阅读说明：本技术 一种（z)-5-氟-2-三氟甲基烯烃衍生物及其制备方法 ((Z) -5-fluoro-2-trifluoromethyl olefin derivative and preparation method thereof ) 是由 罗芳 舒陈云 程存归 张芳 于 2020-06-08 设计创作，主要内容包括：本发明公开了一种(Z)-5-氟-2-三氟甲基烯烃衍生物及其制备方法,将式Ⅱ结构的内炔加入到氟试剂、三氟试剂及硝酸银、氟化铯、双(三氟乙酰氧基)碘苯的溶剂中混合,反应完成后经后处理得到。本发明首次通过炔烃的远程氟-三氟甲基化,一步实现了(Z)-5-氟-2-三氟甲基烯烃衍生物的立体选择性合成。该反应条件温和,底物适用范围广,反应收率良好,操作简单,对于含氟的三氟甲基烯烃化合物的合成提供了新途径。<Image he="177" wi="700" file="DDA0002530380030000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a (Z) -5-fluoro-2-trifluoromethyl olefin derivative and a preparation method thereof, wherein an internal alkyne with a structure shown in a formula II is added into a solvent of a fluorine reagent, a trifluoro reagent, silver nitrate, cesium fluoride and bis (trifluoroacetoxy) iodobenzene for mixing, and the internal alkyne is obtained by post-treatment after the reaction is finished. The invention firstly passes through the long-range fluoro-trifluoromethyl of alkyne, and one stepRealizing the stereoselective synthesis of the (Z) -5-fluoro-2-trifluoromethyl olefin derivative. The method has the advantages of mild reaction conditions, wide substrate application range, good reaction yield and simple operation, and provides a new way for synthesizing fluorine-containing trifluoromethyl olefin compounds.)

1. a (Z) -5-fluoro-2-trifluoromethylolefin derivative having the structure of formula I:

wherein R is one of phenyl, p-methylphenyl, o-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-acetylphenyl, p-cyanophenyl and p-formylphenyl.

2. A process for producing a (Z) -5-fluoro-2-trifluoromethylolefin derivative, which comprises the steps of:

adding the internal alkyne with the structure shown in the formula II into a solvent containing a fluorine reagent, a trifluoro reagent, silver nitrate, cesium fluoride and bis (trifluoroacetoxy) iodobenzene, mixing to form a reaction system, and performing post-treatment after the reaction to obtain the (Z) -5-fluoro-2-trifluoromethyl olefin derivative with the structure shown in the formula I;

in the formula I, R is one of phenyl, p-methylphenyl, o-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-acetylphenyl, p-cyanophenyl or p-formylphenyl.

3. The method for producing (Z) -5-fluoro-2-trifluoromethylolefin derivative according to claim 2, wherein the fluorine reagent is 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt, and the trifluoro reagent is trifluoromethyl trimethylsilane.

4. The process for producing (Z) -5-fluoro-2-trifluoromethylolefin derivative according to claim 2, wherein the solvent is acetonitrile.

5. The method for preparing (Z) -5-fluoro-2-trifluoromethylolefin derivative according to claim 2, wherein the molar ratio of the internal alkyne, the fluorine reagent, the trifluoro reagent, the silver nitrate, the cesium fluoride and the bis (trifluoroacetoxy) iodobenzene having the structure of formula II is 1: 1.5-2.5: 2-3: 1.5-2.5: 2-3: 0.5 to 1.5.

6. The method for preparing (Z) -5-fluoro-2-trifluoromethylolefin derivative according to claim 5, wherein the molar ratio of the internal alkyne, the fluorine reagent, the trifluoro reagent, the silver nitrate, the cesium fluoride and the bis (trifluoroacetoxy) iodobenzene having the structure of formula II is 1: 1.8-2.2: 2.3-2.7: 1.8-2.2: 2.3-2.7: 0.8 to 1.2.

7. The method for producing a (Z) -5-fluoro-2-trifluoromethylolefin derivative according to claim 2, wherein the reaction temperature of the reaction system is 15 to 35 ℃.

8. The process for producing (Z) -5-fluoro-2-trifluoromethylolefin derivative according to claim 2, wherein the reaction time of the reaction system is 14 to 24 hours.

9. The process for preparing (Z) -5-fluoro-2-trifluoromethylolefin derivative according to claim 2, wherein the post-treatment comprises: quenching, extracting, washing an organic phase, drying and separating by column chromatography.

10. The process for preparing (Z) -5-fluoro-2-trifluoromethylolefin according to claim 9, wherein the quenching is performed by adding water, the extraction is performed three times by using ethyl acetate, the washed organic phase is washed by saturated edible water, the drying is performed by using anhydrous sodium sulfate, and the column chromatography is performed by using silica gel column chromatography.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a (Z) -5-fluoro-2-trifluoromethyl olefin derivative and a preparation method thereof.

Background

The C-H bond is the simplest and most common functional group in organic compounds. Its transformation has important significance for the research in the fields of organic synthesis, medicinal chemistry, new materials and the like. Its direct conversion is challenging due to the higher bond energy and stability of the carbon-hydrogen bond. Compared with the conventional functional group conversion reaction, the direct functionalization of carbon-hydrogen bonds avoids pre-functionalization, shortens the steps, and improves the efficiency, thus being of great interest. The selective activation of C-H is realized, generally depending on the design of a proper guide group, and a transition metal is selected as a catalyst to obtain a target product. The carbon-hydrogen bond functionalization can be realized by the transition metal catalysis assisted by the guide group, but the introduction and the removal of the guide group lead to the increase of reaction steps and the reduction of efficiency, so that the development of a new carbon-hydrogen bond functionalization strategy is very important.

In recent years, radical migration reactions have provided a new approach to inert carbon-hydrogen bond functionalization. At present, a remote carbon-hydrogen bond functionalization reaction initiated by alkyne free radical addition can construct a plurality of chemical bonds, even form a plurality of carbocycles or heterocycles, and show high synthesis efficiency and product structure diversity. Despite the progress made, work in this area has begun and, more importantly, there are problems to be solved in that, first, the reaction often undergoes radical addition atom transfer and then is cyclized to form a cyclic compound without the formation of an olefin addition product.

Secondly, the hydrogen-radical addition of alkynes is generally cis-addition, mainly generating thermodynamically stable (E) -alkenes, while the trans-hydrogen-radical addition of alkynes and the preparation of thermodynamically less stable (Z) -alkenes face more challenges. If trans-addition can be realized, the method has important value for synthesizing (Z) -olefin and drug molecules containing (Z) -olefin structural units. Meanwhile, because the activity of the internal alkyne is low and the selectivity of the addition region is difficult to control, the previous research generally refers to that free radicals are added to terminal carbon atoms (alpha-addition) of alkyne, but the beta-addition of non-terminal alkyne is difficult to realize.

Will contain fluorine radicalIntroduction of groups into drug molecules is one of the important strategies for drug modification. On one hand, due to the strong electron withdrawing property of fluorine, the introduction of fluorine into a drug molecule can change the acid-base property of fluorine, thereby improving the lipid solubility of the drug molecule. On the other hand, fluorine has strong electron-withdrawing ability and maximum electronegativity, so that the introduction of fluorine into drug molecules can enhance the oxidation resistance of the drug molecules and improve the stability of the drug molecules. With the development of fluorine chemistry, more and more fluorine-containing compounds are widely applied to the fields of medicines, pesticides, materials and the like. Among these compounds, trifluoromethyl compounds account for a large proportion. Trifluoroolefin compounds are frequently used in the synthesis of pharmaceuticals, fine chemicals and pesticides as important organic synthesis intermediates. Thus, a rational catalytic system, enabling vinyl radical-induced long-range C (sp) initiated by addition of non-terminal alkyne radicals³) The fluorine and trifluoromethyl are selectively introduced simultaneously in the H fluorination reaction to synthesize the (Z) fluorine-containing trifluoroolefin derivative, which has important significance in both theoretical research and practical application.

Disclosure of Invention

The invention provides a (Z) -5-fluoro-2-trifluoromethyl alkene derivative and a preparation method thereof, the preparation method realizes the remote fluoro-trifluoromethyl reaction of alkyne, and the stereoselective synthesis of the (Z) -5-fluoro-2-trifluoromethyl alkene derivative is realized in one step through the reaction process of alkyne trifluoromethyl, intramolecular hydrogen transfer and carbon free radical fluorination. The vinyl radical induced remote C (sp) initiated by alkyne radical addition is realized for the first time³) -H fluorination reaction, efficient implementation of the reaction involving C (sp)²)-CF₃、C(sp²)-H、C(sp³) -construction of multiple chemical bonds. The reaction condition is mild, the substrate application range is wide, the structural diversity synthesis of the preparation method of the (Z) -5-fluoro-2-trifluoromethyl olefin derivative can be realized by changing the substituent, the reaction yield is good, the operation is simple, and a new way is provided for the synthesis of the fluorine-containing trifluoromethyl olefin compound.

A (Z) -5-fluoro-2-trifluoromethylolefin derivative having the structure of formula I:

in the formula I, R is one of phenyl, p-methylphenyl, o-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-acetylphenyl, p-cyanophenyl or p-formylphenyl.

In the invention, trimethyl silicon (TMSCF) is used₃) Is a trifluoro reagent which generates trifluoromethyl free radical under the action of silver nitrate, cesium fluoride and bis (trifluoroacetoxy) iodobenzene, and the trifluoromethyl free radical is added with the internal alkyne to form trifluoromethyl-containing alkenyl free radical which induces remote C (sp)³) H activation, a new radical intermediate produced by 1, 5-hydro migration, followed by attack by a fluoro reagent, ultimately forming the target product of (Z) -fluorotrifluoromethylolefin.

A method for preparing a (Z) -5-fluoro-2-trifluoromethylolefin derivative, comprising the steps of:

adding the internal alkyne with the structure shown in the formula II into a solvent containing a fluorine reagent, a trifluoro reagent, silver nitrate, cesium fluoride and bis (trifluoroacetoxy) iodobenzene, mixing to form a reaction system, and performing post-treatment after the reaction to obtain the (Z) -5-fluoro-2-trifluoromethyl olefin derivative with the structure shown in the formula I;

wherein R is one of phenyl, p-methylphenyl, o-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-acetylphenyl, p-cyanophenyl or p-formylphenyl.

The specific synthetic route involved in the reaction is shown below:

the vinyl free radical induced long-range C (sp) initiated by the free radical addition of the terminal alkyne with the structure of formula II is realized for the first time³) The preparation method is simple and effectively realizes the (Z) -5-fluoro-2-trifluoromethyl olefin derivative.

The fluorine reagent is 1-chloromethyl-4-fluorine-1, 4-diazotization bicyclic 2.2.2 octane bis (tetrafluoroborate) salt, and the trifluoro reagent is trifluoromethyl trimethyl silicon (TMSCF)₃). The solvent is acetonitrile.

The mol ratio of the internal alkyne, the fluorine reagent, the trifluoro reagent, the silver nitrate, the cesium fluoride and the bis (trifluoroacetoxy) iodobenzene with the structure of the formula II is 1: 1.5-2.5: 2-3: 1.5-2.5: 2-3: 0.5 to 1.5, and more preferably 1: 1.8-2.2: 2.3-2.7: 1.8-2.2: 2.3-2.7: 0.8 to 1.2, most preferably 1: 2: 2.5: 2: 2.5: 1.

the reaction temperature of the reaction system is 15-35 ℃, more preferably 20-30 ℃, and most preferably 25 ℃.

The reaction time of the reaction system is 14 to 24 hours, more preferably 16 to 20 hours, and most preferably 18 hours.

The post-treatment comprises the following steps: quenching, extracting, washing an organic phase, drying and separating by column chromatography.

The quenching adopts water quenching, the extraction adopts ethyl acetate for three times, the washing organic phase adopts saturated edible water for washing, the drying adopts anhydrous sodium sulfate for drying, and the column chromatography separation adopts silica gel column chromatography for separation.

Compared with the prior art, the invention has the following advantages:

1. the long-range fluoro-trifluoromethylation reaction of the non-heteroatom substituted terminal alkyne is realized for the first time. .

2. The vinyl radical induced remote C (sp) initiated by alkyne radical addition is realized for the first time³) -H fluorination reaction, which is efficiently realized in one step and comprises C (sp)²)-CF₃、C(sp²)-H、C(sp³) -construction of multiple chemical bonds.

3. The linear fluorine-containing trifluoromethyl olefin compound is firstly synthesized regioselectively through a free radical path.

4. The reaction condition is mild, the operation is simple, the application range of the substrate is wide, the compatibility of functional groups is good, and the application prospect is good; therefore, the invention has higher theoretical innovation value and implementation value.

Detailed Description