JP2007169271A - Method for producing α-trifluoromethyl ketone compound - Google Patents

Abstract

Provided is a method for producing an α-trifluoromethyl ketone compound in high yield using trifluoromethane iodide as a trifluoromethylating agent.
A process for producing an α-trifluoromethyl ketone compound, comprising reacting a lithium enolate compound with trifluoromethane iodide in the presence of a radical initiator.
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Description

  The present invention relates to a method for producing an α-trifluoromethyl ketone compound. More specifically, the present invention relates to a method for producing an α-trifluoromethyl ketone compound by reacting a lithium enolate compound derived from a ketone compound with trifluoromethane iodide.

  Since the α-trifluoromethyl ketone compound exhibits specific physical and chemical properties due to the trifluoromethyl group content, it is extremely useful as a raw material for medical and agricultural chemical intermediates and liquid crystal materials.

  As a method for producing an α-trifluoromethyl ketone compound, a method in which a trifluoromethylating agent and a ketone derivative are reacted is known. The method is roughly classified into methods using trifluoromethane.

  As the former method, Non-Patent Document 1 and Non-Patent Document 2 report a method of reacting a trifluoromethyl chalcogen salt compound and a ketone derivative. In these methods, although the yield of the α-trifluoromethyl ketone compound is relatively high, it is necessary to synthesize a trifluoromethyl chalcogen salt compound as a reaction raw material in advance. At that time, there is a problem that a special apparatus for synthesis and complicated operations are required.

On the other hand, the latter method can be said to be an industrially easy method because iodide trifluoromethane can be easily obtained. However, in the case of this method, there is a problem in that the yield tends to be lowered due to the simultaneous occurrence of a decomposition reaction when the trifluoromethane iodide is reacted with the ketone derivative. As a method for avoiding the decomposition reaction, Non-Patent Document 3 reports a method using a silyl enolate compound as a ketone derivative, and Non-Patent Document 4 reports a method using a germyl enolate compound as a ketone derivative. However, since the reactivity of the ketone derivative is low in these methods, a long reaction time is required and the yield of the target product is not sufficient. Non-Patent Document 5 reports a method using an enamine compound as a ketone derivative. In this method, the process of synthesizing the enamine compound is complicated and the yield of the target product is not sufficient.
J. Am. Chem. Soc., 115, 2156 (1993) J. Org. Chem., 59, 5692 (1994) Bull. Chem. Soc. Jpn., 64, 1542 (1991) Tetrahedron Letters, 31, 6391 (1990) J. Chem. Soc., Perkin Trans. 1, 1365 (1977)

  The present invention has been made in view of these problems. That is, an object of the present invention is to provide a method for producing an α-trifluoromethyl ketone compound in high yield using trifluoromethane iodide as a trifluoromethylating agent.

  As a result of intensive investigations in view of the above problems, the present inventors have obtained a α-trifluoromethyl ketone compound in high yield by reacting a specific ketone derivative with iodotrifluoromethane in the presence of a radical initiator. As a result, the present invention has been completed. That is, the present invention relates to the following gist.

(1) General formula (3)

(In the formula, R1 represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and R2 and R3 each independently represents a hydrogen atom or a substituted group. Or an unsubstituted alkyl group having 1 to 20 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, R1 to R3 may be the same or non-identical, and any two May be bonded to each other with or without heteroatoms to form a cyclic structure.)
A lithium enolate compound represented by the formula (4) is reacted with iodotrifluoromethane in the presence of a radical initiator:

(Wherein R1 to R3 are the same as defined above)
The manufacturing method of the alpha-trifluoromethyl ketone compound represented by these.

(2) The method for producing an α-trifluoromethyl ketone compound according to (1), wherein the radical initiator is a trialkylborane compound and molecular oxygen.

(3) The lithium enolate of the general formula (3) is represented by the general formula (1)

(Wherein R1 to R3 are the same as defined above)
And / or the general formula (2)

(In the formula, R 1 to R 3 are the same as defined above. R 4 to R 6 represent the same or non-identical alkyl group having 1 to 10 carbon atoms.)
The lithium enolate obtained by reacting the silyl enol ether compound represented by formula (II) with a lithium compound having a molar ratio of 0.8 to 1.2 times as described in (1) or (2) -Manufacturing method of a trifluoromethyl ketone compound.

(4) The method for producing α-trifluoromethyl ketone according to (3), wherein the lithium compound is an alkyl lithium compound and / or a lithium amide compound.

(5) The method for producing an α-trifluoromethyl ketone compound according to any one of (1) to (4), wherein the reaction is carried out in the presence of a zinc compound.

(6) The method for producing an α-trifluoromethyl ketone compound according to (5), wherein the zinc compound is dialkylzinc.

(7) The method for producing an α-trifluoromethyl ketone compound according to (5) or (6), wherein a cyclic ether compound is further present in addition to the zinc compound.

According to the present invention, an α-trifluoromethyl ketone compound can be produced in high yield from industrially readily available trifluoromethane iodide as a raw material.

  The present invention is described in further detail below.

  The present invention is characterized in that the α-trifluoromethyl ketone compound of the general formula (4) is produced by reacting the lithium enolate compound of the general formula (3) with trifluoromethane iodide. The present invention comprises a process of producing a lithium enolate compound as a raw material and a process of reacting the lithium enolate compound with trifluoromethane iodide.

  A process for forming a lithium enolate compound, which is a pre-process of the present invention, will be described. The lithium enolate compound is produced by reacting the ketone compound of the general formula (1) and / or the silyl enol ether of the general formula (2) with a lithium compound.

  In the general formulas (1) to (4), the substituent R1 is a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms. The substituents R2 and R3 are a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, and a substituted or unsubstituted aryl group having 6 to 20 carbon atoms. Examples of the unsubstituted alkyl group include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-hexyl group, cyclohexyl group, Examples thereof include an n-octyl group and an n-decyl group. Examples of the alkyl group having a substituent include a methoxymethyl group, a 2-methoxyethyl group, a benzyl group, a 2-phenylethyl group, and a trifluoromethyl group. Examples of the unsubstituted aryl group include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. Examples of the aryl group having a substituent include 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,4,6-trimethylphenyl group, 4-ethylphenyl group, 4-methoxyphenyl group. , 4-fluorophenyl group, 2-methyl-1-naphthyl group and the like. R1 to R3 may be the same or non-identical. In addition, any two substituents R1 to R3 are bonded to each other with a hetero atom intervening or non-intervening to form a cyclic structure such as a cyclopentane ring, a cyclohexane ring, a cycloheptane ring or a cyclooctane ring. May be. Examples of the hetero atom include an oxygen atom and a sulfur atom.

  Examples of such ketone compounds include acetone, methyl ethyl ketone, methyl n-propyl ketone, methyl i-propyl ketone, methyl n-butyl ketone, methyl isobutyl ketone, methyl sec-butyl ketone, 6-undecanone, methyl cyclohexyl ketone, methoxy acetone, Trifluoroacetone, acetophenone, 2′-methylacetophenone, 4′-methylacetophenone, 4′-methoxyacetophenone, 4′-fluoroacetophenone, 2 ′, 4 ′, 6′-trimethoxyacetophenone, propiophenone, n-butyrophenone , Cyclopentanone, cyclohexanone, 2-methylcyclohexanone, 4-t-butylcyclohexanone, 4-oxotetrahydropyran and the like.

  The silyl enol ether compound of the general formula (2) can be obtained by reacting the ketone compound of the general formula (1) with a trialkylsilyl halide compound in the presence of a base. The substituents R4 to R6 in the general formula (2) are alkyl groups having 1 to 10 carbon atoms, and examples thereof include a methyl group, an ethyl group, and an n-butyl group. Examples of the silyl enol ether compound of the general formula (2) include 2- (trimethylsiloxy) propene, 2- (trimethylsiloxy) -2-butene, 2- (trimethylsiloxy) -1-butene, and 6- (trimethylsiloxy). ) -5-undecene, 1-phenyl-1- (trimethylsiloxy) ethylene, 1- (trimethylsiloxy) cyclohexene, 1- (trimethylsiloxy) -6-methylcyclohexene, 1- (trimethylsiloxy) -2-methylcyclohexene and Examples include 1- (trimethylsiloxy) -4-t-butylcyclohexene.

  The lithium compound is an organic lithium compound or metallic lithium, and examples of the organic lithium include alkyl lithium compounds such as methyl lithium, n-butyl lithium, sec-butyl lithium and t-butyl lithium, lithium diisopropylamide and lithium bis (trimethylsilyl). ) Lithium amide compounds such as amides. The lithium amide compound may be produced in a liquid for producing a lithium enolate compound by adding an amine compound such as diisopropylamine or bis (trimethylsilyl) amine and an alkyllithium compound in any order. The amount of the lithium compound used relative to the ketone compound of the general formula (1) and / or the silyl enol ether compound of the general formula (2) is 0.5 to 2, and preferably 0.8 to 1. 2. When the amount of the lithium compound used is less than 0.5, the amount of lithium enolate produced is not sufficient, and when it exceeds 2, the decomposition reaction of the target product when used in the production of the α-trifluoromethyl ketone compound. May progress and the yield may decrease.

  The lithium enolate compound of the general formula (3) may be obtained by reacting the ketone compound of the general formula (1) and / or the silyl enol ether compound of the general formula (2) with a lithium compound in the absence of a solvent. Usually, the reaction is carried out in the presence of an aprotic solvent. Examples of the aprotic solvent include ethers such as diethyl ether and tetrahydrofuran, alkanes such as pentane and hexane, and aromatic hydrocarbons such as benzene and toluene. Although reaction temperature is not specifically limited, Usually, it is -100 degreeC-50 degreeC. The lithium enolate compound may be isolated and used in the production of the α-trifluoromethyl ketone compound, but the reaction solution obtained by reacting the ketone compound and / or the silyl enol ether compound with the lithium compound is used as the α-trifluoromethyl ketone compound. It is easy to use in the production and hardly causes decomposition of the lithium enolate compound.

Next, the process of reacting the lithium enolate compound of the general formula (3) with trifluoromethane iodide will be described.
In the present invention, the α-trifluoromethyl ketone compound of the general formula (4) is produced by reacting the lithium enolate compound of the general formula (3) with trifluoromethane iodide in the presence of a radical initiator.

  Although the usage-amount of the trifluoromethane iodide with respect to the lithium enolate compound of the said General formula (3) is not specifically limited, Usually, it is 0.5-30 times in molar ratio.

  The radical initiator is not particularly limited as long as it can generate a trifluoromethyl radical from trifluoromethane iodide. For example, trialkylborane compounds such as triethylborane and tributylborane, molecular oxygen, azo Examples thereof include azo compounds such as bisisobutyronitrile and peroxide compounds such as di-t-butyl peroxide. Of these, trialkylborane compounds and molecular oxygen are advantageous because they can generate radicals under mild conditions, so that α-trifluoromethyl ketone compounds can be obtained in good yields. The amount of radical initiator used relative to the lithium enolate compound is usually 0.01 to 2 times in molar ratio. In the case of a combination of a trialkylborane compound and molecular oxygen, trialkylborane is added at the above ratio. It is sufficient that a small amount of molecular oxygen is present.

  In addition, an aprotic solvent may be used when the lithium enolate compound of the general formula (3) is reacted with iodinated trifluoromethane. Examples of aprotic solvents include alkanes such as pentane, hexane, octane and cyclohexane, aromatic compounds such as benzene, toluene and xylene, diethyl ether, diisopropyl ether, di-n-butyl ether, monoglyme, diglyme, triglyme, tetrahydrofuran, Examples thereof include ethers such as 1,4-dioxane, anisole and veratrol, sulfides such as diethyl sulfide and di-n-butyl sulfide, and nitriles such as acetonitrile, propionitrile and benzonitrile.

  Although the reaction temperature at the time of making the lithium enolate compound of the said General formula (3) and iodide trifluoromethane react is not specifically limited, Usually, it is -100 degreeC-100 degreeC. The reaction pressure can be carried out at normal pressure or under pressure. The reaction time is usually 1 second to 10 hours. The reaction is desirably performed with sufficient stirring.

  Further, the mixing order of the lithium enolate compound of the general formula (3), the radical initiator, and the trifluoromethane iodide is not particularly limited, but a method of adding the trifluoromethane iodide after mixing the lithium enolate compound and the radical initiator, Alternatively, a method of adding a radical initiator after mixing a lithium enolate compound and trifluoromethane iodide is convenient in terms of operation.

In the method of the present invention, a zinc compound can be added to the lithium enolate compound and allowed to react. The effect of improving the yield may be observed by the addition of the zinc compound.
The zinc compound is a zinc compound having a divalent valence, for example, an organic zinc compound such as dimethyl zinc, diethyl zinc, di-n-butyl zinc, diphenyl zinc, methyl zinc iodide and dicyano zinc, zinc fluoride, Zinc halides such as zinc chloride, zinc bromide and zinc iodide, zinc oxyacid salts such as zinc nitrate, zinc sulfate, zinc phosphate and zinc carbonate, zinc organic acid salts such as zinc acetate, zinc oxide, zinc hydroxide and Examples thereof include zinc hydride. Of these zinc compounds, organic zinc compounds, particularly dialkyl zinc such as diethyl zinc, are preferred in terms of the yield of the α-trifluoromethyl ketone compound. The amount of the zinc compound used relative to the ketone compound of the general formula (1) and / or the silyl enol ether compound of the general formula (2) is 0.5 to 2 in molar ratio. In addition, although the addition time of a zinc compound is not specifically limited, Usually, it adds after producing | generating the lithium enolate compound of the said General formula (3), It is made to react by adding trifluoromethane iodide and a radical initiator.

  In the method of the present invention, a cyclic ether compound can be added in addition to the zinc compound. The yield may be further improved by adding a cyclic ether compound. Examples of the cyclic ether compound include 12-crown-4-ether, 15-crown-5-ether, 18-crown-6-ether and the like. The usage-amount of the cyclic ether compound with respect to the ketone compound of the said General formula (1) and / or the silyl enol ether compound of the said General formula (2) is 0.5-2 in molar ratio. Although the addition time of the cyclic ether compound is not particularly limited, usually, the lithium enolate compound of the general formula (3) is formed, added after the zinc compound, and reacted by adding trifluoromethane iodide and a radical initiator. .

After the reaction, an acid such as acetic acid or hydrochloric acid or water is added to inactivate the reaction reagent, the insoluble matter is removed, and then the above-mentioned general formula (4) is obtained by a known distillation method, recrystallization method or chromatographic separation method. The α-trifluoromethyl ketone compound can be isolated.
EXAMPLES Hereinafter, the present invention will be described in detail using examples, but the present invention is not limited to the examples.

A Schlenk tube was charged with 2 ml of tetrahydrofuran and 28 μl of diisopropylamine, cooled in a dry ice-methanol bath, and the liquid temperature was -78 ° C. Next, 0.13 ml (0.20 mmol) of a 1.58 mol / L n-butyllithium hexane solution was added, followed by stirring at 0 ° C. for 30 minutes. The temperature was again −78 ° C., 20.7 μl (0.20 mmol) of cyclohexanone was added, and the mixture was stirred for 60 minutes. Next, 200 mg (1.0 mmol) of trifluoromethane iodide was added, and then 0.2 ml (0.2 mmol) of a 1 mol / L triethylborane / hexane solution was added in 15 seconds to start the reaction. After 60 minutes, 0.12 ml of a 5 mol / l acetic acid tetrahydrofuran solution was added to stop the reaction. When the reaction solution was analyzed by ¹⁹ F-NMR using benzotrifluoride as an internal standard, the yield of 2- (trifluoromethyl) cyclohexanone was 80%.

Add 2 ml of tetrahydrofuran and 38.9 μl (0.2 mmol) of 1- (trimethylsiloxy) cyclohexene to a Schlenk tube, cool to 0 ° C., and add 0.13 ml (0.20 mmol) of 1.58 mol / L n-butyllithium hexane solution. Added and stirred for 30 minutes.
Next, it is cooled to −78 ° C., 200 mg (1.0 mmol) of trifluoromethane iodide is added, and then 0.2 ml (0.2 mmol) of 1 mol / L triethylborane / hexane solution is added in 15 seconds to start the reaction. I let you. After 2 hours, 0.12 ml of a 5 mol / l acetic acid tetrahydrofuran solution was added to stop the reaction. When the reaction solution was analyzed by ¹⁹ F-NMR using benzotrifluoride as an internal standard, the yield of 2- (trifluoromethyl) cyclohexanone was 77%.

The reaction was conducted in the same manner as in Example 1 except that cyclohexanone was changed to 31 mg (0.2 mmol) of 4-t-butylcyclohexanone and the reaction time was changed to 1 second. When the reaction solution was analyzed by ¹⁹ F-NMR using benzotrifluoride as an internal standard, the yield of 2- (trifluoromethyl) -4-tert-butylcyclohexanone was 71%.

  A Schlenk tube was charged with 2 ml of tetrahydrofuran and 45 μl of diisopropylamine, cooled in a dry ice-methanol bath, and the liquid temperature was adjusted to −78 ° C. Next, 0.20 ml (0.36 mmol) of a 1.58 mol / L n-butyllithium hexane solution was added, followed by stirring at 0 ° C. for 30 minutes. The temperature was again −78 ° C., 20.7 μl (0.20 mmol) of cyclohexanone was added, and the mixture was stirred for 30 minutes. Next, 200 mg (1.0 mmol) of trifluoromethane iodide was added, and then 0.2 ml (0.2 mmol) of a 1 mol / L triethylborane / hexane solution was added in 15 seconds to start the reaction. After 30 minutes, 0.12 ml of a 5 mol / l acetic acid tetrahydrofuran solution was added to stop the reaction.

When the reaction solution was analyzed by ¹⁹ F-NMR using benzotrifluoride as an internal standard, the yield of 2- (trifluoromethyl) cyclohexanone was 41%.

  Add 2 ml of tetrahydrofuran and 31 mg (0.2 mmol) of 1- (trimethylsiloxy) cyclopentene to the Schlenk tube, cool to 0 ° C., add 0.20 ml (0.20 mmol) of 1.0 mol / L methyllithium diethyl ether solution, Stir for 30 minutes.

Next, it is cooled to −78 ° C., 200 mg (1.0 mmol) of trifluoromethane iodide is added, then 0.2 ml (0.2 mmol) of 1 mol / L triethylborane / hexane solution is added in 15 seconds, and the reaction is performed. Started. After 20 hours, 0.12 ml of a 5 mol / l acetic acid tetrahydrofuran solution was added to stop the reaction. When the reaction solution was analyzed by ¹⁹ F-NMR using benzotrifluoride as an internal standard, the yield of 2- (trifluoromethyl) cyclopentanone was 40%.

  Add 1 ml of tetrahydrofuran and 31 mg (0.2 mmol) of 1- (trimethylsiloxy) cyclopentene to a Schlenk tube, cool to 0 ° C., add 0.20 ml (0.20 mmol) of 1.0 mol / L methyllithium diethyl ether solution, Stir for 30 minutes.

  Next, 0.20 ml (0.20 mmol) of 1.0 mol / L diethyl zinc hexane solution was added and stirred for 30 minutes.

Next, it is cooled to −78 ° C., 400 mg (2.0 mmol) of trifluoromethane iodide is added, then 0.2 ml (0.2 mmol) of 1 mol / L triethylborane / hexane solution is added, and 0.5 ml of air is added. The reaction was initiated with a syringe. After 2 hours, 0.12 ml of a 5 mol / l acetic acid tetrahydrofuran solution was added to stop the reaction. When the reaction solution was analyzed by ¹⁹ F-NMR using benzotrifluoride as an internal standard, the yield of 2- (trifluoromethyl) cyclopentanone was 50%.

A Schlenk tube was charged with 2 ml of tetrahydrofuran and 48 mg (0.2 mmol) of 6- (trimethylsiloxy) -5-undecene, cooled to 0 ° C., and 0.20 ml (0.20 mmol) of 1.0 mol / L methyllithium diethyl ether solution was added. Added and stirred for 30 minutes. Next, it is cooled to −78 ° C., 200 mg (1.0 mmol) of trifluoromethane iodide is added, then 0.2 ml (0.2 mmol) of 1 mol / L triethylborane / hexane solution is added in 15 seconds, and the reaction is performed. Started. After 20 hours, 0.12 ml of a 5 mol / l acetic acid tetrahydrofuran solution was added to stop the reaction. When the reaction solution was analyzed by ¹⁹ F-NMR using benzotrifluoride as an internal standard, the yield of 5- (trifluoromethyl) -6-undecanone was 35%.

A Schlenk tube was charged with 1 ml of tetrahydrofuran and 48 mg (0.2 mmol) of 6- (trimethylsiloxy) -5-undecene, cooled to 0 ° C., and 0.20 ml (0.20 mmol) of a 1.0 mol / L methyllithium diethyl ether solution. Added and stirred for 30 minutes. Next, 0.20 ml (0.20 mmol) of a 1.0 mol / L diethyl zinc hexane solution was added and stirred for 30 minutes. Next, it is cooled to −78 ° C., 400 mg (2.0 mmol) of trifluoromethane iodide is added, then 0.2 ml (0.2 mmol) of 1 mol / L triethylborane / hexane solution is added, and 0.5 ml of air is added. The reaction was initiated with a syringe. After 20 hours, 0.12 ml of a 5 mol / l acetic acid tetrahydrofuran solution was added to stop the reaction. When the reaction solution was analyzed by ¹⁹ F-NMR using benzotrifluoride as an internal standard, the yield of 5- (trifluoromethyl) -6-undecanone was 74%.

A Schlenk tube was charged with 1 ml of tetrahydrofuran and 48 mg (0.2 mmol) of 6- (trimethylsiloxy) -5-undecene, cooled to 0 ° C., and 0.20 ml (0.20 mmol) of a 1.0 mol / L methyllithium diethyl ether solution. Added and stirred for 30 minutes. Next, 0.20 ml (0.20 mmol) of 1.0 mol / L diethyl zinc hexane solution was added and stirred for 20 minutes, 35 mg (0.20 mmol) of 12-crown-4-ether was added and stirred for 30 minutes. Next, it is cooled to −78 ° C., 400 mg (2.0 mmol) of trifluoromethane iodide is added, then 0.2 ml (0.2 mmol) of 1 mol / L triethylborane / hexane solution is added, and 0.5 ml of air is added. The reaction was initiated with a syringe. After 20 hours, 0.12 ml of a 5 mol / l acetic acid tetrahydrofuran solution was added to stop the reaction. When the reaction solution was analyzed by ¹⁹ F-NMR using benzotrifluoride as an internal standard, the yield of 5- (trifluoromethyl) -6-undecanone was 86%.

  According to the present invention, an α-trifluoromethyl ketone compound can be produced in high yield using industrially available trifluoromethane iodide. The α-trifluoromethyl ketone compound is extremely useful as an electronic material and a raw material for medical and agricultural chemicals.

Claims (7)

General formula (3)

(In the formula, R1 represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and R2 and R3 each independently represents a hydrogen atom or a substituted group. Or an unsubstituted alkyl group having 1 to 20 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, R1 to R3 may be the same or non-identical, and any two May be bonded to each other with or without heteroatoms to form a cyclic structure.)
A lithium enolate compound represented by the formula (4) is reacted with iodotrifluoromethane in the presence of a radical initiator:

(Wherein R1 to R3 are the same as defined above)
The manufacturing method of the alpha-trifluoromethyl ketone compound represented by these. The method for producing an α-trifluoromethyl ketone compound according to claim 1, wherein the radical initiator is a trialkylborane compound and molecular oxygen.
The lithium enolate of the general formula (3) is represented by the general formula (1)

(Wherein R1 to R3 are the same as defined above)
And / or the general formula (2)

(In the formula, R 1 to R 3 are the same as defined above. R 4 to R 6 represent the same or non-identical alkyl group having 1 to 10 carbon atoms.)
The lithium enolate obtained by the reaction of the silyl enol ether compound represented by formula (II) and a lithium compound having a molar ratio of 0.8 to 1.2 times, α according to claim 1 or 2. -Manufacturing method of a trifluoromethyl ketone compound.   The method for producing α-trifluoromethyl ketone according to claim 3, wherein the lithium compound is an alkyl lithium compound and / or a lithium amide compound.   The method for producing an α-trifluoromethyl ketone compound according to any one of claims 1 to 4, wherein the reaction is carried out in the presence of a zinc compound.   The method for producing an α-trifluoromethyl ketone compound according to claim 5, wherein the zinc compound is dialkylzinc.   The method for producing an α-trifluoromethyl ketone compound according to claim 5 or 6, further comprising a cyclic ether compound in addition to the zinc compound.