JPH0733340B2 - Method for converting carbonyl group to difluoromethylene group - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for converting a carbonyl group into a difluoromethylene group.

[Conventional technology and problems]

Various attempts have been made to obtain a difluoromethylene group by substituting an oxygen atom of a carbonyl group with two atoms of fluorine. For example, a method using sulfur tetrafluoride, which is a gas having a toxicity as high as that of phosgene,
Of Organic Chemistry (J.Org.Chem.), 3
Vol. 6, p. 818 (1971)], Method using molybdenum hexafluoride [Tetrahedron, vol. 27, p. 3965 (1
971)], a method using sulfur trifluoride (diethylamino) sulfur [Journal of Organic Chemistry (J.Org.Chem.), 40, 574 (1975)], etc., to directly fluorinate the carbonyl group. Or a method in which ketones are converted to hydrazone derivatives and then reacted with an excess amount of iodine monofluoride (J.Amer.Chem.So.
c.), 109, 896 (1987)] and the like.

However, these conventional methods have some drawbacks and are problematic in industrial practice. For example,
In the method using sulfur tetrafluoride, its boiling point is −40 ° C. and the reaction temperature is generally 100 to 200 ° C. Therefore, highly toxic gas must be reacted at high temperature and high pressure. I won't. Moreover, even if the conversion yield of carbonyl group to difluoromethylene group by this method is high,
It is about 70%, and is generally as low as 30 to 60%. Furthermore, in order to produce the raw material sulfur tetrafluoride,
Usually, an expensive high corrosion-resistant material such as Hastelloy C autoclave Heiou, sodium fluoride and chlorine are charged and allowed to react at a high temperature (finally 225 to 250 ° C) for a long time, and then the reaction mixture is cooled to a low temperature. It is necessary to purify by distillation at [Journal of the American Chemical Society (J.Amer.Chem.Soc.), Which is an expensive and troublesome method.

In addition, the method using molybdenum hexafluoride requires that boron trifluoride be used as a catalyst, and that the conversion yield of the carbonyl group to the difluoromethylene group is high.
%, And is generally as low as 17-40%.

The method using trifluorinated (diethylamino) sulfur is a fluorinated reagent that can be reacted under relatively mild conditions. However, in order to produce this fluorinated reagent, it is expensive to use sulfur tetrafluoride. However, the disadvantage of using sulfur tetrafluoride is unavoidable.

Furthermore, in reactions using reagents that directly fluorinate carbonyl groups such as sulfur tetrafluoride and molybdenum hexafluoride,
Of the fluorine atoms contained in these fluorination agents,
It is also a problem that what can be effectively used is less than half as shown in, for example, the reaction formulas (A) and (B).

C = O + SF ₄ → CF ₂ + SOF ₂ ...... (A) C = O + MoF ₆ → CF ₂ ＋ MoOF ₄ …… (B) SOF ₂ and MoOF ₄ no longer have the carbonyl group fluorination ability. In order to carry out these methods industrially, a complicated and expensive recovery process for producing SF ₄ and MoF ₆ from SOF ₂ and MoOF ₄ is required.

In addition, the method of reacting ketones with hydrazone derivatives and then reacting them with iodine monofluoride is not so high as a yield of 20 to 75%, and it is difficult to handle iodine monofluoride with molecular fluorine. Must be manufactured from iodine.

As described above, the conventional methods have various problems, and it has been substantially difficult to industrially carry out these methods.

[Means for solving problems]

Therefore, the present inventors have conducted diligent research to find a method for substituting the oxygen atom of a carbonyl group with two atoms of fluorine to easily produce a compound having a difluoromethylene group with high yield and high selectivity. As a result, from cyclohexanone 1,
As a method for producing 1-difluorocyclohexane with high yield and high selectivity, a new method of reacting 1,1-bis (trifluoroacetoxy) cyclohexane obtained from cyclohexanone and trifluoroacetic anhydride with hydrogen fluoride was proposed. Heading, filed earlier (Japanese Patent Application No. 61-187814)
Japanese Patent Application No. 61-198103).

The present invention has found that this reaction is in no way limited to unsubstituted cyclohexanone and complements the previous application. That is, the present invention has the general formula (R and R'represent hydrogen, an aliphatic group, an alicyclic group, an araliphatic group, and an aromatic group, and R and R'may be the same or different. R and R ' May be an element forming a ring with a carbonyl group) (provided that unsubstituted cyclohexanone is excluded),
General formula A compound having a difluoromethylene group represented by (I
In the production of I), a) reacting the carbonyl compound (1) with a perfluoroalkylcarboxylic acid anhydride represented by the general formula (RfCO) ₂ O (III) (Rf represents a perfluoroalkyl group). By the general formula An acylalization step for obtaining an acylal compound (IV) containing a perfluoroalkylcarbonyloxy group represented by
And b) a carbonyl group comprising a fluorination step of obtaining a compound (II) having a difluoromethylene group and a perfluoroalkylcarboxylic acid by reacting the acylal compound (IV) with hydrogen fluoride. Is a difluoromethylene group.

The carbonyl compound used in the present invention has the general formula (I
The compounds represented by I) are ketones and aldehydes (excluding unsubstituted cyclohexanone). Examples of such a carbonyl compound include acetone, methyl ethyl ketone, methyl propyl ketone,
Methyl butyl ketone, methyl hexyl ketone, methyl octyl ketone, diethyl ketone, ethyl propyl ketone, ethyl butyl ketone, ethyl hexyl ketone, dipropyl ketone, propyl butyl ketone, propyl hexyl ketone, dibutyl ketone, butyl hexyl ketone, dipentyl ketone, dihexyl ketone Dialkyl ketones (including each isomer); Aliphatic-aromatic mixed ketones such as acetophenone, propiophenone, butyrophenone; Benzyl methyl ketone, benzyl ethyl ketone, benzyl propyl ketone, phenethyl methyl ketone, etc. Aliphatic-araliphatic mixed ketones; Aliphatic-alicyclic mixture of cyclopentyl methyl ketone, cyclopentyl ethyl ketone, cyclohexyl methyl ketone, cyclohexyl ethyl ketone, etc. Ketones; dicyclopentyl ketones, alicyclic ketones such as dicyclohexyl ketone;
Aromatic aliphatic ketones such as dibenzyl ketone and benzyl (phenylethyl) ketone; aromatic ketones such as benzophenone, naphthophenone and dinaphthyl ketone; cyclic ketones such as cyclopropanone, cyclobutanone, cyclopentanone and cycloheptanone; Further, various substituted cyclohexanones such as methylcyclohexanone, phenylcyclohexanone, and propylcyclohexanone, various styroids having a ketone group and various terpenoids, indanones, ketones such as various cyclic ketones such as tetralones, and formaldehyde. Aliphatic aldehydes such as acetaldehyde, propionaldehyde, butyraldehyde, pentylaldehyde, capronaldehyde; phenylacetaldehyde, phenylpropional Araliphatic aldehydes such as hydrate; cyclopropyl aldehyde, cyclobutyl aldehyde, cyclopentyl aldehyde, alicyclic aldehydes such as cyclohexyl aldehyde; benzaldehyde, aromatic aldehydes such as naphthylaldehyde and the like are used. In addition, these ketones and aldehydes may be substituted with a substituent that does not adversely affect the reaction, for example, a lower aliphatic group, an aromatic group, an alicyclic group or a cyano group.

Further, the perfluoroalkylcarboxylic acid anhydride used in the acylation step of the present invention is a compound represented by the general formula (III), and more specifically, trifluoroacetic acid, perfluoropropionic acid, and perfluoropropionic acid. Perfluoroalkyl monocarboxylic acid anhydrides such as fluorobutyric acid, perfluorovaleric acid, perfluorocaproic acid, perfluoroheptanonic acid, perfluorocaprylic acid, perfluorocapric acid, and perfluorosuccinic anhydride, perfluoro Examples thereof include cyclic acid anhydrides such as glutaric anhydride. Among these perfluoroalkylcarboxylic acid anhydrides, trifluoroacetic acid anhydride is particularly preferable.

The hydrogen fluoride used in the fluorination step of the present invention may have any composition as long as it contains hydrogen fluoride. Usually, hydrogen fluoride or a mixture of hydrogen fluoride and amine is used, and preferably anhydrous hydrogen fluoride or a mixture of anhydrous hydrogen fluoride and amine is used.

The hydrogen fluoride used in the fluorination step usually has a water content of 10% by weight or less, preferably 3% by weight or less, more preferably 1% by weight or less.

Amines that can be used as a mixture with hydrogen fluoride in the fluorination step include aliphatic primary amines such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, cyclohexylamine; dimethylamine, diethylamine, dipropylamine. , Diisopropylamine, dibutylamine, morpholine, piperidine,
Aliphatic secondary amines such as piperazine and dicyclohexylamine; trimethylamine, triethylamine, tripropylamine, tributylamine, tricyclohexylamine, 1,4-diazabicyclo [2,2,2] octane (DABC
O) and other aliphatic tertiary amines; aniline, diphenylamine, triphenylamine and other aromatic amines; pyridine, 2-picoline, 3-picoline, 4-picoline, quinoline, methylquinolines, melamine and other nitrogen-containing aromas Examples include group compounds. Especially butylamine, cyclohexylamine, diethylamine, dibutylamine, triethylamine, tributylamine, aniline, pyridine,
Picolines and melamine are preferably used.

The hydrogen fluoride-amine mixture that can be used in the fluorination step refers to a mixture of the above-mentioned hydrogen fluoride and amine, and its composition is usually expressed by the molar ratio of hydrogen fluoride molecule to amine, 0.1-100, preferably 1
~ 50 is used.

The acylation step in the present invention is carried out by reacting a carbonyl compound (1) with a perfluoroalkylcarboxylic acid anhydride (III) as shown in reaction formula (C) to obtain an acylal group containing a perfluoroalkylcarbonyloxy group. This is the production process of compound (IV).

This acylation reaction is usually carried out without a catalyst,
It can also be carried out using an acid catalyst. Examples of such an acid catalyst include a carboxylic acid (Rf having the same perfluoroalkyl group as the perfluoroalkylcarboxylic acid anhydride used).
COOH), carboxylic acids such as trichloroacetic acid; Lewis acids such as boron trifluoride; organic sulfonic acids such as paratoluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid; mineral acids such as sulfuric acid; perfluoroalkylsulfonic acid groups And cation exchangers having

The amount ratio of the carbonyl compound (II) and the perfluoroalkylcarboxylic acid anhydride (III) used in the acylation step is not particularly limited, but the acid anhydride group is usually 0.01 to 100 times mol relative to the carbonyl group, It is preferably carried out at a ratio of 0.1 to 50 times mol.

This acylation step can be carried out without a solvent,
It is also possible to use a solvent that does not adversely affect the reaction.
For example, ethers such as diethyl ether, tetrahydrofuran, biphenyl ether; carbon disulfide; methylene chloride, chloroform, carbon tetrachloride, dichloroethane,
Halogenated hydrocarbons such as trichloroethane and tetrachloroethane; Halogenated aromatic hydrocarbons such as chlorobenzene, dichlorobenzene, bromobenzene and chloronaphthalene; Nitro compounds such as nitrobenzene, nitrotoluene and nitromethane; Aliphatic hydrocarbons such as hexane Aliphatic hydrocarbons such as cyclohexane are used.

The reaction temperature and reaction time in the case of performing the acylation step differ depending on the amount ratio of raw materials and the presence or absence of a solvent, but usually-
40 to 250 ° C, 5 minutes to 500 hours, preferably 0 to 150
C, 10 minutes to 200 hours.

In the fluorination step of the present invention, as shown in the reaction formula (D), a compound (II) having a difluoromethylene group obtained by reacting an acylal compound (IV) containing a perfluoroalkylcarbonyloxy group with hydrogen fluoride is used. ) Manufacturing process.

In the fluorination step, the compound (II) having the desired difluoromelene group is produced as shown in the above formula, and perfluoroalkylcarboxylic acid is produced as a by-product, but these compounds are usually separated by simple separation such as distillation. It can be purified by operation.

The amount of hydrogen fluoride used in the fluorination step is not particularly limited, but is usually 0.1 to 2,000 times mol, preferably 2 to 1,000 times mol, of the acylal compound (IV).

In the fluorination step, it is also a preferable method to add an acid as a catalyst for the purpose of increasing the reaction rate. Such acids include formic acid, fluoroacetic acid, difluoroacetic acid,
Carboxylic acids such as chloroacetic acid, dichloroacetic acid and trichloroacetic acid; Perfluoroalkylcarboxylic acids such as trifluoroacetic acid and perfluoropononic acid; Sulfones such as methanesulfonic acid, trifluoromethanesulfonic acid, trichloromethanesulfonic acid and paratoluenesulfonic acid Acids; mineral acids such as hydrochloric acid and sulfuric acid; acid Lewis acids such as boron fluoride, aluminum chloride, aluminum fluoride, titanium trichloride, titanium tetrachloride, iron trichloride, iron trifluoride; perfluoroalkyl sulfonic acid groups Examples thereof include cation exchangers. Since perfluoroalkylcarboxylic acid is produced as a byproduct in the fluorination step as the reaction proceeds, using the same perfluoroalkylcarboxylic acid as a catalyst does not require special separation as an acid catalyst. Therefore, it is particularly preferable. In addition, the perfluoroalkylcarboxylic acid that is a by-product also acts as a catalyst,
The amount of acid catalyst added may be small.

When an acid catalyst is added in the fluorination step, its amount varies depending on the acidity of the acid catalyst used, but the acid group is added to the acylal compound (IV) containing a perfluoroalkylcarbonyloxy group as an acid group. , Usually 0.0001 to 1 times mole,
The molar amount is preferably 0.001 to 0.1 times.

In the fluorination step, a metal fluoride such as cesium fluoride, rubidium fluoride, potassium fluoride or sodium fluoride may be added.

The fluorination step can be performed without a solvent, but a solvent that does not adversely influence the reaction can also be used. For example, ethers such as diethyl ether, tetrahydrofuran and biphenyl ether; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane and freons; halogenated aroma such as chlorobenzene and dichlorobenzene Group hydrocarbons; aliphatic hydrocarbons such as hexane, octane and decane; aromatic hydrocarbons such as benzene, toluene and xylene; alicyclic hydrocarbons such as cyclohexane are used.

The reaction temperature and reaction time for carrying out the fluorination step differ depending on the amount ratio of the raw materials used and hydrogen fluoride, the presence and type of catalyst, the presence or absence of solvent, etc.
Minutes to 100 hours, preferably -40 ° C to 100 ° C, 5 minutes to
50 hours.

The perfluoroalkylcarboxylic acid produced as a by-product in the fluorination step can be easily regenerated by reacting a dehydrating agent with the perfluoroalkylcarboxylic acid anhydride. Recycling the carboxylic acid anhydride into the acylal process is a preferred method. Examples of the dehydrating agent having such an effect include acetic anhydride, dicyclohexylcarbodiimide, methoxyacetylene, phosphorus pentoxide, sulfur trioxide and the like. Phosphorus pentoxide and sulfur trioxide are particularly preferable because they can be recovered as phosphoric acid and sulfuric acid, respectively.

In carrying out the method of the present invention, both the acylation step and the fluorination step can be carried out batchwise or continuously.

The reaction pressure may be reduced pressure, normal pressure, or increased pressure,
Usually, the reaction can be carried out at normal pressure, which is a preferable method.

〔The invention's effect〕

By the method of the present invention, a compound having a difluoromethylene group can be easily produced with a high yield and a high selectivity by substituting the oxygen atom of the carbonyl group with fluorine of 2 atoms.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these specific examples.

Example 1 a) Acylation step Cyclopentanone 4.2 g (0.05 mol) and trifluoroacetic anhydride 25.2 g (0.12 mol) were placed in a reactor previously purged with nitrogen and stirred at 25 ° C. for 3 hours. After that, it was allowed to stand at 25 ° C. for 72 hours. By distilling the reaction mixture after distilling off unreacted trifluoroacetic anhydride, 14.5 g (yield 98.6%) of 1,1-bis (trifluoroacetoxy) cyclopentane was obtained.

b) Fluorination step 60.0 g of anhydrous hydrogen fluoride-pyridine mixture (hydrogen fluoride content 70% by weight) (containing 2.1 moles of hydrogen fluoride) was put into a reactor whose system was previously replaced with nitrogen, and the mixture was heated to -30 ° C. After cooling
With stirring, 14.5 g of 1,1-bis (trifluoroacetoxy) cyclopentane and 0.2 g of trifluoroacetic acid were added. After stirring, the reaction temperature was kept at -30 ° C for 2 hours, then gradually heated to 20 ° C in 1 hour, and further kept at 20 ° C for 2 hours. By rectifying the reaction mixture, 11.1 g of trifluoroacetic acid and 5.12 g of 1,1-difluorocyclopentane were obtained. This is based on cyclopentanone, 96 for 1,1-difluorocyclopentane.
It shows that it was obtained in a yield of 6%.

Example 2 Instead of cyclopentanone, 5.6 g of cycloheptanone (0.05
Mol) was used, and an acylation reaction with trifluoroacetic acid anhydride and a fluorination reaction with an anhydrous hydrogen fluoride-pyridine mixture were carried out in the same manner as in Example 1, as a result, 1,1- Difluorocycloheptanone was obtained with a yield of 92% and a selectivity of 97% based on cycloheptanone.

Example 3 5.7 g of di-n-propyl ketone instead of cyclopentanone
An acylation step and a fluorination step were carried out in the same manner as in Example 1 except that (0.05 mol) was used. As a result, 4,4'-difluoro-n-heptane was converted to di-n-
The yield was 93% and the selectivity was 96% based on propyl ketone.

Example 4 Instead of cyclopentanone, 6.0 g of acetophenone (0.05 g
Mol)) and the acylation step and the fluorination step were carried out in the same manner as in Example 1 except that the acylation reaction temperature was 35 ° C. As a result, α, α-difluoroethylbenzene was obtained in a yield of 90%. , Obtained with a selectivity of 92%.

Example 5 Instead of cyclopentanone, 9.1 g of benzophenone (0.05 g
And 126 g (0.6 mol) of triflufuroacetic anhydride were used to carry out an acylation reaction in the same manner as in Example 4. After the reaction, unreacted triflufuroacetic anhydride was distilled off, and this was added to 60.0 g of an anhydrous hydrogen fluoride-pyridine mixture (hydrogen fluoride content 70% by weight) cooled to -30 ° C. Trifluoroacetic acid (0.1 g) was added as a catalyst, and the mixture was stirred and kept at -30 ° C for 1 hour, and then gradually heated to 20 ° C in 1 hour, and further 20 ° C.
As a result of reacting for 5 hours, diphenyldifluoromethane was obtained with a yield of 80% and a selectivity of 88%.

Example 6 4-methylcyclohexanone instead of cyclopentanone
As a result of carrying out the same method as in Example 1 except that 56 g (0.5 mol) was used, 1,1-difluoro-4-methylcyclohexane was obtained with a yield of 94% and a selectivity of 96%.

Example 7 The same procedure as in Example 1 was carried out except that 30 g of perfluoropropionic anhydride was used instead of trifluoroacetic anhydride, and as a result, 1,1-difluorocyclopentane was obtained in a yield of 95.
%, The selectivity was 97%.

Example 8 The reaction was exactly the same as in Example 1 except that trifluoroacetic acid was not added in the fluorination step and the reaction time at 20 ° C. was changed to 4 hours. As a result, 1,1-difluorocyclopentane was obtained. Was obtained with a yield of 93.5%.

Example 9 6.7 g of benzyl methyl ketone instead of cyclopentanone
As a result of carrying out the same method as in Example 1 except that (0.05 mol) was used, 1-phenyl-2,2-difluoropropane was obtained in a yield of 90%.

Example 10 Cyclopentanone instead of cyclopentanone
The same procedure as in Example 1 was carried out except that 6.3 g (0.05 mol) was used, and 1-cyclohexyl-1,1-difluoroethane was obtained in a yield of 92%.

Example 11 The same procedure as in Example 1 was carried out except that 5 g of capronaldehyde was used instead of cyclopentanone, and as a result, 1,1-difluoro-n-hexane was obtained in a yield of 90%.

Example 12 As a result of performing the same method as in Example 1 except that 5.3 g of benzaldehyde was used instead of cyclopentanone, difluoromethylbenzene was obtained with a yield of 85%.

Example 13 Cyclohexyl aldehyde instead of cyclopentanone 5.
As a result of performing the same method as in Example 1 except that 6 g was used,
Difluoromethylcyclohexane was obtained with a yield of 92%.

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Claims (2)

[Claims] 1. A general formula (R and R'represent hydrogen, an aliphatic group, an alicyclic group, an araliphatic group, and an aromatic group, and R and R'may be the same or different. R and R ' May be an element forming a ring with a carbonyl group) (provided that unsubstituted cyclohexanone is excluded),
General formula A compound having a difluoromethylene group represented by (I
In the production of I), a) reacting the carbonyl compound (1) with a perfluoroalkylcarboxylic acid anhydride represented by the general formula (RfCO) ₂ O (III) (Rf represents a perfluoroalkyl group) By the general formula An acylalization step for obtaining an acylal compound (IV) containing a perfluoroalkylcarbonyloxy group represented by
And b) a carbonyl group comprising a fluorination step of obtaining a compound (II) having a difluoromethylene group and a perfluoroalkylcarboxylic acid by reacting the acylal compound (IV) with hydrogen fluoride. To convert a difluoromethylene group 2. The method according to claim 1, wherein the fluorination step is carried out in the presence of an acid catalyst.