阅读说明：本技术 一种利用电化学微通道反应装置连续制备2-芳基-3-卤代-苯并噻吩类化合物的方法 (Method for continuously preparing 2-aryl-3-halogenated-benzothiophene compound by using electrochemical microchannel reaction device ) 是由 郭凯 蔡谨琳 方正 张东 何伟 朱宁 张锴 欧阳平凯 于 2019-11-07 设计创作，主要内容包括：本发明公开了一种利用电化学微通道反应装置连续制备2-芳基-3-卤代-苯并噻吩类化合物的方法,将炔基苯甲硫醚类原料与含碘或含溴的电解质溶解在水和乙腈中制成均相溶液A,然后将制得的均相溶液A利用注射泵单股进样通入电化学微通道反应装置的进料口,在直流电源作用下,反应得到产物2-芳基-3-卤代-苯并噻吩类化合物；电化学微通道反应装置包括阳极电极、阴极电极、电解池支架、反应槽、直流电源以及温度控制模块；所述反应槽位于阳极电极和阴极电极之间,并在阳极电极和阴极电极之间形成一封闭的蛇形流动路径；所述阳极电极和阴极电极安装在电解池支架上；阳极电极和阴极电极的一端相互连接,并与直流电源连接；所述温度控制模块镶嵌在电解池支架内,用于控制反应槽内液体的温度。(The invention discloses a method for continuously preparing 2-aryl-3-halogenated-benzothiophene compounds by using an electrochemical microchannel reaction device, comprising the steps of dissolving alkynyl benzene methyl sulfide raw materials and iodine-containing or bromine-containing electrolyte in water and acetonitrile to prepare a homogeneous solution A, introducing the prepared homogeneous solution A into a feed inlet of the electrochemical microchannel reaction device by using a single-strand sample injection of a syringe pump, and reacting under the action of a direct-current power supply to obtain a product 2-aryl-3-halogenated-benzothiophene compound; the electrochemical microchannel reaction device comprises an anode electrode, a cathode electrode, an electrolytic cell bracket, a reaction tank, a direct current power supply and a temperature control module; the reaction tank is positioned between the anode electrode and the cathode electrode, and a closed serpentine flow path is formed between the anode electrode and the cathode electrode; the anode electrode and the cathode electrode are arranged on the electrolytic cell bracket; one ends of the anode electrode and the cathode electrode are mutually connected and are connected with a direct current power supply; the temperature control module is embedded in the electrolytic cell bracket and is used for controlling the temperature of liquid in the reaction tank.)

1. A method for continuously preparing 2-aryl-3-halogeno-benzothiophene compounds by using an electrochemical microchannel reaction device is characterized in that alkynyl benzene methyl sulfide raw materials and iodine-containing or bromine-containing electrolytes are dissolved in water and acetonitrile to prepare a homogeneous solution A, the prepared homogeneous solution A is introduced into a feed inlet of the electrochemical microchannel reaction device by single-strand sample injection of a syringe pump, and the reaction is carried out under the action of a direct current power supply to obtain a product 2-aryl-3-halogeno-benzothiophene compound;

the electrochemical microchannel reaction device comprises an anode electrode, a cathode electrode, an electrolytic cell bracket, a reaction tank, a direct current power supply and a temperature control module; the reaction tank is positioned between the anode electrode and the cathode electrode, and a closed serpentine flow path is formed between the anode electrode and the cathode electrode; the anode electrode and the cathode electrode are arranged on the electrolytic cell bracket; one ends of the anode electrode and the cathode electrode are mutually connected and are connected with a direct current power supply; the temperature control module is embedded in the electrolytic cell bracket and is used for controlling the temperature of liquid in the reaction tank.

2. The method for continuously preparing 2-aryl-3-halo-benzothiophenes using an electrochemical microchannel reaction device as claimed in claim 1, wherein the alkynylbenzyl sulfide is 2-phenylethynyl benzylsulfide, 2- (4-methylphenylethynyl) benzylsulfide, 2- (4-fluorophenylethynyl) benzylsulfide, 2- (4-chlorophenylethynyl) benzylsulfide, 2- (4-bromophenylethynyl) benzylsulfide, 2- (4-methoxyphenylethynyl) benzylsulfide, 2- (4-nitrophenylethynyl) benzylsulfide, 2- (4-ethylphenylethynyl) benzylsulfide, 2- (4-carbomethoxyphenylethynyl) benzylsulfide, 2- (4-carboxyphenylethynyl) benzylsulfide, 2-halobenzothiophene, 2-alkynylbenzyl-thioethers, 2-phenylethynyl-iodoxymethyl sulfide, 2-carboxyethynyl, 2- (4-trifluoromethylphenylethynyl) thioanisole, 2- (3-methylphenylethynyl) thioanisole, 2- (3-fluorophenylethynyl) thioanisole, 2- (3-chlorophenylethynyl) thioanisole, 2- (3-bromophenylethynyl) thioanisole, 2- (3-thiophene) ethynylthioanisole, 2- (2-methylphenylethynyl) thioanisole, 2- (2-fluorophenylethynyl) thioanisole, 2- (2-chlorophenylethynyl) thioanisole, 2- (2-bromophenylethynyl) thioanisole, 2- (2-thiophene) ethynylthioanisole, 2- (cyclopropylethynyl) thioanisole, 2- (cyclohexylphenylethynyl) thioanisole, 2- (3-methylphenylethynyl) thioanisole, 2- (3-fluorophenylethynyl) thioanisole, 2- (3-fluorophenyl, Any one of 2- (hexynyl) thioanisole and 2- (octynyl) thioanisole;

the iodine-containing electrolyte is KI, NaI and Bu₄NI or Et₄NI, bromine-containing electrolyte is KBr.

3. The method for continuously preparing the 2-aryl-3-halo-benzothiophene compound by using the electrochemical microchannel reaction device as claimed in claim 2, wherein the molar ratio of the alkynyl thiobenzophenone raw material to the iodine-or bromine-containing electrolyte is 1:1 to 1: 3.

4. The method for continuously preparing the 2-aryl-3-halo-benzothiophene compound by using the electrochemical microchannel reaction device as claimed in claim 1, wherein the volume ratio of the acetonitrile to the water is 3-6: 1.

5. The method for continuously preparing 2-aryl-3-halo-benzothiophenes compounds using an electrochemical microchannel reaction device according to claim 3, wherein the concentration of the alkynyl thiobenethione raw material in the homogeneous solution A is 0.02-0.05 mmol/ml.

6. The method for continuously preparing the 2-aryl-3-halogenated-benzothiophene compound by using the electrochemical microchannel reaction device as claimed in claim 5, wherein the flow rate of single-strand sample injection of the homogeneous solution A is 0.03-0.1 ml/min.

7. The method for continuously preparing 2-aryl-3-halo-benzothiophenes using an electrochemical microchannel reaction device as claimed in claim 1, wherein the anode electrode is a carbon sheet or a platinum sheet; the cathode electrode is plated with platinum-titanium alloy.

8. The method for continuously preparing 2-aryl-3-halo-benzothiophenes using an electrochemical microchannel reaction device as claimed in claim 1, wherein the reaction tank is made of polytetrafluoroethylene and has a volume of 0.1-1.0 ml.

9. The method for continuously preparing 2-aryl-3-halo-benzothiophenes using an electrochemical microchannel reaction device as claimed in claim 1, wherein said anode electrode and said cathode electrode are fixed by screws made of teflon.

10. The method for continuously preparing 2-aryl-3-halo-benzothiophenes using an electrochemical microchannel reaction device as claimed in claim 1, wherein the specification of said direct current power supply is 5A, 30V; the current of the reaction flow acting in the micro-channel is controlled between 10 and 20 mA.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a method for continuously preparing 2-aryl-3-halogeno-benzothiophene compounds by using an electrochemical microchannel reaction device.

Background

Benzothiophenes and their derivatives are an important class of heterocyclic compounds that have been widely used in the pharmaceutical industry. Such as antimicrobial agents, antiviral agents, antidepressants, antifungal agents, anti-inflammatory agents, analgesics, estrogen receptor mediators, and the like. Of these, C-2 and C-3 substituted benzothiophenes are particularly important because such scaffolds are widely present in many drug and drug candidate structures. Organic halides are not only valuable building blocks in many pharmaceutical or natural molecules, but also key to the synthesis of fine chemicals by transition metal catalyzed oxidation/reduction cross-coupling reactions. Over the last few years, the introduction of halogens at the C-3 position of benzothiophenes has attracted considerable attention.

Until recently, electrophilic cyclization of 2-phenylethynyl thioanisole proved to be an effective route to 3-halobenzothiophenes. Larock and colleagues reported as I₂The synthesis of 3-halogenobenzothiophene as electrophilic reagent. Kesharwani and coworkers reported copper-mediated electrophilic cyclization reactions and synthesized 3-halobenzothiophenes using sodium halide as the source of halogen atoms. However, in those processes, some less environmentally friendly reagents are used, such as iodine and phenylselenium, which are toxic and corrosive, and certain transition metal catalysts. Therefore, a practical, efficient and environmentally friendly method has been developedThe synthesis of such compounds is of great value.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a method for continuously preparing 2-aryl-3-halogeno-benzothiophene compounds by utilizing an electrochemical microchannel reaction device, so as to solve the problems of environmental pollution, high design requirement on a reactor, poor selectivity, high energy consumption and the like in the prior art.

In order to achieve the above-mentioned problem, the technical solution adopted by the present invention is as follows:

a method for continuously preparing 2-aryl-3-halogeno-benzothiophene compounds by using an electrochemical microchannel reaction device comprises the steps of dissolving alkynyl benzene methyl sulfide raw materials and iodine-containing or bromine-containing electrolytes in water and acetonitrile to prepare a homogeneous solution A, introducing the prepared homogeneous solution A into a feed inlet of the electrochemical microchannel reaction device by single-strand sample injection of a syringe pump, and reacting under the action of a direct current power supply to obtain a product 2-aryl-3-halogeno-benzothiophene compound;

the electrochemical microchannel reaction device comprises an anode electrode, a cathode electrode, an electrolytic cell bracket, a reaction tank, a direct current power supply and a temperature control module; the reaction tank is positioned between the anode electrode and the cathode electrode, and a closed serpentine flow path is formed between the anode electrode and the cathode electrode; the anode electrode and the cathode electrode are arranged on the electrolytic cell bracket; one ends of the anode electrode and the cathode electrode are mutually connected and are connected with a direct current power supply; the temperature control module is embedded in the electrolytic cell bracket and controls the temperature of liquid in the reaction tank through the RTD resistance.

Specifically, the alkynyl methylthiophene ether raw material is 2-phenylethynyl thioanisole, 2- (4-methylphenylethynyl) thioanisole, 2- (4-fluorophenylethynyl) thioanisole, 2- (4-chlorophenylethynyl) thioanisole, 2- (4-bromophenylethynyl) thioanisole, 2- (4-methoxyphenylethynyl) thioanisole, 2- (4-nitrophenylethynyl) thioanisole, 2- (4-ethylphenylethynyl) thioanisole, 2- (4-carbomethoxyphenylethynyl) thioanisole, 2- (4-trifluoromethylphenylethynyl) thioanisole, 2- (3-methylphenylethynyl) thioanisole, 2- (3-fluorophenylethynyl) thioanisole, 2- (4-bromophenylethynyl) thioanisole, or, Any one of 2- (3-chlorophenylethynyl) thioanisole, 2- (3-bromophenylethynyl) thioanisole, 2- (3-thiophene) ethynylthioanisole, 2- (2-methylphenylethynyl) thioanisole, 2- (2-fluorophenylethynyl) thioanisole, 2- (2-chlorophenylethynyl) thioanisole, 2- (2-bromophenylethynyl) thioanisole, 2- (2-thiophene) ethynylthioanisole, 2- (cyclopropylethynyl) thioanisole, 2- (cyclohexylphenylethynyl) thioanisole, 2- (hexynyl) thioanisole, and 2- (octynyl) thioanisole;

the iodine-containing electrolyte is KI, NaI and Bu₄NI or Et₄NI, bromine-containing electrolyte is KBr.

Specifically, the molar ratio of the alkynyl phenyl methyl sulfide raw material to the iodine or bromine-containing electrolyte is 1: 1-1: 3, and the preferable molar ratio is 1: 2.

Specifically, the volume ratio of the acetonitrile to the water is 3-6: 1, and preferably 5: 1.

Specifically, the concentration of the alkynyl phenyl methyl sulfide raw material in the homogeneous solution A is 0.02-0.05 mmol/ml, preferably 0.03 mmol/ml.

Specifically, the flow rate of single-strand sample injection of the homogeneous solution A is 0.03-0.1 ml/min, and the preferable flow rate is 0.05 ml/min.

Specifically, the anode electrode is a carbon sheet or a platinum sheet; the cathode electrode is plated with platinum-titanium alloy.

Specifically, the reaction tank is made of polytetrafluoroethylene, and the volume of the reaction tank is 0.1-1.0 ml, and the optimal volume is 0.1 ml.

Specifically, the anode electrode and the cathode electrode are fixed through a screw, and the screw is made of polytetrafluoroethylene.

Specifically, the specification of the direct current power supply is 5A, 30V; the current of the reaction flow acting in the microchannel is controlled to be 10-20 mA, the preferred current of the 2-aryl-3-iodine-benzothiophene compound is 16mA, and the preferred current of the 2-aryl-3-bromine-benzothiophene compound is 20 mA.

Electrochemical anodic oxidation provides an efficient and environmentally friendly synthesis for C-H functionalization as an ideal alternative to chemical oxidants. With increasing attention to electrochemistry, electrochemical oxidation, for example, for the construction of C-C, C-N, C-O and C-S bonds, has made considerable progress.

Inspired by these outstanding studies on electrochemical synthesis, the present application carried out a study by reacting 2-phenylethynyl benzylsulfide with KI at constant current using a graphite anode and a platinum cathode. In the reaction, KI was selected not only as an iodine source but also as an electrolyte, and CH was used₃CN/H₂O (v/v ═ 5/1) as a solvent. Good yields of 2-aryl-3-halo-benzothiophenes were obtained at a constant current of 16 mA. Flow chemistry has been strongly driven by the advent of continuous micro-processing technology, which is likely to exceed batch processing limits. Continuous flow systems provide short diffusion paths by increasing the contact area, improve quality and heat transfer rates, and result in higher yields and more uniform particle distribution compared to conventional batch reactors. Thus, the present application applies the reaction to a continuous flow microreactor.

Has the advantages that:

compared with the prior art, (1) the invention utilizes green electrooxidation to synthesize the 2-aryl-3-halogeno-benzothiophene compound with high efficiency and high selectivity by a continuous flow technology; compared with the common reaction, the reaction is green, environment-friendly and efficient; (2) compared with the common reaction time, the method for continuously preparing the 2-aryl-3-halogeno-benzothiophene compound by using the electrochemical micro-reaction device has the advantages of shortened reaction time, improved reaction yield, stable product, easy operation, low reaction temperature, high safety, continuous and uninterrupted production, capability of effectively overcoming the defects of the traditional reaction kettle and good industrial application prospect. (3) The product yield of the invention is as high as 98.2%.

Drawings

The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.

FIG. 1 is a schematic view of an electrochemical microchannel reaction apparatus and a preparation process thereof.

FIG. 2 is a photograph showing a reaction vessel in the electrochemical microchannel reactor of the present invention.

FIG. 3 is a NMR spectrum of 2-phenyl-3-iodo-benzothiophene prepared in example 1.

FIG. 4 is a NMR carbon spectrum of 2-phenyl-3-iodo-benzothiophene prepared in example 1.

FIG. 5 is a graph of the redox potential of Cyclic Voltammetry (CV).

Detailed Description

The invention will be better understood from the following examples.

The structures, proportions, and dimensions shown in the drawings and described in the specification are for understanding and reading the present disclosure, and are not intended to limit the scope of the present disclosure, which is defined in the claims, and are not essential to the skilled in the art. In addition, the terms "upper", "lower", "front", "rear" and "middle" used in the present specification are for clarity of description, and are not intended to limit the scope of the present invention, and the relative relationship between the terms and the relative positions may be changed or adjusted without substantial technical changes.

First, the redox potential of the substrate was investigated by Cyclic Voltammetry (CV) experiments. Cyclic voltammograms of 1a, KI, KBr, KCl were performed at room temperature under nitrogen in a three electrode cell connected to a schlenk wire. The working electrode is a stable glassy carbon disk electrode and the counter electrode is a platinum wire. The reference is an Ag/AgCl electrode immersed in a saturated aqueous KCl solution. (1) In cyclic voltammetry experiments, 1a (0.4mmol) and a mixture containing n-Bu₄NBF₄(0.8mmol) of a mixed solvent (CH)₃CN/H₂O-5/1, 12mL) was poured into the electrochemical cell. The scan rate was 0.10V/s, ranging from 0V to 2.5V. (2) KI (0.4mmol) and a mixture containing n-Bu₄NBF₄(0.8mmol) of a mixed solvent (CH)₃CN/H₂O-5/1, 12mL) was used to inject electrochemical cells in cyclic voltammetry experiments. The scan rate was 0.10V/s, ranging from 0V to 2.5V. (3) KBr (0.4mmol) and a solution containing n-Bu₄NBF₄(0.8mmol) of a mixed solvent (CH)₃CN/H₂O-5/1, 12mL) was used to inject electrochemical cells in cyclic voltammetry experiments. The scan rate was 0.10V/s, ranging from 0V to 2.5V. (4) KCl (0.4mmol) and n-Bu₄NBF₄(0.8mmol) of a mixed solvent (CH)₃CN/H₂O-5/1, 12mL) was used to inject electrochemical cells in cyclic voltammetry experiments. The scan rate was 0.10V/s, ranging from 0V to 2.5V. (5)1a (0.4mmol) + KI (0.8mmol) and mixed solvent (CH)₃CN/H₂O-5/1, 12mL), where n-in cyclic voltammetry experiments, Bu₄NBF₄(0.8mmol) was poured into an electrochemical cell. The scan rate was 0.10V/s, ranging from 0V to 2.5V.

As a result, as shown in FIG. 5, the oxidation peaks of KI and KBr were observed at 0.79V and 1.24V, respectively, while the oxidation peak of 2-phenylethynylthioanisole (1a) was observed at 1.83V. This phenomenon suggests that KI and KBr are preferentially oxidized at the anode. In addition, KCl was also detected in this experiment, and the oxidation peak of KCl was detected at 2.07V, indicating that no 3-chlorinated product could be obtained in this conversion.