WO2009102034A1 - Method for producing fluoro-compound - Google Patents

Abstract

Disclosed is a commercially suitable method for efficiently producing fluoro-compounds having various molecular structures, in which two fluorine atoms are bonded to a carbon atom, in a single-step reaction. Specifically disclosed is a method for producing a fluoro-compound represented by formula (B), which is characterized in that a compound represented by formula (A) is reacted with IF5.

Description

Method for producing fluoro compound

The present invention relates to a method for producing a fluoro compound. More specifically, the present invention relates to a method for producing a fluoro compound having a carbon atom to which two fluorine atoms are bonded.

Generally, when producing a fluoro compound by fluorinating an organic compound, a fluorinating agent is used. For example, a compound having a carbonyl group, a method of fluorinating with SF ₄ or DAST (diethylaminosulfur trifluoride) is known. However, the handling of these fluorinating agents is not easy and the price is expensive, and there is a problem that is not advantageous as a fluorinating agent used in an industrial production method.
Therefore, a fluorination method using IF ₅ has been proposed as a fluorinating agent that is easy to handle (Patent Document 1).
In Patent Document 1, specific examples represented by the following formulas (a) to (c) are given as a method for producing a fluoro compound having a carbon atom to which two fluorine atoms are bonded using IF _5. Yes.

However, the symbol Et used in the formulas (a) to (c) represents an ethyl group, Me represents a methyl group, rt represents a reaction at room temperature (23 ° C.), and hr represents a reaction time. Further, Hexane is hexane as the reaction solvent, _CH 2 Cl ₂ indicates that using _CH 2 Cl ₂ as the reaction solvent.
In addition, IF ₅ / Et ₃ N-3HF (1: 1 molar ratio) is a mixed reagent of IF ₅ and Et ₃ N and HF so that the amount of Et ₃ N relative to IF ₅ is an equimolar mole ( It shows that the reaction was carried out using a fluorinating agent mixed with Et ₃ N: HF = 1: 3 molar ratio.
International Publication No. 01/96263 Pamphlet

However, the fluoro compound obtained by the formulas (a) and (b) has a sulfide group in the molecule, and a further reaction step is required to obtain a compound excluding this sulfide group.
In the reaction of formula (c), the raw material has a special structure with a heterocycle containing two sulfur atoms. Therefore, it is difficult to obtain other than the specific raw material in the reaction of the formula (c), and the structure of the resulting fluoro compound is limited. Further, in order to synthesize the raw material of the formula (c), it was necessary to use HS—CH ₂ CH ₂ —SH having a strong odor.
The present invention has been made in view of such problems of the prior art, and efficiently produces fluoro compounds having various molecular structures having carbon atoms to which two fluorine atoms are bonded by a one-step reaction, Moreover, it is an object to provide a manufacturing method suitable for industrialization.

As a result of intensive studies to solve the above-described problems, the present inventors have reacted monosulfides with IF ₅ to form a one-step reaction between a sulfide group and a hydrogen atom bonded to the α-position carbon atom of the sulfide group. It discovered that it could substitute by a fluorine atom by reaction. That is, the gist of the present invention is as follows.

[1] A method for producing a fluoro compound represented by the following formula (B), comprising reacting a compound represented by the following formula (A) with IF ₅ .
X represents a group selected from an aryl group, a monovalent heterocyclic group, and an alkyl group, or a group in which one or more hydrogen atoms in the selected group are substituted, and Y represents an aryl group, a monovalent group, or a monovalent group. R represents a group selected from a heterocyclic group, an alkyl group, an acyl group, and an aryloxy group, or a group in which one or more of hydrogen atoms in the selected group are substituted, a cyano group, or an alkoxycarbonyl group. A group selected from an aryl group and an alkyl group, or a group in which one or more hydrogen atoms of the selected group are substituted.

[2] X is a group selected from an aryl group and a monovalent heterocyclic group, or a group in which at least one hydrogen atom in the selected group is substituted, and Y is a cyano group, an alkoxycarbonyl group, an acyl group The production method according to the above [1], which is a group, a halogenated alkyl group, or a halogenated acyl group.
[3] The production method according to the above [1] or [2], wherein R is an aryl group, an alkyl group, or a halogenated aryl group.
[4] The production method according to any one of [1] to [3] above, wherein the reaction temperature is −50 to 100 ° C.

Monosulfides which are the raw material compounds of the present invention are easy to produce. Moreover, there is almost no restriction on the structure of the group bonded to the sulfide group. Therefore, fluoro compounds having various molecular structures can be easily obtained.
In addition, IF ₅ which is a fluorinating agent has no problem in handling such as explosiveness and is inexpensive. Therefore, the production method of the present invention is suitable for industrialization.
Moreover, the production method of the present invention can introduce two fluorine atoms in one step with respect to one carbon atom. Therefore, according to this invention, the fluoro compound which has a carbon atom which two fluorine atoms couple | bonded can be manufactured efficiently.

In the present specification, the compound represented by the formula (A) is also referred to as “compound (A)”. The same applies to compounds represented by other formulas.
The production method of the present invention is a method for producing compound (B) by reacting compound (A) with IF ₅ as shown below.

X represents a group selected from an aryl group, a monovalent heterocyclic group, and an alkyl group, or a group in which one or more hydrogen atoms in the selected group are substituted, and Y represents an aryl group, a monovalent group, or a monovalent group. R represents a group selected from a heterocyclic group, an alkyl group, an acyl group, and an aryloxy group, or a group in which one or more of hydrogen atoms in the selected group are substituted, a cyano group, or an alkoxycarbonyl group. A group selected from an aryl group and an alkyl group, or a group in which one or more hydrogen atoms of the selected group are substituted.

[Compound (A)]
Compound (A) is a compound in which one hydrogen atom is bonded to the α-position carbon atom of the sulfide group and two substituents represented by X and Y are bonded.
X in the compound (A) is a group selected from an aryl group, a monovalent heterocyclic group, and an alkyl group, or a group in which one or more hydrogen atoms in the selected group are substituted.

Examples of the aryl group constituting X include a phenyl group and a naphthyl group.
Examples of the monovalent heterocyclic group constituting X include a thienyl group and a furanyl group.
The alkyl group constituting X may be a linear structure, a branched structure, a ring structure, a group having a partially branched structure, and / or a group having a partially ring structure. The alkyl group is preferably an alkyl group having 1 to 10 carbon atoms, and particularly preferably an alkyl group having 1 to 6 carbon atoms. Specific examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. Is mentioned.

X may be a group in which one or more hydrogen atoms in the above groups are substituted.
Examples of the substituent with hydrogen atoms in the group, is preferably selected from inert groups in the fluorination reaction using IF _5. Examples of the inert group in the fluorination reaction include a halogen atom, a nitro group, and a cyano group. As a halogen atom, a chlorine atom, a fluorine atom, or a bromine atom is preferable. In addition, as a substituent that substitutes for a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms is also preferable.

The substituted aryl group constituting X (a group in which one or more hydrogen atoms in the aryl group are substituted) is preferably a halogenated aryl group, and examples thereof include a chlorophenyl group, a bromophenyl group, and a 2,3-difluorophenyl group. It is done.
The substituted monovalent heterocyclic group constituting X (a group in which one or more hydrogen atoms in the monovalent heterocyclic group are substituted) includes a 5-methyl-2-thienyl group and a 4-methyl-2-thienyl group Etc.
The substituted alkyl group constituting X (a group in which one or more hydrogen atoms in the alkyl group are substituted) is preferably an alkyl group substituted with a fluorine atom, more preferably a fluoroalkyl group having one or more fluorine atoms. Preferred is a trifluoromethyl group.

Y in the compound (A) is a group selected from an aryl group, a monovalent heterocyclic group, an alkyl group, an acyl group, and an aryloxy group, or a group in which one or more hydrogen atoms in the selected group are substituted, A cyano group or an alkoxycarbonyl group.

The aryl group, monovalent heterocyclic group and alkyl group constituting Y can be selected from the same groups as those which can be selected as X. In addition, a substituted aryl group, a substituted monovalent heterocyclic group and a substituted alkyl group in which one or more hydrogen atoms in these groups are substituted are the same as those which can be selected as X.
Among these groups that can be selected as Y, preferred groups are the same as the preferred groups for X.

As the acyl group constituting Y, an alkanoyl group or a benzoyl group is preferable. As the alkanoyl group, a group having 1 to 10 carbon atoms is preferable, and a group having 1 to 6 carbon atoms is particularly preferable. Specific examples of the alkanoyl group include groups such as an acetyl group, a propionyl group, and an n-butyryl group.
Examples of the aryloxy group constituting Y include a phenoxy group and a naphthoxy group.

Examples of the substituted acyl group constituting Y (a group in which one or more hydrogen atoms in the acyl group are substituted) include a chloroacetyl group, a bromoacetyl group, and a trifluoroacetyl group.
Examples of the substituted aryloxy group constituting Y (a group in which one or more hydrogen atoms of the aryloxy group are substituted) include 4-nitrophenoxy group, 4-cyanophenoxy group, 4-bromophenoxy group, 4-chlorophenoxy group Group, 4-fluorophenoxy group, 4-methylphenoxy group, 4-tert-butylphenoxy group and the like.

The alkoxycarbonyl group constituting Y is preferably a group having 1 to 9 carbon atoms in the alkyl group portion, more preferably a group having 1 to 5 carbon atoms. The structure of the alkyl group moiety may be a linear structure or a branched structure. Examples of the alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butoxycarbonyl group and the like.

In the production method of the present invention, X and Y in the compound (A) become X and Y in the compound (B) while maintaining the structure. Therefore, X and Y in the compound (A) may be selected from those of the target compound (B).
However, from the viewpoint of the reactivity of the fluorination reaction, it is preferable to adopt a group having no electron withdrawing property or weak electron withdrawing property as X and selecting an electron withdrawing group as Y.
The reason is considered as follows based on the reaction mechanism in the production method of the present invention.

First, the reaction in the production method of the present invention is considered to proceed by the following mechanism. In the following description, the case where X is a phenyl group and Y is an ethoxycarbonyl group is taken as an example.
First, as shown in the following formula, IF ₅ generates IF ₄ ⁺ and F ⁻ by an equilibrium reaction.

As shown in the following formula (I), the compound (A) in which X is a phenyl group and Y is an ethoxycarbonyl group has an unshared electron pair on a sulfur atom. The reaction is initiated by the sharing of this unshared electron pair by the sulfur atom and IF ₄ ⁺ .
Next, as shown in the following formula (II), F ⁻ formed from IF ₅ pulls out the hydrogen atom bonded to the carbon atom at the benzyl position, and generates a stable cation shown in the following formula (III). F ⁻ reacts with this cation again, and first, one fluorine atom is bonded to the carbon atom at the benzyl position.
Next, as shown in the following formula (IV), the sulfur atom and IF ₄ ⁺ share the unshared electron pair of the sulfur atom. Finally, F as shown in the following equation (V) ^- by IF ₃ and RS-F is released by the reaction is considered to difluoro body of interest (VI) is produced.

Initiation of the reaction in the above mechanism requires the presence of an unshared electron pair on the sulfur atom of compound (A). If both X and Y are electron-withdrawing groups, the electron density of the unshared electron pair of the sulfur atom is lowered and the reaction is difficult to start. Therefore, it is considered preferable to employ a group having no electron withdrawing property or weak electron withdrawing property as X.
On the other hand, it is preferable to select an electron-withdrawing group as Y. When Y is an electron donating group R ′, the unshared electron pair of the sulfur atom can be shared with IF ₄ ⁺ as shown in the following formula (VII). But then, the higher the stability of the cation represented by the formula (VIII), the cation is F ^- and react to produce the mono-fluoro body shown in formula (IX) by side reaction resulting in progress simultaneously. Therefore, the yield of the target difluoro compound (VI) is considered to be low.
If Y is an “electron-withdrawing group”, the cation represented by the formula (III), which is an intermediate substance of the reaction, is more stable than the cation similar to the cation represented by the formula (VIII). The reaction of II) → (III) → (IV) occurs preferentially, and the side reaction is considered to be suppressed.

From the above, when “group having no electron withdrawing property or weak electron withdrawing property” is selected as X and “electron withdrawing group” is selected as Y, the reaction is easy to start and side reaction Therefore, it is considered that the target difluoro compound (VI) is produced with higher yield.

Therefore, X preferable from the viewpoint of reactivity includes a group selected from an aryl group and a monovalent heterocyclic group, or a group in which one or more hydrogen atoms in the selected group are substituted. Here, the substituent that replaces the hydrogen atom in the “group in which one or more hydrogen atoms are substituted” is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, or a cyano group. 1 or more selected from nitro groups.
From the viewpoint of reactivity, X is more preferably an aryl group or a halogenated aryl group, and particularly preferably an alkyl-substituted aryl group or an alkoxy-substituted aryl group.
In addition, Y preferable from the viewpoint of reactivity includes a cyano group, an alkoxycarbonyl group, an acyl group, a halogenated alkyl group, and a halogenated acyl group. From the viewpoint of reactivity, Y is more preferably an alkoxycarbonyl group or an acyl group, and particularly preferably a cyano group or a halogenated alkyl group.

R in the compound (A) is a group selected from an aryl group and an alkyl group, or a group in which one or more hydrogen atoms of the selected group are substituted.
The aryl group and alkyl group constituting R can be selected from the same groups as those selected as X. In addition, substituted aryl groups and substituted alkyl groups in which one or more hydrogen atoms in these groups are substituted are the same as those that can be selected as X.
In the production method of the present invention, R in compound (A) does not remain in compound (B). Therefore, R can be selected from the viewpoint of availability of compound (A) and reactivity with IF ₅ .
Preferable R from the viewpoint of reactivity with IF ₅ includes an aryl group, an alkyl group, a halogenated aryl group, and a halogenated alkyl group. From the viewpoint of reactivity, R is more preferably an aryl group, an alkyl group, or a halogenated aryl group, and particularly preferably an alkyl group or a halogenated aryl group. The halogen atom in the halogenated aryl group is preferably a fluorine atom or a chlorine atom.
If R is an alkyl group or a halogenated aryl group, the electron density on the sulfur atom will not be extremely reduced, so it is considered preferable for the progress of the fluorination reaction.
Moreover, as a preferable R from a viewpoint of the availability of a compound (A), an aryl group, an alkyl group, or a halogenated aryl group is mentioned. R is more preferably an aryl group or an alkyl group from the viewpoint of easy availability of the compound (A), and particularly preferably an alkyl group.
More preferred R is a methyl group. The compound (A) in which R is a methyl group is easy to obtain and synthesize. In addition, the compound (A) in which R is a methyl group has good reactivity with IF ₅ .
In addition, although the manufacturing method of a compound (A) is mentioned later, it can also obtain as a commercial item.

[Fluorination reaction]
In the reaction of the present invention, the compound (A) is reacted with IF ₅ to fluorinate the hydrogen atom bonded to the α-position carbon atom of the sulfide group and the sulfide group in a one-step reaction, thereby bonding the two fluorine atoms. Reaction for obtaining a fluoro compound having a carbon atom.

The amount of IF ₅ is preferably 1 to 10-fold mol amount, particularly preferably 1.5 to 2.0-fold mol amount based on Compound (A).
From the viewpoint of ease of handling, it is preferable to add IF ₅ previously dissolved in a solvent to the reaction system. The solvent may be the same as or different from the solvent that can be used in the fluorination reaction described below.
The solvent used for dissolving IF ₅ can be selected from the same solvents that can be used for the fluorination reaction described below. Among these, methylene chloride (CH ₂ Cl ₂ ) is particularly preferable from the viewpoint of solubility.
The amount of the solvent is preferably 1 to 10 times the molar amount relative to IF _{5 and} more preferably 3 to 5 times the molar amount.

The reaction temperature of the fluorination reaction is preferably −50 to 100 ° C., particularly preferably −20 to 30 ° C. If the reaction temperature is 100 ° C. or lower, it is preferable that the loss of IF ₅ can be prevented by being lower than the boiling point of IF ₅ (100.5 ° C.). Moreover, if it is 30 degrees C or less, since reaction other than the objective (for example, side reactions, such as another fluorination reaction), is suppressed, it is preferable. On the other hand, a reaction temperature of −50 ° C. or higher is preferable because the reaction can be carried out in the liquid phase. Further, it is more preferable that the temperature is −20 ° C. or higher because precipitation of most raw materials can be prevented.
The reaction time is not particularly limited, and is preferably the time until the raw material disappears or the reaction does not proceed.

The fluorination reaction may be performed in the absence of a solvent or in the presence of a solvent, and is preferably performed in the presence of a solvent. When the compound (A) is in a liquid state, the compound (A) serves as a solvent, so that the reaction can be carried out without using a solvent.
When the reaction is performed in the presence of a solvent, examples of the solvent include chlorinated solvents such as methylene chloride and chloroform, hydrocarbon solvents such as toluene, hexane, and pentane, fluorine-based solvents such as tetrahydrofuran, diethyl ether, and t-butyl ethyl ether. And ether solvents such as dimethylformamide, dimethyl sulfoxide, and acetonitrile. Of these, hexane and methylene chloride are preferred.

The reaction crude product containing the compound (B) obtained by the fluorination reaction is diluted by adding water as a normal post-treatment, and then neutralized, extracted, dried, and the like. Examples of the neutralizing agent used for the neutralization operation include aqueous solutions of sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, and the like, and sodium hydrogen carbonate is preferably used from the viewpoint of handling. As the solvent for extraction, the same solvent as used for the reaction can be used, but diethyl ether and methylene chloride are preferable. Examples of the desiccant used for drying include anhydrous magnesium sulfate and anhydrous sodium sulfate.
Moreover, you may perform the refinement | purification process for obtaining the purity according to the objective after neutralization operation, extraction, drying, etc. Examples of the purification treatment include methods such as column chromatography, distillation, and recrystallization.

[Production Method of Compound (A)]
Compound (A) which is a starting material for the reaction of the present invention can be produced by applying a method described in Y. Tamura et al. Tetrahedron Lett., 1980, 21, 2547-2548. .
The production method of the compound (A) is preferably one of the following methods 1 to 3.

[Method 1]
A compound represented by the following formula (1) is reacted with a chlorinating agent to form a compound represented by the following formula (2), and the compound represented by the formula (2) is represented by the formula (3): To obtain a compound (A). However, R, Y, and X in a formula represent the same meaning as the above.
R—S—CH ₂ —Y (1)
R—S—CHCl—Y (2)
HX (3)

Examples of the chlorinating agent include N-chlorosuccinimide, sulfuryl chloride and the like, and it is preferable to use 1 to 1.5 times the molar amount of the compound (1).
The reaction with the chlorinating agent is preferably carried out in the presence of a solvent such as carbon tetrachloride, chloroform or methylene chloride. The reaction temperature between the compound (1) and the chlorinating agent is preferably 0-100 ° C, more preferably 10-30 ° C.
The reaction between compound (2) and compound (3) is preferably carried out in the presence of a solvent such as methylene chloride. In addition, when a compound (3) is liquid, it can also carry out without a solvent. The reaction temperature of the compound (2) and the compound (3) is preferably 0 to 100 ° C, more preferably 0 to 20 ° C.

[Method 2]
A method of obtaining a compound (A) by reacting a compound represented by the following formula (4) with a compound represented by the formula (5). However, R, Y, and X in a formula represent the same meaning as the above.
X-CHCl-Y (4)
RSNa (5)
The reaction is preferably carried out by reacting an aqueous solution of the compound (5) with the compound (4). The reaction temperature is preferably 0 to 100 ° C., more preferably 0 to 20 ° C.

[Method 3]
A method of obtaining a compound (A) by reacting a compound represented by the following formula (6), a compound represented by the following formula (7) and a compound represented by the following formula (8) in the presence of a Lewis acid. However, R, Y, and X in a formula represent the same meaning as the above.
HX (6)
RSH (7)
Y—CH (OH) ₂ (8)
The reaction is preferably carried out in the presence of a solvent such as methylene chloride, and the reaction temperature is preferably 0 to 100 ° C., more preferably 0 to 20 ° C. Examples of the Lewis acid used include boron trifluoride-diethyl ether.

Examples of the present invention will be described below, but the scope of the present invention is not limited to these examples. The structure of the produced compound was determined by comparison with known NMR data. The yield of the compound was determined by quantifying the raw materials used and the mass of the product.
The meanings of symbols used in the examples are as follows. Ph represents a phenyl group, Et represents an ethyl group, Bu represents a butyl group, t-Bu represents a tertiary butyl group, and n-Bu represents normal butyl. Rt indicates that the reaction was performed at room temperature (23 ° C.).

[Example 1] Preparation Example of Compound (A) [Example 1-1] Synthesis Example of Compound (A-1) To a solution of 3.9 g (29 mmol) of ethyl methylthioacetate in carbon tetrachloride (100 ml), 0 At 0 ° C., 4.0 g (30 mmol) of N-chlorosuccinimide was added little by little. After the addition was completed, the mixture was stirred at room temperature (23 ° C.) for 6 hours. After filtering off the solid, the filtrate was distilled at 91 ° C. under a reduced pressure of 10 mmHg to obtain 4.3 g (25.6 mmol) of ethyl methylthiochloroacetate.
Of the obtained ethyl methylthiochloroacetate, 1.68 g (10 mmol) was dissolved in benzene to obtain a benzene solution (5 ml). To this solution, 2.6 g (10 mmol) of SnCl ₄ was slowly added dropwise. After stirring for 30 minutes, water was added and the mixture was extracted with diethyl ether, dried over anhydrous magnesium sulfate, concentrated on a rotary evaporator, and purified by silica gel column chromatography (silica gel, hexane-diethyl ether) to obtain ethyl methylthiophenyl acetate (A -1) 1.89 g (9 mmol) was obtained. The yield was 80%.

[Example 1-2 to Example 1-7]
The following compounds (A-2), (A-3), (A-5) to (A-7) were synthesized using the same method as in Example 1-1 except that the starting material was changed. Table 1 shows the relationship between the starting material and the produced compound (A). Further, the following compound (A-4) was synthesized using the same method as in Example 1-1 except that the starting material was changed. Table 1 shows the relationship between the starting material and the resulting compound (A).

[Example 1-8]
To a solution of 5 g (22 mmol) of 2-chloro-1,2-diphenylethanone dissolved in cyclohexane (40 ml) was added 20 ml of a 15% aqueous solution of methylthiosodium, and the mixture was stirred at room temperature (23 ° C.) for 14 hours. After extraction with diethyl ether, drying over anhydrous magnesium sulfate, concentration with a rotary evaporator and purification by silica gel column chromatography (silica gel, hexane-diethyl ether), 1,2-diphenyl-2-methylthioethanone (A-8 4.8 g (20 mmol) was obtained. The yield was 91%.

[Example 1-9]
The following compound (A-9) was synthesized using the same method as in Example 1-8 except that the starting material was changed. Table 1 shows the relationship between the starting material and the produced compound (A).

[Example 1-10]
1.5 g (8.1 mmol) of trifluoroacetaldehyde hydrate, 0.74 g (8.2 mmol) of butanethiol and 2.25 g (16.8 mmol) of tert-butylbenzene were dissolved in 25 ml of methylene chloride. To this methylene chloride solution was added BF ₃ —H ₂ O (1: 1 (molar ratio) mixture of BF ₃ and H ₂ O. 1.5 ml) at room temperature (23 ° C.) and stirred at the same temperature for 2 hours. . Water was added and the mixture was extracted with methylene chloride. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. Dried over anhydrous magnesium sulfate, concentrated on a rotary evaporator and purified by silica gel column chromatography (silica gel, hexane-diethyl ether) to give butyl-2,2,2-trifluoro-1- (tert-butylphenyl) ethyl sulfide 0.76 g (2.5 mmol) of (A-10) was obtained. The yield was 31%.

[Example 2]
And IF _5, was a _CH 2 Cl ₂ solution of the IF ₅ as a mixture of 5-fold molar amount of methylene chloride IF ₅ (hereinafter referred to as _"IF 5 / _{5CH 2} Cl 2".).
A container made of tetrafluoroethylene was charged with 1 g of IF ₅ / 5CH ₂ Cl ₂ (1.5 mmol as IF ₅ ) and 2 ml of hexane, and 210 mg (1) of ethyl methylthiophenylacetate (A-1) at 0 ° C. 0.0 mmol) was added and stirred at room temperature for 2 hours. The obtained mixture was poured into 20 ml of water placed in a tetrafluoroethylene beaker, neutralized with an aqueous sodium hydrogen carbonate solution, extracted with diethyl ether, and the organic layer was washed with aqueous sodium thiosulfate. The extract was dried over anhydrous magnesium sulfate, concentrated by a rotary evaporator, and purified by silica gel column chromatography to obtain 146 mg (0.73 mmol) of ethyl 2,2-difluorophenylacetate (B-1). The yield was 73%.

[Examples 3 to 11]
The compound (A) described in Table 2 was used as a raw material. The reaction was carried out in the same manner as in Example 2 except that the reaction conditions were changed to those described in Table 2. The obtained compound (B) and yield are shown in Table 2.

The identification material of the compound manufactured in the Example is shown below.
Compound (B-1): ¹ H-NMR (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 1.31 (t, 3H, 7.2 Hz), 4.3 (q, 2H, 7 2 Hz), 7.44-7.52 (m, 3H), 7.60-7.62 (m, 2H). ¹⁹ F-NMR (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): −104.5 (s, 2F).

Compound (B-2): ¹ H-NMR (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 2.3 (t, 3H, 1.5 Hz), 7.45 to 7.56 (m 5H). ¹⁹ F-NMR (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): −107.4 (s, 2F).

Compound (B-3): ¹ H-NMR (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 7.53 to 7.69 (m, 5H). ¹⁹ F-NMR (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): −83.8 (s, 2F).

Compound (B-4): ¹ H-NMR (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 1.23 (t, 3H, 7.3 Hz), 4.3 (q, 2H, 7 .3 Hz), 7.5 to 7.6 (m, 3H), 7.85 to 7.98 (m, 3H), 8.2 (d, 1H, 8.4 Hz). ¹⁹ F-NMR (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): −100.7 (s, 2F).

Compound (B-5): ¹ H-NMR (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 6.8 to 7.0 (m, 2H), 7.46-7.61 (m 5H), 7.79-7.85 (m, 1H). ¹⁹ F-NMR (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): −102.7 to −102.6 (m, 1F), −100.6 (s, 1F), −100.6 (S, 1F), −100.1 to −100.2 (m, 1F).

Compound (B-6): ¹ H-NMR (ortho form) (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 1.33 (t, 3H, 7.4 Hz), 4.36 (q 2H, 7.2 Hz), 7.34-7.65 (m, 3H), 7.74 (d, 1H, 7.8 Hz).
¹⁹ F-NMR (ortho form) (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): −102.51 (s, 2F). ¹ H-NMR (para form) (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 1.31 (t, 3 H, 7.3 Hz), 4.36 (q, 2 H, 7.2 Hz) 7.48 (d, 2H, 8.4 Hz), 7.60 (d, 2H, 8.5 Hz). ¹⁹ F-NMR (para form) (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): −104.73 (s, 2F).

Compound (B-7): ¹ H-NMR (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 1.36 (t, 3H, 7.3 Hz), 4.37 (q, 2H, 7 .1 Hz), 7.07 (t, 1 H, 4.3 Hz), 7.40 (s, 1 H), 7.49 (d, 1 H, 5.0 Hz). ¹⁹ F-NMR (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): −93.45 (s, 2F).

Compound (B-8): ¹ H-NMR (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 7.42-7.48 (m, 5H), 7.57-7.63 (m 3H), 8.03 (d, 2H, 8.0 Hz). ¹⁹ F-NMR (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): -98.2 (s, 2F).

Compound (B-9): ¹ H-NMR (ortho form) (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 1.35 (s, 9H,), 7.40-7.60 ( m, 4H). ¹⁹ F-NMR (ortho form) (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): −85.41 (t, 3F, 2.2 Hz), −115.29 (q, 2F, 2. 1 Hz). ¹ H-NMR (para form) (400 MHz, solvent: CDCl ₃ , standard: TMS) δ (ppm): 1.35 (s, 9H,), 7.52 (s, 4H). ¹⁹ F-NMR (para form) (376 MHz, solvent CDCl ₃ , standard: CFCl ₃ ) δ (ppm): −85.43 (t, 3F, 2.1 Hz), −115.18 (t, 2F, 1. 8 Hz).

Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.
This application is based on Japanese Patent Application No. 2008-034626 filed on Feb. 15, 2008, the contents of which are incorporated herein by reference.

The fluoro compound having a carbon atom to which two fluorine atoms are bonded obtained by the production method of the present invention is useful, for example, as a synthetic intermediate for pharmaceuticals and agricultural chemicals.

Claims (4)

A method for producing a fluoro compound represented by the following formula (B), wherein the compound represented by the following formula (A) is reacted with IF ₅ .
X represents a group selected from an aryl group, a monovalent heterocyclic group, and an alkyl group, or a group in which one or more hydrogen atoms in the selected group are substituted, and Y represents an aryl group, a monovalent group, or a monovalent group. R represents a group selected from a heterocyclic group, an alkyl group, an acyl group, and an aryloxy group, or a group in which one or more of hydrogen atoms in the selected group are substituted, a cyano group, or an alkoxycarbonyl group. A group selected from an aryl group and an alkyl group, or a group in which one or more hydrogen atoms of the selected group are substituted.

X is a group selected from an aryl group and a monovalent heterocyclic group, or a group in which at least one hydrogen atom in the selected group is substituted; Y is a cyano group, an alkoxycarbonyl group, an acyl group, a halogen atom The production method according to claim 1, which is an alkyl group or an acyl halide group. 3. The production method according to claim 1, wherein R is an aryl group, an alkyl group, or a halogenated aryl group. The process according to any one of claims 1 to 3, wherein the reaction temperature is -50 to 100 ° C.