阅读说明：本技术 2-三氟甲基苯并呋喃衍生物的合成方法 (Synthesis method of 2-trifluoromethyl benzofuran derivative ) 是由 贺世瑜 张兴国 张小红 于 2019-10-22 设计创作，主要内容包括：本发明涉及一种2-三氟甲基苯并呋喃衍生物的合成方法,包括以下步骤：以1-溴-2-(2-氯-3,3,3-三氟丙-1-烯-1-基)苯为反应底物,氢氧化钾为氧源,磷酸钾作碱,碘化亚铜作催化剂,1,10-菲啰啉作配体,二甲基亚砜作溶剂,于80-100℃氮气条件下,搅拌反应10-12小时。具有反应条件温和,原料简单易得,制备工艺新颖、污染少、耗能低的优点。(The invention relates to a synthetic method of a 2-trifluoromethyl benzofuran derivative, which comprises the following steps: taking 1-bromo-2- (2-chloro-3, 3, 3-trifluoropropyl-1-en-1-yl) benzene as a reaction substrate, potassium hydroxide as an oxygen source, potassium phosphate as a base, cuprous iodide as a catalyst, 1, 10-phenanthroline as a ligand and dimethyl sulfoxide as a solvent, and stirring for reaction for 10-12 hours at 80-100 ℃ under the condition of nitrogen. Has the advantages of mild reaction conditions, simple and easily obtained raw materials, novel preparation process, less pollution and low energy consumption.)

1. A method for synthesizing 2-trifluoromethyl benzofuran derivatives comprises the following steps: taking 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene as a reaction substrate, potassium hydroxide as an oxygen source, sodium carbonate, cesium carbonate, potassium tert-butoxide or potassium phosphate as alkali, cuprous chloride, cuprous bromide, thiophene-2-copper formate or cuprous iodide as a catalyst, 1, 10-phenanthroline as a ligand, and acetonitrile, N-dimethylformamide or dimethyl sulfoxide as a solvent, and stirring at 80-110 ℃ for reaction for 10-12 hours, wherein the chemical reaction formula is as follows:

and the-R is one of hydrogen, 4-methyl, 5-methoxyl, 4-fluorine, 4-chlorine, 5-bromine and 5-trifluoromethyl.

2. The method for synthesizing 2-trifluoromethylbenzofuran derivative according to claim 1, wherein: the catalyst is cuprous iodide.

3. The method for synthesizing 2-trifluoromethylbenzofuran derivative according to claim 1, wherein: the base is potassium phosphate.

4. The method for synthesizing 2-trifluoromethylbenzofuran derivative according to claim 1, wherein: the solvent is dimethyl sulfoxide.

5. The method for synthesizing 2-trifluoromethylbenzofuran derivative according to claim 1, wherein: and after the reaction is finished, filtering, washing the filtrate by using a saturated sodium chloride solution, extracting by using ethyl acetate, carrying out rotary evaporation on the combined organic layers by using a rotary evaporator, removing the solvent to obtain a residue, carrying out column layer separation on the residue through a silica gel column, leaching by using an eluent, collecting an effluent containing the target product, combining the effluent, and removing the solvent by vacuum concentration to obtain the target product.

6. The method for synthesizing 2-trifluoromethylbenzofuran derivative according to claim 1, wherein: the reaction was carried out under nitrogen atmosphere.

Technical Field

The present invention relates to a process for the preparation of 2-trifluoromethylbenzofuran derivatives.

Background

Benzofuran derivatives are widely present in natural products and non-natural compounds with biopharmacological potential (J.Nat.Prod.2016,79,784-79; J.Med.chem.2013,56, 832-52842; J.Med.chem.2005,48,5279-5294) and show a wide range of activities including antiviral, antibacterial, anti-inflammatory, anti-angiogenic and anti-mitotic activities, etc. (ACS Comb.Sci.2017,19, 370-376; J.Med.chem.2015,97, 561-581). It is well known that the introduction of trifluoromethyl groups into molecules can significantly alter the solubility, metabolic stability, polarity, lipophilicity and chemical and biological activity of compounds (adv. synth. catal,2010,352, 2745-. Although there have been many reports on the synthesis of trifluoromethyl substituted benzofuran compounds, as in 2013, axionnat et al reported an iridium-catalysed hydrogen transfer reaction in the presence of p-benzoquinone: substituted benzofuran, benzothiophene and indole derivatives (org. Lett.2013,15,3876-3879) were synthesized from benzyl alcohol. In 2014 Yuan et al reported palladium-catalyzed reaction of alkynyl substituted phenylalkynes and aryl halides to synthesize 2, 3-disubstituted benzofuran derivatives (org. Lett.2014,16,193-195) in moderate yields. In 2014, Murakami et al reported a practical, modular, and general synthetic scheme for benzofuran by extending the Pummerer loop/cross-coupling strategy (Angew. chem. int. Ed.2014,53, 7510-. The traditional method has the trouble of multi-step reaction, is not high in economy, is mostly provided by direct trifluoromethylation of benzofuran and free radical or electrophilic reagent, and has the defects of low yield and poor regioselectivity.

Disclosure of Invention

Aiming at the defects existing in the prior stage, the invention provides the method for preparing the 2-trifluoromethyl benzofuran derivative, which takes 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene and potassium hydroxide as reaction raw materials, and has the advantages of simple technical process, high yield, less pollution, environmental protection and safety.

In order to achieve the purpose, the invention adopts the technical scheme that:

the synthesis method of the 2-trifluoromethyl benzofuran derivative comprises the following steps: taking 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene as a reaction substrate, potassium hydroxide as an oxygen source, sodium carbonate, cesium carbonate, potassium tert-butoxide or potassium phosphate as alkali, cuprous chloride, cuprous bromide, thiophene-2-copper formate or cuprous iodide as a catalyst, 1, 10-phenanthroline as a ligand, and acetonitrile, N-dimethylformamide or dimethyl sulfoxide as a solvent, and stirring at 80-110 ℃ for reaction for 10-12 hours, wherein the chemical reaction formula is as follows:

and the-R is one of hydrogen, 4-methyl, 5-methoxyl, 4-fluorine, 4-chlorine, 5-bromine and 5-trifluoromethyl.

The preparation method adopted by the invention is to synthesize the 2-trifluoromethyl benzofuran derivative by catalyzing the reaction of 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene and potassium hydroxide, has simple process, does not need to use special instruments or modes, is very suitable for the operation of people in the field, and has the advantages of simple and convenient operation, easy obtaining of products and the like.

In a further arrangement of the invention, the catalyst is cuprous iodide.

In a further development of the invention, the base is potassium phosphate.

In a further embodiment of the present invention, the solvent is dimethyl sulfoxide.

According to a further development of the invention, the reaction is carried out in a nitrogen atmosphere.

The method can directly synthesize the target product, does not need to separate intermediate products, can obtain the target product only by stirring and reacting under normal pressure, can eliminate the interference of oxygen under the condition of nitrogen, has the highest yield of 65 percent, greatly simplifies the process engineering, reduces the energy consumption and has excellent yield; in addition, the waste solution is less in the reaction process, and other polluted gases and liquid are not discharged, so that the method reduces the discharge of the waste solution, and has the advantages of protecting the environment and ensuring the health of operators; in addition, a series of 2-trifluoromethyl benzofuran derivatives can be prepared, and the method has better substrate universality. Therefore, the invention fills the blank of the method for preparing the 2-trifluoromethyl benzofuran derivative at the present stage, promotes the development of the polysubstituted 2-trifluoromethyl benzofuran derivative and provides a powerful guarantee for developing the biological medicine containing the 2-trifluoromethyl benzofuran.

The mechanism of the invention is as follows: taking 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene 1a as an example, first, the substrate 1a is eliminated in the presence of a base to obtain o-bromophenylpropyne A. And (3) carrying out oxidative addition on the intermediate A and CuI to provide B, and carrying out ligand exchange and reductive elimination on the B and KOH to obtain an intermediate C. In the intermediate C, a carbon-carbon triple bond is coordinated with copper salt, and then the coordination is performed with phenol oxygen anion to perform intramolecular nucleophilic addition reaction, so as to obtain a cyclic intermediate D. And further adding the intermediate D with another molecule of o-bromophenyl propyne A to form an intermediate vinyl copper E. Finally, the protonation of the vinyl copper E gives the product 2a and regenerates the Cu (I). Possible reaction mechanisms the chemical reaction formula is as follows:

Detailed Description

The invention discloses a synthesis method of a 2-trifluoromethyl benzofuran derivative, which comprises the following steps of taking 1-bromo-2- (2-chloro-3, 3, 3-trifluoroprop-1-en-1-yl) benzene as a reaction substrate, potassium hydroxide as an oxygen source, sodium carbonate, cesium carbonate, potassium tert-butoxide or potassium phosphate as alkali, cuprous chloride, cuprous bromide, thiophene-2-copper formate or cuprous iodide as a catalyst, 1, 10-phenanthroline as a ligand, and acetonitrile, N-dimethylformamide or dimethyl sulfoxide as a solvent, and carrying out stirring reaction for 10-12 hours at 80-110 ℃ under the condition of nitrogen; the chemical reaction formula is as follows:

the-R is one of hydrogen, 4-methyl, 5-methoxyl, 4-fluorine, 4-chlorine, 5-bromine and 5-trifluoromethyl; after the reaction, filtering, washing the filtrate with saturated sodium chloride solution, extracting with ethyl acetate, performing rotary evaporation on the combined organic layers by using a rotary evaporator, and removing the solvent to obtain a residue. Eluting the residue with petroleum ether eluent through silica gel column, collecting eluate according to actual gradient, detecting by TLC, mixing the eluates containing the target product, removing solvent by rotating the mixed eluates with rotary evaporator, and vacuum drying to obtain the target product.