CN115652346A - Method for synthesizing 3-mercaptoindolizine compound by electrocatalytic oxidation - Google Patents

Abstract

The invention relates to the technical field of organic compound synthesis, in particular to a method for synthesizing a 3-mercaptoindolizine compound by electrocatalytic oxidation, which comprises the steps of adding the indolizine compound, thiophenol and potassium iodide into an organic solvent containing a supporting electrolyte, and electrifying the solution to enable reaction substrates to generate electrocatalytic oxidation reaction so as to synthesize the 3-mercaptoindolizine compound. The method utilizes the electrochemical reaction, realizes the preparation of the product by the electron loss of the reactant on the electrode without adding extra oxidant and metal catalyst, reduces the material consumption, has mild reaction conditions, simple process flow, simple, convenient and safe operation and high yield of the obtained product, develops a new synthetic route and a new method for the preparation of the 3-mercaptoindolizine compound, and has good application potential and research value.

Description

Method for synthesizing 3-mercaptoindolizine compound by electrocatalytic oxidation

Technical Field

The invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for synthesizing a 3-mercaptoindolizine compound by electrocatalytic oxidation.

Background

Indolizines are important heterocyclic compounds in many natural products and have potent pharmaceutical activity and fluorescent properties. The functionalized indolizides, in particular C-3 derivatives, can be used for preparing medicaments with antidiabetic, antitubercular and anti-inflammatory activities. Among them, 3-mercaptoindolizine compounds are considered as ligands of G protein coupled receptors, can be used for treating chronic respiratory diseases, and can also be applied to the fields of synthetic intermediates of bioactive molecules and fluorescent molecular materials.

The 3-mercaptoindolizine compound can be obtained by cross-coupling reaction of the indolizine compound and a sulfur-containing nucleophilic reagent. The main sulfur sources may be: trifluoromethanesulfonyl chloride, sodium benzenesulfinate, benzenesulfonyl chloride, disulfide, and thiol. Among the most common and readily available are the disulfides and mercaptans, but the disulfides are generally synthesized starting from mercaptans. In the reaction of synthesizing 3-thioindole compounds by reacting sulfur-containing nucleophiles with indolizine compounds, transition metal catalysts or stoichiometric oxidants are often used, and harsh reaction conditions are also needed under many conditions, which greatly affects the application of the compound in practical production.

The literature (European Journal of Organic Chemistry 2019, 1588-1593) reports that 2-phenylindolizines and disulfides are catalyzed by palladium chloride and copper chloride at 120 ^o C, reacting for 12 hours to prepare the disubstituted thioindolizine compound, but the method can only prepare the disubstituted product, and the disulfide compound is prepared by using mercaptan as a raw material. Recently, there have been reports of hydrogen peroxide as an oxidizing agent at 60 deg.f ^o C, synthesizing thioindolizine by taking 2-phenyl indolizine and aryl mercaptan as raw materials (Org Lett 2018, 20 (11), 3291-3295). Each of the above methods has advantages, but there are also limitations such as the need for a metal catalyst, additional oxidizing agent, high temperature conditions, low reaction yield, etc. Therefore, the development of a more economical, environment-friendly and efficient method for synthesizing the 3-mercaptoindolizine framework compound with a diversified structure has important research value.

Disclosure of Invention

The invention aims to provide a method for synthesizing a 3-mercaptoindolizine compound by electrocatalytic oxidation, the method for preparing the 3-mercaptoindolizine compound does not need to add extra metal catalyst and oxidant, the reaction does not need high temperature condition, the process flow is simple, the operation is simple, convenient and safe, and the yield is high.

In order to achieve the purpose, the invention is realized by the following technical scheme:

a method for synthesizing 3-mercaptoindolizine compounds by electrocatalytic oxidation comprises the following steps:

(1) Adding a reaction substrate to an organic solvent containing a supporting electrolyte;

the reaction substrate comprises indolizine compounds, thiophenol and potassium iodide;

(2) Electrifying the solution obtained in the step (1) to enable electrocatalytic oxidation reaction to occur between reaction substrates, and synthesizing a 3-mercaptoindolizine compound;

the structural formula of the indolizine compound is shown in the specification

The structural formula of the thiophenol is shown in the specification

，

The structural formula of the 3-mercaptoindolizine compound is shown in the specification

；

Wherein R is ¹ Is one of H, halogen, C1-C4 alkyl and C1-C4 alkoxy, R ² Is one of H, halogen, C1-C4 alkyl and C1-C4 alkoxy, R ³ Is one of phenyl, substituted phenyl, heteroaromatic group, substituted heteroaromatic group, naphthyl and substituted naphthyl.

Compared with the closest existing organic synthesis method of the thioindolizine compound, the electrochemical method for synthesizing the 3-mercaptoindolizine compound has the advantages of simple, convenient and safe operation, no need of adding additional metal catalyst and oxidant in the synthesis reaction process, mild reaction conditions and the like, and the product has high yield and is easy to separate and purify.

The preparation scheme for synthesizing the 3-mercaptoindolizines compound by electrochemical catalysis can be described as follows: a three-electrode system is adopted, the cathode and the anode are both platinum sheet electrodes, and 0.1 mol/L silver nitrate acetonitrile solution is used as a reference electrode. Adding indolizine compound, thiophenol and potassium iodide into organic solvent containing supporting electrolyte, stirring and electrolyzing at a certain temperature under constant voltage, and after the reaction is finished, carrying out post-treatment on reaction liquid to obtain the product 3-mercaptoindolizine compound. The electrochemical reaction is realized by the electron gain and loss of the reactant on the electrode, no additional oxidant or metal catalyst is added, the material consumption is reduced, and the reaction condition is mild, so that the method is very favorable for saving energy and reducing equipment investment.

The above reaction process can be represented by the following reaction formula:

wherein R is ¹ Is one of H, halogen, C1-C4 alkyl and C1-C4 alkoxy, R ² Is one of H, halogen, C1-C4 alkyl and C1-C4 alkoxy, R ³ Is one of phenyl, substituted phenyl, heteroaromatic group, substituted heteroaromatic group, naphthyl and substituted naphthyl. R ³ The heteroaryl group in (1) may be an aryl group containing a heteroatom such as N, O, S or the like in the ring. The substituted phenyl, substituted heteroaromatic group and substituted naphthyl refer to that hydrogen on a benzene ring, a heteroaromatic ring and a naphthalene ring is substituted by one or more substituents, and the substituents are independently selected from one of the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy, amino and hydroxyl.

Preferably, R is ¹ Is one of H, cl and methyl, and the R ² Is one of H and methyl, and the R ³ Is one of phenyl, halogenated phenyl, alkyl substituted phenyl, alkoxy substituted phenyl and thienyl.

Preferably, the supporting electrolyte in step (1) is LiClO ₄ 、 ⁿ Bu ₄ NBF ₄ 、 ⁿ Bu ₄ ClO ₄ 、NaClO ₄ Wherein the organic solvent is N, N-dimethylformamide or dimethyl sulfoxide.

Preferably, the supporting electrolyte in step (1) is LiClO ₄ The organic solvent is N, N-dimethylformamide.

In the experiment of synthesizing the 3-mercaptoindolizine compound by electrocatalytic oxidation, the added supporting electrolyte is LiClO ₄ 、 ⁿ Bu ₄ NBF ₄ 、 ⁿ Bu ₄ ClO ₄ 、NaClO ₄ Wherein the organic solvent is N, N-dimethylformamide or dimethyl sulfoxide. In the experimental process, the LiClO is selected although the supporting electrolyte and the organic solvent are selected to realize the preparation of the 3-mercaptoindolizine compound ₄ The reaction yield of N, N-dimethylformamide as an organic solvent is high as a supporting electrolyte.

Preferably, the amount concentration of the supporting electrolyte in the organic solvent in the step (1) is 0.05 to 0.2mol/L.

Preferably, in the step (1), the ratio of the amounts of the indolizine compound to the thiophenol and potassium iodide is 100:100 to 200:10 to 40.

Preferably, in the step (1), the ratio of the amounts of the indolizine compound to the thiophenol and potassium iodide is 100:120 to 180:10 to 20.

Preferably, the mass concentration of the indolizine compound in the organic solvent is 0.005 to 0.03mol/L.

In the synthesis experiment, the ratio of the content of the indolizine compound to the content of the thiophenol and the content of the potassium iodide is 100:100 to 200: the yield of the 3-mercaptoindolizine compound is 10 to 40, wherein the proportion range is 100:120 to 180: the yield of the product is high when the concentration is 10 to 20, and the content of the substance in the organic solvent is 0.005 to 0.03mol/L, which is more beneficial to the smooth operation of the synthesis experiment.

Preferably, the electrolysis temperature in the step (2) is 15 to 45 ℃, the electrolysis voltage is 0.1 to 0.4V, and the electrolysis time is 3 to 8 hours.

The invention also provides a purification method of the 3-mercaptoindolizine compound prepared by the method, which comprises the following steps:

(1) Taking out the solution containing the 3-mercaptoindolizine compound after the electrolysis reaction is finished, evaporating the solvent under reduced pressure, performing column chromatography separation, and collecting the eluent containing the target compound;

(2) And distilling off the solvent to obtain the product 3-mercaptoindolizine compound.

After the reaction is finished, taking out the reaction liquid, carrying out reduced pressure distillation on the reaction liquid to remove the solvent, and then carrying out column chromatography separation, wherein the volume ratio of ethyl acetate/n-hexane is 1: and (5) taking the mixed solution of 60 as an eluent, collecting the eluent containing the target compound, and evaporating the solvent to obtain the product, namely the 3-mercaptoindolizine compound.

The invention has the following beneficial effects:

(1) The method for synthesizing the 3-mercaptoindolizine compound by electrocatalytic oxidation has the advantages of high product yield, simple and safe operation;

(2) The reaction condition is mild, high temperature is not needed, and extra oxidant and metal catalyst are not needed, so that the material consumption is reduced, and the separation and purification of the product are facilitated;

(3) The product is synthesized by adopting an electrochemical method, clean electric energy is used as an oxidation reducing agent, the electrochemical reaction is realized by losing electrons of reactants on an electrode, the experimental conditions and the process are more environment-friendly, excessive pollution can not be generated, the environmental cost is greatly reduced, and a new synthetic route and a new method can be developed for the preparation of the 3-mercaptoindolizine compound.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of the compound obtained in example 1 of the present invention.

FIG. 2 shows the nuclear magnetic carbon spectrum of the compound obtained in example 1 of the present invention.

Detailed Description

The invention is further described with reference to the drawings and the specific embodiments. Those skilled in the art will be able to practice the invention based on these descriptions. Moreover, the embodiments of the present invention described in the following description are generally only some embodiments of the present invention, and not all embodiments. Therefore, all other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without making creative efforts shall fall within the protection scope of the present invention.

The structural formulas of the 3-mercaptoindolizines prepared in the following examples are respectively shown as formulas (I-1) - (I-17):

。

example 1: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

A three-electrode system is adopted in the reaction, the cathode and the anode are both platinum sheet electrodes, and 0.1 mol/L silver nitrate acetonitrile solution is used as a reference electrode. A30 mL beaker was charged with a solution containing 0.1 mol/L LiClO ₄ N, N-dimethylformamide (15 mL), 2-phenylindolizine (0.2 mmol), p-chlorothiophenol (0.3 mmol) and potassium iodide (0.03 mmol). 25. Electrolyzing at constant potential of 0.2V at the temperature of 5h, and finishing the reaction. And (3) evaporating the solvent under reduced pressure, and performing column chromatography separation, wherein the volume ratio of ethyl acetate to normal hexane is 1:60 as eluent, collecting the eluent containing the target compound, evaporating to remove the solvent to obtain the product 2-phenyl-3-p-chlorobenzenethiol indolizine, separating and collectingThe rate was 85%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (d, J=7.1 Hz, 1H), 7.55 (d, J=7.2 Hz, 2H), 7.26-7.19 (m, 3H), 7.16-7.10 (m, 1H), 6.93 (d, J=8.4 Hz, 2H), 6.67 (d, J=6.7 Hz, 1H), 6.63 (d, J=6.9 Hz, 3H), 6.42-6.34 (m, 1H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 137.2, 136.1, 135.9, 135.0, 131.2, 129.4, 128.9, 128.4, 127.3, 126.4, 123.8, 120.1, 118.9, 111.5, 104.0, 100.4。

example 2: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure was as in example 1, except that the organic solvent was changed to dimethyl sulfoxide and the isolated yield of 2-phenyl-3-p-chlorophenylindolizine was 70%.

Example 3: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure was the same as in example 1, except that the supporting electrolyte was changed to ⁿ Bu ₄ NBF ₄ The isolation yield of 2-phenyl-3-p-chlorobenzenethioindolizine was 57%.

Example 4: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure was the same as in example 1, except that the supporting electrolyte was changed to ⁿ Bu ₄ ClO ₄ The isolation yield of 2-phenyl-3-p-chlorobenzenethioindolizine was 72%.

Example 5: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure was the same as in example 1, except that the supporting electrolyte was changed to NaClO ₄ The isolated yield of 2-phenyl-3-p-chlorobenzenethioindolizine was 68%.

Example 6: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure was the same as in example 1, except that the reaction voltage was changed to 0.3V and the reaction time was changed to 4h, and that the isolation yield of 2-phenyl-3-p-chlorophenylindolizine was 82%.

Example 7: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine of formula I-1

The reaction procedure was as in example 1, except that the reaction voltage was changed to 0.4V and the reaction time was changed to 3h, and that the isolation yield of 2-phenyl-3-p-chlorophenylindolizine was 75%.

Example 8: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure is as in example 1 except that the reaction voltage is changed to 0.1V and the reaction time is changed to 8h, and the isolation yield of 2-phenyl-3-p-chlorobenzenethioindolizine is 42%.

Example 9: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure was as in example 1, except that the reaction temperature was changed to 35 ℃ and the isolated yield of 2-phenyl-3-p-chlorophenylindolizine was 84%.

Example 10: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure was the same as in example 1, except that the reaction temperature was changed to 15 ℃ and LiClO was used ₄ The concentration of (A) was changed to 0.2mol/L, and the isolation yield of 2-phenyl-3-p-chlorophenylindolizine was 75%.

Example 11: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine of formula I-1

The reaction procedure was the same as in example 1, except that the reaction temperature was changed to 45 ℃ and LiClO was used ₄ The concentration of (A) was changed to 0.05 mol/L, and the isolation yield of 2-phenyl-3-p-chlorophenylindolizine was 80%.

Example 12: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure was as in example 1, except that the amount of p-chlorothiophenol added was changed to 0.24mmol, the amount of potassium iodide was changed to 0.02mmol, and the isolation yield of 2-phenyl-3-p-chlorothioindoxazine was 79%.

Example 13: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure was as in example 1, except that the amount of p-chlorothiophenol added was changed to 0.36mmol, the amount of potassium iodide added was changed to 0.04mmol, and the isolation yield of 2-phenyl-3-p-chlorothioindoxazine was 83%.

Example 14: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine of formula I-1

The reaction procedure was as in example 1, except that the amount of p-chlorothiophenol added was changed to 0.2mmol, the amount of potassium iodide was changed to 0.08mmol, and the isolation yield of 2-phenyl-3-p-chlorothioindoxazine was 61%.

Example 15: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine of formula I-1

The reaction procedure was as in example 1, except that the amount of p-chlorothiophenol added was changed to 0.4mmol, the amount of potassium iodide added was changed to 0.03mmol, and the isolation yield of 2-phenyl-3-p-chlorothioindoxazine was 64%.

Example 16: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine of formula I-1

The reaction procedure was as in example 1, except that the amount of 2-phenylindolizine added was changed to 0.075mmol, the amount of p-chlorothiophenol was changed to 0.105mmol, the amount of potassium iodide was changed to 0.015mmol, and the isolation yield of 2-phenyl-3-p-chlorothioindolizine was 83%.

Example 17: preparation of 2-phenyl-3-p-chlorobenzenethioindolizine (formula I-1)

The reaction procedure was as in example 1, except that the amount of 2-phenylindolizine added was changed to 0.45mmol, the amount of p-chlorothiophenol added was changed to 0.72mmol, the amount of potassium iodide was changed to 0.045mmol, and the isolation yield of 2-phenyl-3-p-chlorothioindolizine was 72%.

Example 18: preparation of 2-phenyl-3-p-bromophenylsulfanylindazine (formula I-2)

The reaction procedure is as in example 1 except that p-chlorothiophenol is replaced by p-bromothiophenol and the isolated yield of the product 2-phenyl-3-p-bromothiophenyl indolizine is 80%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20-8.17 (m, 1H), 7.69-7.66 (m, 2H), 7.46 (d, J=8.9 Hz, 1H), 7.41-7.36 (m, 2H), 7.33-7.26 (m, 3H), 6.90-6.84 (m, 1H), 6.79 (s, 1H), 6.76-6.72 (m, 2H), 6.62-6.57 (m, 1H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 137.3, 136.7, 136.2, 135.1, 132.3, 129.0, 128.5, 127.4, 126.8, 123.9, 120.2, 119.1, 119.0, 111.6, 103.9, 100.5。

example 19: preparation of 2-phenyl-3-p-fluorophenylthioindolizine (formula I-3)

The reaction procedure was as in example 1, except that p-chlorothiophenol was changed to p-fluorothiophenol and the isolated yield of the product, 2-phenyl-3-p-fluorophenylthioindolizine, was 88%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J=6.5 Hz, 1H), 7.73-7.68 (m, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.41-7.37 (m, 2H), 7.33-7.29 (m, 1H), 6.90-6.84 (m, 5H), 6.79 (s, 1H), 6.63-6.58 (m, 1H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 161.0 (d, J=244.8 Hz), 136.8, 135.7, 134.9, 131.9(d, J=3.0 Hz), 128.7, 128.2, 127.0, 126.7 (d, J=7.9 Hz), 123.6, 119.8, 118.7, 116.1 (d, J=22.0 Hz), 111.2, 104.6, 100.1。

example 20: preparation of 2-phenyl-3-p-tolylthioindolizine (formula I-4)

The reaction procedure was as in example 1, except that p-chlorothiophenol was changed to p-methylthiophenol, and the isolated yield of the product, 2-phenyl-3-p-tolylthioindolizine, was 78%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J=8.0 Hz, 1H), 7.72 (d, J=7.1 Hz, 2H), 7.42 (d, J=8.9 Hz, 1H), 7.39-7.35 (m, 2H), 7.31-7.26 (m, 1H), 6.97 (d, J=7.9 Hz, 2H), 6.84-6.77 (m, 4H), 6.57- 6.53 (m, 1H), 2.23 (s, 3H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 136.9, 135.9, 135.4, 135.3, 133.6, 130.1, 129.0, 128.4, 127.2, 125.3, 124.1, 119.9, 118.9, 111.3, 105.2, 100.2, 21.0。

example 21: preparation of 2-phenyl-3-p-tert-butylmercaptoindolizine (formula I-5)

The procedure is as in example 1, except that p-chlorothiophenol is replaced by p-tert-butylphenylthiophenol and the isolated yield of the product, 2-phenyl-3-p-tert-butylphenylthioindolizine, is 78%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31- 8.21 (m, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.49 (d, J=7.7 Hz, 1H), 7.42-7.37 (m, 2H), 7.31-7.25 (m, 1H), 7.21-7.16 (m, 3H), 6.84-6.78 (m, 4H), 6.63-6.54 (m, 1H), 1.23 (s, 9H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 148.5, 136.9, 135.9, 135.4, 133.7, 130.8, 129.1, 128.4, 128.0, 127.2, 126.4, 125.1, 124.2, 119.9, 118.8, 111.3, 105.2, 100.2, 34.4, 31.5。

example 22: preparation of 2-phenyl-3-p-isopropylphenylthioindolizine (formula I-6)

The reaction procedure is as in example 1 except that p-chlorothiophenol is replaced by p-isopropylthiophenol and the isolated yield of the product 2-phenyl-3-p-isopropylthiophenylindolizine is 81%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (d, J=7.0 Hz, 1H), 7.73 (d, J=7.3 Hz, 2H), 7.44 (d, J=8.9 Hz, 1H), 7.40 -7.35 (m, 2H), 7.31-7.26 (m, 1H), 7.03 (d, J=8.2 Hz, 2H), 6.87-6.77 (m, 4H), 6.60- -6.53 (m, 1H), 1.17 (d, J=6.9 Hz, 6H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 146.3, 136.9, 135.9, 135.4, 134.0, 129.1, 128.4, 127.5, 127.5, 127.2, 125.4, 124.2, 119.9, 118.9, 111.3, 105.3, 100.2, 33.7, 24.0。

example 23: preparation of 2-phenyl-3-o-chlorothiophenyl indolizine (formula I-7)

The reaction procedure was as in example 1 except that p-chlorothiophenol was changed to o-chlorothiophenol and the isolation yield of the product, 2-phenyl-3-o-chlorothioindoxazine, was 76%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J=Hz, 1H), 7.67 (d, J=Hz, 2H), 7.46 (d, J=Hz, 1H), 7.40-7.26 (m, 4H), 7.03- 6.98 (m, 1H), 6.94- 6.85 (m, 2H), 6.81 (s, 1H), 6.61-6.56 (m, 1H), 6.22 (d, J=7.9 Hz, 1H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 137.7, 136.4, 136.3, 135.0, 130.7, 129.9, 128.9, 128.5, 127.5, 127.4, 126.3, 125.6, 124.0, 120.3, 119.0, 111.6, 103.0, 100.6。

example 24: preparation of 2-phenyl-3-o-tolylthioindolizine (formula I-8)

The reaction procedure was as in example 1, except that p-chlorothiophenol was changed to o-methylthiophenol and the isolated yield of 2-phenyl-3-o-tolylthioindolizine was 70%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, J=7.1 Hz, 1H), 7.59 (d, J=7.6 Hz, 2H), 7.33 (d, J=8.9 Hz, 1H), 7.28-7.23 (m, 2H), 7.19-7.15 (m, 1H), 7.04 (d, J=7.4 Hz, 1H), 6.90-6.86 (m, 1H), 6.80-6.70 (m, 3H), 6.45-6.41 (m, 1H), 6.18 (d, J=Hz, 1H), 2.36 (s, 3H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 137.3, 136.2, 136.1, 135.3, 134.7, 130.6, 129.0, 128.4, 127.2, 126.9, 125.2, 124.1, 119.9, 118.9, 111.3, 104.0, 100.4, 19.8。

example 25: preparation of 2-phenyl-3-m-chlorophenylindolizine (formula I-9)

The reaction procedure was as in example 1, except that p-chlorothiophenol was changed to m-chlorothiophenol and the isolation yield of 2-phenyl-3-m-chlorothioindoxazine was 83%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (d, J=Hz, 1H), 7.68 (d, J=Hz, 2H), 7.44 (d, J=Hz, 1H), 7.40-7.35 (m, 2H), 7.32-7.26 (m, 1H), 7.08-7.02 (m, 2H), 6.91-6.83 (m, 2H), 6.79 (s, 1H), 6.69 (d, J=Hz, 1H), 6.61-6.55 (m, 1H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 139.7, 137.4, 136.3, 135.3, 135.1, 130.4, 129.0, 128.5, 127.4, 125.8, 124.9, 123.9, 123.2, 120.3, 119.0, 111.7, 103.5, 100.6。

example 26: preparation of 2-phenyl-3-m-tolylthioindolizine (formula I-10)

The reaction procedure was as in example 1, except that p-chlorothiophenol was changed to m-methylthiophenol and the isolated yield of 2-phenyl-3-m-methylthioindolizine was 75%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J=Hz, 1H), 7.67-7.62 (m, 2H), 7.37 (d, J=Hz, 1H), 7.33-7.27 (m, 2H), 7.24-7.19 (m, 1H), 6.99-6.94 (m, 1H), 6.83-6.69 (m, 4H), 6.57-6.47 (m, 2H), 2.14 (s, 3H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 139.2, 137.1, 137.0, 136.0, 135.4, 129.1 (d, J = 16.4 Hz), 128.4, 127.2, 126.4, 125.8, 124.1, 122.2, 120.0, 119.0, 111.4, 104.9, 100.2, 21.6。

example 27: preparation of 2-phenyl-3-m-methoxyphenylthioindolizine (formula I-11)

The reaction procedure was as in example 1, except that p-chlorothiophenol was changed to m-methoxythiophenol and the voltage was changed to 0.3V, and the isolation yield of 2-phenyl-3-m-methoxythiophenylindolizine was 85%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (d, J=Hz, 1H), 7.72 (d, J=Hz, 2H), 7.41-7.33 (m, 3H), 7.27 (d, J=Hz, 1H), 7.04-6.99 (m, 1H), 6.86 (d, J=Hz, 1H), 6.83-6.77 (m, 3H), 6.62 (d, J=7.8 Hz, 1H), 6.54-6.50 (m, 1H), 2.18 (s, 3H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 139.1, 137.1, 137.0, 136.0, 135.3, 129.2，129.0, 128.4, 127.2, 126.4, 125.8, 124.1, 122.2, 119.9, 118.8, 111.3, 104.8, 100.2, 21.5。

example 28: preparation of 2-phenyl-3- (thien-2-yl) thioindolizine (formula I-12)

The reaction procedure is the same as in example 1, except that the p-chlorothiophenol is changed to 2-thiophenethiol and the reaction time is changed to 6 hours, and the isolation yield of the product 2-phenyl-3- (thiophen-2-yl) thioindolizine is 78%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45-8.36 (m, 1H), 7.76-7.68 (m, 2H), 7.40-7.33 (m, 3H), 7.29-7.25 (m, 1H), 7.06-7.02 (m, 1H), 6.83-6.76 (m, 3H), 6.66-6.54 (m, 2H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 136.2, 136.1, 135.7, 135.4, 129.4, 128.4, 127.6, 127.3, 126.9, 124.0, 120.0, 119.0, 111.4, 107.6, 100.4。

example 29: preparation of 2-phenyl-5-methyl-3-p-chlorobenzenethioindolizine (formula I-13)

The procedure is as in example 1, except that 2-phenylindolizine is changed to 2-phenyl-5-methylindolizine and the isolated yield of the product 2-phenyl-5-methyl-3-p-chlorophenylindolizine is 82%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J=7.1 Hz, 1H), 7.71-7.64 (m, 2H), 7.40 – 7.35 (m, 2H), 7.31-7.27 (m, 1H), 7.22 (s, 1H), 7.15-7.12 (m, 2H), 6.82-6.78 (m, 2H), 6.65 (s, 1H), 6.46-6.42 (m, 1H), 2.32 (s, 3H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 137.4, 136.6, 136.4, 135.3, 131.2, 130.7, 129.4, 128.9, 128.5, 127.3, 126.4, 123.4, 117.3, 114.3, 102.9, 99.0, 21.2。

example 30: preparation of 2-phenyl-6-methyl-3-p-chlorobenzenethioindolizine (formula I-14)

The reaction procedure is as in example 1, except that 2-phenylindolizine is replaced by 2-phenyl-6-methylindolizine and the isolated yield of the product 2-phenyl-6-methyl-3-p-chlorophenylindolizine is 80%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.60-7.56 (m, 2H), 7.31-7.27 (m, 3H), 7.22-7.18 (m, 1H), 7.08-7.04 (m, 2H), 6.74-6.71 (m, 2H), 6.68-6.65 (m, 2H), 2.15 (s, 3H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 136.9, 136.4, 135.3, 135.1, 131.3, 129.4, 128.9, 128.4, 127.2, 126.5, 123.5, 121.5, 121.2, 118.5, 103.6, 100.2, 18.7。

example 31: preparation of 2-p-tolyl-3-p-chlorophenylindolizine (formula I-15)

The reaction procedure is as in example 1 except that 2-phenylindolizine is replaced by 2-p-tolylindolizine and the isolated yield of the product, 2-p-methylphenyl-3-p-chlorophenylindolizine, is 72%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13-8.07 (m, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.35 (d, J=Hz, 1H), 7.13-7.09 (m, 2H), 7.07-7.01 (m, 2H), 6.80-6.74 (m, 1H), 6.73-6.67 (m, 3H), 6.52-6.46 (m, 1H), 2.27 (s, 3H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 137.4, 137.2, 136.2, 136.1, 132.2, 131.3, 129.4, 129.2, 128.8, 126.5, 123.9, 120.1, 118.9, 111.5, 104.0, 100.3, 21.3。

example 32: preparation of 2-p-chlorophenyl-3-p-chlorobenzenethioindolizine of formula I-16

The reaction procedure is as in example 1, except that 2-phenylindolizine is replaced by 2-p-chlorophenylindolizine and the isolated yield of the product 2-p-chlorophenyl-3-p-chlorophenylindolizine is 77%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13-8.10 (m, 1H), 7.55-7.51 (m, 2H), 7.38 (d, J=8.9 Hz, 1H), 7.29-7.25 (m, 2H), 7.08-7.05 (m, 2H), 6.84-6.80 (m, 1H), 6.72-6.68 (m, 3H), 6.56-6.53 (m, 1H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 137.2, 136.1, 135.9, 135.0, 131.2, 129.4, 128.9, 128.4, 127.3, 126.4, 123.8, 120.1, 118.9, 111.5, 104.0, 100.4。

example 33: preparation of 2-p-chlorophenyl-5-methyl-3-p-chlorobenzenethioindolizine (formula I-17)

The procedure is as in example 1, except that 2-phenylindolizine is replaced by 2-p-chlorophenyl-5-methylindolizine and the isolated yield of the product 2-p-chlorophenyl-5-methyl-3-p-chlorophenylindolizine is 73%.

The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J=7.2 Hz, 1H), 7.53-7.50 (m, 2H), 7.29 (s, 2H), 7.25 (d, J=8.6 Hz, 2H), 7.06-7.04 (m, 2H), 6.70-6.66 (m, 2H), 6.53 (s, 1H), 6.38-6.35 (m, 1H), 2.23 (s, 3H)；

the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 136.6, 136.1, 133.7, 133.2, 132.9, 131.8, 131.4, 130.9, 130.1, 129.5, 128.6, 128.3, 126.4, 123.4, 117.3, 114.5, 103.1, 98.9, 21.1。

Claims (10)

1. a method for synthesizing 3-mercaptoindolizine compounds by electrocatalytic oxidation is characterized by comprising the following steps:

(1) Adding a reaction substrate to an organic solvent containing a supporting electrolyte;

the reaction substrate comprises indolizine compounds, thiophenol and potassium iodide;

(2) Electrifying the solution obtained in the step (1) to enable electrocatalytic oxidation reaction to occur between reaction substrates, and synthesizing the 3-mercaptoindolizine compound;

the structural formula of the indolizine compound is shown in the specification

The structural formula of the thiophenol is shown in the specification

，

The structural formula of the 3-mercaptoindolizine compound is shown in the specification

；

Wherein R is ¹ Is one of H, halogen, C1-C4 alkyl and C1-C4 alkoxy, R ² H, halogen, C1-C4 alkyl, C1-C4 alkoxyOne of the radicals, R ³ Is one of phenyl, substituted phenyl, heteroaromatic group, substituted heteroaromatic group, naphthyl and substituted naphthyl.

2. The method for synthesizing 3-mercaptoindolizines by electrocatalytic oxidation of claim 1, wherein R is ¹ Is one of H, cl and methyl, and the R ² Is one of H and methyl, and the R ³ Is one of phenyl, halogenated phenyl, alkyl substituted phenyl, alkoxy substituted phenyl and thienyl.

3. The method for synthesizing 3-mercaptoindolizines by electrocatalytic oxidation according to claim 1, wherein the supporting electrolyte in step (1) is LiClO ₄ 、 ⁿ Bu ₄ NBF ₄ 、 ⁿ Bu ₄ ClO ₄ 、NaClO ₄ Wherein the organic solvent is N, N-dimethylformamide or dimethyl sulfoxide.

4. The method for synthesizing 3-mercaptoindolizines by electrocatalytic oxidation according to claim 1 or 3, wherein the supporting electrolyte in step (1) is LiClO ₄ The organic solvent is N, N-dimethylformamide.

5. The method for synthesizing 3-mercaptoindolizines by electrocatalytic oxidation according to claim 1 or 3, wherein the supporting electrolyte in the organic solvent in the step (1) has a concentration of 0.05 to 0.2mol/L.

6. The method for synthesizing 3-mercaptoindolizines by electrocatalytic oxidation as set forth in claim 1, wherein the ratio of the amount of indolizines to the amount of thiophenol and potassium iodide in step (1) is 100:100 to 200:10 to 40.

7. The method for synthesizing 3-mercaptoindolizines by electrocatalytic oxidation as claimed in claim 1 or 6, wherein the ratio of the amount of indolizines to the amount of thiophenol and potassium iodide in step (1) is 100:120 to 180:10 to 20.

8. The method for synthesizing 3-mercaptoindolizine according to claim 1, wherein the concentration of the indolizine compound in the organic solvent is 0.005 to 0.03mol/L.

9. The method for synthesizing 3-mercaptoindolizines through electrocatalytic oxidation as claimed in claim 1, wherein the electrolysis temperature in step (2) is 15 to 45 ℃, the electrolysis voltage is 0.1 to 0.4V, and the electrolysis time is 3 to 8h.

10. A method for purifying a 3-mercaptoindolizine compound prepared by the method of any one of claims 1 to 9, comprising the steps of:

(1) Taking out the solution containing the 3-mercaptoindolizine compound after the electrolysis reaction is finished, evaporating the solvent under reduced pressure, performing column chromatography separation, and collecting the eluent containing the target compound;

(2) And evaporating to remove the solvent to obtain the product 3-mercaptoindolizine compound.

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