CN109912579B

CN109912579B - Preparation method of 2, 2-disubstituted tetrahydrofuran derivative

Info

Publication number: CN109912579B
Application number: CN201910062829.7A
Authority: CN
Inventors: 王时俊; 夏桑; 唐翔鹰
Original assignee: Huazhong University of Science and Technology
Current assignee: Huazhong University of Science and Technology
Priority date: 2019-01-23
Filing date: 2019-01-23
Publication date: 2021-01-08
Anticipated expiration: 2039-01-23
Also published as: CN109912579A

Abstract

The invention provides a preparation method of 2,2-disubstituted tetrahydrofuran derivatives, and relates to the technical field of preparation of tetrahydrofuran. The present invention relates to a preparation method of 2,2-disubstituted tetrahydrofuran derivatives, comprising the following steps: preparing aromatic hydrocarbon compounds, 4-hydroxy-1-(substituent)-1-butanone, tris(pentafluorophenyl) ) borane is added to the solvent and mixed, and the reaction is carried out at 30-55 ° C; after the reaction is completed, it is purified by flash column chromatography to obtain a 2,2-disubstituted tetrahydrofuran derivative. In the present invention, a large sterically hindered boron Lewis acid catalyst is used, which is difficult to coordinate with the 2,2-disubstituted furan product to avoid the further reaction of the aromatic hydrocarbon compound with the product to generate a symmetrical biaryl derivative. The boron Lewis acid catalyst used in the present invention is an organic substance, and there is no transition metal residue in the reaction, which is beneficial to the later modification of the natural product.

Description

Preparation method of 2, 2-disubstituted tetrahydrofuran derivative

Technical Field

The invention belongs to the technical field of tetrahydrofuran preparation, and particularly relates to a preparation method of a 2, 2-disubstituted tetrahydrofuran derivative.

Background

Tetrahydrofuran derivatives are oxygen-containing heterocyclic compounds with good biological activity and pharmacological activity, and have excellent activity in the aspects of antibiosis, antitumor, coccidiosis resistance, anticancer and the like, thereby arousing great interest of medical researchers. 2, 2-disubstituted tetrahydrofuran compounds are an important class of derivatives and are receiving increasing attention. The research shows that it has the bioactivity of resisting bacteria, tumor, cancer, etc. and the annonaceous acetogenins compound has the structural unit of the compound. In addition, the 2, 2-disubstituted tetrahydrofuran compounds are easy to form various metal salts under certain conditions to form a ring structure, and become antibiotic drugs. Tetrahydrofuran compounds have been widely studied in the fields of heterocyclic chemistry, combinatorial chemistry, and the like because of their unique biological activities in medicine.

In recent years, the synthesis research of the compounds at home and abroad is active, new synthesis methods are emerging continuously, and the main synthesis methods comprise: 1) performing intramolecular addition reaction on a primary amine-secondary amine diamine catalytic system; 2) performing intramolecular cyclization reaction on the polysubstituted allene molecule under the action of a metal catalyst; 3) catalyzing three-component cycloaddition reaction of dihydrofuran, glyoxylate and a nucleophilic reagent by using Lewis acid such as titanium and the like; 4) the anthranilic acid cyanide reacts with dibromotoluene. Generally speaking, the reaction efficiency of the synthesis method is continuously improved, but the problems of long reaction time, high reaction temperature, use of transition metal catalysts, metal residues and the like still exist. Therefore, the method has the advantages of simple process steps, mild conditions, low cost and high yield. In addition, in the prior art, when 2, 2-disubstituted furan is prepared, the 2, 2-disubstituted furan product generated in the preparation process can react with aromatic hydrocarbon or aromatic hydrocarbon analogues in reactants to generate other products, so that the 2, 2-disubstituted tetrahydrofuran is mixed with other products, the mixed impurity products are difficult to separate, and the medicinal value of the 2, 2-disubstituted furan derivative is inevitably influenced in the actual use process.

In the prior art, a chlorinated railway lewis acid is commonly used as a catalyst when preparing a 2, 2-disubstituted furan derivative, taking the reaction of an indole derivative and 4-hydroxy-1- (substituent) -1-butanone as an example, the mechanism of the catalytic reaction is shown as the following formula: firstly, activating 4-hydroxy-1-substituted butanone by using iron catalyst, dewatering to obtain closed-ring oxonium ion, then making the indole and oxonium ion produce Friedel-crafts reaction so as to obtain 2, 2-disubstituted furan product. However, under the condition of iron catalysis, the furan product can be further activated, and then the furan product and indole continue to have Friedel-crafts reaction to obtain a symmetrical bis-indole product. Therefore, the yield of the 2, 2-disubstituted furan derivative is low and the purification is difficult.

Disclosure of Invention

In view of the above, the present invention provides a method for preparing a 2, 2-disubstituted tetrahydrofuran derivative, in which the 2, 2-disubstituted tetrahydrofuran derivative generated in the preparation process does not continue to react with aromatic hydrocarbon compounds, and meanwhile, the reaction temperature is not high, the conditions are mild, and the problem of metal residue is avoided.

The invention relates to a preparation method of a 2, 2-disubstituted tetrahydrofuran derivative, which comprises the following steps: adding an aromatic hydrocarbon compound, 4-hydroxy-1- (substituent) -1-butanone and tris (pentafluorophenyl) borane into a solvent, mixing, and reacting at 30-55 ℃; after the reaction is finished, the 2, 2-disubstituted tetrahydrofuran derivative is obtained by purifying through flash column chromatography.

Preferably, the molar mass ratio of the aromatic hydrocarbon compound to the 4-hydroxy-1- (substituent) -1-butanone to the tris (pentafluorophenyl) borane is 1: 1.2-1.5: 0.01-0.05.

The reaction equation of the present invention is as follows:

the aromatic compound refers to

Wherein the structural general formula of the 2, 2-disubstituted tetrahydrofuran derivative is as follows:

wherein R is¹Can be hydrogen atom, alkyl, aryl, substituted aryl, heterocyclic aryl, substituted heterocyclic aryl; r²Can be aryl, substituted aryl, heterocyclic aryl and substituted heterocyclic aryl.

The aryl or substituted aryl is one of benzene, substituted phenyl, naphthalene, biphenyl, anthracene, phenanthrene, pyrene, perylene, fluorene or spirofluorene; the heterocyclic aryl or substituted heterocyclic aryl is one of pyrrole, pyridine, furan, thiophene, carbazole, silafluorene, quinoline, isoquinoline, phthalazine, pyrimidine, pyridazine, pyrazine, phenothiazine, acridine, acridone, phenanthroline, indole, thiazole, oxadiazole, triazole, benzodiazole or benzothiazole. The substituent for the aryl or substituted aryl is a halogen, alkyl, alkoxy, amino, hydroxyl, mercapto, ester, borate, cyano, aryl, or heterocyclic substituent. The number of the substituents of the aryl group or the heterocyclic aryl group is single or plural.

Wherein the aromatic hydrocarbon can be indole, indole derivatives, aniline derivatives. The substituent group indicated by the 4-hydroxy-1- (substituent) -1-butanone in the reaction substrate may be one or more of a hydrogen atom, an alkyl group, an aryl group, a substituted aryl group, a heterocyclic aryl group, a substituted heterocyclic aryl group, and an aliphatic group, and for example, the substituent group may be a methyl group.

In addition, the solvent may be 1, 2-dichloroethane.

The mechanism of the catalytic reaction in the present invention: the boron catalyst firstly activates 4-hydroxy-1- (substituent) -1-butanone, the oxonium ions of the closed ring are obtained by dehydration, and then the aromatic hydrocarbon compounds and the oxonium ions generate Friedel-crafts reaction to obtain the 2, 2-disubstituted furan derivatives. Due to larger steric hindrance, the boron Lewis acid is difficult to coordinate with the 2, 2-disubstituted furan product, so that the 2, 2-disubstituted furan product does not continuously generate Friedel-crafts reaction with the aromatic hydrocarbon compound as a reactant, thereby avoiding the generation of side reaction products with symmetrical structures and obtaining pure 2, 2-disubstituted furan.

When aromatic hydrocarbon compounds and 4-hydroxy-1- (substituent) -1-butanone react, 4-hydroxy-1- (substituent) -1-butanone can be dehydrated to obtain closed-ring oxonium ions under the action of a catalyst, the catalyst added in the prior art has high activity, and can continuously activate furan products at low temperature or high temperature to enable the furan products to react with the aromatic hydrocarbon compounds, so that side reactions exist. The catalyst uses tris (pentafluorophenyl) borane, fluorine atoms in the tris (pentafluorophenyl) borane have a strong electron-withdrawing effect, and meanwhile, a benzene ring is arranged between the boron atoms and the fluorine atoms, so that the Lewis acidity of the catalyst can be enhanced, and the catalyst can be effectively catalyzed; in addition, three groups on the tris (pentafluorophenyl) borane are larger, the kinetic energy between molecules is lower at the lower temperature of 30-55 ℃, and the tris (pentafluorophenyl) borane catalyst is difficult to coordinate with a 2, 2-disubstituted furan product due to large steric hindrance, so that the aromatic hydrocarbon compound is prevented from further reacting with the 2, 2-disubstituted furan product to generate symmetrical bi-aromatic hydrocarbon or aromatic hydrocarbon analogue derivatives.

In the invention, a boron Lewis acid catalyst with large steric hindrance is adopted, and the boron Lewis acid catalyst is difficult to coordinate with a 2, 2-disubstituted furan product at a lower temperature of 30-55 ℃, so that an aromatic hydrocarbon compound is prevented from further reacting with the product to generate a symmetrical biaryl derivative. The boron Lewis acid catalyst adopted by the invention is an organic matter, has no residual transition metal in the reaction, and is beneficial to the later modification of natural products.

Drawings

FIG. 1 is a NMR spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -1H-indole prepared in example 1 according to the invention;

FIG. 2 is a NMR carbon spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -1H-indole prepared in example 1 according to the invention;

FIG. 3 is a NMR spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -4-hydroxy-1H-indole prepared in example 2 according to the invention;

FIG. 4 is a NMR carbon spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -4-hydroxy-1H-indole prepared in example 2 according to the invention;

FIG. 5 is a NMR spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -4-fluoro-1H-indole prepared in example 3 according to the invention;

FIG. 6 is a NMR carbon spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -4-fluoro-1H-indole prepared in example 3 according to the invention;

FIG. 7 is a NMR fluorine spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -4-fluoro-1H-indole prepared in example 3 of the invention;

FIG. 8 is a NMR spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -6-fluoro-1H-indole prepared in example 4 according to the invention;

FIG. 9 is a NMR carbon spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -6-fluoro-1H-indole prepared in example 4 according to the invention;

FIG. 10 is a NMR fluorine spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -6-fluoro-1H-indole prepared in example 4 according to the invention;

FIG. 11 is a NMR spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -7-bromo-1H-indole prepared in example 5 according to the invention;

FIG. 12 is a NMR carbon spectrum of 3- (tetrahydro-2-methyl-2-furanyl) -7-bromo-1H-indole prepared in example 5 according to the invention;

FIG. 13 is a NMR spectrum of 3- (tetrahydro-2-phenyl-2-furanyl) -1H-indole prepared in example 6 according to the invention;

FIG. 14 is a NMR carbon spectrum of 3- (tetrahydro-2-phenyl-2-furanyl) -1H-indole prepared in example 6 according to the invention;

FIG. 15 is a NMR spectrum of 1-methyl-3- (tetrahydro-2-methyl-2-furanyl) indole prepared in example 7 of the invention;

FIG. 16 is a NMR carbon spectrum of 1-methyl-3- (tetrahydro-2-methyl-2-furanyl) indole prepared in example 7 of the invention;

FIG. 17 is a NMR spectrum of 2-methyl-2- (4- (N, N-dimethylphenyl)) tetrahydrofuran prepared in example 8 of the present invention;

FIG. 18 is a NMR carbon spectrum of 2-methyl-2- (4- (N, N-dimethylphenyl)) tetrahydrofuran prepared in example 8 of the present invention;

FIG. 19 is a NMR spectrum of 2-methyl-2- (4- (N-isopropylphenyl)) tetrahydrofuran prepared in example 9 of the present invention;

FIG. 20 is a NMR carbon spectrum of 2-methyl-2- (4- (N-isopropylphenyl)) tetrahydrofuran prepared in example 9 of the present invention.

Detailed Description

The present invention will be described in detail with reference to specific embodiments.

A method for preparing a 2, 2-disubstituted tetrahydrofuran derivative comprises the following steps: the molar mass ratio of the aromatic hydrocarbon and the aromatic hydrocarbon analogue to the 4-hydroxy-1- (substituent) -1-butanone to the tris (pentafluorophenyl) borane is 1: 1.2-1.5: 0.01-0.05, adding 1, 2-dichloroethane, mixing, and reacting at 30-55 ℃; after the reaction is finished, the 2, 2-disubstituted tetrahydrofuran derivative is obtained by purifying through flash column chromatography.

Among them, the substituent is one or more of hydrogen atom, alkyl, aryl, substituted aryl, heterocyclic aryl, substituted heterocyclic aryl, and aliphatic group, and preferably, the substituent is methyl.

The aromatic hydrocarbon is one or more of indole, indole derivatives, aniline and aniline derivatives.

The reaction equation of indole, indole derivatives and 4-hydroxy-1- (substituent) -1-butanone is as follows:

wherein R can be alkyl and aryl, substituted aryl, heterocyclic aryl, substituted heterocyclic aryl; r¹May be a hydrogen atom, an alkyl group, an aryl group, a substituted aryl group, a heterocyclic aryl group, a substituted heterocyclic aryl group.

The reaction equation of aniline or an aniline derivative with 4-hydroxy-1- (substituent) -1-butanone is as follows:

wherein R can be alkyl and aryl, substituted aryl, heterocyclic aryl, substituted heterocyclic aryl; r²、 R³Can be alkyl, aryl, substituted aryl, heterocyclic aryl, substituted heterocyclic aryl.

Example 1; synthesis of 2-methyl-2- (3-indolyl) -tetrahydrofuran

117 mg (1 mmol) of indole, 122.4 mg (1.2 mmol) of 5-hydroxy-2-pentanone and 25.6 mg (0.05 mmol) of tris (pentafluorophenyl) boron were taken, added to a 10 mL reaction tube, the reaction was stirred at 30 ℃ and monitored by TLC until indole disappeared, the reaction mixture was extracted with 3X 20 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent ethyl acetate was evaporated under reduced pressure, and column chromatography (petroleum ether: ethyl acetate = 20: 1) gave 165 mg of 2-methyl-2- (3-indolyl) -tetrahydrofuran product in a yield: 82 percent. From FIGS. 1 and 2, it can be analyzed that the 2-methyl-2- (3-indolyl) -tetrahydrofuran prepared in this example is very pure, and the number of hydrogen atoms in the aromatic region is 5, which is the same as the number of aromatic hydrogen atoms in an indolyl group, indicating that there is no product as an impurity.

Example 2; synthesis of 2-methyl-2- (3- (7-methoxy) -indolyl) -tetrahydrofuran

Taking 147 mg (1 mmol) of 7-methoxyindole, 153 mg (1.5 mmol) of 5-hydroxy-2-pentanone and 5.12 mg (0.01 mmol) of tris (pentafluorophenyl) boron, adding the mixture into a 10 mL reaction tube, stirring the reaction at 55 ℃, monitoring by TLC until indole disappears, extracting the reaction mixture with 3X 20 mL ethyl acetate, combining organic phases, washing with saturated saline, drying over anhydrous sodium sulfate, evaporating the solvent ethyl acetate under reduced pressure, and performing column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 153 mg of 3- (tetrahydro-2-methyl-2-furyl) -7-methoxy-1H-indole product, wherein the yield is as follows: 66 percent. From FIGS. 3 and 4, it can be analyzed that the 2-methyl-2- (3- (7-methoxy) -indolyl) -tetrahydrofuran prepared in this example is very pure, has 5 hydrogen atoms in the aromatic region, and has the same number of aromatic hydrogen atoms as an indolyl group, indicating no impurity product.

Example 3: synthesis of 3- (tetrahydro-2-methyl-2-furyl) -4-fluoro 1H-indole

135 mg (1 mmol) of 4-fluoroindole, 132.6 mg (1.3 mmol) of 5-hydroxy-2-pentanone and 20.48 mg (0.04 mmol) of tris (pentafluorophenyl) boron were added to a 10 mL reaction tube, the reaction was stirred at 40 ℃ and monitored by TLC until indole disappeared, 3X 20 mL of ethyl acetate was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent ethyl acetate was distilled off under reduced pressure, and column chromatography (petroleum ether: ethyl acetate = 20: 1) was performed to obtain 175 mg of 3- (tetrahydro-2-methyl-2-furyl) -4-fluoro 1H-indole product, yield: 80 percent. From FIGS. 5, 6 and 7, it can be analyzed that the 3- (tetrahydro-2-methyl-2-furanyl) -4-fluoro-1H-indole prepared in this example is very pure, with 4 hydrogen atoms in the aromatic region, which is the same as the aromatic hydrogen atoms in an indolyl group, indicating no impurity product.

Example 4: synthesis of 3- (tetrahydro-2-methyl-2-furanyl) -6-fluoro-1H-indole

135 mg (1 mmol) of 6-fluoroindole, 122.4 mg (1.2 mmol) of 5-hydroxy-2-pentanone and 25.6 mg (0.05 mmol) of tris (pentafluorophenyl) boron were added to a 10 mL reaction tube, the reaction was stirred at 40 ℃, TLC was performed until indole disappeared, the reaction mixture was extracted with 3X 20 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent ethyl acetate was evaporated under reduced pressure, and column chromatography was performed (petroleum ether: ethyl acetate = 20: 1) to obtain 147 g of 3- (tetrahydro-2-methyl-2-furyl) -6-fluoro-1H-indole product, yield: 67%. From FIGS. 8, 9 and 10, it can be analyzed that the 3- (tetrahydro-2-methyl-2-furanyl) -6-fluoro-1H-indole prepared in this example is very pure, with 4 hydrogen atoms in the aromatic region, which is the same as the aromatic hydrogen atoms in one indolyl group, indicating no impurity product.

Example 5: synthesis of 3- (tetrahydro-2-methyl-2-furanyl) -7-bromo-1H-indole

196mg (1 mmol) of 7-bromoindole, 122.4 mg (1.2 mmol) of 5-hydroxy-2-pentanone and 25.6 mg (0.05 mmol) of tris (pentafluorophenyl) boron were taken and added to a 10 mL reaction tube, the reaction was stirred at 40 ℃, TLC was carried out until indole disappeared, the reaction mixture was extracted with 3X 20 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent ethyl acetate was evaporated under reduced pressure, and column chromatography was carried out (petroleum ether: ethyl acetate = 20: 1) to obtain 258 mg of 3- (tetrahydro-2-methyl-2-furyl) -7-bromo 1H-indole product, yield: 92 percent. From FIGS. 11 and 12, it can be analyzed that the 3- (tetrahydro-2-methyl-2-furanyl) -7-bromo-1H-indole prepared in this example is very pure, with 5 hydrogen atoms in the aromatic region, which is the same as the aromatic hydrogen atoms in an indolyl group, indicating no impurity product.

Example 6: synthesis of 3- (tetrahydro-2-phenyl-2-furyl) -1H-indole

117 mg (1 mmol) of indole, 197 mg (1.2 mmol) of 4-hydroxy-1-phenyl-1-butanone and 25.6 mg (0.05 mmol) of tris (pentafluorophenyl) boron were added to a 10 mL reaction tube, the reaction was stirred at 40 ℃ and monitored by TLC until indole disappeared, the reaction mixture was extracted with ethyl acetate (3X 20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent ethyl acetate was evaporated under reduced pressure, and column chromatography was performed (petroleum ether: ethyl acetate = 20: 1) to obtain 224 mg of 3- (tetrahydro-2-phenyl-2-furyl) -1H-indole product in yield: 85 percent. From FIGS. 13 and 14, it can be analyzed that the 3- (tetrahydro-2-phenyl-2-furanyl) -1H-indole prepared in this example is very pure, with 10 hydrogen atoms in the aromatic region, which is the same as the aromatic hydrogen atoms in an indolyl group, indicating no impurity product.

Example 7: synthesis of 1-methyl-3- (tetrahydro-2-methyl-2-furyl) indole

Taking 131 mg (1 mmol) of N-methylindole, 122.4 mg (1.2 mmol) of 5-hydroxy-2-pentanone and 25.6 mg (0.05 mmol) of tris (pentafluorophenyl) boron, adding the mixture into a 10 mL reaction tube, stirring the reaction at 40 ℃, monitoring by TLC until indole disappears, extracting the reaction mixture with ethyl acetate (3X 20 mL), combining organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, evaporating the solvent ethyl acetate under reduced pressure, and performing column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain 206 mg of 1-methyl-3- (tetrahydro-2-methyl-2-furyl) indole product, wherein the yield is as follows: 96 percent. From FIGS. 15 and 16, it can be analyzed that the 1-methyl-3- (tetrahydro-2-methyl-2-furanyl) indole prepared in this example is very pure, and the number of hydrogen atoms in the aromatic region is 10, which is the same as the number of aromatic hydrogen atoms in an indolyl group, indicating that there is no impurity product.

Example 8: synthesis of 2-methyl-2- (4- (N, N-dimethylphenyl)) tetrahydrofuran;

taking 121 mg (1 mmol) of N, N-dimethylaniline, 122.4 mg (1.2 mmol) of 5-hydroxy-2-pentanone and 25.6 mg (0.05 mmol) of tris (pentafluorophenyl) boron, adding the mixture into a 10 mL reaction tube, stirring the reaction at 40 ℃, monitoring by TLC until the N, N-dimethylaniline disappears, extracting the reaction mixture with ethyl acetate (3X 20 mL), combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, evaporating the solvent ethyl acetate under reduced pressure, and separating by column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain 184.5 mg of 2-methyl-2- (4- (N, N-dimethylphenyl)) tetrahydrofuran product, yield: 90 percent. From FIGS. 17 and 18, it can be analyzed that the 2-methyl-2- (4- (N, N-dimethylphenyl)) tetrahydrofuran prepared in this example is very pure, has 4 hydrogen atoms in the aromatic region, and has the same number of aromatic hydrogen atoms as that of one indolyl group, indicating no impurity product.

Example 9: synthesis of 2-methyl-2- (4- (N-isopropylphenyl)) tetrahydrofuran;

135 mg (1 mmol) of N-isopropylaniline, 122.4 mg (1.2 mmol) of 5-hydroxy-2-pentanone and 25.6 mg (0.05 mmol) of tris (pentafluorophenyl) boron were charged into a 10 mL reaction tube, the reaction was stirred at 40 ℃ and monitored by TLC until the N-isopropylaniline disappeared, the reaction mixture was extracted with ethyl acetate (3X 20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent ethyl acetate was distilled off under reduced pressure, and column chromatography (petroleum ether: ethyl acetate = 20: 1) was performed to obtain 158 mg of 2-methyl-2- (4- (N, N-diethylphenyl)) tetrahydrofuran product in a yield: 72 percent. From FIGS. 19 and 20, it can be analyzed that 2-methyl-2- (4- (N-isopropylphenyl)) tetrahydrofuran produced in this example was very pure, and the number of hydrogen atoms in the aromatic region was 4, which was the same as the number of aromatic hydrogen atoms in one indolyl group, indicating no impurity products.

In the invention, a boron Lewis acid catalyst with large steric hindrance is adopted, and the boron Lewis acid catalyst is difficult to coordinate with a 2, 2-disubstituted furan product at a lower temperature, so that aromatic hydrocarbon or aromatic hydrocarbon analogues are prevented from further reacting with the product to generate a symmetrical biaryl derivative. The boron Lewis acid catalyst adopted by the invention is an organic matter, has no residual transition metal in the reaction, and is beneficial to the later modification of the natural product. The method has the advantages of cheap and easily-obtained raw materials, simple post-treatment, environmental friendliness, high chemical selectivity of reaction and suitability for industrial production.

The present invention is not limited to the above-described specific embodiments, and various modifications and variations are possible. Any modifications, equivalents, improvements and the like made to the above embodiments in accordance with the technical spirit of the present invention should be included in the scope of the present invention.

Claims

1. a preparation method of 2,2-disubstituted tetrahydrofuran derivatives, is characterized in that, comprises the following steps: aromatic hydrocarbon compounds

, 4-hydroxy-1-(substituent)-1-butanone, and tris(pentafluorophenyl)borane were added to the solvent and mixed, and reacted at 30-55 °C; after the reaction was completed, it was purified by flash column chromatography to obtain 2,2-disubstituted tetrahydrofuran derivatives,

The reaction equation is as follows:

Wherein, R is a hydrogen atom, an alkyl group, an aryl group,

The aromatic hydrocarbon compound is one or more of indole, indole derivatives, aniline, and aniline derivatives,

The structural formula of the indole derivative is as follows:

Wherein, R ¹ is an alkyl group, an aryl group,

The structural formula of the aniline derivative is as follows:

Wherein, R ³ is an alkyl group or an aryl group.

2. The preparation method of a 2,2-disubstituted tetrahydrofuran derivative according to claim 1, wherein the aromatic hydrocarbon compound, 4-hydroxy-1-(substituent)-1-butanone The molar mass ratio of tris(pentafluorophenyl)borane is 1:1.2-1.5:0.01-0.05.

3. The preparation method of a 2,2-disubstituted tetrahydrofuran derivative according to claim 1, wherein the solvent is 1,2-dichloroethane.

4. The preparation method of a 2,2-disubstituted tetrahydrofuran derivative according to claim 3, wherein the R is a methyl group.