WO2014117452A1

WO2014117452A1 - Synthesis and application of difluoro methylene phosphorus inner salt

Info

Publication number: WO2014117452A1
Application number: PCT/CN2013/075347
Authority: WO
Inventors: 肖吉昌; 郑剑; 蔡吉
Original assignee: 中国科学院上海有机化学研究所
Priority date: 2013-02-04
Filing date: 2013-05-08
Publication date: 2014-08-07
Also published as: CN103965242B; CN103965242A

Abstract

The present invention provides synthesis and application of difluoro methylene phosphorus inner salt, wherein the compound has a structure shown in Formula A: (R¹R²R³)P⁺CF₂CO₂ ^-. The definitions of substituent groups are described in the specification. The present invention also provides a method for preparing difluorocarbene and a method for difluoro alkenylation. The compound in Formula A is used as a difluorocarbene reagent and a difluoro alkenylation reagent, and during synthesis, difluoro substituted alkyl or difluoro substituted alkenyl is introduced in molecules. The reaction condition of the difluoro methylene phosphorus inner salt as a reagent is mild, the production yield is high, and the application is wide.

Description

Synthesis and application of difluoromethylene scale salt

The invention relates to the field of organic synthesis, in particular, the invention provides a novel difluoromethylene scale salt and a synthesis method thereof, and the application of the compound in the production of difluorocarbene and difluoroalkenylation reaction, etc. . Background technique

The introduction of a fluorine atom into a compound can cause a relatively large change in the biological activity and physical properties of the compound, resulting in the production of a series of drugs and new materials. Therefore, in the field of compound synthesis, it is necessary to find a method for efficiently introducing a fluorine atom into a compound molecule, and introducing a fluorine atom by using difluorocarbene as an active intermediate is an important method. A series of compounds with difluoro-substituted groups synthesized from difluorocarbene have great applications in medicine, pesticides, materials and fine chemicals, or directly as medicines, pesticides, materials and fine chemicals. Or precursors for synthetic medicines, pesticides, materials and fine chemicals.

Since the birth and capture of difluorocarbene in I960, the research of difluorocarbene has been widely concerned, however, due to the highly toxic reagents and harsh conditions (/. Fluorine Chem., 2004, 125, 459), The difluorocarbene reagent in the technology is difficult to be widely used. Therefore, there is an urgent need in the art to develop a safer, easier to prepare, easy to handle, and highly efficient difluorocarbene reagent.

The Wi tt ig method is a very good method for synthesizing fluorine-containing olefins (Fluorine Chem., 1983, 23, 339; Chem. Rev. 1996, 96, 1641), using difluoro-substituted witt ig reagents with aldehydes and ketones. A witt ig reaction occurs to form a difluoroolefin. Partially difluoroalkenylated olefins also play an important role in the fields of medicine, pesticides, materials and fine chemicals, and can carry out a large number of conversion reactions. By this method, a monomer of a fluorine-containing polymer can be synthesized, and many precursors of medicine can be synthesized. However, there is currently no satisfactory method for the gentle and efficient preparation of witt ig reagents.

Therefore, there is an urgent need in the art to develop improved processes capable of producing difluorocarbene reagents and/or witt ig reagents. Summary of the invention

It is an object of the present invention to provide novel difluoromethylene scale salts and processes and uses thereof. In a first aspect of the invention, there is provided a difluoromethylene scale salt compound of formula A,

(R ¹ R ² R ³ )PCF ₂ C0 _{2 (A)}

Wherein RR ² and R ³ are each independently selected from the group consisting of substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C3 to C20 cyclodecyl, substituted or unsubstituted C 1 to C 30 aryl Or a heteroaryl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted C1~C30 decyloxy group, a substituted or unsubstituted C1~C30 aryloxy group a substituted, unsubstituted or substituted C1 to C30 diarylamino group, a substituted or unsubstituted C1 to C30 diarylamine group, or a combination thereof;

Wherein the one or more hydrogen atoms on the substituent group are substituted with a substituent selected from the group consisting of: C1~C20 fluorenyl, C3~C10 cyclodecyl, halogen, hydroxy, carboxyl, aldehyde, acyl And an amino group; the phenyl group comprises an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents selected from the group consisting of halogen, C1-C20 fluorenyl, OH, nitro.

In another preferred embodiment, the compound of formula A is isolated or purified.

In another preferred embodiment, the compound of the formula A has a purity of 30% by weight, preferably 50% by weight, more preferably 70% by weight, most preferably 99% by weight.

In another preferred embodiment, Ι^=Ι ² = Ι ³ .

In another preferred embodiment, the RR ² and R ³ are each independently selected from the group consisting of a substituted or unsubstituted phenyl group, a substituted or unsubstituted linear or branched butyl group; wherein the substitution is as defined above Said.

According to a second aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect of the invention, comprising the steps of:

(a) reacting a compound of formula B with a compound of formula C in an inert solvent to form a compound of formula A; XCF ₂ CO- ₂ M+ + (R ¹ R ² R ³ )P (R ¹ R ² R ³ )PCF ₂ CO ₂

B C A

Wherein X is a leaving group, preferably selected from the group consisting of: Cl, Br, I, -OTf, -OTs, -OMs, or a combination thereof;

M is an alkali metal or alkaline earth metal cation and/or ammonium ion, preferably selected from the group consisting of Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba, Al, NH ₄ ;

In the formula, RR ² and R ³ are as defined above.

In another preferred embodiment, the solvent is a polar solvent.

In another preferred embodiment, the polar solvent includes, but is not limited to: water, methanol, ethanol, propanol, isopropanol, tert-butanol, diethyl ether, diphenyl ether, diethylene glycol dimethyl ether , petroleum ether, acetonitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, two Methyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl benzoate, methylene chloride, trichloromethane or a combination thereof; preferably, the solvent is selected from the group consisting of Lower group: water, dimethyl sulfoxide, hydrazine, hydrazine-dimethylformamide, or a combination thereof.

In another preferred embodiment, the reaction system contains no or substantially no one or more components selected from the group consisting of ketones, aldehydes or combinations thereof.

In another preferred embodiment, the said "substantially free" means the percentage in the reaction system

5wt%.

In another preferred embodiment, the reaction temperature is -20 to 150 ° C, preferably -10 to 120 ° C, more preferably 10 to 100 ° C. In another preferred embodiment, the reaction is carried out under conditions of removal of water and oxygen.

In another preferred embodiment, the reaction is carried out without removing water and removing oxygen.

In another preferred embodiment, the reaction is carried out under reduced pressure, normal pressure or pressurized conditions.

In another preferred embodiment, the reaction time is > 0.5 h.

In another preferred embodiment, the molar ratio of the compound of the formula B to the compound of the formula C is 0.1 to 10:

0·8~1 ·2.

According to a third aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect of the invention, comprising the steps of:

XCF ₂ CO ₂ Si(R ⁴ R ⁵ R ⁶ ) is reacted with (Ι^Ι ³ )Ρ and a fluorine anion under an inert solvent to obtain (R^I^R^P+CFsC,

XCF ₂ CO ₂ Si( ^{4 5 6} ) + (R^I^R^P + fluoroanion → (R^I^R^P+CFsC wherein X is a leaving group, preferably selected from the group consisting of: Cl, Br, I, -OTf, -OTs, -OMs, or a combination thereof;

1 , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are each independently selected from substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C3 to C20 cyclodecyl, substituted or unsubstituted C1 ~C30 aryl or heteroaryl, substituted or unsubstituted benzyl, substituted or unsubstituted C1~C30 decyloxy, substituted or unsubstituted C1~C30 aryloxy, substituted or unsubstituted C1~C30 a mercaptoamine group, a substituted or unsubstituted C1 to C30 diarylamine group, or a combination thereof;

In another preferred embodiment, the XCF ₂ CO ₂ Si (R ⁴ R ⁵ R ⁶ ) is prepared by the following method (i) or (ii): (i) directing XCF ₂ CO ₂ — M ⁺ directly in concentrated sulfuric acid Acidification to XCF ₂ CO ₂ H, and then reacting with ClSi(R ⁴ R ⁵ R ⁶ ) in an inert solvent or without solvent to form XCF ₂ CO ₂ Si(R ⁴ R ⁵ R ⁶ );

(ϋ) reacting with XCF ₂ CO ₂ _M ⁺ and ClSi (R ⁴ R ⁵ R ⁶ ) in an inert solvent or without solvent

XCF ₂ CO ₂ Si ( ^{4 5 6} ) _;

Wherein, the concentrated sulfuric acid is a sulfuric acid solution having a volume ratio of sulfuric acid: water of 50%, preferably 70%, more preferably 80%, and most preferably 90%.

In another preferred embodiment, the inert solvent is a polar solvent, preferably an organic polar solvent. In another preferred embodiment, the polar solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, tert-butanol, diethyl ether, diphenyl ether, diethylene glycol dimethyl ether, three Ethylene glycol dimethyl ether, petroleum ether, acetonitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethyl Phosphorus triamine, dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl benzoate, dichloromethane, chloroform or a combination thereof; preferably, The solvent is selected from the group consisting of water, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.

In another preferred embodiment, the fluorine anion is a compound capable of providing a fluorine anion. In another preferred embodiment, the reaction temperature is -20 to 150 ° C, preferably -10 to 120 ° C, and most preferably 0 to 100 ° C.

In another preferred embodiment, the reaction is carried out under conditions of removal of water and oxygen.

In another preferred embodiment, the reaction time is > 0.5 h.

In another preferred embodiment, the molar ratio of the compound XCF ₂ CO ₂ Si(R ⁴ R ⁵ R ⁶ ) to the compound (Ι^Ι ³ )Ρ is 0.1 to 10: 0.8 to 1.2.

According to a fourth aspect of the invention, there is provided a method for producing a difluorocarbene which is produced by thermal decomposition of a hydrazine compound according to the first aspect of the invention in an inert solvent.

In another preferred embodiment, the production of the difluorocarbene comprises the steps of:

(R ¹ R ² R ³ )PCF ₂ CO ₂ ^ : CF ₂

A

In another preferred embodiment, the difluorocarbene is used to prepare a compound containing a difluoromethylene group.

In another preferred embodiment, the difluorocarbene is used to prepare a difluoromethyl compound.

According to a fifth aspect of the invention, there is provided a use of a compound of the formula A according to the first aspect of the invention for the preparation of a fluorinated compound, wherein the fluoro compound is selected from the group consisting of: a compound of the formula I, a compound of the formula II and/or Or a compound of formula III:

I II III

In the above formulas, AA ² , A ³ , AA ⁵ , and A ⁶ are each independently selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1 to C20 linear or branched fluorenyl group, a substituted or unsubstituted C1~ C20 linear or branched decyloxy, substituted or unsubstituted C1 to C20 linear or branched decylamino; substituted or unsubstituted C3~C20 cyclononyl and heterocyclic fluorenyl, substituted or unsubstituted C5 ~C30 aryl, substituted or unsubstituted C1~C30 heteroaryl, substituted or unsubstituted benzyl;

R' is selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1 to C20 linear or branched fluorenyl group, a substituted or unsubstituted C1 to C20 linear or branched decyloxy group, a substituted or unsubstituted C1~ C20 straight or branched fluorenyl; substituted or unsubstituted C3~C20 cyclodecyl, substituted or unsubstituted C1~C20 heterocyclic fluorenyl; substituted or unsubstituted C5~C30 aryl; substituted or unsubstituted a C1 to C30 heteroaryl group; a substituted or unsubstituted benzyl group, and the like;

D ¹ , D ² , D ³ , D ^{4 are} independently selected from the group consisting of C, N, 0, S, P;

B is selected from the group consisting of: 0, S, N, P, C;

Wherein, the definition of substitution is as described above. According to a sixth aspect of the invention, there is provided a process for the preparation of a compound of formula I, comprising the steps of: reacting a compound of formula la with a compound of formula A according to the first aspect of the invention in an inert solvent;

La AI

In the above formulas, the definition of each group is as described above.

In another preferred embodiment, the inert solvent is an aprotic solvent, preferably an organic solvent. More preferably, the solvent is selected from the group consisting of diethyl ether, diphenyl ether, diethylene glycol dimethyl ether. , petroleum ether, acetonitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, two Methyl sulfoxide, sulfolane, 1,4. Hexacyclohexane, tetrahydrofuran, ethyl acetate, methyl benzoate, amyl pentane, hexanyl, octyl, benzene, toluene, toluene, chlorobenzene, dichlorobenzene, dichloromethyl垸, chloroform, or a combination thereof.

In another preferred embodiment, the reaction temperature is from 20 to 200 °C.

In another preferred embodiment, the reaction is carried out under reduced pressure, normal pressure or elevated pressure.

In another preferred embodiment, the reaction time is > 0.5 h.

In another preferred embodiment, the molar ratio of the compound of the formula la to the compound of the formula A is from 0.1 to 10: 0·8 to 1 · 2.

According to a seventh aspect of the invention, there is provided a process for the preparation of a compound of formula II, comprising the steps of: reacting a compound of formula Ila with a hydrazine compound of the first aspect of the invention in an inert solvent to provide a compound of formula II;

+ _

R'- BH + (R ¹ R ² R ³ )PCF ₂ CO ₂ ^ R'BCF ₂ H

I la A I I

In the above formulas, the definition of each group is as described above.

Wherein, the definition of substitution is as described above.

In another preferred embodiment, the inert solvent is an aprotic solvent, preferably an organic solvent. More preferably, the solvent includes, but is not limited to, the following groups: diethyl ether, diphenyl ether, diethylene glycol Alcohol dimethyl ether, triethylene glycol dimethyl ether, petroleum ether, acetonitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, methyl-2-pyrrolidone , hexamethylphosphoric triamide, dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl benzoate, amyl pentane, hexamidine, octyl, benzene, toluene, Xylene, chlorobenzene, dichlorobenzene, methylene chloride, trichloromethane, carbon tetrachloride, or a combination thereof.

In another preferred embodiment, the reaction temperature is 20 to 200 °C.

In another preferred embodiment, the reaction is carried out under conditions of removal of water and oxygen. In another preferred embodiment, the reaction is carried out without removing water and removing oxygen.

In another preferred embodiment, the reaction time is > 0.5 h.

In another preferred embodiment, the molar ratio of the compound of the formula Ila to the compound of the formula A is from 0.1 to 10: 0·8 to 1 · 2.

According to an eighth aspect of the present invention, there is provided a process for the preparation of a compound of formula III, comprising the steps of: reacting a compound of formula Ilia with a hydrazine compound of the first aspect of the invention in an inert solvent to provide a compound of formula III;

_A _{5_} _D 3 _{≡D 4_} _A 6 + (Rl R2 _R 3)pc _F2 CO:

Ilia A III

In the above formulas, the definition of each group is as described above.

In another preferred embodiment, the inert solvent is an aprotic solvent, preferably an organic solvent. More preferably, the solvent includes, but is not limited to, the following groups: diethyl ether, diphenyl ether, diethylene glycol Alcohol dimethyl ether, triethylene glycol dimethyl ether, petroleum ether, acetonitrile, benzonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, methyl-2-pyrrolidone , hexamethylphosphoric triamide, dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl benzoate, amyl pentane, hexamidine, octyl, benzene, toluene, Xylene, chlorobenzene, dichlorobenzene, methylene chloride, trichloromethane, carbon tetrachloride, or a combination thereof.

In another preferred embodiment, the reaction temperature is 20 to 200 °C.

In another preferred embodiment, the reaction time is > 0.5 h.

In another preferred embodiment, the molar ratio of the compound of the formula Ilia to the compound of the formula A is from 0.1 to 10: 0·8 to 1 · 2.

According to a ninth aspect of the invention, there is provided the use of a compound according to the first aspect of the invention, which is used as a difluoroalkenylating agent for the preparation of a structure of a di-difluoroolefin compound:

Wherein Y ¹ and Y ² are each independently selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1 to C20 linear or branched fluorenyl group, a decyloxy group, a decylamino group; a substituted or unsubstituted C3~ C20 cyclodecyl, heterocycloalkyl; substituted or unsubstituted C5 to C30 aryl; substituted or unsubstituted C1 to C30 heteroaryl; substituted or unsubstituted benzyl, or Y ¹ and Y ² Structure: -(CH ₂ ) _n -, wherein n is an integer of from 1 to 30, and a hydrogen atom on the fluorenyl group may be optionally substituted; In the above formulas, the definition of substitution is as described above.

According to a tenth aspect of the invention, there is provided a process for the preparation of a compound of formula IV, comprising the steps of: reacting a compound of formula IVa with a compound of formula A according to the first aspect of the invention in an inert solvent to provide a compound of formula IV;

0 ^r Y""

II + I

丫1Into 2 + (R ¹ R ² R ³ )PCF ₂ C0 ₂丫1人丫2 IVa A IV

In the above formulas, the definition of each substituent is as described above.

In another preferred embodiment, the inert solvent is an aprotic solvent, preferably an organic solvent. More preferably, the solvent includes, but is not limited to, the following groups: diethyl ether, diphenyl ether, diethylene glycol Alcohol dimethyl ether, triethylene glycol dimethyl ether, petroleum ether, acetonitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrole Anthrone, hexamethylphosphoric triamide, dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl benzoate, pentamidine, hexanthene, octyl, benzene, Toluene, xylene, chlorobenzene, dichlorobenzene, methylene chloride, trichloromethane, carbon tetrachloride, or a combination thereof.

In another preferred embodiment, the reaction temperature is 20 to 200 °C.

In another preferred embodiment, the reaction time is > 0.5 h.

In another preferred embodiment, the molar ratio of the compound of the formula IVa to the compound of the formula A is from 0.1 to 10: 0·8 to 1 · 2.

In another preferred embodiment, the hydrazine compound undergoes a decarboxylation reaction under heating to form a difluorosubstituted wittig reagent in situ, which is then reacted with a compound of formula IVa to form a compound of formula IV.

According to an eleventh aspect of the present invention, there is provided a use of a compound of the formula (a) for use as a difluorocarbene reagent; (b) as a difluoroalkenylation reagent; or (c) for in situ A difluoro substituted wittig reagent is produced.

In another preferred embodiment, the compound of formula A is used to introduce a difluoro-substituted fluorenyl group in the molecule of the compound. In another preferred embodiment, the compound of formula A is used to prepare difluorocyclopropene and its derivatives.

In another preferred embodiment, the compound of formula A is used to prepare a compound having a difluoromethyl group and/or a difluoromethylene group.

In another preferred embodiment, the compound of formula A is used to introduce a difluoromethylene group into the molecule of the compound. In another preferred embodiment, the compound of formula A is used to introduce a difluoromethyl group into the molecule of the compound.

In another preferred embodiment, the compound of formula A is used to prepare difluorocyclopropene or heterodifluorocyclopropene and derivatives thereof.

In another preferred embodiment, the compound of formula A is used to prepare difluorocyclopropene or heterodifluorocyclopropene and derivatives thereof. In another preferred embodiment, the difluoro-substituted Wittig reagent has the structure shown in Formula V:

(R ¹ R ² R ³ )PCF ₂ γ

The definition of each group in the formula is as described above.

In another preferred embodiment, the preparation of the compound of formula V comprises the steps of:

(R ¹ R ² R ³ )PCF ₂ C0 ₂ (R ¹ R ² R ³ )PCF ₂

A V

The compound of formula A is converted to the compound of formula V under heating.

According to a twelfth aspect of the invention, there is provided a process for the preparation of a difluoroalkenylating agent which is produced by the compound of the formula A according to the first aspect of the invention.

In another preferred embodiment, the difluoroalkenylation reagent is used to prepare a difluoroolefin.

In another preferred embodiment, the difluoroalkenylation reagent is used to introduce a vinylidene fluoride group into the molecule.

In another preferred embodiment, the difluoroalkenylating agent is a wittig reagent.

In another preferred embodiment, the difluoroalkenylating agent is produced by heating a compound of formula A. It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here. detailed description

After long-term and intensive research, the present inventors have for the first time prepared a novel difluoromethylene scale salt compound represented by Formula A, which can be used as a difluorocarbene reagent for preparing a series of difluoro substitutions. The compound, or as a difluoro-substituted Wi tt ig reagent, is used to prepare a difluoroolefin. On the basis of this, the inventors have completed the present invention.

The difluorocarbene reagent provided by the invention has mild reaction conditions, simple operation, no toxicity, no additional alkali addition, and some reactions of difluorocarbene, such as difluorocyclopropionation, difluorocyclopropene, and difluorocarbazone. It has a wide range of application values in reactions such as basicization.

The wi tt i g reagent produced by the invention has mild reaction conditions and simple operation, and is used for the difluoroalkenylation reaction, and can easily and efficiently synthesize a difluoroolefin. the term

As used herein, the term "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: C1 to C4 fluorenyl, C3 to C10 cyclodecyl, halogen, hydroxy, carboxy, aldehyde a phenyl group, an acyl group, an amino group, a phenyl group; the phenyl group comprising an unsubstituted phenyl group or a substituted phenyl group having 1 to 5 substituents selected from the group consisting of halogen, C1-C4 fluorenyl, OH, Nitro; and similar groups.

The term "C5-C30 aryl" refers to an aryl group having 5 to 30 carbon atoms, including monocyclic, bicyclic, tricyclic Or a polycyclic aryl group such as phenyl, naphthyl, anthracenyl, or the like.

The term "C1 to C30 heteroaryl" means a heteroaryl group having 1 to 30 carbon atoms, such as a pyrrolyl group, a pyridyl group, a furyl group, or the like.

The term "C1~C20 fluorenyl" refers to a straight or branched fluorenyl group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Tert-butyl, or a similar group.

The term "C3 to C20 cyclodecyl" means a cycloalkyl group having 3 to 20 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cycloheptyl group, or the like.

The term "C1 to C20 heterocyclic fluorenyl" means a heterocyclic fluorenyl group having 1 to 20 carbon atoms such as an epoxyethyl group, a tetrahydrofuranyl group, a tetrahydropyrrolyl group, or the like.

The term "halogen" means? , Cl, Br and I.

The term "C1~C20垸oxy" means a straight or branched decyloxy group having 1 to 20 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy, tert-butoxy, or the like.

The term "C1~C20 guanamine" means a straight or branched guanamine group having 1 to 20 carbon atoms, such as methylamino, ethylamino, propylamino, isopropylamine, butylamine, isobutylamine A sec-butylamino group, a tert-butylamino group, or the like. Difluoromethylene scale salt compound

The present invention provides a difluoromethylene scale salt compound having the structure of formula A:

(R ¹ R ² R ³ )PCF ₂ C0 ₂

Wherein RR ² and R ³ are each independently selected from the group consisting of substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C3 to C20 cyclodecyl, substituted or unsubstituted C 1 to C 30 aryl or a heteroaryl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted C1 to C30 decyloxy group, a substituted or unsubstituted C1 to C30 aryloxy group, a substituted or unsubstituted C1 to C30 dimethylamino group, a substituted or unsubstituted C1~C30 diarylamine group, or a combination thereof; wherein the definition of the substituent is as described above.

In another preferred embodiment, Ι^=Ι ² = Ι ³ .

In another preferred embodiment, said RR ² , R ³ are each independently selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted straight or branched butyl.

The compound is in a separated state or has a high purity, and can usually be 30% by weight or more, for example, 50% by weight, preferably 70% by weight, and more preferably 99% by weight.

The compound prepared by the present invention is solid under ordinary conditions and is chemically stable, so that it is very convenient for transportation and storage. Preparation of difluoromethylene scale salt compound

The preparation method of the compound includes: XCF ₂ CO ₂ — M ^{+ is} reacted with (Ι^Ι ² Ι ³ ) 在 in an inert solvent to form a hydrazine compound; wherein X is a leaving group including, but not limited to, Cl, Br, I, -OTf, -OTs, -OMs, etc., leaving groups, or a combination thereof;

M is a cation, preferably an alkali metal or alkaline earth metal cation and/or an ammonium ion, including but not limited to Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba, Al, ammonium ions;

In the formula, RR ² and R ³ are as defined above.

Or the compound of formula A can be prepared by the following method:

XCF ₂ CO ₂ Si(R ⁴ R ⁵ R ⁶ ) is reacted with (Ι^Ι ³ )Ρ and a fluorine anion under an inert solvent to obtain (R^I^R^P+CFsC;

XCF ₂ CO ₂ Si( ^{4 5 6} ) + (R^R ³ )? + fluorine anion → ( ^{1 2 3} )P ⁺ CF ₂ CO ₂ " where X, M, ¹ , R ² , R ³ are as defined above As stated in the text;

R ⁴ , R ⁵ and R ⁶ are each independently selected from substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C3 to C20 cyclodecyl, substituted or unsubstituted C1 to C30 aryl or heteroaryl. , substituted or unsubstituted benzyl, substituted or unsubstituted C 1 -C30 decyloxy, substituted or unsubstituted C1 to C30 aryloxy, substituted or unsubstituted C1 to C30 dimercaptoamine, substituted or An unsubstituted C1~C30 diarylamine group, or a combination thereof; wherein the XCF ₂ CO ₂ Si (R ⁴ R ⁵ R ⁶ ) can be prepared by a conventional method, including but not limited to the following method ( i) or (ii)

(i) XCF ₂ CO ₂ - M ^{+ is} directly acidified in concentrated sulfuric acid to XCF ₂ CO ₂ H, and then reacted with ClSi (R ⁴ R ⁵ R ⁶ ) in an inert solvent or without solvent to form XCF ₂ CO ₂ Si ( R ⁴ R ⁵ R ⁶ ); or

(ii) reacting with XCF ₂ CO ₂ _M ⁺ and ClSi (R ⁴ R ⁵ R ⁶ ) in an inert solvent or without solvent

XCF ₂ CO ₂ Si ( ^{4 5 6} ) _;

Wherein, the concentrated sulfuric acid is a sulfuric acid solution having a volume ratio of sulfuric acid: 50% by water, preferably 70%, more preferably 80%, most preferably 90%.

The solvent used in the preparation method is an inert solvent such as a polar solvent, preferably an organic polar solvent, including but not limited to: water, methanol, ethanol, propanol, isopropanol, tert-butanol, diethyl ether , diphenyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, petroleum ether, acetonitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl benzoate, dichloromethyl Preferably, the solvent is selected from the group consisting of water, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.

The reaction system may or may not contain other impurities. Preferably, the reaction system contains no or substantially no one or more components selected from the group consisting of ketones, aldehydes or combinations thereof. Wherein said substantially does not contain a percentage of 5% by weight of the reaction system.

The reaction temperature is 150 ° C, preferably -20 to 150 ° C, more preferably -10 to 120 ° C, most preferably 10 to 100 ° C. The reaction system may optionally be dehydrated with or without water and deoxygenated, optionally under reduced pressure, atmospheric pressure or elevated pressure.

The reaction time is not particularly limited and is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours. The ratio of the reactants is not particularly limited. Preferably, the molar ratio of the halodifluoroacetate to the trivalent phosphine is 0.1 to 10: 0.8 to 1.2; preferably 0.2 to 6: 0.9 to 1.1. Difluorocarbene reagent

The compound of the formula A can be used directly as a difluorocarbene reagent or can be thermally decomposed to produce a difluorocarbene. The difluorocarbene reagent or difluorocarbene can be used to introduce a difluoro-substituted thiol group into a compound molecule, or to prepare a compound having a difluoro-substituted fluorenyl group.

In a preferred embodiment of the invention, the compound of formula A can be used in the compound of formula I, the compound of formula II and/or the compound of formula III.

I II III

In the above formulas, AA ² , A ³ , AA ⁵ , and A ⁶ are each independently selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1 to C20 linear or branched fluorenyl group, a substituted or unsubstituted C3~ a C20 cyclodecyl group, a substituted or unsubstituted C5 to C30 aryl group, a substituted or unsubstituted C1 to C30 heteroaryl group, a substituted or unsubstituted benzyl group, and the like;

D ¹ , D ² , D ³ , D ⁴ may each independently be selected from the group consisting of: C, N, O, S, P, etc.;

B is selected from the group consisting of: O, S, N, P, C, etc.;

Wherein, the definition of substitution is as described above. Application of difluoromethylene scale salt as difluorocarbene reagent

a) difluorocyclopropionation

The method for preparing the compound of the formula I, comprising the steps of: reacting a compound of the formula la with a compound of the formula A in an inert solvent to obtain a compound of the formula I;

La AI

In the above formulas, the definition of each group is as described above.

The inert solvent is preferably an aprotic solvent, more preferably an organic solvent, and the solvent includes, but is not limited to, the following groups: diethyl ether, diphenyl ether, diethylene glycol dimethyl ether, triethyl ether Diol dimethyl ether, petroleum ether, acetonitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorus Acetamide, dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl benzoate, amyl pentane, hexanyl, octyl, benzene, toluene, xylene, chlorobenzene , dichlorobenzene, methylene chloride, trichloromethane, or a combination thereof.

Preferably, the reaction temperature is 20 to 200 °C.

The reaction system may optionally be dehydrated with or without water or deoxygenated, or optionally under reduced pressure, atmospheric pressure or elevated pressure.

The reaction time is not particularly limited and is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours. The ratio of the reactant is not particularly limited. Preferably, the molar ratio of the compound of the formula la to the compound of the formula A is 0.1 to 10: 0.8 to 1.2; preferably 0.2 to 6: 0.9 to 1.1. b) difluoromethylation

A process for the preparation of a compound of formula II comprising the steps of: reacting a compound of formula Ila with a compound of formula A in an inert solvent to provide a compound of formula II;

+ ―

R'- BH + (R ¹ R ² R ³ )PCF ₂ CO ₂ R'BCF ₂ H

Ila A II In the above formulas, RR ² , R ³ , R′ and B are as defined above;

The inert solvent is preferably an aprotic solvent, more preferably an organic solvent, including but not limited to the following groups: diethyl ether, diphenyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl Ether, petroleum ether, acetonitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, Dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl benzoate, amyl pentane, hexanyl, octyl, benzene, toluene, xylene, chlorobenzene, dichlorobenzene , chloroform, chloroform, carbon tetrachloride, or a combination thereof.

Preferably, the reaction temperature is 20 to 200 °C.

The reaction system may optionally be dehydrated with or without water and deoxygenated, and may optionally be carried out under reduced pressure, atmospheric pressure or elevated pressure.

The reaction time is not particularly limited, and is preferably >0.5 h.

The ratio of the reactant is not particularly limited, and preferably, the compound of the formula Ila and the compound of the formula A are The molar ratio is 0.1 to 10: 0·8 to 1 · 2; preferably 0.2 to 6: 0·9 to 1 · 1. c) difluorocyclopropene

The method for preparing the compound of the formula III, comprising the steps of: reacting a compound of the formula Ilia with a compound of the formula A in an inert solvent to obtain a compound of the formula III;

_A 5_ _D 3= _D 4_ _A 6 + (R1 R2R3)PCF ₂ CO:

Ilia A III

In the above formulas, the definition of each group is as described above.

The inert solvent, preferably an aprotic solvent, more preferably an organic solvent, including but not limited to: diethyl ether, diphenyl ether, diethylene glycol dimethyl ether, triethylene glycol Alcohol, petroleum ether, acetonitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoryl Triamine, dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl benzoate, pentamidine, hexanyl, octyl, benzene, toluene, xylene, chlorobenzene, Dichlorobenzene, methylene chloride, trichloromethane, carbon tetrachloride, or a combination thereof.

Preferably, the reaction temperature is 20 to 200 °C.

The reaction time is not particularly limited and is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours. The ratio of the reactant is not particularly limited. Preferably, the molar ratio of the compound of the formula Ilia to the compound of the formula A is 0.1 to 10: 0·8 to 1 · 2; preferably 0.2 to 6: 0.9 to 1.1. Difluoroalkenylation reagent

The hydrazine compound of the formula can be used as a difluoroalkenylation reagent for the preparation of a meta-difluoroolefin or for introducing a difluoroalkenyl group into a molecule.

In a preferred embodiment, the compound of the structure shown by the compound of formula A:

Wherein Y ¹ and Y ² are each independently selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1 to C20 linear or branched fluorenyl group, a decyloxy group, a decylamino group; a substituted or unsubstituted C3~ C20 cyclodecyl, heterocycloalkyl; substituted or unsubstituted C5 to C30 aryl; substituted or unsubstituted C1 to C30 heteroaryl; substituted or unsubstituted benzyl, or Y ¹ and Y ² Structure: -(CH ₂ ) _n -, wherein n is an integer of 1 to 30, and a hydrogen atom on the fluorenyl group may be optionally substituted; in the above formulae, the definition of the substitution is as described above. Application of difluoromethylene scale salt as difluoroalkenylation reagent Difluoroalkenylation of carbonyl

The preparation method of the compound of formula IV includes the following steps:

Reaction of a compound of formula IVa with a compound of formula A in an inert solvent to provide a compound of formula III;

IVa A IV

Preferably, the compound of formula IVa can be an aldehyde or a ketone.

The inert solvent is preferably an aprotic solvent, more preferably an organic solvent, and the solvent includes, but is not limited to, the following groups: diethyl ether, diphenyl ether, diethylene glycol dimethyl ether, triethyl ether Diol dimethyl ether, petroleum ether, acetonitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorus Acetamide, dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, methyl benzoate, amyl pentane, hexanyl, octyl, benzene, toluene, xylene, chlorobenzene , dichlorobenzene, methylene chloride, trichloromethane, carbon tetrachloride, or a combination thereof.

Preferably, the reaction temperature is 20 to 200 °C.

The reaction time is not particularly limited and is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours. The ratio of the reactant is not particularly limited. Preferably, the molar ratio of the compound of the formula IVa to the compound of the formula A is 0.1 to 10: 0·8 to 1 · 2; preferably 0.2 to 6: 0.9 to 1.1.

In another preferred embodiment, the hydrazine compound undergoes a decarboxylation reaction upon heating to form a difluoro-substituted wittig reagent in situ, which is then reacted with a compound of formula IVa to form a compound of formula IV. The main advantages of the invention

The invention produces a high-purity difluoromethylene scale salt, which is solid at normal temperature, stable in solid state, and easy to transport and store.

The difluoromethylene scale salt can be conveniently used as a difluorocarbene reagent or a difluoroalkenylation reagent for introducing a difluoromethylene group or a difluorosubstituted alkenyl group into the molecule during the synthesis, under the conditions. Mild, easy to control, and almost quantitative yields of methylene scales, difluoromethylene substituted series of small ring compounds with tension, a series of compounds containing difluoromethyl substitutions and difluoro Olefins. The reaction condition is mild, the applicability is wide, and the yield is high, so it has great industrial application value.

The difluoromethylene scale salt provided by the invention is used as a difluorocarbene reagent or a difluoroalkenylation reagent, and the operation is very simple, and no external base or some other initiator is needed, and only heating can be used to generate the desired in situ. Difluorocarbene or Wi tt ig reagent. The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. Synthesis of difluoromethylene scale salt

Example 1

In a 25 mL single-mouth bottle, Ph ₃ P (2.62 g, 10 mmol) and ClCF ₂ C00Li (L 36 g, 10 mmol) were dissolved in a mixed solvent of ethanol and dimethyl sulfoxide, and the reaction was sealed at 0 ° C for 20 h. Then the reaction was stopped, filtered to give a white solid, which was washed with dimethyl sulphate two to three times, and then three times with diethyl ether. The obtained solid was dissolved in isobutanol, and the upper clear solution was evaporated to dryness under reduced pressure to yield product ( 3. 20 g) , isolated yield: 90%.

Ph ₃ P ⁺ CF ₂ CO ₂ ": 1H NM (300 MHz, MeOD) δ 7.89-7.61 (m, 15H), ¹⁹ F NM (282 MHz, CDCl ₃ ) 5 -91.47 (d, 2F).

Ph ₃ P (2.62 g, 10 mmol) and BrCF ₂ C00K (2·12 g, 10 mmol) were dissolved in N,N-dimethylformamide in a 25 mL one-necked flask, and sealed at 25 ° C for 10 h. Then, the reaction was stopped, and the mixture was filtered to give a white solid, which was washed twice with diethyl ether and then washed three times with diethyl ether. The obtained solid was dissolved in methanol, and the supernatant was evaporated to dryness to give the product (3. 38 g). Rate: 95%.

Ph ₃ P ⁺ CF ₂ CO ₂ ": 1H NM (300 MHz, MeOD) 5 7.89-7.6 l(m, 15H), ¹⁹ F NMR (282

MHz, CDC1 ₃ ) δ -91.47(d, 2F). Example 3

In a 25 mL single-mouth bottle, Ph ₃ P ( 2.62 g, 10 mmol) and ClCF ₂ C00Li (1.36 g, 10 mmol), NaF (0.42 g, 10 mmol) were dissolved in a mixed solvent of ethanol and dimethyl sulfoxide. The reaction was sealed at 40 ° C for 20 h. Then the reaction was stopped, filtered to give a white solid, which was washed with dimethyl sulfoxide two to three times, and then washed three times with diethyl ether. The obtained solid was dissolved in isobutanol, and the upper clear solution was evaporated to dryness under reduced pressure. (3. 20 g ) , isolated yield: 90%.

Ph ₃ P ⁺ CF ₂ CO ₂ ": 1H NM (300 MHz, MeOD) 5 7.89-7.6 l (m, 15H), ¹⁹ F NMR (282 MHz, CDCI3) δ -91.47 (d, 2F).

In a 25 mL single-mouth bottle, Bu ₃ P (2.02 g, 10 mmol) and ClCF ₂ C00Na (L 52 g, 10 mmol) were dissolved in a mixed solvent of dimethylformamide, and the reaction was sealed at room temperature for 40 h. The reaction was then quenched and filtered to give a white solid which was washed twice twice with diethyl ether and three times with diethyl ether. The upper clear solution was evaporated to dryness under reduced pressure to give the product (2.70 g), isolated yield: 91%.

Bu ₃ P ⁺ CF ₂ CO ₂ ": 1HNM (300 MHz, MeOD) 51.29-1.48 (m, 3H), 51.61-1.89 (m, 2H) 51.80-2.01 (m, 2H), 52.04-2.13 (m, 2H) ), ¹⁹ F NM (282 MHz, CDCl ₃ ) δ -99.1 l(d, 2F). Difluoromethylene scale salt as difluorocarbene reagent for synthesis of difluoro-substituted compound difluorocarbene for SH insertion

Example 5

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (0.57 g, 1.6 匪ol) and 2-mercaptobenzothiazole (0.13 g, 0.8 mmol) were dissolved in tetrahydrofuran at 60 ° Under C, the tube was sealed for 8 h. Then, the heating was stopped, and after the reaction was cooled, the system was directly subjected to column chromatography (petroleum ether: dichloromethane = 4:1), yield: 87%.

: Ή NM (300 MHz, CDC1 ₃ ) δ 7.97 (d, 1H), 7.78 (d, 1H),

7.51-7.41 (m, 1H), 7.41-7.30 (m, 1H) 57.62(t, 1H), ¹⁹ F NMR (282 MHz, CDC1 ₃ ) δ

Insertion of HF by difluorocarbene

Example 6

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (0.57 g, 1.6 匪ol) and p-nitrophenol (0.11 g, 0.8 匪ol) were dissolved in n-pentamidine at 55 At °C, the tube was sealed for 4 h. Then, the heating is stopped, and after the reaction is cooled, the system is directly subjected to column chromatography (dichloromethane) to obtain the product (0.11 g), yield: 70%.

H NMR (300 MHz, CDC1 ₃ ) δ 8.27 (d, 2H), 7.26 (d, 2H), 6.66

(t, lH), ¹⁹ F NMR (282 MHz, CDC1 ₃ ) δ -82.53 (d, 2F). Example 7

In a 5 mL sealed tube, triphenyldifluoromethylene (0.57 g, 1.6 匪 ol) and a constant

Precursor of pantoprazole for the treatment of stomach diseases

(0.30 g, 0.8 mmol) was dissolved in toluene, and the reaction was sealed at 80 ° C for 8 h. Then, the heating is stopped. After the reaction is cooled, the system is hydrolyzed with an excess of K0H, acidified, extracted three times with diethyl ether and water (10 mL: 10 mL), and separated by column chromatography (petroleum ether: methylene chloride 5:1). The desired product (0.245 g) was obtained, yield: 80%.

: Ή NM (300 MHz, CDC13), δ 12.28 (bs, 1H), 8.18 (d, 1H), 7.72 (bs, 1H), 7.49 (bs, 1H), 7.12 (dd, 1H), 6.81 (d, 1H), 6.54 (t, 1H), 4.87 and 4.70 (2H), 3.88 (s, 3H), 3.85 (s, 3H). Insertion of NH with difluorocarbene

Example 8

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (0.57 g, 1.6 匪ol) and benzimidazole (94.5 mg, 0.8 匪ol) were dissolved in p-chloroform at 70 ° C. , sealed tube reaction for 6h. Then, the heating was stopped, and after the reaction was cooled, the system was directly subjected to column chromatography (petroleum ether: methylene chloride = 4:1) to obtain a product (0. rate: 81%).

: Ή NM (300 MHz, CDC1 ₃ ) δ 8.18(s, 1Η), 7.92-7.80 (m, 1H), 7.65(dd,lH), 7.47-7.37(m, 2H), 7.35(t, 1H), ¹⁹ F NM (282 MHz, CDC1 ₃ ) δ -93.70 (d, 2F). Synthesis of difluoromethylene compounds by difluoromethylene scale salt as difluorocarbene reagent

Example 9

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (0.57 g, 1.6 匪ol) and p-methoxystyrene (107.3 mg, 0.8 mmol) were dissolved in p-xylene. The tube was sealed at 60 ° C for 2 h. Then, the heating was stopped, and after the reaction was cooled, the column was separated by direct chromatography (petroleum ether) to obtain the product (135.8 mg).

: Ή NM (300 MHz, CDC1 ₃ ) δ 7.16 (t, 2H), 6.85 (d, 2H), 3.76 (s, 3H), 2.94-2.53 (m, 1H), 1.74 (tdd, 1H), 1.52 ( Dtd,lH), ¹⁹ F NMR (282 MHz, CDC1 ₃ ) δ

■ 126.15 (dtd, lF), -142.32 (ddd, lF). Example 10

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (178 mg, 0.5 匪ol) and 4- styrene (45. lmg, 0.25 mmol) were dissolved in n-hexane, at 70 ° Under C, the tube was sealed for 2 h. Then, the heating is stopped, and after the reaction is cooled, the system is directly subjected to column chromatography (dichloromethane) to obtain the product (44.7 mg).

: Ή NM (300 MHz, CDC1 ₃ ) δ 7.53-7.44 (m, 4H), 7.35 (t, 2H) 7.26 (dd, 1H), 7.21 (d, 2H), 2.82-2.53 (m, 1H), 1.88-1.66 (m, 1H), 1.56 (tdd, lH), ' ^y F NM (282 MHz, CDC1 ₃ ) δ -125.76 (dtd, lF), -142.20 (ddd, lF). Example 11

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (0.57 g, 1.6 匪ol) and p-bromostyrene (146.4 mg, 0.8 mmol) were dissolved in ethyl acetate at 90 ° C. Next, the tube was sealed for 2 hours. Then, the heating was stopped, and after the reaction was cooled, the system was directly subjected to column chromatography (petroleum ether: diethyl ether = 5:1) to give the product (143.9 mg), yield: 77%.

: 'HNMR (400 MHz, cdcl ₃ ) δ 7.45 (m, 2H), 7.10 (d, 2H), 2.70 (td, 1H), 1.92-1.76 (m, 1H), 1.59 (dtd, 1H), ¹⁹ F NMR (282 MHz, CDC1 ₃ ) δ -126.01 (dtd, IF), -142.20 (ddd, 1F). Example 12

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (0.57 g, 1.6 匪ol) and p-methylphenylacetylene (92.9 mg, 0.8 匪ol) were dissolved in dimethyl sulfoxide. The tube was sealed at 110 ° C for 8 h. Then, the heating was stopped, and after the reaction was cooled, the system was directly subjected to column chromatography (petroleum ether: diethyl ether = 9:1) to give the product (113.Omg), yield: 85%.

: Ή NM (300 MHz, cdcl ₃ ) 57.55 (d, 2H), 7.37 (t, 1H), 7.28 (d, 2H)

2.42 (s, 3H), ' ^y F NMR (282 MHz, CDC1 ₃ ) δ -106.8 (s, 2F). Difluoromethylene chloride scaly salt as difluoroalkenylation reagent mono- aldehyde difluoroalkenylation

Example 13

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (0.57 g, 1.6 匪ol) and p-bromobenzaldehyde (148 mg, 0.8 mmol) were dissolved in 7 ^methylpyrrolidone. At 60 ° C, the tube was reacted for 1 h. Then, the heating was stopped, and after the reaction was cooled, water and diethyl ether were extracted and separated by column chromatography (petroleum ether) to obtain a product (15 ratio: 90%).

H NM (300 MHz, CDC1 ₃ ) δ 7.42 (d, 2H), 7.5 (d, 2H), 5.20 (dd,

1H), ^iy F NMR (282 MHz, CDC1 ₃ ) δ -81.30 (dd, IF), -83.11 (dd, 1F). Example 14

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (0.57 g, 1.6 匪ol) and p-nitrobenzaldehyde (120.9 mg, 0.8 mmol) were dissolved in 1,4-dioxane. In the case, at 80 ° C, the tube was reacted for 1.5 h. Then, the heating was stopped, and after the reaction was cooled, the system was directly subjected to column chromatography (petroleum ether: ethyl acetate = 4:1). That is, the yield: 95%.

H NM (300 MHz, CDC1 ₃ ) δ 8.20(d, 2Η), 7.49(d, 2H), 5.41

(dd, 1H), ' ^y F NMR (282 MHz, CDC1 ₃ ) δ -77.26 (dd, IF), -78.66 (d, 1F). Example 15

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (0.57 g, 1.6 匪ol) and p-ethynyl benzaldehyde (104. lmg, 0.8 mmol) were dissolved in dimethyl. In formamide, the tube was sealed at 60 ° C for 4 h. Then, the heating is stopped, and after the reaction is cooled, it is extracted three times with water and ethyl acetate. The organic phase is combined, dried over anhydrous Na ₂ SO _{4 for} 6 h, and then the crude product is concentrated to 1 mL solvent, and the column is subjected to column chromatography (petroleum ether) ) 9. 5 mg ) , Yield: 91%.

H NM (300 MHz, CDC1 ₃ ) δ 7.45(d, 2H), 7.27(d, 2H), 5.26

(dd, 1H), 3.10 (s, 1H), ' ^y F NMR (282 MHz, CDC1 ₃ ) δ -80.54 (t, IF), -82.53 (dd, 1F). Example 16

In a 5 mL sealed tube, triphenyldifluoromethylene scale salt (0.57 g, 1.6 匪ol) and trifluoromethyl acetophenone (139. 3 mg, 0.8 mmol) were dissolved in two In methyl sulfoxide, the tube was sealed at 80 ° C for 4 h. Then, the heating is stopped. After the reaction is cooled, the system is extracted with water and ethyl acetate, and the mixture is separated. The aqueous phase is washed with diethyl ether three times (5 mL of X 3 ), and the crude product is concentrated and then separated by column chromatography ( petroleum ether: acetic acid Ester = 6 : 1 ), that is, 6 mg), yield: 70%.

: 1H NMR (300 MHz, CDC1 ₃ ) δ 7.21-7.50 (m, 5H), ¹⁹ F NMR (282

MHz, CDC1 ₃ ) δ -75.76 (m, IF), -77.50 (dd, IF), δ -59.32 (dd, 3F). The above examples show that the difluoromethylene scale salt provided by the present invention is simple and easy to obtain, and is widely used as a difluorocarbene reagent and a difluoroalkenylation reagent. The final product of the synthesis is a series of compounds substituted with difluoromethyl, difluoroalkenyl and difluoromethylene, which are important and widely used in the fields of medicine, pesticides, materials and fine chemicals. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it is to be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims

Rights request

1. A difluoromethylene phosphonium internal salt compound represented by formula A, characterized by:

(R ¹ R ² R ³ )PCF ₂ C0 _{2 (A)}

In the formula, I ¹ , R ² and R ³ are each independently selected from the following group: substituted or unsubstituted C1~C20 alkyl group, substituted or unsubstituted C3~C20 cycloalkyl group, substituted or unsubstituted C1~C30 Aryl or heteroaryl, substituted or unsubstituted benzyl, substituted or unsubstituted C1~C30 alkyloxy, substituted or unsubstituted C1~C30 aryloxy, substituted or unsubstituted C1~C30 dialkyl Amino group, substituted or unsubstituted C1~C30 diarylamine group, or a combination thereof;

Wherein, the substitution means that one or more hydrogen atoms on the group are substituted by a substituent selected from the following group: C1~C20 alkyl group, C3~C10 cycloalkyl group, halogen, hydroxyl group, carboxyl group, aldehyde group, acyl group , amino, phenyl; the phenyl group includes unsubstituted phenyl or substituted phenyl with 1-5 substituents, and the substituents are selected from: halogen, C1-C20 alkyl, OH, nitro.

2. A method for preparing a compound as claimed in claim 1, characterized by comprising the following steps: (a) reacting a compound of formula B with a compound of formula C in an inert solvent to form a compound of formula A;

XCF ₂ CO— ₂ M+ + (R ¹ R ² R ³ )P (R ¹ R ² R ³ )PCF ₂ CO ₂

B C A

Among them, X is a leaving group, preferably selected from the following group: Cl, Br, I, -OTf, -OTs, -OMs, or a combination thereof;

M is an alkali metal or alkaline earth metal cation and/or ammonium ion, preferably selected from the following group: Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba, Al, NH ₄ ;

In the formula, RR ² and R ³ are defined as above.

3. A method for preparing the compound according to claim 1, characterized in that it includes the following steps: in an inert solvent, combining XCF ₂ CO ₂ Si (R ⁴ R ⁵ R ⁶ ) and (Ι^I ³ ) P reacts with fluoride anions to obtain (R^I^R^P+CFsC;

XCF ₂ CO ₂ Si( ^{4 5 6} ) + (R^I^R^P + fluoride anion → (R^I^R^P+CFsC) Where, X is a leaving group, preferably selected from the following group: Cl, Br, I, -OTf, -OTs, -OMs, or combinations thereof;

^RR2 , ^R3 , ^RR5 , R6 are each independently selected from substituted or unsubstituted C1~C20 alkyl, substituted or unsubstituted C3~C20 cycloalkyl, substituted or unsubstituted C1~C30 aryl or hetero Aryl group, substituted or unsubstituted benzyl group, substituted or unsubstituted C1~C30 alkyloxy group, substituted or unsubstituted C1~C30 aryloxy group, substituted or unsubstituted C1~C30 dialkylamino group, substituted or unsubstituted C1~C30 diarylamine group, or its combination.

4. A method for producing difluorocarbene, characterized in that it is produced by thermal decomposition of the compound of formula A described in claim 1 in an inert solvent.

5. The use of the compound of formula A according to claim 1, characterized in that it is used to prepare fluorinated compounds, and the II compound II:

I II III

In the above formulas, AA ² , A ^: AA ⁵ , and A ⁶ are each independently selected from the following group: hydrogen atom, substituted or unsubstituted C1~C20 linear or branched alkyl group, substituted or unsubstituted C1~C20 Linear or branched alkyloxy group, substituted or unsubstituted C1~C20 linear or branched alkylamine group; substituted or unsubstituted C3~C20 cycloalkyl and heterocyclic alkyl group, substituted or unsubstituted C5~ C30 aryl, substituted or unsubstituted C1~C30 heteroaryl, substituted or unsubstituted benzyl;

R' is selected from the following group: hydrogen atom, substituted or unsubstituted C1~C20 linear or branched alkyl group, substituted or unsubstituted C1~C20 linear or branched alkyloxy group, substituted or unsubstituted C1~ C20 linear or branched alkylamine group; substituted or unsubstituted C3~C20 cycloalkyl group, substituted or unsubstituted C1~C20 heterocyclic alkyl group; substituted or unsubstituted C5~C30 aryl group; substituted or unsubstituted C1~C30 heteroaryl; substituted or unsubstituted benzyl, and similar groups;

D ¹ , D ² , D ³ and D ⁴ are independently selected from the following group: C, N, O, S, P;

B is selected from the following group: O, S, N, P, C;

Wherein, substitution is defined as above.

6. A method for preparing a compound of formula I, characterized by comprising the steps of: reacting a compound of formula la with a compound of formula A according to claim 1 in an inert solvent to obtain a compound of formula I

la AI

In each of the above formulas, the definitions of each group are as described above.

7. A method for preparing a compound of formula II, which is characterized by comprising the steps of: reacting a compound of formula Ila with a compound of formula A described in claim 1 in an inert solvent to obtain a compound of formula II;

+

R'— BH + (R ¹ R ² R ³ )PCF ₂ CO ₂ ^ R'BCF ₂ H

Ila A II

In the above formulas, the definitions of each group are as mentioned above; wherein, the definition of substitution is as mentioned above.

8. A method for preparing a compound of formula III, characterized in that it includes the steps of: in an inert solvent, The compound of formula Ilia reacts with the compound of formula A according to claim 1 to obtain the compound of formula III; A ⁵ - D ³ ≡D ⁴ -A ⁶ + (R ¹ R ² R ³ )PCF ₂ CO ₂ ^

A ⁵ ' , A ⁶

Ilia A III

9. Use of the compound according to claim 1, wherein the compound is used as a difluoroalkylation reagent for preparing olefin compounds of formula IV:

In the formula, Y ¹ and Y ² are each independently selected from the following group: hydrogen atom, substituted or unsubstituted C1~C20 linear or branched alkyl group, alkyloxy group, alkylamine group; substituted or unsubstituted C3~ C20 cycloalkyl, heterocyclic alkyl; substituted or unsubstituted C5~C30 aryl; substituted or unsubstituted C1~C30 heteroaryl; substituted or unsubstituted benzyl, or Y ¹ and Y ² together constitute the following Structure: -(CH ₂ ) _n -, where n is an integer from 1 to 30, and the hydrogen atoms on the alkyl group can be optionally substituted;

In each of the above formulas, substitution is defined as above.

10. A method for preparing a compound of formula IV, which is characterized by comprising the following steps: reacting a compound of formula IVa with a compound of formula A described in claim 1 in an inert solvent to obtain a compound of formula IV;

_Y 1

IVa A IV

In each of the above formulas, the definitions of each substituent are as described above.

1 1. The use of a compound of formula A, characterized in that the compound (a) is used as a difluorocarbene reagent; (b) is used as a difluoroalkylation reagent; or (c) is used to generate difluorocarbene in situ Fluorine substituted wittig reagent.

12. A method for preparing a difluoroalkylation reagent, characterized in that it is produced from the compound of formula A described in claim 1.