JPH02273626A - Fluorination of halogenated aromatic compound - Google Patents

Abstract

PURPOSE:To obtain a fluorine aromatic compound useful as an intermediate for drugs and agricultural chemicals in high yield and in high purity by using a palladium compound and a phosphine-based compound as a catalyst and reacting a halogenated aromatic compound with an alkali metal fluoride. CONSTITUTION:A palladium compound such as palladium-carbon or palladium chloride and a phosphine-based compound such as a compound shown by formula I (R<1> to R<3> are alkyl, phenyl or phenoxy) or compound shown by formula II (R<4> is alkyl or phenyl; X is 1 to 4C alkylene, group shown by formula III, binaphthyl, etc.) are used as a catalyst and a halogenated aromatic compound containing at least one halogen atom except fluorine atom on the benzene nucleus is reacted with an alkali metal fluoride (preferably spray-dried potassium fluoride) at 100 to 300 deg.C, preferably 150 to 220 deg.C to give a fluorine aromatic compound. The reaction is advanced at relatively low temperature and in a short time and the compounds used as the catalyst can be recovered.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for fluorinating halogenated aromatic compounds. This invention relates to a novel method for fluorinating aromatic compounds.

Fluorine substitution is achieved by reacting a halogenated aromatic compound with a strong electron-withdrawing substituent such as a nitro group, cyano group, or trifluoromethyl group on the aromatic ring with an alkali metal fluoride in an aprotic polar solvent. Methods for producing aromatic compounds are conventionally known.

Recently, Japanese Patent Application Laid-Open No. 60-228456 describes aromatic compounds that do not have a strong electron-withdrawing substituent in one aromatic ring and have a chlorine atom or bromine atom with low reactivity, as quaternary ammonium salts. , discloses a method for fluorinating aromatic compounds by adding a quaternary phosphonium salt as a phase transfer catalyst and reacting it with a metal fluoride without a solvent or in an aprotic organic solvent. Also, 63-205656
No. 65-1700332 discloses a method for fluorinating halogenated aromatic compounds in the presence of a pyridinium compound as an auxiliary agent for the fluorine substitution reaction, and No. 65-1700332 discloses a method for fluorinating halogenated aromatic compounds containing halogen atoms other than fluorine atoms. A halogenated benzaldehyde is reacted with a metal fluoride by combining 18i selected from quaternary phosphonium salts and quaternary ammonium salts as a catalyst and at least one selected from crown ethers and polyalkylene glycols. A method for producing fluorobenzaldehydes is disclosed.

When a halogenated aromatic compound containing a cyano group, etc., which is a weaker electron-withdrawing group than a nitro group, is reacted with a metal fluoride in an aprotic organic solvent, the reaction temperature may be high and the reaction may be slow. Although it took a long time, a sufficient yield could not be obtained.

Also, 4th. Methods using phase transfer catalysts such as lj ammonium salts and crown ethers as catalysts are disadvantageous from an economic point of view because these materials are expensive.

In order to solve the above problems, the present inventors have conducted intensive research and found that palladium compounds and phosphine compounds are used as catalysts in the fluorination of halogenated aromatic compounds, which were conventionally considered to have poor reactivity. In particular, the present invention was completed by discovering that fluorinated aromatic compounds can be produced with high yield.The use of palladium compounds and phosphine compounds as catalysts in the production of these compounds is completely new. This is a great finding.

The advantage of the production method of the present invention is that a halogenated aromatic compound, which is an easily available industrial raw material, is used as a raw material, and halogen, which was conventionally thought to have low reactivity among these halogenated aromatic compounds, is used as a raw material. Even with fluorinated aromatic compounds, the reaction proceeds at a relatively low reaction temperature and in a short time, and the desired fluorinated aromatic compound can be produced in high yield and purity. Furthermore, the palladium compound and phosphine compound used as catalysts can be recovered and reused, making the production method industrially economical.

The invention can be illustrated, for example, diagrammatically as follows. That is, - membrane mark (in the formula, X represents a halogen atom which may be the same or different, n represents an integer of 1 to 5, Y represents a formyl group, a cyano group, a nitro group, a haloalkyl group, -COR '(wherein, R
i represents a halogen atom, a lower alkyl group, a lower alkoxy group, or an aryl group. ), -OR' (in the formula, R6 represents a lower alkyl group or an aryl group), -3R7 (in the formula, R7 represents a lower alkyl group or an aryl group),
-5o! A halogenated aromatic compound represented by R'' (in the formula, Ra represents a halogen atom, a lower alkyl group, or an aryl group) or an inthiocyanate group is used as a catalyst in the presence of a palladium compound and a phosphine compound. Below, it is reacted with an alkali metal fluoride to form a compound of the general formula (M (wherein, 7 atoms, a lower alkyl group, a lower alkoxy group or an aryl group), -OR'' (in the formula, R- is the same as above), -SR? (in the formula, R7 is the same as above). ), So, RIO, (where RIO is a fluorine atom,
Indicates a lower alkyl group or an aryl group. ) or inthiocyanate group.

m represents an integer of 1 to 5, and n' represents an integer of 0 to 4.

However, m+n'=n. n is the same as above. ) is a method for producing a fluorinated aromatic compound.

Typical compounds of the general formula (represented by IID) and rogenated aromatic compounds that can be used in the present invention include, for example, tt
Benzaldehydes such as 2-chlorobenzaldehyde, 4-chlorobenzaldehyde, 2,4-dichlorobenzaldehyde, 2-chloro-6-fluoropenzaldehyde, 2,6-dichlorobenzaldehyde, 3,4-dichlorobenzaldehyde, 2-chloro Nopenzonitrile such as benzonitrile, 4-chlorobenzonitrile, 2-chloro-6-fluorobenzonitrile, 2,6-cyclopenzonitrile, 3,4-dichlorobenzonitrile, 2-chloronitrobenzene, 4-chloronitrobenzene, etc. nitrobenzenes, benzoyl I such as 2-chlorobenzoyl chloride, 4-chlorobenzoyl chloride, etc.
~ride ljl, 4-chloroacetophenone, 4-chlorobenzophenone, s, a-dichlorobenzophenone,
4. Aromatic ketones such as 4'-dichlorobenzophenone, pensene sulfonyl halide a such as 2-/lolobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-chlorophenylmethylsulfone, 4.
Examples include aromatic sulfones or sulfoxides such as 4'-dichlorodiphenyl sulfone and 4,4'-dichlorodiphenyl sulfoxide, and aromatic ethers such as 4,4'-dichlorodiphenyl ether. It is not limited to.

The palladium compound that can be used as a catalyst in the present invention may be used in combination with a phosphine compound. Examples of the palladium compound include metal palladium, palladium carbon, palladium alumina, palladium chloride, palladium bromide, vinegar 51 palladium, dichlorobis(cyanophenyl ) Palladium, dichlorobis()IJ phenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)nipalladium, and other palladium compounds can be used.

Examples of the phosphine compounds used in combination with the palladium compound in the present invention include triisopropylphosphine, tributylphosphine, triphenylphosphine, triparafluorophenylphosphine, tripentafluorophenylphosphine, trihalatolylphenylphosphine, triphenoxyphosphine, dimethyl Examples of phosphine compounds such as phenylphosphine, methyldiphenylphosphine, and pentafluorophenylphosphine, and phosphine compounds represented by the general formula (■) include 1,1-bis(dimethylphosphino)methane,
1,1-bis(diethylphosphino)methane, 1,2-
Bis(dialkylphosphino) such as bis(dimethylphosphino)ethane, 1,2-bis(diethylphosphine)ethane, 1,5-bis(dimethylphosphino)propane, 1,4-bis(dimethylphosphino)butane, etc. Alkanes, 1.1-bis(diphenylphosphino)methane, 1
, 2-bis(diphenylphosphino)ethane, 1,3-
Bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1,5-bis(diphenylphosphino)pentane, 1,6-bis(diphenylphosphino)hexane, 2゜3-0- Impropylidene-2,5-dihydroxy-/-1,4-bis(diphenylphosphino)butane, bis(diphenylphosphino)
Examples include phosphine compounds such as 7 erocene and bis(diphenylphosphino)binaphthyl.

In the present invention, a palladium compound and a phosphine compound may be used in combination, each may be added to the reaction system alone, or may be prepared in advance in the form of a complex.
The amount of palladium compound and phosphine compound added is 41
Although not limited to PK, general formula (I/logenated aromatic compound 1 represented by
It may be used in a molar range of 1 to α5 times, preferably in a range of 0001 to α1 times molar.

The phosphine compound and the palladium compound may be added at a ratio of 101 to 1000 times, preferably (11 to 10 times) per mole of the palladium compound.
It may be used in a 0-fold molar range.

Examples of the alkali metal 7] compound used in the present invention include potassium heptafluoride and cesium heptafluoride. Preferably, spray-dried potassium fluoride is used.

The amount of alkali metal heptadide to be used is usually 1 to 5 times the mole of the alkali metal fluoride per one halogen atom to be substituted in the general formula (represented by @) and the halogenated aromatic compound. You can use .

The reaction of the present invention can be carried out in the presence or absence of an inert solvent, and inert solvents that can be used include:
Any solvent may be used as long as it does not significantly inhibit the progress of this reaction. For example, in addition to aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, dimethylsulfone, and sulfolane, benzene, acetonitrile, pentonitrile,
Inert solvents such as hexamethylphosphoramide (HMPA), dimethylacetamide, diethylacetamide, N-methylformanilide, etc. can be used.

The reaction of the present invention can be carried out under normal pressure or under increased pressure, and industrially it is preferable to carry out the reaction under normal pressure.

The reaction temperature of the present invention may be appropriately selected from the range of 100 to 300°C, preferably within the range of 150 to 220°C.

The reaction time is not constant depending on the reaction amount, reaction temperature, etc.
- It is sufficient that the reaction progress is completed, and the reaction usually ends within a range of 1 to 8 hours.

After the reaction is completed, the catalyst is recovered from the reaction solution containing the target product according to a conventional method, and the target product is extracted. is not limited to these.

Example t Preparation of 4-fluorobenzophenone.

-1-1゜ 100sI7 three-bottle flask 1c4- equipped with a cooling tube
Chlorobenzophenone 2A79 (10 mmol), spray-dried potassium fluoride 2.911F (50 mmol), tetrakis(triphenylphosphine)palladium α0579 ((105 mmol), triphenylphosphine 1.31F (5 mmol) and benzonitrile 12d was added, and the reaction was carried out for 9 hours under heating and reflux in an atmosphere of argon gas.

After the reaction was completed, the reaction solution was cooled, and the target product was extracted with ethyl acetate. After drying the extract, it was analyzed by gas chromatography using dibenzyl as an internal standard. As a result, the target product, 4-fluorobenzophenone, was produced in an amount of 4a3%.

In addition, a standard product of 4-fluorobenzophenone was used to identify the compound.

1-2 ~ & The reaction was carried out under the conditions shown in Table 1, and the other conditions were the same as in Example 1-1. The results are shown in Table 1.

Using Table 1 (α025 mmol) and carrying out the reaction in the same manner as in 1-1 except for the other conditions, 4-fluorobenzophenone was produced at a production rate of 3 & 9 degrees.

lt[f12.414'-difluoroben”/7 x
Manufacture of /n.

・ 4-chlorobenzophenone K of 1-4゜Example 1-1 instead of 4-
Bromobenzophenone 2.61f (10 mmol), potassium fluoride K instead of cesium heptadide 14f (1025
mmol) and tetrakis (triphenylphosphine)
Palladium (LO57r (+105 mmol)) K was placed in a 100d three-necked flask equipped with a 0.029t-2-1° cooling tube at 4°4'-
Dichlorobenzophenone λ51f (10 mmol),
Spray-dried potassium fluoride 2.912 (50 mmol), palladium chloride α0089t ([LO5 mlJ
mole), triphenylphosphine 1.31? (5 mmol) and 12 mj of sulfolane were added, and the reaction was carried out at 200° C. for 4.5 hours in an argon gas atmosphere.

After the reaction was completed, the same procedure as in Example 1-1 was carried out and analysis was performed by gas chromatography.
Difluorobenzopheno7 produced 3&7%.

-2-2 to 6° In Examples 2-2 to 6, the inert solvent and reaction temperature used in Example 2-1 were changed to the conditions K shown in Table 2, and the other conditions were 2-
This was done in the same manner as in step 1.

The results are shown in Table 2.

Table 2 Example work 3-chloro-4-fluorobenzof Manufacture of Enon.

A 100-inch three-necked flask equipped with a condenser [3° 4-dichlorobenzophenone 2-51f (10 mmol), spray-dried potassium fluoride 2-91·t (so mmol), palladium chloride 144f (125 mmol),
) IJ phenylphosphine 1.31f (5 mmol) and sulfolane 12m were added, under an argon gas atmosphere,
The reaction was carried out at 200°C for 4.5 hours.

After the reaction was completed, the same procedure as in Example 1-1 was carried out, and the target product, 4,4'-difluorobenzophenone, was found to be 74.511% by gas chromatography. generated.

The desired product was isolated from the reaction extract by wet column chromatography to obtain 2.015' of 5-chloro-4-fluorobenzophenone, which was the desired product.

Yield: 8 & 7 yen Examples 4-12 and Comparative Examples 1-i Reactions were carried out in the same manner as in Example 1 under the conditions shown in Table 3. The results are shown in Table 3.

implementation? 1Jt4. Production of 4-fluorobenzaldehyde.

4-chlorobenzaldehyde 7, Of (50 mmol), spray-dried potassium fluoride 44f (75 mmol), in a 100 d capacity stainless steel autoclave.
Add palladium chloride α044f (125 mmol) and triphenylphosphine 1b55f (25 mmol), and after purging with argon gas several times, fill with argon gas at 1 oh/- and react at 200°C for 4.5 hours with stirring. Ta.

After the reaction was completed, the same procedure as in Example 1-1 was carried out, and as a result of analysis by gas chromatography, 41.4 tons of 4-fluorobenzaldehyde, which was the target product, was produced.

Example 15. 3. Production of 4-difluorobenzotrifluoride.

3,4-dichloropenzotrifluoride 2.15? (1
0 mmol), cesium fluoride 5.549 (22 mmol), tetrakis(triphenylphosphine)palladium (1057? (1 mouthful 5 mmol), triphenylphosphine 1.319 (5 mmol) and sulfolane 1
2-, and after replacing with argon gas several times, 10kf
4. Filled with argon gas and heated at 200°C with stirring.
The reaction was carried out for 5 hours.

After the reaction was completed, the same procedure as in Example 1-1 was carried out and analysis was performed by gas chromatography. As a result, the target product 3,4-
Difluoropenzotrifluoride is 1 t2% and 3-
Chloro 4-fluorobenzotrifluoride is 59.31
The production rate was

that's all Procedural amendment

Claims (6)

[Claims] (1) A halogenated aromatic compound having at least one halogen atom other than a fluorine atom in the benzene nucleus is reacted with an alkali metal fluoride using a palladium compound and a phosphine compound as a catalyst. Fluorination method. (2) The method for fluorinating aromatic halogens according to claim 1, wherein the palladium compound is palladium metal, palladium metal supported on a solid, or a zero-valent, divalent or tetravalent complex. (3) The method for fluorinating aromatic halogens according to claim 2, wherein the palladium compound is palladium carbon, palladium chloride, or palladium acetate. (4) A phosphine compound has the general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1, R^2 and R^3 may be the same or different, and substituents may be 2. The method for fluorinating aromatic halogen according to claim 1, which is a compound represented by the following formula: an alkyl group that may have a substituent, a phenyl group that may have a substituent, or a phenoxy group that may have a substituent. (5) The phosphine compound has the general formula (II) (R^4)_2-P-X-P-(R^4)_2(II)(
In the formula, R^4 represents an alkyl group or a phenyl group which may have a substituent; , there are tables, etc. ▼, -CH_2CH_
2-P(Ph)-CH_2CH_2- (in the formula, Ph represents a phenyl group) or a pinaphthyl group. ) The method for fluorinating an aromatic halogen according to claim 1, which is a compound represented by the following formula. (6) The method for fluorinating aromatic halogens according to claim 1, wherein the alkali metal fluoride is potassium fluoride or cesium fluoride.