1 type microwave reactor, and place a conical flask containing 50ml of water as a microwave absorber, set the power to 250W, and microwave at 50°C and a frequency of 2450MHz. The reaction was carried out for 15 minutes. Dichloromethane, water and excess trifluoroacetic acid were evaporated under reduced pressure, placed in an ice-water bath and cooled to 0°C, added pH=10, 15ml of ammonia-ammonium chloride buffer solution with a concentration of 2M, stirred for 10min, and filtered to obtain a solid .

The solid was dissolved in 30 ml of dichloromethane. Dissolve 0.15 ml of hydrogen peroxide (30% by mass) in 5 ml of methanol, add the above solution dropwise, stir at 45° C. for 1 h, spin dry, and wash the obtained solid with ethanol. The target product (compound represented by formula II, R is terpyridyl, X is O) 0.22 g was obtained by recrystallization in a dichloromethane-ethanol mixed solution, and the yield was 45.5%. ¹ H NMR (600MHz, CDCl ₃ ) δ 3.77-3.83 (m, 16H, O-CH ₂ CH ₂ -O), 4.84 (m, 8H, Ph-CH ₂ -O), 7.33-7.37 (m, 4H ,tpy),7.86-7.90(dt,J ₁ =6.7Hz,J ₂ =1.8Hz,4H,tpy),7.97(s,4H,-Ph),8.66-8.67(d,J=7.9Hz,4H, tpy), 8.71-8.73 (d, J=4.3 Hz, 4H, tpy), 8.73 (s, 4H, tpy). Mass spectrum: 942 (M+H ⁺ ). Elemental analysis: Calculated C 68.92%, H 5.14%, N 8.93%, measured C 68.77%, H 5.08%, N 8.91%.

Various embodiments of the present invention have been described above, and the foregoing descriptions are exemplary, not exhaustive, and not limiting of the disclosed embodiments. Numerous modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.

Claims (8)

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 ℃.