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CN-121991047-A - Method for synthesizing benzothiophene coupling product by nonmetal participating anchoring-migration strategy

CN121991047ACN 121991047 ACN121991047 ACN 121991047ACN-121991047-A

Abstract

The invention relates to the technical field of organic chemistry, in particular to a method for synthesizing a benzothiophene coupling product by using a non-metal participating anchor-migration strategy. The method comprises the steps of taking a benzothiophene compound or a benzothiophene sulfoxide compound as a reaction substrate, mixing the reaction substrate with an aryl nucleophilic reagent in the presence of an anhydride activator and a solvent, carrying out nucleophilic substitution reaction to obtain a benzothiophene sulfonium salt, mixing the benzothiophene sulfonium salt with an organic solvent, carrying out intramolecular migration reaction without metal catalysis, and forming a carbon-carbon bond at a C2 position of benzothiophene to obtain a benzothiophene coupling product. The preparation method has mild preparation conditions and simple and convenient operation, replaces the traditional oxidation addition-reduction elimination process by an anchoring-migration strategy, does not need noble metal catalyst, complex ligand, strong base or inert gas protection, and fundamentally solves the problems of high cost, metal residue, harsh reaction conditions and limited substrate applicability in the prior art.

Inventors

  • HUANG JIRONG
  • DENG HONGTAO
  • ZHAO CHEN

Assignees

  • 华中科技大学

Dates

Publication Date
20260508
Application Date
20260401

Claims (9)

  1. 1. A method for synthesizing a benzothiophene coupling product by a nonmetallic participation "anchor-migration" strategy, which is characterized by comprising the following steps: using a benzothiophene compound or a benzothiophene sulfoxide compound as a reaction substrate, mixing the reaction substrate with an aryl nucleophilic reagent in the presence of an anhydride activator and a solvent, and carrying out nucleophilic substitution reaction to obtain benzothiophene sulfonium salt; Wherein the aryl nucleophile is selected from 4-hydroxycoumarin, 5-chloro-4-hydroxycoumarin, 4-hydroxy-6-methylcoumarin, 4-hydroxy-6-methoxycoumarin, 6-chloro-4-hydroxycoumarin, 6-bromo-4-hydroxycoumarin, 4-hydroxy-7-methylcoumarin, 4-hydroxy-7-methoxycoumarin, 7-bromo-4-hydroxycoumarin, 4-hydroxy-8-methylcoumarin, 8-bromo-4-hydroxycoumarin, 4-hydroxy-2H-thiochroman-2-one, 4-hydroxy-1-methylquinolin-2 (1H) -one, 4-hydroxy-6-methyl-2H-pyran-2-one, 4-hydroxyquinoline, antipyrine, 2-hydroxynaphthalene-1, 4-dione, 1, 3-cyclopentanedione, 1, 3-cyclohexanedione, thiophene, toluene, anisole, piperonyl or mesitylene; Mixing benzothiophene sulfonium salt with an organic solvent, carrying out metal-free intramolecular migration reaction, and after carbon-hydrogen bond polarization of C2 position of the benzothiophene sulfonium salt, migrating alpha-carbon segment of an aryl nucleophilic reagent from sulfur atom to C2 position, simultaneously breaking C-S + bond, and finally forming new C-C bond at C2 position of the benzothiophene sulfonium salt to obtain a benzothiophene coupling product; wherein the condition of the intramolecular migration reaction is that stirring reaction is carried out for 3-24 hours at 90-150 ℃.
  2. 2. The method of claim 1, wherein the aryl nucleophile is used in an amount of 1.1 to 2.0 equivalents and the anhydride activator is used in an amount of 1.5 to 3.0 equivalents based on 1.0 equivalent of the reaction substrate.
  3. 3. The method according to claim 1, wherein the benzothiophene compound is selected from the group consisting of 。
  4. 4. The method according to claim 1, wherein the benzothiophene sulfoxide compound is selected from the group consisting of 。
  5. 5. The method according to claim 1, wherein the nucleophilic substitution reaction is carried out under stirring at-40 ℃ or-78 ℃ for 0.5h to 1h.
  6. 6. A benzothiophene coupling product prepared by the method of any one of claims 1 to 5, wherein the benzothiophene coupling product is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  7. 7. A polycyclic heteroarene compound, characterized in that the polycyclic heteroarene compound is prepared from the benzothiophene coupling product of claim 6 by a photo cyclization reaction; wherein the benzothiophene coupling product is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  8. 8. The polycyclic aromatic hydrocarbon compound according to claim 7, wherein the conditions for the cyclization reaction are that the reaction is carried out for 2 to 6 hours at room temperature under the illumination condition of wavelengths 365nm to 455nm and intensities 15W.
  9. 9. The polycyclic heteroaromatics according to claim 7, characterized in that the polycyclic heteroaromatics are 、 、 、 、 、 、 、 Or (b) 。

Description

Method for synthesizing benzothiophene coupling product by nonmetal participating anchoring-migration strategy Technical Field The invention relates to the technical field of organic chemistry, in particular to a method for synthesizing a benzothiophene coupling product by using a non-metal participating anchor-migration strategy. Background Benzothiophenes are an important class of drug core dominant frameworks, which are widely found in organic molecules with pharmacological activity. Although its derivatives exhibit diverse biological activities, there are significantly fewer cases of drugs on the market that were successfully developed based on the benzothiophene backbone, compared to the structural analog indole. The reason for this is that benzothiophenes are more inert than indoles in their chemical reactivity, and thus there are significant challenges in efficiently constructing a complex molecular library using them as the basic building blocks. Currently, direct modification of benzothiophenes is mainly dependent on transition metal catalytic systems by inert hydrocarbon bond activation and cross-coupling with halogenated aromatic hydrocarbons. Taking C2-site arylation as an example, typically, aryl bromine is adopted as a coupling reagent, and in a system of palladium/substituted 1, 10-phenanthroline complex (DPP-NNC Pd) catalysis, potassium carbonate as alkali and tertiary amyl alcohol as an additive, the reaction is carried out for 20 hours in dimethylacetamide solvent at 150 ℃, so that an aromatic ring can be introduced into the C2-site benzothiophene. Similarly, by changing the catalytic conditions, the aromatic ring can be selectively modified at the C3 position of benzothiophene, for example, the aromatic ring is used as a coupling object, pd 2(dba)3·CHCl3 is used as a catalyst, silver carbonate is used as an additive, hexafluoroisopropanol is used as a solvent, and the reaction is carried out for 16 hours, so that the C3 arylated benzothiophene derivative can be obtained with high selectivity. However, the method needs expensive palladium metal and ligand, relies on alkali or other additives, has the problems of high catalyst and ligand cost, metal residue, harsh reaction conditions, limited substrate application range and poor selectivity, and severely restricts the large-scale synthesis and development process of benzothiophene drugs. In addition, the prior studies report that the C2 and C3 arylation of benzothiophene is realized through interrupted pummerer reaction and [3,3] -migration strategies, but the substrate of the condition is mainly limited to the arylation of phenol and eneyne compounds, and the application condition is limited. Disclosure of Invention Aiming at the defects existing in the prior art, the invention provides a method for synthesizing a benzothiophene coupling product by a nonmetal-participated anchoring-migration strategy, and provides a novel preparation method for the C2-site arylation of the benzothiophene by using a benzothiophene compound or a benzothiophene sulfoxide compound as a reaction substrate, carrying out nucleophilic substitution reaction with an aryl nucleophilic reagent under the action of an anhydride activator to obtain a benzothiophene sulfonium salt, and then mixing the benzothiophene sulfonium salt with an organic solvent to realize the selective arylation of the C2-site of the benzothiophene by virtue of metal-free catalytic intramolecular migration reaction to obtain the benzothiophene coupling product. The preparation method has mild preparation conditions and simple and convenient operation, replaces the traditional oxidation addition-reduction elimination process by an anchoring-migration strategy, does not need noble metal catalyst, complex ligand, strong base or inert gas protection, fundamentally solves the problems of high cost, metal residue, harsh reaction conditions and limited substrate applicability in the prior art, and provides a green, efficient and economic preparation way for constructing the benzothiophene molecular library. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: A first object of the present invention is to provide a method for synthesizing benzothiophene coupling products by a non-metal participating "anchor-migration" strategy, comprising the steps of: S1, using a benzothiophene compound or a benzothiophene sulfoxide compound as a reaction substrate, mixing the reaction substrate with an aryl nucleophilic reagent in the presence of an anhydride activator and a solvent, and carrying out nucleophilic substitution reaction to obtain the benzothiophene sulfonium salt. In the nucleophilic substitution reaction process, the S-O bond of the benzothiophene sulfoxide compound has strong polarity, and oxygen atoms are easy to give electrons so as to enhance the electron deficiency of sulfur atoms; the electrophilic capability of the activated sulfur atom is obviously