阅读说明：本技术 一种1,1-二氟烯烃化合物的合成方法 (Synthesis method of 1, 1-difluoroolefin compound ) 是由 徐俊 马翠翠 戴建军 许华建 于 2020-05-09 设计创作，主要内容包括：本发明公开了一种1,1-二氟烯烃化合物的合成方法,是以三氟甲基炔烃化合物为原料,在碱、催化剂、配体、硼试剂存在下,对三氟甲基炔烃进行选择性的C-F键的活化,分离提纯后得到1,1-二氟烯烃化合物。本发明特点,绿色、高效、反应条件比较温和、操作方便、反应时间比较短、副产物比较少,并且适合于大规模生产。(The invention discloses a synthesis method of a 1, 1-difluoroalkene compound, which takes a trifluoromethyl alkyne compound as a raw material, activates a selective C-F bond of the trifluoromethyl alkyne in the presence of alkali, a catalyst, a ligand and a boron reagent, and obtains the 1, 1-difluoroalkene compound after separation and purification. The method has the characteristics of greenness, high efficiency, mild reaction conditions, convenient operation, short reaction time and fewer byproducts, and is suitable for large-scale production.)

1. a method for synthesizing a 1, 1-difluoroolefin compound, which is characterized by comprising the following steps: reacting trifluoromethyl alkyne serving as a raw material in the presence of a catalyst, alkali, a ligand and a boron reagent, and separating and purifying to obtain a 1, 1-difluoroalkene compound;

the structural formula of the trifluoromethyl alkyne is as follows:

wherein: r is Br, Ph, COOEt, thiophene group or naphthalene group.

2. The method of synthesis according to claim 1, characterized in that:

dissolving trifluoromethyl alkyne in a solvent under the conditions of 110 ℃ and argon protection, reacting in the presence of a catalyst, alkali, a ligand and a boron reagent, and separating and purifying after the reaction to obtain a target product.

3. The method of synthesis according to claim 2, characterized in that:

the reaction temperature is 110 ℃, and the reaction time is 2-6 h.

4. The method of synthesis according to claim 2, characterized in that:

the solvent is acetonitrile, dichloromethane, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, methanol, acetone, dimethyl sulfoxide, diethylene glycol dimethyl ether, ethyl acetate or tetrahydrofuran.

5. The method of synthesis according to claim 2, characterized in that:

the alkali is at least one of tert-butyl potassium alkoxide, tert-butyl lithium alkoxide, tert-butyl sodium alkoxide, sodium hydroxide, sodium hydride, tetramethylguanidine, lithium methoxide and sodium methoxide, and the used amount is 1-3 times of equivalent.

6. The method of synthesis according to claim 2, characterized in that:

the catalyst is at least one of cuprous oxide, cuprous bromide, cuprous chloride, cuprous cyanide, copper acetate, copper tartrate, copper acetylacetonate, copper-thiophene-2-carboxylic acid, copper tris (triphenylphosphine) bromide, copper citrate, copper trifluoromethanesulfonate and copper tetraacetonitrile hexafluorophosphate, and the amount of the catalyst is 0.1-1 equivalent.

7. The method of synthesis according to claim 2, characterized in that:

the ligand is at least one of 1.3-bis (diphenylphosphino) propane, 1.10-phenanthroline, 2.9-dimethyl-1.10-phenanthroline, 3.4.7.8-tetramethyl-1.10-phenanthroline, tris (dimethylamino) phosphine, 4.7-diphenyl-1.10-phenanthroline and triphenylphosphine, and the amount of the ligand is 1-3 times of equivalent.

8. The method of synthesis according to claim 2, characterized in that:

the boron reagent is B₂Pin₂、HBPin、B₂Cat₂、B₂Cat₂The amount of boron reagent is 1-4 times equivalent.

9. The method of synthesis according to claim 2, characterized in that:

and the separation and purification comprises the steps of adding a proper amount of water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and separating and purifying by column chromatography to obtain the target product.

10. The method of synthesis according to claim 9, characterized in that:

the eluent in the column chromatography separation and purification is petroleum ether: and ethyl acetate is 50: 1-100: 1, v/v.

Technical Field

The invention relates to a synthesis method of a 1, 1-difluoroalkene compound, which synthesizes the 1, 1-difluoroalkene compound by selectively activating a C-F bond of a trifluoromethyl alkyne compound, and belongs to the field of organic synthesis.

Background

The fluoro organic molecule can obviously change the physical, chemical and biological properties of the molecule, and the novel organic fluorination is carried out along with the fields of medicine and materialsThe growing demand for compounds, organofluorine chemistry, has developed rapidly in recent years^[1]. The defluorination function of the fluorine-containing compound also has good application prospect because the defluorination function provides a novel synthetic path for fluorine-containing functional molecules which are difficult to prepare by the conventional method. Medicines or agricultural chemicals having a difluoroolefin structure are also widely used, for example, a novel triazolopyrimidine drug modified with a difluoroolefin structure and having high efficacy for controlling tomato late blight and cucumber sour mold^[2]. In recent years, the synthesis of 1, 1-difluoroolefin compounds has been intensively studied and has made significant progress^[3]. However, these methods still have a series of disadvantages, such as weak functional group tolerance and harsh reaction conditions. There is therefore still a need for novel and convenient processes for the synthesis of 1, 1-difluoroolefin compounds. A method for synthesizing 1, 1-difluoroolefin using a trifluoromethyl alkyne compound as a starting material has not been reported. Therefore, it is apparent that research into methods for synthesizing 1, 1-difluoroolefin compounds has great significance.

Reference documents:

[1](a)Harrie J.M.Gijsen,Sergio A.Alonso de Diego,Michel De Cleyn,Nigel Austin,Herman Borghys,Deborah Dhuyvetter,and Diederik Moechars,J.Med.Chem.2018,61,5292-5303；(b)Schlosser,M.Angew.Chem.,Int.Ed.2006,45,5432.(c)Muller,K.；Faeh,C.；Diederich,F.Science 2007,317,1881.(d)Purser,S.；Moore,P.R.；Swallow,S.；Gouverneur,V.Chem.Soc.Rev.2008,37,320.(e)K.Uneyama,in:Organofluorine Chemistry,Blackwell Publishing,Oxford,UK,2006.

[2](a)Yue Pan,J.Q.,and Richard B.Silverman；[J]；J.Med.Chem；2003,46,5292-5293.(b)M.Bobek,f.I.K.,t and E.De Clercq,[J]；J.Med.Chem；1987,30(8),1494-1497.

[3](a)Sankarganesh Krishnamoorthy,Jotheeswari Kothandaraman,Jacqueline Saldana,and G.K.Surya Prakash,Eur.J.Org.Chem.2016,4965-4969；(b)Minyan Wang,Xinghui Pu,Yunfei Zhao,Panpan Wang,Zexian Li,Chendan Zhu,andZhuangzhi Shi,J.Am.Chem.Soc.2018,140,9061-9065；(c)Dr.Kohei Fuchibe，HibikiHatta，Dr.Ken Oh，Rie Oki，Prof.Dr.Junji Ichikawa,Angew.Chem.Int.Ed.2017,56,5890-5893；(d)Beatriz Calvo,Jan Wuttke,Thomas Braun,and Erhard Kemnitz,ChemCatChem 2016,8,1945-1950；(e)Qiao-Qiao Min,Zengsheng Yin,Zhang Feng,Wen-Hao Guo,and Xingang Zhang,J.Am.Chem.Soc.2014,136,1230-1233.(f)Ohashi,M.；Ishida,N.；Ando,K.；Hashimoto,Y.；Shigaki,A.；Kikushima,K.；Ogoshi,S.Chem.-Eur.J.2018,24,9794-9798.(g)Kojima,R.；Akiyama,S.；Ito,H.Angew.Chem.,Int.Ed.2018,57,7196-7199.

disclosure of Invention

Aiming at the defects of the existing synthetic route, the invention provides a synthetic method of a 1, 1-difluoroalkene compound, which has the advantages of easily obtained raw materials, simple process, mild condition, convenient operation, higher yield, fewer byproducts and the like.

The invention relates to a synthesis method of a 1, 1-difluoroalkene compound, which takes trifluoromethyl alkyne as a raw material to react in the presence of a catalyst, alkali, a ligand and a boron reagent, and the 1, 1-difluoroalkene compound is obtained after separation and purification.

Specifically, trifluoromethyl alkyne is dissolved in a solvent under the conditions of 110 ℃ and argon protection, reaction is carried out in the presence of a catalyst, alkali, a ligand and a boron reagent, and a target product is obtained by separation and purification after the reaction is finished.

The structural formula of the trifluoromethyl alkyne is as follows:

wherein: r is Br, Ph, COOEt, thiophene group or naphthalene group.

The reaction temperature of the synthetic method is 110 ℃, and the reaction time is 2-6 h.

The solvent is acetonitrile, dichloromethane, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, methanol, acetone, dimethyl sulfoxide, diethylene glycol dimethyl ether, ethyl acetate or tetrahydrofuran.

The alkali is at least one of tert-butyl potassium alkoxide, tert-butyl lithium alkoxide, tert-butyl sodium alkoxide, sodium hydroxide, sodium hydride, tetramethylguanidine, lithium methoxide and sodium methoxide, and the used amount is 1-3 times of equivalent.

The catalyst is at least one of cuprous oxide, cuprous bromide, cuprous chloride, cuprous cyanide, copper acetate, copper tartrate, copper acetylacetonate, copper-thiophene-2-carboxylic acid, copper tris (triphenylphosphine) bromide, copper citrate, copper trifluoromethanesulfonate and copper tetraacetonitrile hexafluorophosphate, and the amount of the catalyst is 0.1-1 equivalent.

The ligand is at least one of 1.3-bis (diphenylphosphino) propane, 1.10-phenanthroline, 2.9-dimethyl-1.10-phenanthroline, 3.4.7.8-tetramethyl-1.10-phenanthroline, tris (dimethylamino) phosphine, 4.7-diphenyl-1.10-phenanthroline and triphenylphosphine, and the amount of the ligand is 1-3 times of equivalent.

The boron reagent is B₂Pin₂、HBPin、B₂Cat₂、B₂Cat₂The amount of boron reagent is 1-4 times equivalent.

And the separation and purification comprises the steps of adding a proper amount of water into the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and separating and purifying by column chromatography (petroleum ether: ethyl acetate is 50: 1-100: 1, v/v) to obtain the target product.

The reaction process of the invention is as follows:

the invention has the beneficial effects that:

1. the synthesis method has mild conditions; the reaction time is short, and the operation is simple, convenient and safe.

2. The synthetic method has the advantages of wide substrate applicability, high yield, less by-products, compatibility with various functional groups and preparation of trifluoromethyl alkyne with various substituent groups.

Detailed Description

To further illustrate the features and advantages of the present invention, the following description of the embodiments of the present invention is provided in conjunction with the accompanying drawings. However, the following examples are intended to further illustrate the invention, but not to limit it.