阅读说明：本技术 一种以醛类化合物为原料制备单氟代烯烃的合成方法 (Synthetic method for preparing monofluoroolefin by taking aldehyde compound as raw material ) 是由 陆晓雨 孙晓梅 殷文婧 于 2021-10-15 设计创作，主要内容包括：本发明属于有机合成领域,公开了一种以醛类化合物为原料制备单氟代烯烃的合成方法,以氟代丙烯酸与醛类物质为原料,乙酸亚铁为催化剂、二叔丁基过氧化物为氧化剂,氯苯为溶剂,在110℃下反应16小时,得到具有Z构型单氟代烯烃化合物,该方法原料来源易得,价格便宜,产物选择性高,操作简单,无需使用危险的化学药品,方法经济、成本低,合成应用价值高。(The invention belongs to the field of organic synthesis, and discloses a synthetic method for preparing monofluoroolefin by taking aldehyde compounds as raw materials, wherein fluoroacrylic acid and the aldehyde compounds are taken as raw materials, ferrous acetate is taken as a catalyst, di-tert-butyl peroxide is taken as an oxidant, chlorobenzene is taken as a solvent, and the monofluoroolefin compound with Z configuration is obtained by reacting for 16 hours at 110 ℃.)

1. A synthetic method for preparing monofluoro olefin by taking aldehyde compounds as raw materials is characterized in that: fluoroacrylic acid and alkyl aldehyde are taken as raw materials, ferrous acetate is taken as a catalyst, di-tert-butyl peroxide (DTBP) is taken as an oxidant, chlorobenzene is taken as a solvent to react for 16 hours at 110 ℃ according to the following reaction formula, and the Z-configuration monofluoro olefin compound with the general formula (I) is obtained.

2. The synthesis process for preparing monofluoroalkenes starting from aldehydes as claimed in claim 1, wherein: the amount of ferrous acetate was 10% of the amount of the fluoroacrylic acid material.

3. The synthesis process for preparing monofluoroalkenes starting from aldehydes as claimed in claim 1, wherein: the amount of the substance of the alkylaldehyde is 3 times the amount of the substance of the fluoroacrylic acid.

4. The synthesis process for preparing monofluoroalkenes starting from aldehydes as claimed in claim 1, wherein: the amount of the di-tert-butyl peroxide material was 3 times the amount of the fluoroacrylic acid material.

Technical Field

The invention relates to compound preparation, and belongs to the field of organic synthesis. In particular to a synthesis method for preparing monofluoro olefin by taking aldehyde compounds as raw materials.

Background

The monofluoro olefin is an important organic compound, widely exists in various bioactive molecules and drug molecules, and has wide application potential. It is an isostere of amido bond, so it has important application value in drug discovery and material science. Such as ribonucleotide reductase inhibitors, retinoid X receptor modulators, T cell surface antigen inhibitors, and the antitumor drug capecitabine (formula 1), all have a monofluoro olefin structural fragment. The synthesis of monofluoroolefins is therefore an important research area for organic synthesis.

Formula 1. active drug molecules containing monofluoroolefins

The monofluoroolefin can be synthesized by a ring-opening coupling reaction, an elimination reaction, etc. of difluorocyclopropane. Among them, the most used is the dehydrofluorination coupling reaction of a vinylidene fluoride. The organodifluoroolefin was reacted with an alkyl Grignard reagent (org. Lett.2016, 18, 4284-. However, the grignard reagent has high activity and poor functional group compatibility (formula 2).

Reaction of a harmonically difluoroolefin with an alkyl Grignard reagent

Recently, the Fu Yao topic group reported the coupling reaction of a harmonically difluoroolefin with an alkyl halide for the construction of a monofluoroolefin (formula 3), which requires the use of expensive bis- (1, 5-cyclooctadiene) nickel as a catalyst, equivalent amount of pinacol diboride as a reducing agent, and the addition of a very basic potassium phosphate as the base of the reaction (j.am.chem.soc.2017, 139, 12632-.

Reaction of a harmonically difluoroolefin of formula 3 with an alkyl halide

Recently, methods for constructing a harmonically difluoroolefin by coupling the harmonically difluoroolefin with an alkylcarboxylic acid have also been reported (formula 4, org. Lett.2018, 20, 4579-4583). However, the reaction requires the use of three equivalent zinc powders, which are controlled chemicals, have high activity and can release flammable hydrogen when in contact with water, acids or alkali metal hydroxides. Reaction with the oxidant can cause combustion or explosion. The powder and air can form an explosive mixture.

Reaction of a harmonically difluoro olefin with an alkyl carboxylate

The Fu and Li groups realize decarboxylation coupling of photo-catalytic harmonically difluoro alkene with alkyl carboxylic acid, but the reaction substrate type has limited reaction selectivity for monoaryl substrate products, a cis-trans alkene mixture is obtained, and product separation is difficult (formula 5, org. chem. front.2019, 6, 2365; chem. Commun.2017, 53, 10299).

Formula 5 reaction of a harmonically difluoro olefin with an alkyl carboxylic acid

The aldehyde compounds are rich, cheap and easily available organic raw materials and are widely used in the perfume industry. The aldehyde compound is used as a raw material, and the monofluoroolefin is directly constructed through decarbonylation reaction, so that the important application value is achieved, and the reaction is not reported. Therefore, it is of great significance to develop a novel method for constructing monofluoroolefins by decarburization reaction with aldehydes as raw materials.

Disclosure of Invention

Aiming at the aldehyde compound as a raw material, the decarboxylation and decarbonization reaction of the fluoroacrylic acid as the raw material and the aldehyde are invented to efficiently synthesize the monofluoroalkene without realizing the decarbonization reaction for constructing the monofluoroalkene.

In order to solve the technical problems, the invention adopts the following technical scheme: a synthetic method for preparing monofluoro olefin by taking aldehyde compounds as raw materials is characterized in that: the method takes fluoroacrylic acid and alkyl aldehyde as raw materials, ferrous acetate as a catalyst, di-tert-butyl peroxide (DTBP) as an oxidant and chlorobenzene as a solvent to react for 16 hours at 110 ℃ according to the following reaction formula to obtain the Z-configuration monofluoroolefin compound with the general formula (I).

Wherein R is₁Is an aryl or alkenyl substituent; r₂，R₃Is an alkyl substituent;

preferably, the amount of ferrous acetate is 10% of the amount of the species of fluoroacrylic acid;

preferably, the amount of the substance of the alkylaldehyde is 3 times the amount of the substance of the fluoroacrylic acid;

preferably, the amount of the substance of di-tert-butyl peroxide is 3 times the amount of the substance of fluoroacrylic acid;

the method provides a synthetic method for synthesizing monofluoro olefin, which has cheap and easily obtained raw materials, is simple to operate and does not need to use dangerous chemical reagents. The method has high cis-trans isomer ratio of the product. Provides an efficient, convenient and economic synthesis method for monofluoro olefin.

Drawings

FIG. 1 is a NMR chart of a synthesized monofluoroalkene 1;

FIG. 2 is a nuclear magnetic resonance fluorine spectrum of the synthesized monofluoroalkene 1;

FIG. 3 is a NMR carbon spectrum of the synthesized monofluoroalkene 1;

FIG. 4 is a NMR spectrum of the synthesized monofluoroalkene 2;

FIG. 5 is a nuclear magnetic resonance fluorine spectrum of the synthesized monofluoroalkene 2;

FIG. 6 is a NMR carbon spectrum of the synthesized monofluoroalkene 2;

FIG. 7 is a NMR spectrum of the synthesized monofluoroalkene 3;

FIG. 8 is a nuclear magnetic resonance fluorine spectrum of the synthesized monofluoroalkene 3;

FIG. 9 is a NMR carbon spectrum of the synthesized monofluoroalkene 3;

FIG. 10 is a NMR spectrum of the synthesized monofluoroalkene 4;

FIG. 11 is a NMR fluorine spectrum of the synthesized monofluoroalkene 4;

FIG. 12 is a NMR carbon spectrum of the synthesized monofluoroalkene 4;

FIG. 13 is a NMR spectrum of the synthesized monofluoroalkene 5;

FIG. 14 is a NMR fluorine spectrum of the synthesized monofluoroalkene 5;

FIG. 15 is a NMR carbon spectrum of the synthesized monofluoroalkene 5;

FIG. 16 is a NMR spectrum of a synthesized monofluoroalkene 21;

FIG. 17 is a NMR fluorine spectrum of a synthesized monofluoroalkene 21;

FIG. 18 is a NMR carbon spectrum of a synthesized monofluoroalkene 21;

FIG. 19 is a NMR spectrum of a synthesized monofluoroalkene 22;

FIG. 20 is a NMR fluorine spectrum of a synthesized monofluoroalkene 22;

FIG. 21 is a NMR carbon spectrum of a synthesized monofluoroalkene 22;

FIG. 22 is a NMR spectrum of a synthesized monofluoroalkene 23;

FIG. 23 is a NMR fluorine spectrum of a synthesized monofluoroalkene 23;

FIG. 24 is a NMR carbon spectrum of synthetic monofluoroalkene 23;

FIG. 25 is a NMR spectrum of synthetic monofluoroalkene 24;

FIG. 26 is a NMR fluorine spectrum of the synthesized monofluoroalkene 24;

FIG. 27 is a NMR carbon spectrum of synthetic monofluoroalkene 24;

FIG. 28 is a NMR spectrum of synthetic monofluoroalkene 25;

FIG. 29 is a NMR fluorine spectrum of synthetic monofluoroalkene 25;

FIG. 30 is a NMR carbon spectrum of the synthesized monofluoroalkene 25.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments:

example 1, the reaction formula for this example is as follows:

(1) alpha-fluorocinnamic acid (0.2mmol), Fe (OAc) under air₂(10 mol%) and a magneton were added to a reaction tube with a branch tube, argon gas was pumped three times, 1mL of chlorobenzene, cyclohexanecarboxaldehyde (0.6mmol) and di-t-butyl peroxide (0.6mmol) were added, and the reaction was carried out at 110 ℃ for 16 hours;

(2) and (2) adding ethyl acetate into the material obtained in the step (1), fully mixing, and performing column chromatography by using a short silica gel column, wherein the eluent is petroleum ether, the separation yield is 80%, and the product purity is 100%.

Example 2

The reaction formula for this example is shown below:

(1) alpha-fluoro-3-iodocinnamic acid (0.2mmol), Fe (OAc) under air₂(10 mol%) and a magneton were added to a reaction tube with a branch tube, argon gas was pumped three times, 1mL of chlorobenzene, cyclohexanecarboxaldehyde (0.6mmol) and di-t-butyl peroxide (0.6mmol) were added, and the reaction was carried out at 110 ℃ for 16 hours;

(2) and (2) adding ethyl acetate into the material obtained in the step (1), fully mixing, and performing column chromatography by using a short silica gel column, wherein an eluant is petroleum ether, the separation yield is 77%, and the product purity is 100%.

Example 3

The reaction formula for this example is shown below:

(1) alpha-fluoro-3, 4-dimethoxycinnamic acid (0.2mmol), Fe (OAc) under air₂(10 mol%) and a magneton were added to a reaction tube with a branch tube, argon gas was pumped three times, 1mL of chlorobenzene, cyclohexanecarboxaldehyde (0.6mmol) and di-t-butyl peroxide (0.6mmol) were added, and the reaction was carried out at 110 ℃ for 16 hours;

(2) and (2) adding ethyl acetate into the material obtained in the step (1), fully mixing, and performing column chromatography by using a short silica gel column, wherein the eluent is petroleum ether, the separation yield is 80%, and the product purity is 100%.

Example 4

The reaction formula for this example is shown below:

(1) alpha-fluoro-3, 4-dimethoxycinnamic acid (0.2mmol), Fe (OAc) under air₂(10 mol%) and a magneton were added to a reaction tube with a branch tube, argon gas was pumped three times, 1mL of chlorobenzene, isobutyraldehyde (0.6mmol) and di-t-butyl peroxide (0.6mmol) were added, and a reaction was carried out at 110 ℃ for 16 hours;

(2) and (2) adding ethyl acetate into the material obtained in the step (1), fully mixing, and performing short silica gel column chromatography, wherein the eluent is petroleum ether, the separation yield is 81%, and the product purity is 100%.

Example 5

The reaction formula for this example is shown below:

(1) alpha-fluoro-3, 4-dimethoxycinnamic acid (0.2mmol), Fe (OAc) under air₂(10 mol%) and a magneton were added to a reaction tube with a branch tube, argon gas was pumped three times, 1mL of chlorobenzene, 2-methylpentanal (0.6mmol) and di-t-butyl peroxide (0.6mmol) were added, and the reaction was carried out at 110 ℃ for 16 hours;

(2) and (2) adding ethyl acetate into the material obtained in the step (1), fully mixing, and performing short silica gel column chromatography, wherein the eluent is petroleum ether, the separation yield is 82%, and the product purity is 100%.

The present invention has been described in detail, and it should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

The following are specific examples of monofluoroalkenes synthesized in this manner.