CN111910208B - Electrochemical synthesis method of 3-thiophenyl quinolinone - Google Patents
Electrochemical synthesis method of 3-thiophenyl quinolinone Download PDFInfo
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Abstract
The invention discloses an electrochemical synthesis method of 3-thiophenyl quinolinone. The method comprises the steps of taking a hexafluoroisopropanol solution containing 4-quinolinone, thiophenol and an iodide salt as an electrolyte, placing an iron anode and a copper cathode in the electrolyte, and introducing direct current to carry out electrochemical reaction to obtain 3-thiophenylquinolinone; the method has the advantages of mild conditions, simple and convenient operation, environmental protection, easily obtained raw materials, high reaction yield and the like.
Description
Technical Field
The invention relates to an electrochemical synthesis method of 3-thiophenyl quinolinone, in particular to a method for synthesizing 3-thiophenyl quinolinone by oxidative dehydrogenation coupling reaction of thiophenol and 4-quinolinone under the catalysis of iodide salt under the action of direct current without an external oxidant, belonging to the technical field of organic intermediate synthesis.
Background
The 3-thiophenyl quinolinone and the derivative thereof have wide biological activity and play an important role in the field of drug research and development. Methods for synthesizing 3-phenylthioquinolinone and Derivatives thereof using diphenyl disulfide as a sulfurizing agent have been reported in various documents, but diphenyl disulfide generally requires the preparation of thiophenol as a starting material, such as (Chengcai Xia, Zhenjiang Wei, Yong Yang, Wenbo Yu, Hanxiao Liao, Chao Shen, Pengfei Zhang, Palladium-catalyst Thioetherification of Quinolone Devative via Decboxyla) C-S Cross-Coulings, chem.Asian J.,2016,11(3): 360-containing amino acid, Tao Guo, Ammonium-mediated catalytic synthesis reaction chain reaction of microorganisms with hydrolytic cleavage and degradation, Synthron, Ammonium-mediated reaction chain reaction of microorganisms with cleavage, and degradation, synthesis, 22, 2017, 35-containing reaction product, 25, modification
Thiophenol is a very readily available raw material, and the C-H/C-S oxidative dehydrogenation coupling reaction of 4-quinolinone and thiophenol is one of the ideal methods for directly preparing 3-arylthioquinolinone and derivatives thereof. However, only Sajal Das in India reports that dimethyl sulfoxide is used as a solvent, 3 times equivalent of tert-butyl peroxy alcohol (TBHP) is used as an oxidant, 3 times equivalent of sodium iodide is used as a promoter, and the oxidative dehydrogenation reaction of thiophenol and 2-substituted quinolinone is promoted to generate a 3-thiophenyl quinolinone compound (J.Org.chem.,2018,83, 12411-12419) under the high temperature condition of 100 ℃, as shown in the following reaction formula (a). The method is only suitable for the 2-substituted quinolinone substrate, needs to use excessive iodized salt, oxidant and thiophenol, has high reaction cost and large difficulty in separation and purification, and has safety problem in large-scale reaction.
Disclosure of Invention
Aiming at the defects of the method for synthesizing 3-thiophenyl quinolinone in the prior art, the invention aims to provide the electrochemical synthesis method of 3-thiophenyl quinolinone, which does not need to add oxidant and electrolyte, obtains the 3-thiophenyl quinolinone under mild conditions with high selectivity and high yield, has high reaction atom efficiency, low cost, environmental friendliness, simple separation and no need of chromatographic purification, and is beneficial to industrial production and application.
In order to achieve the technical purpose, the invention provides an electrochemical synthesis method of 3-thiophenylquinolinone, which comprises the steps of taking hexafluoroisopropanol solution containing 4-quinolinone, thiophenol and iodide as electrolyte, placing an iron anode and a copper cathode in the electrolyte, and introducing direct current to carry out electrochemical reaction to obtain the product.
The 4-quinolinone has the structure of formula 1:
the thiophenol has the structure of formula 2:
PhSH
formula 2
The 3-thiophenylquinolinone has the structure of formula 3:
as a preferred scheme, the iron anode is a foam iron electrode; the copper cathode is a foam copper electrode. The choice of electrode pair is important for the efficiency of the oxidative dehydrogenation coupling reaction between thiophenol and 4-quinolinone. Iron electrodes, copper electrodes, platinum electrodes or graphite electrodes can be selected as the anode and the cathode, and oxidative dehydrogenation coupling reaction between thiophenol and 4-quinolinone can be realized, but a large number of experiments show that when the iron electrodes are selected as the anode and the copper electrodes are selected as the cathode, the reaction effect is better than that of other electrodes. Particularly, when the anode is made of foam iron and the cathode is made of foam copper, the reaction effect is best, the specific surface area of the foam iron and the foam copper is large, more active sites are provided, and the reaction activity is higher than that of a common iron electrode and a common copper electrode.
As a preferred embodiment, the iodine salt is at least one of tetraalkylammonium iodide, ammonium iodide, sodium iodide and potassium iodide. As a preferred embodiment, the iodide salt is sodium iodide. The alkyl group in tetraalkylammonium iodides is generally a short chain alkyl group, commonly C1～C4Linear alkyl group of (1).
In a preferred embodiment, the amount of the iodonium salt is 5-15% of the molar amount of the 4-quinolinone.
In a preferable mode, the molar ratio of the 4-quinolinone to the thiophenol is 1: 0.8-1.2. 4-quinolinone and thiophenol can react according to the molar ratio to obtain higher yield, excessive thiophenol is not needed, the cost of raw materials is greatly reduced, and the separation process of subsequent products is simplified.
As a preferred scheme, the conditions of the electrochemical reaction are as follows: under the condition of room temperature, the direct current is introduced to 12-20 mA for 15-25 hours. The direct current is in a range of 12-20 mA, the yield of the target product reaches the highest when the current is increased to 16mA, the yield of the target product slightly decreases when the current is further increased, and the target product cannot be obtained basically when the current is less than 8 mA. Therefore, the current for the oxidative dehydrogenation coupling reaction between thiophenol and 4-quinolinone should be controlled within 12-20 mA, preferably 14-18 mA.
Preferably, the concentration of the 4-quinolinone in the electrolyte is 0.2-0.8 mol/L.
As a preferable scheme, after the electrochemical reaction is finished, adding excessive water into the electrolyte, precipitating 3-thiophenyl quinolinone crystals, and filtering to obtain the 3-thiophenyl quinolinone. Excess water means that the volume of water is not less than the volume of solvent in the electrolyte. The technical scheme of the invention has the characteristic of easy separation of target products.
The route of the dehydrogenation cross-coupling reaction of 4-quinolinone and thiophenol is as follows:
the invention also provides a reaction mechanism for synthesizing the 3-thiophenyl quinolinone compound. The iodine negative ions lose electrons on the surface of the anode and are oxidized to generate molecular iodine, and the molecular iodine reacts with the thiophenol (2) to generate iodine negative ions and a thiophenyl positive ion intermediate (4). The intermediate (4) reacts with the quinolinone (1) to generate an active sulfonium ion intermediate (5), and the intermediate (5) is easily converted into an imine positive ion intermediate (6). The intermediate 6 is easy to generate dehydroaromatization to generate a more stable target product 3-thiophenyl quinolinone compound (3). And the electrons obtained by the protons on the cathode surface are reduced to generate hydrogen.
Compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:
1) the invention adopts electrons as traceless oxidant, is safe, cheap and easy to obtain;
2) the invention does not use transition metal catalyst and oxidant, has high reaction selectivity, easy separation and purification of the product and high yield.
3) The method has mild reaction conditions, can be carried out at room temperature, is easy to separate and purify the product, is simple to operate, and is beneficial to large-scale production.
4) The 4-quinolinone compound and the thiophenol can be quantitatively reacted in a ratio of 1:1, excessive thiophenol is not needed, and high yield can be obtained, so that the raw material cost is saved, and the subsequent product separation difficulty can be reduced.
Detailed Description
The following specific examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.
Example 1
The specific operation steps are as follows: in a 25mL three-necked round-bottomed flask, 4-quinolinone (5mmol), thiophenol (5mmol), sodium iodide (0.5mmol), hexafluoroisopropanol (10mL), a 15 mm. times.15 mm. times.4 mm foam iron electrode as an anode and a 15 mm. times.15 mm. times.4 mm foam copper electrode as a cathode were added in this order. And stirring the obtained mixed solution in 16mA direct current for reaction at room temperature for 20 hours, adding 10mL of water product after the reaction is finished, precipitating, filtering and drying to obtain a pure product.
1H NMR(400MHz,CDCl3)δ7.08–7.14(m,3H),7.23(t,J＝7.8Hz,2H),7.41(t,J＝7.8Hz,1H),7.62(d,J＝7.8Hz,1H),7.68–7.72(m,1H),8.12(d,J＝7.8Hz,1H),8.39(d,J＝6.0Hz,1H),12.32(d,J＝5.2Hz,1H)
13C NMR(100MHz,CDCl3)δ109.4,118.5,124.0,125.0,125.1,125.4,126.4,128.9,132.1,137.6,139.8,145.4,174.8。
Comparative example 1
The following control experiment groups 1 to 23 are processes for searching and screening the optimal reaction conditions of 4-quinolinone and thiophenol, the reaction conditions of example 1 are the optimal reaction conditions, the optimal reaction conditions are used as standard reaction conditions, the experimental results are compared,
the specific operation steps are as follows: adding 4-quinolinone (5mmol), thiophenol (5mmol), an iodine reagent (0.05-0.1 equiv.), a solvent (10mL) into a 25mL three-neck round-bottom flask in sequence, placing an anode and a cathode, stirring the obtained mixed solution at room temperature and under the condition of 8-20 mA direct current for reaction, tracking the reaction process by using a thin layer chromatography plate, reacting for 20 hours, and analyzing the yield by using nuclear magnetic crude spectrum.
The following control experiment groups 1 to 23 are described by comparison with reference to standard reaction conditions:
a platinum sheet electrode: 15mm × 15mm × 0.3 mm;
iron sheet, copper sheet electrode: 15mm × 15mm × 1 mm;
a graphite sheet electrode: 15mm × 15mm × 3 mm;
foam iron electrode, foam copper electrode: 15mm × 15mm × 4 mm;
in the table, experiment groups 1-5 investigate the influence of a reaction medium on the oxidative dehydrogenation coupling reaction of 4-quinolinone and thiophenol, and experiments show that the reaction can not be smoothly carried out by adopting methanol and acetone as reaction solvents; when N, N-dimethylformamide and dimethyl sulfoxide are used as reaction solvents, moderately low reaction yield can be obtained, and hexafluoroisopropanol is the best reaction solvent for the reaction, which shows that the reaction is sensitive to the solvent, and higher yield can be obtained only by using special hexafluoroisopropanol as a reaction medium, which is unexpected.
In the table, experiment groups 1, 6-13 investigate the influence of different electrode materials on the oxidative dehydrogenation coupling reaction of 4-quinolinone and thiophenol, and experiments show that the contact area of the same metal material electrode and the reactant is large, so that the reaction effect is better than that of a metal sheet electrode; the method adopts foamed iron, iron sheet, foamed copper, platinum sheet or graphite sheet as the anode and foamed iron, copper sheet, foamed copper, platinum sheet or graphite sheet as the cathode, but the reaction effect is best when the foamed iron is adopted as the anode and the foamed copper is adopted as the cathode, so the foamed iron as the anode and the foamed copper as the cathode are the best electrode pair for the reaction.
In the above table, experiment groups 1 and 14-16 investigate the influence of an iodide catalyst on the oxidative dehydrogenation coupling reaction of 4-quinolinone and thiophenol, and experiments show that the reaction can be smoothly carried out when sodium iodide, potassium iodide, tetrabutylammonium iodide or ammonium iodide is used as the catalyst, and sodium iodide is the best catalyst for the reaction.
In the table, experiment groups 1 and 17-18 investigate the influence of the usage amount of sodium iodide on the oxidative dehydrogenation coupling reaction of 4-quinolinone and thiophenol, and experiments show that the usage amount of 0.1 time equivalent of sodium iodide is the optimal usage amount of the reaction, the usage amount of sodium iodide is lower than 0.1 time equivalent, the yield of the target product is obviously reduced, and the yield is not increased basically when the usage amount of sodium iodide is higher than 0.1 time equivalent.
In the table, experiment groups 1 and 19-21 investigate the influence of direct current intensity on oxidative dehydrogenation coupling reaction of 4-quinolinone and thiophenol, increase the current intensity and do not improve the reaction yield; the current intensity is reduced to 12mA, and the yield is obviously reduced; the current intensity is continuously reduced to 8mA, and the reaction can not be carried out; experiments have shown that a direct current of 16mA is the optimum current intensity for the reaction.
The experimental group 22 in the above table considers the effect of iodide on the oxidative dehydrogenation coupling reaction of 4-quinolinone and thiophenol, and experiments show that the reaction cannot occur under the condition without iodide, which indicates that an iodide salt catalyst is a necessary condition for the reaction.
The effect of current on the oxidative dehydrogenation coupling reaction of 4-quinolinone with thiophenol was examined by panel 23 in the above table, which indicated that the reaction could not occur in the absence of current.
Claims (8)
1. An electrochemical synthesis method of 3-thiophenyl quinolinone is characterized in that: taking a hexafluoroisopropanol solution containing 4-quinolinone, thiophenol and an iodonium salt as an electrolyte, placing an iron anode and a copper cathode in the electrolyte, and introducing direct current to carry out electrochemical reaction to obtain the copper-doped lithium iron phosphate electrolyte; the conditions of the electrochemical reaction are as follows: under the condition of room temperature, the direct current is introduced to 12-20 mA for 15-25 hours.
2. The electrochemical synthesis method of 3-thiophenyl quinolinone as claimed in claim 1, characterized in that: the iron anode is a foam iron electrode; the copper cathode is a foam copper electrode.
3. The electrochemical synthesis method of 3-thiophenyl quinolinone as claimed in claim 1, characterized in that: the iodine salt is at least one of tetraalkylammonium iodide, ammonium iodide, sodium iodide and potassium iodide.
4. The electrochemical synthesis method of 3-thiophenyl quinolinone as claimed in claim 3, characterized in that: the iodine salt is sodium iodide.
5. The electrochemical synthesis method of 3-thiophenylquinolinone as claimed in claim 1, 3 or 4, wherein: the dosage of the iodized salt is 5-15% of the molar weight of the 4-quinolinone.
6. The electrochemical synthesis method of 3-thiophenyl quinolinone as claimed in claim 1, characterized in that: the molar ratio of the 4-quinolinone to the thiophenol is 1: 0.8-1.2.
7. The electrochemical synthesis method of 3-thiophenyl quinolinone as claimed in claim 1, characterized in that: the concentration of the 4-quinolinone in the electrolyte is 0.2-0.8 mol/L.
8. The electrochemical synthesis method of 3-thiophenyl quinolinone as claimed in claim 1, characterized in that: and after the electrochemical reaction is finished, adding excessive water into the electrolyte, separating out 3-thiophenyl quinolinone crystals, and filtering to obtain the 3-thiophenyl quinolinone.
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