阅读说明：本技术 一种单氟代烯烃的合成方法 (Synthesis method of monofluoroolefin ) 是由 陆晓雨 夏泽杰 陈星珂 于 2021-09-10 设计创作，主要内容包括：本发明属于有机合成领域,公开了一种单氟代烯烃的合成方法,以氟代丙烯酸与烷基羧酸酯为原料,在光催化剂,可见光照射的条件下,于溶剂中在室温下进行反应,得到具有Z构型单氟代烯烃化合物,采用本发明方法合成的单氟代烯烃反应操作简单、产率高、原料价格便宜、产物选择性高,无需使用危险的化学药品,合成应用价值高。另外该方法底物兼容广泛,方法经济、成本低。(The invention belongs to the field of organic synthesis, and discloses a synthetic method of monofluoro-olefin, which takes fluoroacrylic acid and alkyl carboxylic ester as raw materials to react in a solvent at room temperature under the conditions of photocatalyst and visible light irradiation to obtain a monofluoro-olefin compound with Z configuration. In addition, the method has wide substrate compatibility, economic method and low cost.)

1. A method for synthesizing monofluoroolefin, which is characterized in that: fluoroacrylic acid and alkyl carboxylic ester are taken as raw materials, under the condition that a photocatalyst is iridium tris (2-phenylpyridine) and visible light is irradiated, the raw materials react in a solvent according to the following reaction formula at room temperature for 15 hours to obtain the Z-configuration monofluoro olefin compound with the following general formula (I).

2. A method of synthesizing a monofluoroalkene according to claim 1, wherein: the visible light wavelength is 465 nm.

3. A method of synthesizing a monofluoroalkene according to claim 1, wherein: the solvent is N, N-dimethylacetamide.

4. A method of synthesizing a monofluoroalkene according to claim 1, wherein: the amount of the substance of the photocatalyst iridium (tri (2-phenylpyridine)) is 1% of the amount of the substance of the alkyl carboxylic ester.

5. A method of synthesizing a monofluoroalkene according to claim 1, wherein: the amount of the substance of the fluoroacrylic acid is 2 times the amount of the substance of the alkylcarboxylic ester.

Technical Field

The invention relates to compound preparation, and belongs to the field of organic synthesis. In particular to a synthetic method of monofluoro olefin.

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 ideal peptide bond mimetic and therefore has wide 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. Therefore, the synthesis of the monofluoroolefin has important application value.

At present, the monofluoroolefin is synthesized mainly through a fluoroidene coupling reaction, such as the reaction of the fluoroidene and an alkyl Grignard reagent reported by the Cao Song project group, so as to construct the monofluoroolefin (Org.Lett.2016, 18, 4284-4287). However, the Grignard reagent has high activity and poor functional group compatibility; and the reaction needs toxic toluene as a solvent, and the reaction is carried out under the reflux condition, and the reaction condition is severe (formula 2).

Recently, Fu Yao topic group reported the coupling reaction of a harmonically difluoro olefin with an alkyl halide for the construction of a monofluoro olefin (formula 3), which requires the use of expensive bis- (1, 5-cyclooctadiene) nickel as a catalyst, equivalent amount of pinacol ester diborate as a reducing agent, and the addition of a very basic potassium phosphate as the base of the reaction. The synthesis cost is high (J.Am.chem.Soc.2017, 139, 12632-12637).

Alkyl carboxylic acid is an important organic molecule and widely exists in various natural products and drug molecules. The decarboxylation of alkyl carboxylic acids to construct new compounds has been an important method of organic synthesis. Although the coupling of alkyl carboxylates to harmonically fluorinated olefins to make monofluorinated olefins has been recently accomplished (formula 4, org. lett.2018, 20, 4579-4583), the reaction requires the use of three equivalents of zinc powder, which is a controlled chemical, is highly reducing and releases flammable hydrogen when contacted with water, acids or alkali metal hydroxides. Reaction with the oxidant can cause combustion or explosion. The powder and air can form explosive mixture, and is easy to ignite by open fire to cause explosion, and the moist dust is easy to self-heat and burn in the air. And is irritating, so the method has great danger in synthesis.

Although the Fu and Li groups have recently achieved the decarboxylation coupling of photocatalytic chlorodifluoromethenes to alkyl carboxylic acids, this reaction substrate type has limited reaction selectivity for monoaryl substrate products, resulting in cis-trans olefin mixtures with difficult product separation (formula 5, org. chem. front.2019, 6, 2365; chem. commun.2017, 53, 10299).

The monofluoroolefin exists widely in active molecules of medicaments, and the efficient, convenient and economic synthesis of the monofluoroolefin has great value in medicament discovery. Alkyl carboxylic acid is an important organic compound, and the decarboxylation of the alkyl carboxylic acid for constructing monofluoro olefin currently needs to use equivalent zinc powder, so that the reaction operation is dangerous and easy to explode. The novel and mild coupling reagent is used for decarboxylation of alkyl carboxylic acid to construct monofluoro olefin, and has great synthesis value.

Disclosure of Invention

Aiming at the defects of the existing synthesis method of monofluoro-olefin, the invention provides a method for synthesizing monofluoro-olefin, which has simple operation, does not need to use dangerous chemicals and has mild reaction conditions. The reaction reagent is cheap, the dosage is less, and the synthesis cost is economical.

In order to solve the technical problems, the invention adopts the following technical scheme: a method for synthesizing monofluoroolefin, which is characterized in that: fluoroacrylic acid and alkyl carboxylic ester are taken as raw materials, and the reaction is carried out in a solvent under the conditions of photocatalyst and visible light irradiation according to the following reaction formula at room temperature to obtain the Z-configuration monofluoro olefin compound with the general formula (I). The method is simple to operate, does not need to use dangerous chemicals, and has high synthesis and application values.

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

preferably, the visible wavelength is 465 nm;

preferably, the amount of the iridium tri (2-phenylpyridine) compound is 1% of the amount of the alkyl carboxylate compound;

preferably, the amount of the substance of fluoroacrylic acid is 2 times the amount of the substance of alkylcarboxylate;

preferably, the reaction is carried out in N, N-dimethylacetamide solvent at room temperature for 15 hours.

The method provides a synthetic method for synthesizing monofluoro olefin, which has the advantages of economic raw materials, simple operation, mild reaction conditions and no need of using dangerous chemical reagents. The method has wide functional group compatibility and high yield. The cis-trans isomer ratio of the product is high. Provides a high-efficiency, convenient, economic and safe synthetic 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 the synthesized monofluoroalkene 6;

FIG. 17 is a NMR fluorine spectrum of the synthesized monofluoroalkene 6;

FIG. 18 is a NMR carbon spectrum of synthetic monofluoroalkene 6;

FIG. 19 is a NMR spectrum of the synthesized monofluoroalkene 7;

FIG. 20 is a NMR fluorine spectrum of the synthesized monofluoroalkene 7;

FIG. 21 is a NMR carbon spectrum of the synthesized monofluoroalkene 7;

FIG. 22 is a NMR spectrum of synthesized monofluoroalkene 8;

FIG. 23 is a NMR fluorine spectrum of the synthesized monofluoroalkene 8;

FIG. 24 is a NMR carbon spectrum of synthetic monofluoroalkene 8;

FIG. 25 is a NMR spectrum of synthesized monofluoroalkene 9;

FIG. 26 is a NMR fluorine spectrum of the synthesized monofluoroalkene 9;

FIG. 27 is a NMR carbon spectrum of synthetic monofluoroalkene 9;

FIG. 28 is a NMR spectrum of synthesized monofluoroalkene 11;

FIG. 29 is a NMR fluorine spectrum of the synthesized monofluoroalkene 11;

FIG. 30 is a NMR carbon spectrum of the synthesized monofluoroalkene 11.

FIG. 31 is a NMR spectrum of synthetic monofluoroalkene 45;

FIG. 32 is a NMR fluorine spectrum of a synthesized monofluoroalkene 45;

FIG. 33 is a NMR carbon spectrum of synthetic monofluoroalkene 45;

FIG. 34 is a NMR spectrum of a synthesized monofluoroalkene 46;

FIG. 35 is a NMR fluorine spectrum of the synthesized monofluoroalkene 46;

FIG. 36 is a NMR carbon spectrum of a synthesized monofluoroalkene 46;

FIG. 37 is a NMR spectrum of synthetic monofluoroalkene 47;

FIG. 38 is a NMR fluorine spectrum of synthesized monofluoroolefin 47;

FIG. 39 is a NMR carbon spectrum of synthetic monofluoroalkene 47;

FIG. 40 is a NMR spectrum of synthesized monofluoroalkene 48;

FIG. 41 is a NMR fluorine spectrum of a synthesized monofluoroalkene 48;

FIG. 42 is a NMR carbon spectrum of a synthesized monofluoroalkene 48;

FIG. 43 is a NMR spectrum of synthesized monofluoroalkene 49;

FIG. 44 is a NMR fluorine spectrum of synthesized monofluoroalkene 49;

FIG. 45 is a NMR carbon spectrum of synthesized monofluoroalkene 49.

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 (0.4mmol), cyclohexanecarboxylate (0.2mmol), iridium tris (2-phenylpyridine) (1mg) and a magneton were charged into a reaction tube with a branch tube under air, argon gas was pumped three times, 1mL of N, N-dimethylacetamide was added, and the reaction was carried out under visible light irradiation at 465nm for 15 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 83%, and the product purity is 100%.

Example 2

The reaction formula for this example is shown below:

(1) alpha-fluoro-3-iodocinnamic acid (0.4mmol), cyclohexanecarboxylate (0.2mmol), iridium tris (2-phenylpyridine) (1mg) and a magneton were added to a reaction tube with a branch tube under air, argon gas was pumped three times, 1mL of N, N-dimethylacetamide was added, and the reaction was carried out under visible light irradiation at 465nm for 15 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 83%, and the product purity is 100%.

Example 3

The reaction formula for this example is shown below:

(1) alpha-fluoro-3, 4-dimethoxycinnamic acid (0.4mmol), 3-bromoadamantanecarboxylate (0.2mmol), iridium tris (2-phenylpyridine) (1mg) and one magneton were added to a reaction tube with a branch tube under air, argon gas was evacuated three times, 1mL of N, N-dimethylacetamide was added, and the reaction was carried out for 15 hours under visible light irradiation at 465 nm;

(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 eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 87%, and the product purity is 100%.

Example 4

The reaction formula for this example is shown below:

(1) alpha-fluoro-3, 4-dimethoxycinnamic acid (0.4mmol), pivalate (0.2mmol), tris (2-phenylpyridine) iridium (1mg) and a magneton were added to a reaction tube with a branch tube under air, argon gas was pumped three times, 1mL of N, N-dimethylacetamide was added, and the reaction was carried out for 15 hours under visible light irradiation at 465 nm;

(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 eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 85%, and the product purity is 100%.

Example 5

The reaction formula for this example is shown below:

(1) alpha-fluorothiophene acrylic acid (0.4mmol), cyclohexanecarboxylate (0.2mmol), iridium tris (2-phenylpyridine) (1mg) and a magneton were added to a reaction tube with a branch tube under air, argon gas was pumped three times, 1mL of N, N-dimethylacetamide was added, and the reaction was carried out for 15 hours under visible light irradiation at 465 nm;

(2) adding ethyl acetate into the material obtained in the step (1), fully mixing, performing short silica gel column chromatography,

the eluent is petroleum ether, the separation yield is 82 percent, and the product purity is 100 percent. The amounts of the substances used and the reaction conditions were experimentally expanded as in the examples to demonstrate that the technical solution of the invention has good functional group compatibility.

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.