A method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds

Abstract

The present invention relates to the technical field of organic compound synthesis, and particularly to a method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds. By adding indolizine compounds, thiophenols and potassium iodide into an organic solvent containing a supporting electrolyte, and then applying an electric current to the solution, an electrocatalytic oxidation reaction occurs between the reaction substrates to synthesize 3-mercaptoindolizine compounds. The present invention utilizes an electrochemical reaction to prepare products by the gain and loss of electrons of reactants on the electrode, without adding additional oxidants or metal catalysts, reducing material consumption, and having mild reaction conditions, a simple process flow, simple and safe operation, and a high yield of the obtained products, opening up a new synthetic route and method for the preparation of 3-mercaptoindolizine compounds, and having good application potential and research value.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds. Background Art

[0002] Indolizine substances are important heterocyclic compounds in many natural products, having effective pharmaceutical activities and fluorescence characteristics. Functionalized indolizine substances, especially C-3 derivatives, can be used to prepare anti-diabetic, anti-tuberculosis and anti-inflammatory active drugs. Among them, 3-mercaptoindolizine compounds have been considered as ligands of G protein-coupled receptors, can be used to treat chronic respiratory diseases, and can also be applied to the field of synthetic intermediates of bioactive molecules and fluorescent molecular materials.

[0003] 3-Mercaptoindolizine compounds can be obtained by cross-coupling reactions of indolizine compounds and sulfur-containing nucleophiles. The main sulfur sources can be: trifluoromethanesulfonyl chloride, sodium benzenesulfinate, benzenesulfonyl chloride, disulfides and thiols. Among them, the most commonly used and easily available are disulfides and thiols, but disulfides are generally synthesized from thiols as raw materials. In the reaction of sulfur-containing nucleophiles with indolizine compounds to synthesize 3-thioindole compounds, transition metal catalysts or stoichiometric oxidants are often used, and in many cases, relatively harsh reaction conditions are also required, which greatly affect their application in actual production.

[0004] The literature (European Journal of Organic Chemistry 2019, 1588-1593) reported that 2-phenylindolizine compounds and disulfides reacted at 120 o °C for 12 hours under the catalysis of palladium chloride and copper chloride to prepare bis-substituted thioindolizine compounds, but this method can only prepare bis-substituted products, and disulfide compounds need to be prepared from thiols as raw materials. Recently, there is a literature report on a method for synthesizing thioindolizine using hydrogen peroxide as an oxidant at 60 o °C, with 2-phenylindolizine and aryl thiols as raw materials (Org Lett 2018, 20 (11), 3291-3295). Each of the above methods has its own advantages, but there are also limitations, such as the need for metal catalysts, additional oxidants, high-temperature conditions, and low reaction yields. Therefore, it is of important research value to develop a more economical, environmentally friendly and efficient method for synthesizing 3-mercaptoindolizine skeleton compounds with diverse structures. Summary of the Invention

[0005] The object of the present invention is to provide a method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds. By using this method to prepare 3-mercaptoindolizine compounds, no additional metal catalyst or oxidant needs to be added, the reaction does not require high-temperature conditions, the process flow is simple, the operation is simple and safe, and the yield is high.

[0006] To achieve the above object of the invention, the present invention is realized through the following technical solutions:

[0007] A method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds, comprising the following steps:

[0008] (1) Adding a reaction substrate into an organic solvent containing a supporting electrolyte;

[0009] The reaction substrate includes indolizine compounds, thiophenols and potassium iodide;

[0010] (2) Electrifying the solution obtained in step (1) to cause an electrocatalytic oxidation reaction between the reaction substrates to synthesize 3-mercaptoindolizine compounds;

[0011] The structural formula of the indolizine compound is The structural formula of the thiophenol is ,

[0012] The structural formula of the 3-mercaptoindolizine compound is ;

[0013] wherein, R 1 is one of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, R 2 is one of H, halogen, C1-C4 alkyl, C1-C4 alkoxy, and R 3 is one of phenyl, substituted phenyl, heteroaromatic group, substituted heteroaromatic group, naphthyl, substituted naphthyl.

[0014] The present invention synthesizes 3-mercaptoindolizine compounds by an electrochemical method. Compared with the closest existing organic synthesis method for thioindolizine compounds, it not only has the advantages of simple and safe operation, no need to add additional metal catalysts or oxidants during the synthesis reaction, mild reaction conditions, etc., but also has a high yield of the product and is easy to separate and purify.

[0015] The preparation scheme for synthesizing 3-mercaptoindolizine compounds through electrochemical catalysis can be described as follows: Using a three-electrode system, both the cathode and anode are platinum sheet electrodes, and a 0.1 mol / L silver nitrate acetonitrile solution is used as the reference electrode. In an organic solvent containing a supporting electrolyte, indolizine compounds, thiophenols, and potassium iodide are added, and electrolysis is carried out with stirring under certain temperature and constant voltage conditions. After the reaction ends, the reaction solution is post-treated to obtain the product 3-mercaptoindolizine compounds. Since the electrochemical reaction is achieved by the gain and loss of electrons of reactants on the electrodes, there is no need to add additional oxidants or metal catalysts, reducing material consumption, and the reaction conditions are mild, which is very beneficial for saving energy and reducing equipment investment.

[0016] The above reaction process can be represented by the following reaction formula:

[0017]

[0018] Among them, R 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, heteroaryl, substituted heteroaryl, naphthyl, and substituted naphthyl. The heteroaryl described in R 3 can be an aryl containing heteroatoms such as N, O, S, etc. in the ring. The substituted phenyl, substituted heteroaryl, and substituted naphthyl refer to the hydrogen on the benzene ring, heteroaromatic ring, and naphthalene ring being substituted by one or more substituents, and the substituents are each independently selected from one of the following: halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, and hydroxyl.

[0019] Preferably, the R 1 is one of H, Cl, and methyl, 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 thiophenyl.

[0020] Preferably, the supporting electrolyte in the step (1) is one of LiClO4, n Bu4NBF4, n Bu4ClO4, and NaClO4, and the organic solvent is N,N-dimethylformamide or dimethyl sulfoxide.

[0021] Preferably, the supporting electrolyte in the step (1) is LiClO4, and the organic solvent is N,N-dimethylformamide.

[0022] In the experiment of synthesizing 3-mercaptoindolizine compounds by electrocatalytic oxidation, the supporting electrolyte added is one of LiClO4, n Bu4NBF4, n Bu4ClO4, and NaClO4, and the organic solvent is N,N-dimethylformamide or dimethyl sulfoxide. Among them, it was found during the experiment that although the preparation of 3-mercaptoindolizine compounds can be achieved by using these supporting electrolytes and organic solvents, the reaction yield is higher when LiClO4 is selected as the supporting electrolyte and N,N-dimethylformamide is selected as the organic solvent.

[0023] Preferably, the molar concentration of the supporting electrolyte in the organic solvent in step (1) is 0.05 - 0.2 mol / L.

[0024] Preferably, the molar ratio of the indolizine compound to thiophenol and potassium iodide in step (1) is 100:100 - 200:10 - 40.

[0025] Preferably, the molar ratio of the indolizine compound to thiophenol and potassium iodide in step (1) is 100:120 - 180:10 - 20.

[0026] Preferably, the molar concentration of the indolizine compound in the organic solvent is 0.005 - 0.03 mol / L.

[0027] In the synthesis experiment, when the molar ratio of the indolizine compound to thiophenol and potassium iodide is 100:100 - 200:10 - 40, the yield of 3-mercaptoindolizine compounds will occur. Among them, when the ratio range is 100:120 - 180:10 - 20, the yield of the product is higher. And it was found during the experiment that when the molar concentration of the indolizine compound in the organic solvent is 0.005 - 0.03 mol / L, it is more beneficial to the smooth progress of the synthesis experiment.

[0028] Preferably, the electrolysis temperature in step (2) is 15 - 45 °C, the electrolysis voltage is 0.1 - 0.4 V, and the electrolysis time is 3 - 8 h.

[0029] The present invention also provides a purification method for 3-mercaptoindolizine compounds prepared by the above method, including the following steps:

[0030] (1) Take out the solution containing 3-mercaptoindolizine compounds after the electrolysis reaction ends, evaporate the solvent under reduced pressure, and then perform column chromatography separation to collect the eluate containing the target compound;

[0031] (2) Evaporate the solvent to obtain the product 3-mercaptoindolizine compounds.

[0032] After the reaction is completed, the reaction solution is taken out, the solvent is removed by distillation under reduced pressure, and then column chromatography separation is carried out. A mixed solution with a volume ratio of ethyl acetate / n-hexane of 1:60 is used as the eluent, and the eluent containing the target compound is collected. After removing the solvent, the product 3-mercaptoindolizine compound is obtained.

[0033] The present invention has the following beneficial effects:

[0034] (1) The method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds provided by the present invention has a high yield of the obtained product, and the operation is simple and safe;

[0035] (2) The reaction conditions are relatively mild, without the need for high temperature, nor additional oxidants and metal catalysts, reducing material consumption and being beneficial to the separation and purification of products;

[0036] (3) The product is synthesized by an electrochemical method. Since clean electric energy is used as the redox agent, the electrochemical reaction is achieved by the gain and loss of electrons of the reactants on the electrode. The experimental conditions and process are more environmentally friendly, without generating excessive pollution, greatly reducing the environmental cost, and can open up new synthetic routes and methods for the preparation of 3-mercaptoindolizine compounds. Brief Description of the Drawings

[0037] Figure 1 1H NMR spectrum of the compound obtained in Example 1 of the present invention.

[0038] Figure 2 13C NMR spectrum of the compound obtained in Example 1 of the present invention. Detailed Embodiments

[0039] The present invention will be further described below in conjunction with the drawings of the specification and specific embodiments. Those of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention described below are generally only a part of the embodiments of the present invention, rather than all of the embodiments. Therefore, all other embodiments obtained by those of ordinary skill in the art without creative efforts based on the embodiments of the present invention shall fall within the scope of protection of the present invention.

[0040] The structural formulas of the 3-mercaptoindolizine compounds prepared in the following embodiments are respectively shown as formulas (I-1) to (I-17):

[0041]

[0042]

[0043]

[0044] 。

[0045] Example 1: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0046] The reaction adopted a three-electrode system. Both the cathode and the anode were platinum sheet electrodes, and a 0.1 mol / L silver nitrate acetonitrile solution was used as the reference electrode. In a 30 mL beaker, add N,N-dimethylformamide (15 mL) containing 0.1 mol / L LiClO4, 2-phenylindolizine (0.2 mmol), 4-chlorothiophenol (0.3 mmol), and potassium iodide (0.03 mmol). Electrolyze at a constant potential of 0.2 V at 25 °C. After 5 h, the reaction ended. The solvent was removed by distillation under reduced pressure, and then column chromatography separation was carried out. A mixed solution with a volume ratio of ethyl acetate / n-hexane of 1:60 was used as the eluent. The eluent containing the target compound was collected, and the solvent was removed by distillation to obtain the product 2-phenyl-3-(4-chlorophenylthio)indolizine, and the separation yield was 85%.

[0047] The data of the 1H nuclear magnetic resonance spectrum of the obtained product are as follows:

[0048] 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J J = 7.1 Hz, 1H), 7.55 (d, J J = 7.2 Hz,2H), 7.26 - 7.19 (m, 3H), 7.16 - 7.10 (m, 1H), 6.93 (d, J J = 8.4 Hz, 2H), 6.67 (d, J J = 6.7 Hz, 1H), 6.63 (d, J J = 6.9 Hz, 3H), 6.42 - 6.34 (m, 1H);

[0049] The data of the 13C nuclear magnetic resonance spectrum of the obtained product are as follows:

[0050] 13 C NMR (101 MHz, CDCl3) 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。

[0051] Example 2: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0052] The reaction steps are the same as those in Example 1, except that the organic solvent is changed to dimethyl sulfoxide, and the separation yield of 2-phenyl-3-(4-chlorophenylthio)indolizine is 70%.

[0053] Example 3: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0054] The reaction steps are the same as those in Example 1, except that the supporting electrolyte is changed to n Bu4NBF4, and the separation yield of 2-phenyl-3-(4-chlorophenylthio)indolizine is 57%.

[0055] Example 4: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0056] The reaction steps are the same as those in Example 1, except that the supporting electrolyte is changed to n Bu4ClO4, and the separation yield of 2-phenyl-3-(4-chlorophenylthio)indolizine is 72%.

[0057] Example 5: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0058] The reaction steps are the same as those in Example 1, except that the supporting electrolyte is changed to NaClO4, and the separation yield of 2-phenyl-3-(4-chlorophenylthio)indolizine is 68%.

[0059] Example 6: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0060] The reaction steps are the same as those in Example 1, except that the reaction voltage is changed to 0.3 V and the reaction time is changed to 4 h, and the separation yield of 2-phenyl-3-(4-chlorophenylthio)indolizine is 82%.

[0061] Example 7: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0062] The reaction steps are the same as those in Example 1, except that the reaction voltage is changed to 0.4 V and the reaction time is changed to 3 h, and the separation yield of 2-phenyl-3-(4-chlorophenylthio)indolizine is 75%.

[0063] Example 8: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0064] The reaction steps are the same as those in Example 1, except that the reaction voltage is changed to 0.1 V and the reaction time is changed to 8 h, and the separation yield of 2-phenyl-3-(4-chlorophenylthio)indolizine is 42%.

[0065] Example 9: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0066] The reaction procedure was the same as that in Example 1, except that the reaction temperature was changed to 35 °C, and the isolated yield of 2-phenyl-3-(4-chlorophenylthio)indolizine was 84%.

[0067] Example 10: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0068] The reaction procedure was the same as that in Example 1, except that the reaction temperature was changed to 15 °C and the concentration of LiClO4 was changed to 0.2 mol / L, and the isolated yield of 2-phenyl-3-(4-chlorophenylthio)indolizine was 75%.

[0069] Example 11: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0070] The reaction procedure was the same as that in Example 1, except that the reaction temperature was changed to 45 °C and the concentration of LiClO4 was changed to 0.05 mol / L, and the isolated yield of 2-phenyl-3-(4-chlorophenylthio)indolizine was 80%.

[0071] Example 12: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0072] The reaction procedure was the same as that in Example 1, except that the amount of 4-chlorothiophenol added was changed to 0.24 mmol and the amount of potassium iodide added was changed to 0.02 mmol, and the isolated yield of 2-phenyl-3-(4-chlorophenylthio)indolizine was 79%.

[0073] Example 13: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0074] The reaction procedure was the same as that in Example 1, except that the amount of 4-chlorothiophenol added was changed to 0.36 mmol and the amount of potassium iodide added was changed to 0.04 mmol, and the isolated yield of 2-phenyl-3-(4-chlorophenylthio)indolizine was 83%.

[0075] Example 14: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0076] The reaction procedure was the same as that in Example 1, except that the amount of 4-chlorothiophenol added was changed to 0.2 mmol and the amount of potassium iodide added was changed to 0.08 mmol, and the isolated yield of 2-phenyl-3-(4-chlorophenylthio)indolizine was 61%.

[0077] Example 15: Preparation of 2-phenyl-3-(4-chlorophenylthio)indolizine (Formula I-1)

[0078] The reaction procedure was the same as that in Example 1, except that the amount of 4-chlorothiophenol added was changed to 0.4 mmol and the amount of potassium iodide added was changed to 0.03 mmol, and the isolated yield of 2-phenyl-3-(4-chlorophenylthio)indolizine was 64%.

[0079] Example 16: Preparation of 2-Phenyl-3-(p-chlorophenylthio)indolizine (Formula I-1)

[0080] The reaction steps are the same as those in Example 1, except that the amount of 2-phenylindolizine added is changed to 0.075 mmol, the amount of p-chlorothiophenol added is changed to 0.105 mmol, and the amount of potassium iodide added is changed to 0.015 mmol. The isolated yield of 2-phenyl-3-(p-chlorophenylthio)indolizine is 83%.

[0081] Example 17: Preparation of 2-Phenyl-3-(p-chlorophenylthio)indolizine (Formula I-1)

[0082] The reaction steps are the same as those in Example 1, except that the amount of 2-phenylindolizine added is changed to 0.45 mmol, the amount of p-chlorothiophenol added is changed to 0.72 mmol, and the amount of potassium iodide added is changed to 0.045 mmol. The isolated yield of 2-phenyl-3-(p-chlorophenylthio)indolizine is 72%.

[0083] Example 18: Preparation of 2-Phenyl-3-(p-bromophenylthio)indolizine (Formula I-2)

[0084] The reaction steps are the same as those in Example 1, except that p-chlorothiophenol is changed to p-bromothiophenol. The isolated yield of the product 2-phenyl-3-(p-bromophenylthio)indolizine is 80%.

[0085] The data of the 1H NMR spectrum of the obtained product are as follows:

[0086] 1 H NMR (400 MHz, CDCl3) 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);

[0087] The data of the 13C NMR spectrum of the obtained product are as follows:

[0088] 13 C NMR (101 MHz, CDCl3) 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。

[0089] Example 19: Preparation of 2-Phenyl-3-(p-fluorophenylthio)indolizine (Formula I-3)

[0090] The reaction procedure was the same as that of Example 1, except that p-chlorothiophenol was replaced by p-fluorothiophenol, and the isolated yield of the product 2-phenyl-3-(p-fluorophenylthio)indolizine was 88%.

[0091] The data of the 1H NMR spectrum of the obtained product are as follows:

[0092] 1 H NMR (400 MHz, CDCl3) δ 8.23 (d, J J = 6.5 Hz, 1H), 7.73 - 7.68 (m, 2H), 7.45 (d, J 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);

[0093] The data of the 13C NMR spectrum of the obtained product are as follows:

[0094] 13 C NMR (101 MHz, CDCl3) δ 161.0 (d, J J = 244.8 Hz), 136.8, 135.7, 134.9, 131.9 (d, J J = 3.0 Hz), 128.7, 128.2, 127.0, 126.7 (d, J J = 7.9 Hz), 123.6, 119.8, 118.7, 116.1 (d, J J = 22.0 Hz), 111.2, 104.6, 100.1。

[0095] Example 20: Preparation of 2-Phenyl-3-(p-tolylthio)indolizine (Formula I-4)

[0096] The reaction procedure was the same as that of Example 1, except that p-chlorothiophenol was replaced by p-methylthiophenol, and the isolated yield of the product 2-phenyl-3-(p-tolylthio)indolizine was 78%.

[0097] The data of the 1H NMR spectrum of the obtained product are as follows:

[0098] 1 H NMR (400 MHz, CDCl3) 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);

[0099] The data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

[0100] 13 C NMR (101 MHz, CDCl3) 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.

[0101] Example 21: Preparation of 2 - phenyl - 3 - (p - tert - butylphenylthio)indolizine (Formula I - 5)

[0102] The reaction procedure was the same as that in Example 1, except that p - chlorothiophenol was replaced by p - tert - butylthiophenol, and the isolated yield of the product 2 - phenyl - 3 - (p - tert - butylphenylthio)indolizine was 78%.

[0103] The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

[0104] 1 H NMR (400 MHz, CDCl3) 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);

[0105] The data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

[0106] 1313C NMR (101 MHz, CDCl3) 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。

[0107] Example 22: Preparation of 2-Phenyl-3-(p-isopropylphenylthio)indolizine (Formula I-6)

[0108] The reaction procedure was the same as that in Example 1, except that p-chlorothiophenol was replaced by p-isopropylthiophenol, and the isolated yield of the product 2-phenyl-3-(p-isopropylphenylthio)indolizine was 81%.

[0109] The data of the 1H nuclear magnetic resonance spectrum of the obtained product are as follows:

[0110] 1 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J J = 7.0 Hz, 1H), 7.73 (d, J J = 7.3 Hz, 2H), 7.44 (d, J J = 8.9 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.31 - 7.26 (m, 1H), 7.03 (d, J J = 8.2 Hz, 2H), 6.87 - 6.77 (m, 4H), 6.60 - 6.53 (m, 1H), 1.17 (d, J J = 6.9 Hz, 6H);

[0111] The data of the 13C nuclear magnetic resonance spectrum of the obtained product are as follows:

[0112] 13 13C NMR (101 MHz, CDCl3) 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。

[0113] Example 23: Preparation of 2-Phenyl-3-(o-chlorophenylthio)indolizine (Formula I-7)

[0114] The reaction steps are the same as those in Example 1, except that p-chlorothiophenol is replaced with o-chlorothiophenol, and the isolated yield of the product 2-phenyl-3-(o-chlorophenylthio)indolizine is 76%.

[0115] The data of the 1H NMR spectrum of the obtained product are as follows:

[0116] 1 H NMR (400 MHz, CDCl3) 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);

[0117] The data of the 13C NMR spectrum of the obtained product are as follows:

[0118] 13 C NMR (101 MHz, CDCl3) 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.

[0119] Example 24: Preparation of 2-phenyl-3-(o-tolylthio)indolizine (Formula I-8)

[0120] The reaction steps are the same as those in Example 1, except that p-chlorothiophenol is replaced with o-methylthiophenol, and the isolated yield of 2-phenyl-3-(o-tolylthio)indolizine is 70%.

[0121] The data of the 1H NMR spectrum of the obtained product are as follows:

[0122] 1 H NMR (400 MHz, CDCl3) 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);

[0123] The data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

[0124] 13 C NMR (101 MHz, CDCl3) 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.

[0125] Example 25: Preparation of 2 - phenyl - 3 - (3 - chlorophenylthio) indolizine (Formula I - 9)

[0126] The reaction procedure is the same as that in Example 1, except that p - chlorothiophenol is replaced by 3 - chlorothiophenol, and the isolated yield of 2 - phenyl - 3 - (3 - chlorophenylthio) indolizine is 83%.

[0127] The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:

[0128] 1 H NMR (400 MHz, CDCl3) 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);

[0129] The data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:

[0130] 1313C NMR (101 MHz, CDCl3) 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。

[0131] Example 26: Preparation of 2-Phenyl-3-(m-tolylthio)indolizine (Formula I-10)

[0132] The reaction procedure was the same as that in Example 1, except that p-chlorothiophenol was replaced with m-methylthiophenol. The isolated yield of 2-phenyl-3-(m-methylthio)phenyl indolizine was 75%.

[0133] The 1H NMR data of the obtained product are as follows:

[0134] 1 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J J = Hz, 1H), 7.67 - 7.62 (m, 2H), 7.37 (d, J 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);

[0135] The 13C NMR data of the obtained product are as follows:

[0136] 13 13C NMR (101 MHz, CDCl3) 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。

[0137] Example 27: Preparation of 2-Phenyl-3-(m-methoxyphenylthio)indolizine (Formula I-11)

[0138] The reaction procedure was the same as that in Example 1, except that p-chlorothiophenol was replaced with m-methoxythiophenol and the voltage was changed to 0.3 V. The isolated yield of 2-phenyl-3-(m-methoxyphenylthio)indolizine was 85%.

[0139] The data of the 1H NMR spectrum of the obtained product are as follows:

[0140] 1 H NMR (400 MHz, CDCl3) 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);

[0141] The data of the 13C NMR spectrum of the obtained product are as follows:

[0142] 13 C NMR (101 MHz, CDCl3) 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.

[0143] Example 28: Preparation of 2 - phenyl - 3 - (thiophen - 2 - yl)thioindolizine (Formula I - 12)

[0144] The reaction procedure was the same as that in Example 1, except that p - chlorothiophenol was replaced by 2 - thiophenethiol and the reaction time was changed to 6 h. The isolated yield of the product 2 - phenyl - 3 - (thiophen - 2 - yl)thioindolizine was 78%.

[0145] The data of the 1H NMR spectrum of the obtained product are as follows:

[0146] 1 H NMR (400 MHz, CDCl3) 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);

[0147] The data of the carbon nuclear magnetic resonance spectrum of the obtained product are as follows:

[0148] 13 C NMR (101 MHz, CDCl3) 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。

[0149] Example 29: Preparation of 2-phenyl-5-methyl-3-(4-chlorophenylthio)indolizine (Formula I-13)

[0150] The reaction steps are the same as those in Example 1, except that 2-phenylindolizine is replaced by 2-phenyl-5-methylindolizine, and the isolated yield of the product 2-phenyl-5-methyl-3-(4-chlorophenylthio)indolizine is 82%.

[0151] The data of the proton nuclear magnetic resonance spectrum of the obtained product are as follows:

[0152] 1 H NMR (400 MHz, CDCl3) 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);

[0153] The data of the carbon nuclear magnetic resonance spectrum of the obtained product are as follows:

[0154] 13 C NMR (101 MHz, CDCl3) 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。

[0155] Example 30: Preparation of 2-phenyl-6-methyl-3-(4-chlorophenylthio)indolizine (Formula I-14)

[0156] The reaction procedure was the same as that in Example 1, except that 2-phenylindolizine was replaced by 2-phenyl-6-methylindolizine. The isolated yield of the product 2-phenyl-6-methyl-3-(4-chlorophenylthio)indolizine was 80%.

[0157] The data of the 1H NMR spectrum of the obtained product are as follows:

[0158] 1 H NMR (400 MHz, CDCl3) 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);

[0159] The data of the 13C NMR spectrum of the obtained product are as follows:

[0160] 13 C NMR (101 MHz, CDCl3) 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.

[0161] Example 31: Preparation of 2-(p-tolyl)-3-(4-chlorophenylthio)indolizine (Formula I-15)

[0162] The reaction procedure was the same as that in Example 1, except that 2-phenylindolizine was replaced by 2-(p-tolyl)indolizine. The isolated yield of the product 2-(p-methylphenyl)-3-(4-chlorophenylthio)indolizine was 72%.

[0163] The data of the 1H NMR spectrum of the obtained product are as follows:

[0164] 1 H NMR (400 MHz, CDCl3) 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);

[0165] The data of the carbon nuclear magnetic resonance spectrum of the obtained product are as follows:

[0166] 13 C NMR (101 MHz, CDCl3) 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。

[0167] Example 32: Preparation of 2-(p-chlorophenyl)-3-(p-chlorophenylthio)indolizine (Formula I-16)

[0168] The reaction steps are the same as those in Example 1, except that 2-phenylindolizine is replaced by 2-(p-chlorophenyl)indolizine, and the isolated yield of the product 2-(p-chlorophenyl)-3-(p-chlorophenylthio)indolizine is 77%.

[0169] The data of the proton nuclear magnetic resonance spectrum of the obtained product are as follows:

[0170] 1 H NMR (400 MHz, CDCl3) 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);

[0171] The data of the carbon nuclear magnetic resonance spectrum of the obtained product are as follows:

[0172] 13 C NMR (101 MHz, CDCl3) 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。

[0173] Example 33: Preparation of 2-(p-chlorophenyl)-5-methyl-3-(p-chlorophenylthio)indolizine (Formula I-17)

[0174] The reaction steps are the same as those in Example 1, except that 2-phenylindolizine is replaced by 2-(4-chlorophenyl)-5-methylindolizine, and the isolated yield of the product 2-(4-chlorophenyl)-5-methyl-3-(4-chlorophenylthio)indolizine is 73%.

[0175] The data of the 1H NMR spectrum of the obtained product are as follows:

[0176] 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J J = 7.2 Hz, 1H), 7.53 - 7.50 (m, 2H), 7.29 (s, 2H), 7.25 (d, J 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);

[0177] The data of the 13C NMR spectrum of the obtained product are as follows:

[0178] 13 C NMR (101 MHz, CDCl3) 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

1. A method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds, characterized in that, It includes the following steps: (1) Add reaction substrates into an organic solvent containing a supporting electrolyte; The reaction substrates include indolizine compounds, thiophenols, and potassium iodide; (2) Electrify the solution obtained in step (1) to cause an electrocatalytic oxidation reaction between the reaction substrates to synthesize 3-mercaptoindolizine compounds; The structural formula of the indolizine compound is The structural formula of the thiophenol is R 3 ·SH The structural formula of the 3-mercaptoindolizine compound is Among them, R 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, heteroaryl, substituted heteroaryl, naphthyl, and substituted naphthyl; The molar concentration of the supporting electrolyte in the organic solvent in step (1) is 0.05 - 0.2 mol / L; In step (1), the molar ratio of the indolizine compound to the thiophenol and potassium iodide is 100:100 - 200:10 - 40; The molar concentration of the indolizine compound in the organic solvent is 0.005 - 0.03 mol / L; The electrolysis temperature in step (2) is 15 - 45 °C, the electrolysis voltage is 0.1 - 0.4 V, and the electrolysis time is 3 - 8 h.

2. The method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds according to claim 1, wherein The R 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 thiophenyl.

3. The method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds as claimed in claim 1, wherein The supporting electrolyte in the step (1) is one of LiClO4, n Bu4NBF4, n Bu4ClO4, and NaClO4, and the organic solvent is N,N-dimethylformamide or dimethyl sulfoxide.

4. The method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds according to claim 1 or 3, characterized in that, The supporting electrolyte in step (1) is LiClO4, and the organic solvent is N,N-dimethylformamide.

5. The method for electrocatalytic oxidation synthesis of 3-mercaptoindolizine compounds according to claim 1, characterized in that, In step (1), the molar ratio of the indolizine compound to the thiophenol and potassium iodide is 100:120 - 180:10 - 20.

6. A purification method for 3-mercaptoindolizine compounds prepared by the method according to any one of claims 1 to 5, characterized in that, It includes the following steps: (1) Take out the solution containing 3-mercaptoindolizine compounds after the electrolysis reaction, remove the solvent under reduced pressure, and then perform column chromatography separation to collect the eluate containing the target compound; (2) Remove the solvent to obtain the product 3-mercaptoindolizine compounds.

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