1. A gem-difluorovinyltransfer reagent, characterized in that: the compound shown in the structural formula 1 is shown in the specification,

wherein R is hydrogen, halogen, trifluoromethyl or methyl.

2. The geminal difluoroethenyl transfer reagent of claim 1, wherein: as shown in the following formula,

3. a process for the preparation of a geminal difluorovinyltransfer reagent as claimed in claim 1 or 2, wherein: comprises that

In a first step, cyano (phenyl) - λ³Dissolving iodotrifluoromethanesulfonate in an organic solvent, placing the solution in a reaction vessel, introducing nitrogen into the reaction vessel for protection, and cooling to-40 ℃;

secondly, dissolving the gem-difluorovinyl tributyltin in the same organic solvent, dropwise adding the same into the product obtained in the first step, slowly heating to room temperature after the materials are added, and stirring for 1-2 hours at room temperature;

and thirdly, spin-drying the reaction product on a rotary evaporator, adding ether, separating out a solid, washing with ether, and filtering to obtain a final product.

4. A process for the preparation of a geminal difluorovinyltransfer reagent as claimed in claim 3, wherein: cyano (phenyl) -lambda in the first step³The concentration of the-iodotrifluoromethane sulfonate in the organic solvent is 0.05mol/L to 0.15 mol/L.

5. A process for the preparation of a geminal difluorovinyltransfer reagent as claimed in claim 3, wherein: the concentration of the geminal difluorovinyltributyltin in the second step in the organic solvent is 0.2-0.4 mol/L.

6. A process for the preparation of a geminal difluorovinyltransfer reagent as claimed in claim 3, wherein: the organic solvent is dichloromethane.

7. A process for the preparation of a geminal difluorovinyltransfer reagent as claimed in claim 3, wherein: the cyano (phenyl) -lambda³The molar ratio of iodotrifluoromethane sulfonate to gem-difluorovinyltributyltin is preferably 1: 1-1.3.

8. Use of a geminal difluorovinyltransfer reagent according to claim 1 or 2 for the preparation of geminal difluorovinylcarboxylic acids/amides.

9. A method for preparing gem-containing difluorovinyl carboxylic acid/amide, which is characterized in that: obtained by the direct reaction of a geminal difluorovinyltransferase compound of claim 1 or 2 with a nucleophile in one step.

10. The process for the preparation of geminal difluorovinyl carboxylic acids/amides as claimed in claim 9, wherein: the nucleophile is an amide or a carboxylic acid.

Background

Gem-difluoroolefin (CH)₂＝CF₂VDF) is a characteristic structure contained in many biologically active compoundsThe unit (J.Med.chem.2003,46,5292.) is also often used as a biological isostere of a metabolically sensitive carbonyl group in drug research (J.Med.chem.2011,54,2529.), and the introduction of the unit into a molecule can effectively improve the lipid solubility of the molecule and enhance the penetrability of the molecule to a cell membrane. Due to the unique properties of the gem-difluorovinyl group, the gem-difluorovinyl group has wide application in the fields of medicines, pesticides, materials, fluorine-containing daily necessities and the like. Additionally, the geminal difluorovinyl group as an important synthon may be carboxylated or trifluoromethylated, for example, to its C-F bond (J.org.chem.2019,84,6557; ACS Catal.2019,9,6987.). Therefore, how to effectively introduce the geminal difluorovinyl functional group into the molecule becomes one of the research hotspots in the organic fluorine chemical industry at present.

Over the last several decades chemists have developed methods to introduce geminal difluorovinyl groups into molecules. However, the majority of the methods are indirect introduction of the geminal difluoroethylene, and the current methods for introducing the geminal difluoroethylene group still mainly rely on synthesis of a suitable precursor compound and subsequent conversion for preparation. Such as based on a carbonyl compound as a precursor and a difluoromethylphosphine ylide reaction (j. fluor. chem.2014,163,38.), based on a difluorocarbene precursor utilizing a diazo compound and a TMSCF₃The reaction (J.Am.chem.Soc.2013,135,17302.), or the multi-step preparation of alpha-trifluoromethyl-substituted olefins by C-F bond elimination reaction (ACS Catal.2019,9,775.). Compared with the methods which need multi-step preparation of the precursor, the method for directly introducing the gem-difluorovinyl into the molecule by utilizing the gem-difluorovinyl transfer reagent is undoubtedly the most convenient, fast and efficient, so that the development of the novel gem-difluorovinyl transfer reagent for directly introducing the gem-difluorovinyl into the molecule has a very wide application prospect.

The development of high-valent iodine has been over a hundred years since the first organic high-valent iodine reagent, iodosobenzene dichloride, was discovered. During this time, many novel high-valent iodine reagents have been reported, such as the togni reagent, the EBX reagent, and the like. Or the traditional high-valence iodine reagent is used for a plurality of novel reactions due to the unique reactivity, such as diaryl iodonium salt is often used as a C-H bond activation substrate instead of halogenated aromatic hydrocarbon and is used as aryl-like positive ion to participate in the reaction, and the application range of the high-valence iodine reagent is greatly shown. Generally, high-valent iodine reagents have several major advantages as follows: (1) the organic high-valence iodine reagent has similar reactivity with a transition metal complex, and the reaction in which the high-valence iodine reagent participates is often summarized as steps of ligand exchange, oxidative addition, reductive elimination, ligand coupling and the like. (2) The organic high-valence iodine reagent is an environment-friendly compound, and is convenient to use and store. The toxicity, danger and environmental protection problems caused by heavy metals do not exist; (3) some important organic high-valent iodine reagents such as PIDA, PIFA, DMP are already commercially available, and other high-valent iodine reagents can also be prepared by a simple method according to the relevant literature.

Based on the advantages of organic trivalence iodine reagent and the knowledge of the laboratory about the preparation and reaction properties of the trivalence iodine reagent, the first example of electrophilic geminal difluoroethenyl transfer reagent (2, 2-difluoroethenyl) (phenyl) -lambda based on organic trivalence iodine compound is designed and synthesized³-iodotrifluoromethane sulphonate enabling direct incorporation of gem-difluorovinyl groups into the molecule.

Disclosure of Invention

The invention aims to overcome the defects of the existing gem-difluorovinyl transfer reagent and develop a novel gem-difluorovinyl transfer reagent compound (2, 2-difluorovinyl) (phenyl) -lambda³The iodine-based trifluoromethanesulfonate and the preparation method thereof utilize the unique reactivity of a trivalent iodine reagent to realize the direct geminal difluoroethenylation of some compounds, and the reagent compound has the advantages of convenient synthesis, easily obtained raw materials, wide application range and the like. The gem-difluorovinylation transfer reagent can react with a series of nucleophiles to obtain a gem-difluorovinylated product with high yield.

In order to solve the technical problem, the invention provides a compound (2, 2-difluorovinyl) (phenyl) -lambda as shown in a structural formula 1 of a gem-difluorovinyl transfer reagent³-an iodonium trifluoromethanesulfonate salt,

wherein R is hydrogen, halogen, trifluoromethyl or methyl.

Further preferably, the gem-difluoro vinyltransfer reagent compound has a structural formula shown as the following formula:

R＝H,4-F,3,5-(CF₃)₂，4-CF₃，3,5-(CF₃)₂

the preparation method of the gem-difluoro vinyl transfer reagent compound comprises the following steps:

in a first step, cyano (phenyl) - λ³Dissolving the iodonium trifluoromethanesulfonate 2 in an organic solvent, placing the solution in a reaction vessel, introducing nitrogen into the reaction vessel for protection, and cooling the solution to-40 ℃;

secondly, dissolving the gem-difluorovinyl tributyltin 1 in the same organic solvent, dropwise adding the same into the product obtained in the first step, slowly heating to room temperature after the materials are added, and stirring at room temperature for 1-2 hours;

and thirdly, spin-drying the reaction product on a rotary evaporator, adding ether, separating out a solid, washing with ether, and filtering to obtain a final product.

Cyano (phenyl) -lambda in the first step³The concentration of the-iodotrifluoromethane sulfonate in the organic solvent is 0.05mol/L to 0.15 mol/L.

The concentration of the geminal difluorovinyltributyltin in the second step in the organic solvent is 0.2-0.4 mol/L.

The organic solvent is preferably dichloromethane.

The cyano (phenyl) -lambda³The molar ratio of iodotrifluoromethane sulfonate to gem-difluorovinyltributyltin is preferably 1: 1-1.3.

The invention also provides a preparation method of the geminal difluorovinyl carboxylic acid/amide, which is specifically obtained by one-step direct reaction of the geminal difluorovinyl transfer reagent compound and a nucleophilic reagent.

The nucleophile is an amide or a carboxylic acid.

The invention has the advantages of

The invention provides a geminal difluoroethenyl transfer reagent (2, 2-difluoroethenyl) (phenyl) -lambda based on an organic trivalent iodine compound³The-iodo-trifluoromethanesulfonate is a novel electrophilic gem-difluorovinyl transfer reagent, and has the advantages of simple synthesis method, simple and easily-obtained raw materials, simple and convenient reaction operation, high product yield, wide substrate range, reaction diversity, environmental friendliness and the like. The reagent can overcome the defect that the conventional introduction of geminal difluorovinyl into a molecule requires multiple steps to prepare proper substrates, and can realize the geminal difluorovinyl of carboxylic acid and amide under mild conditions. In addition, the reagent is extremely convenient to store and use.

Drawings

FIG. 1 shows the NMR spectrum of the product of example 1, gem-difluorovinyltransfer reagent 1.

FIG. 2 shows the NMR spectrum of the product of example 1, gem-difluorovinyltransfer reagent 1.

FIG. 3 is a NMR spectrum of N- (2, 2-difluorovinyl) -2-naphthamide, a product of example 2.

FIG. 4 is a NMR fluorine spectrum of N- (2, 2-difluorovinyl) -2-naphthamide, a product of example 2.

FIG. 5 is a NMR chart of 2, 2-difluorovinyl 4-iodobenzoate, example 3.

FIG. 6 is a NMR fluorine spectrum of 2, 2-difluorovinyl 4-iodobenzoate, example 3.

Detailed Description

The invention provides a compound (2, 2-difluorovinyl) (phenyl) -lambda as shown in a structural formula 1 of a gem-difluorovinyl transfer reagent³-iodonium trifluoromethanesulfonate:

wherein R is hydrogen, halogen, trifluoromethyl or methyl.

Further preferably, the gem-difluoro vinyltransfer reagent compound has a structural formula shown as the following formula:

R＝H,4-F,3,5-(CF₃)₂，4-CF₃，3,5-(CF₃)₂

the preparation method of the gem-difluoro vinyl transfer reagent compound comprises the following steps:

in a first step, cyano (phenyl) - λ³Dissolving the iodonium trifluoromethanesulfonate 2 in an organic solvent, placing the solution in a reaction vessel, introducing nitrogen into the reaction vessel for protection, and cooling the solution to-40 ℃;

secondly, dissolving the gem-difluorovinyl tributyltin 1 in the same organic solvent, dropwise adding the same into the product obtained in the first step, slowly heating to room temperature after the materials are added, and stirring at room temperature for 1-2 hours;

and thirdly, spin-drying the reaction product on a rotary evaporator, adding ether, separating out a solid, washing with ether, and filtering to obtain a final product.

Cyano (phenyl) -lambda in the first step³The concentration of the-iodo trifluoromethanesulfonate in the organic solvent is from 0.05mol/L to 0.15mol/L, and more preferably 0.1 mol/L.

The concentration of the geminal difluorovinyltributyltin in the second step in the organic solvent is 0.2mol/L-0.4mol/L, and more preferably 0.3 mol/L.

The organic solvent is preferably dichloromethane.

The cyano (phenyl) -lambda³The molar ratio of iodotrifluoromethane sulfonate to gem-difluorovinyltributyltin is preferably 1: 1-1.3.

The specific reaction formula is as follows:

the invention also provides a preparation method of the geminal difluorovinyl carboxylic acid/amide, which is specifically obtained by one-step direct reaction of the geminal difluorovinyl transfer reagent compound and a nucleophilic reagent.

The nucleophile is an amide or a carboxylic acid.

The invention also provides a preparation method of N- (2, 2-difluorovinyl) -2-naphthamide, which comprises the steps of sequentially adding 2-naphthamide, the gem-difluorovinyl transfer reagent and silver carbonate into a reaction vessel according to the molar ratio of 1:1:0.1 in a nitrogen atmosphere, then adding an organic solvent, stirring at room temperature for reaction for 12 hours, and carrying out column chromatography purification after the reaction is finished.

The invention also provides a preparation method of 2, 2-difluorovinyl 4-iodobenzoate, which comprises the steps of sequentially adding p-iodobenzoic acid, the geminal difluorovinyl transfer reagent and silver carbonate into a reaction vessel according to the molar ratio of 1:1:2 in a nitrogen atmosphere, then adding an organic solvent, stirring and reacting for 12 hours at room temperature, and carrying out column chromatography purification after the reaction is finished.

The following embodiments are described in detail to solve the technical problems by applying technical means to the present invention, and the implementation process of achieving the technical effects can be fully understood and implemented.

Example 1: synthesis of geminal Difluorovinyl transfer reagent 1

Under nitrogen protection, 1.90g (5mmol) of cyano (phenyl) -lambda³Iodophortriflate was added to a 100ml Schlenk tube, followed by addition of 45ml of ultra-dry dichloromethane and cooling to-40 ℃ and by dropwise addition of a solution of 1.77g (5mmol) of gem-difluorovinyltributyltin in dichloromethane (14ml), slow warming to room temperature after completion of addition, stirring at room temperature for 1-2 hours, spin-drying to about 5ml and addition of diethyl ether to precipitate a large amount of solid, and filtering the solid with a small amount of diethyl ether two to three times to give pure gem-difluorovinyltransferase 1 as a colorless solid in 56% yield.

¹H NMR(400MHz,DMSO-d₆)δ8.17(d,J＝8.1Hz,2H),7.72(t,J＝7.5Hz,1H),7.58(t,J＝7.8Hz,2H),6.98(dd,J＝26.5,1.6Hz,1H)；¹⁹F NMR(376MHz,DMSO-d6)δ-64.99(dd,J＝26.0,6.5Hz,1F),-67.52(d,J＝6.2Hz,1F),-77.66(s,3F).

The experimental procedure for preparing the corresponding geminal difluorovinylphenyl iodide salt when the geminal difluorovinylbenzene ring carries different substituents (including halogen, trifluoromethyl and methyl) is as above.

Example 2: synthesis of N- (2, 2-difluorovinyl) -2-naphthamide

Under nitrogen atmosphere, 2-naphthylamide (0.2mmol,34.2mg), the gem-difluoroethenyl transfer reagent prepared in example 1 (0.2mmol, 83.2mg), silver carbonate (0.02mmol, 5.5mg) and dichloromethane (2mL) were sequentially added into a 25mL sealed tube previously provided with a stirrer, and reacted at room temperature for 12h, after the reaction was finished, column chromatography purification was performed to obtain N- (2, 2-difluoroethenyl) -2-naphthylamide with a yield of 42%, and the obtained product was a white solid.¹H NMR(400MHz,Chloroform-d)δ8.30(s,1H),7.97–7.76(m,4H),7.57(dt,J＝15.6,7.0Hz,2H),7.40(d,J＝9.5Hz,1H),6.48(dd,J＝20.8,9.5Hz,1H)；¹⁹F NMR(376MHz,Chloroform-d)δ-93.77(dd,J＝67.0,21.5Hz,1F),-108.34(d,J＝66.6Hz,1F).

Example 3: synthesis of 2, 2-difluorovinyl 4-iodobenzoate

Under nitrogen atmosphere, sequentially adding p-iodobenzoic acid (0.2mmol,49.6mg), the gem-difluorovinylon transfer reagent prepared in example 1 (0.2mmol, 83.2mg), silver carbonate (0.4mmol, 110mg) and dichloromethane (2ml) into a 25ml sealed tube which is provided with a stirrer in advance, stirring at room temperature for 12 hours, and after the reaction is finished, performing column chromatography purification to obtain 2, 2-difluorovinyl 4-iodobenzoate, wherein the yield is 52 percent, and the obtained product is a white solid;¹H NMR(400MHz,Chloroform-d)δ7.85(d,J＝8.6Hz,2H),7.78(d,J＝8.6Hz,2H),6.97(dd,J＝15.8,3.1Hz,1H)；¹⁹F NMR(376MHz,Chloroform-d)δ-92.93(dd,J＝63.9,15.7Hz,1H),-113.99(dd,J＝63.9,3.2Hz,1H).

all of the above mentioned intellectual property rights are not intended to be restrictive to other forms of implementing the new and/or new products. Those skilled in the art will take advantage of this important information, and the foregoing will be modified to achieve similar performance. However, all modifications or alterations are based on the new products of the invention and belong to the reserved rights.

The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.