JP2016121121A - Method for producing (fluoroalkyl) arene - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing fluoroalkyl arene, which is important as synthetic raw materials for medicines and functional materials.SOLUTION: A fluoroalkyl arene is produced by the reaction between an aryl metal species represented by formula (2) and a fluoroalkyl halide represented by formula (3) in the presence of a cobalt compound and an ethylenediamine derivative. In the formula (2) shown in the following figure, R-Rindependently represent H, a C1-C4 alkyl group or the like. In the formula (3): Y-Rf, Y is Cl or the like; Rf is a C2-C3 fluoroalkyl group.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing (fluoroalkyl) arene used as a synthetic raw material for pharmaceuticals and functional materials.

  (Fluoroalkyl) arene is used as a raw material for synthesizing drugs and functional materials. In particular, (1,1-difluoroethyl) arene is a useful compound as a raw material for pharmaceuticals (for example, Patent Document 1). Most of the methods for producing (fluoroalkyl) arene disclosed so far are various substituents such as alkyl groups, alkenyl groups, alkynyl groups, formyl groups, carboxyl groups, alkylcarbonyl groups on aromatic rings. It converts to a fluoroalkyl group with a fluorinating agent (for example, Patent Documents 2 and 3, Non-Patent Documents 1 and 2).

  On the other hand, as a method for producing a (fluoroalkyl) arene by a reaction between a (fluoroalkyl) halide and an aryl metal species using a transition metal as a catalyst, 2,2,2-trifluoro-1-iodoethane using a palladium catalyst is used. There is only known a method for producing a (2,2,2-trifluoroethyl) benzene derivative by the reaction of benzene and arylboric acid (or its ester) (Non-patent Documents 3 and 4).

WO2011-154298. JP, 2014-5213, A. JP2013-180976.

Chemical Communications, page 654, 2005. Journal of the American Chemical Society, 135, 17494, 2013. Chemical Communications, 48, 8273, 2012. Angelwandte Chemie International Edition, 51, 1033, 2012.

  The production method of the already reported (fluoroalkyl) arene needs to use an expensive fluorinating agent and a copper compound whose use is restricted due to toxicity. Also, the method using a palladium catalyst is expensive.

  An object of the present invention is to provide a method for producing a (fluoroalkyl) arene using an easily available, inexpensive and less toxic reagent.

As a result of intensive investigations in view of the above problems, the present inventors have obtained a good yield by reacting an easily available and inexpensive aryl metal species with a (fluoroalkyl) halide in the presence of a cobalt compound and an ethylenediamine derivative. It has been found that (fluoroalkyl) arene can be produced at a high rate, and the present invention has been completed.
That is, the present invention
(I) Cobalt compound and general formula (1)

(Wherein R ¹ , R ² , R ³ and R ⁴ each independently represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a phenyl group. R ⁵ , R ⁶ , R ⁷ and R ⁸ are each Independently, it represents an alkyl group having 1 to 8 carbon atoms, and R ² and R ³ together represent a tetramethylene-1,4-diyl group or 9,10-dihydro-9,10-ethanoanthracene-11, R ¹ and R ⁵ may be combined to form a trimethylene-1,3-diyl group or a tetramethylene-1,4-diyl group, and R ⁵ and R ⁶ may be a 12-diyl group. May be combined to form a tetramethylene-1,4-diyl group or a benzo [b] butane-1,4-diyl group, and R ⁷ and R ⁸ are combined to form tetramethylene-1, 4-diyl group or benzo [b] butane-1,4-diyl May become .R ⁵ and R ⁸ are bonded may .R ⁶ and R ⁷ may become an ethylene group and is bonded to the ethylene diamine derivative represented by may be a ethylene group.) In the presence of general formula (2)

(Wherein R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are each independently substituted with a hydrogen atom or a C 1-4 alkyl group optionally substituted with a halogen atom, or a halogen atom. C2-C4 alkenyl group, C1-C6 alkoxy group, (C1-C4 alkoxy) carbonyl group, C2-C5 acyl group, C2-C5 acyloxy A group, a halogen atom, a cyano group, or a phenyl group, R ¹¹ and R ¹² may be combined with a carbon atom to form a benzene ring, and R ¹² and R ¹³ may be A benzene ring may be formed together, M represents a magnesium atom or a zinc atom, X represents a chlorine atom, a bromine atom or an iodine atom.) And a general formula (3 )

(Wherein Y represents a chlorine atom, a bromine atom or an iodine atom, Rf represents a fluoroalkyl group having 2 or 3 carbon atoms), and a (fluoroalkyl) halide represented by General formula (4)

(Wherein R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and Rf have the same contents as above), a method for producing a (fluoroalkyl) arene represented by
(Ii) The production method according to (i), wherein Rf of (fluoroalkyl) halide is a 1,1-difluoroethyl group,
(Iii) The ethylenediamine derivative is N, N, N ′, N ′, 2-pentamethyl-1,2-propanediamine, 1,2-bis (dimethylamino) cyclohexane or 1-[(1-methylpyrrolidine-2- Yl) methyl] piperidine (i) or the production method according to either (ii),
(Iv) The production method according to any one of (i) to (iii), wherein X is a chlorine atom or a bromine atom;
(V) The production method according to any one of (i) to (iv), wherein the cobalt compound is cobalt (II) chloride, cobalt (II) bromide or cobalt (II) iodide,
(Vi) General formula (5)

(Wherein R ²¹ and R ²² each independently represents an alkyl group having 1 to 4 carbon atoms, m represents an integer of 1 to 3), and the reaction is carried out in the presence of a polyether represented by The production method according to any one of (i) to (v),
(Vii) The production method according to (vi), wherein R ²¹ and R ²² are methyl groups.

  The present invention is described in detail below.

The alkyl group having 1 to 8 carbon atoms represented by R ¹ , R ² , R ³ and R ⁴ in the general formula (1) may be linear, branched or cyclic, and specifically includes a methyl group, ethyl Examples thereof include a group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, cyclohexyl group, octyl group, and cyclooctyl group. R ² and R ³ may be combined together to form a tetramethylene-1,4-diyl group or a 9,10-dihydro-9,10-ethanoanthracene-11,12-diyl group.

The alkyl group having 1 to 8 carbon atoms represented by R ⁵ , R ⁶ , R ⁷ and R ⁸ in the general formula (1) may be linear, branched or cyclic, and specifically includes a methyl group, ethyl Examples thereof include a group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, cyclohexyl group, octyl group, and cyclooctyl group. R ¹ and R ⁵ may be combined to form a trimethylene-1,3-diyl group or a tetramethylene-1,4-diyl group. R ⁵ and R ⁶ may be combined to form a tetramethylene-1,4-diyl group or a benzo [b] butane-1,4-diyl group. R ⁷ and R ⁸ may be combined to form a tetramethylene-1,4-diyl group or a benzo [b] butane-1,4-diyl group. R ⁵ and R ⁸ may combine to form an ethylene group. R ⁶ and R ⁷ may combine to form an ethylene group.

Examples of the ethylenediamine derivative (1) that can be represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ include (1a) to (1q) shown below. It can be illustrated.

  Among these ethylenediamine derivatives, (1i), (1l), and (1p ′) are different from each other in (1i), (1l), and (1p) in the relative configuration of the two dialkylamino groups shown below. Although it exists, (1i), (1l), and (1p) in which the relative configuration of the two dialkylamino groups is trans are preferable from the viewpoint of good yield.

  The ethylenediamine derivative may be any of (1a) to (1q), (1i ′), (1l ′), and (1p ′), but N, N, N ′, N′-tetra is preferable in terms of good yield. Methyl-1,2-propanediamine (1b), N, N, N ′, N ′, 2-pentamethyl-1,2-propanediamine (1d), trans-1,2-bis (dimethylamino) cyclohexane (1i) ) Or 1-[(1-methylpyrrolidin-2-yl) methyl] piperidine (1n).

  The ethylenediamine derivative (1) may be easily obtained as a commercial product, but can also be synthesized by alkylation of the corresponding amine by an Escheriler-Clark reaction described in, for example, Organic Synthesis, 25, 89, 1945. .

The alkyl group having 1 to 4 carbon atoms represented by R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ in the general formula (2) may be linear or branched, and specifically includes a methyl group, Examples thereof include an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.

  These alkyl groups may be substituted with a halogen atom, specifically, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2, Examples include 2,2-trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, perfluoroisopropyl group, chloromethyl group, 2-chloroethyl group and the like.

The alkenyl group having 2 to 4 carbon atoms represented by R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ in the general formula (2) may be linear or branched, and specifically, an ethenyl group, Examples include 1-methylethenyl group, 1-propenyl group, 2-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, etc. can do.

  These alkenyl groups may be substituted with a halogen atom, specifically, 1,2,2-trifluoroethenyl group, 1- (trifluoromethyl) ethenyl group, 3,3,3-trifluoro. -1-propenyl group, 3,3-difluoro-1-propenyl group, 1,2,2-trichloroethenyl group, 1- (trichloromethyl) ethenyl group, 3,3,3-trichloro-1-propenyl group, A 3,3-dichloro-1-propenyl group and the like can be exemplified.

The alkoxy group having 1 to 6 carbon atoms represented by R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ in the general formula (2) may be linear, branched or cyclic. Specifically, methoxy Examples thereof include a group, an ethoxy group, a propoxy group, an isopropyloxy group, a butoxy group, an isobutyloxy group, a sec-butyloxy group, a tert-butyloxy group, a hexyloxy group, a cyclohexyloxy group, and a phenoxy group.

The (carbon number 1-4 alkoxy) carbonyl group represented by R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ in the general formula (2) may be either linear or branched. Examples include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropyloxycarbonyl group, butoxycarbonyl group, isobutyloxycarbonyl group, sec-butyloxycarbonyl group, tert-butyloxycarbonyl group and the like.

The acyl group having 2 to 5 carbon atoms represented by R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ in the general formula (2) may be either linear or branched. Specifically, an acetyl group, Examples thereof include a propionyl group, an isopropionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, and a pivaloyl group.

The acyloxy group having 2 to 5 carbon atoms represented by R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ in the general formula (2) may be either linear or branched. Specifically, an acetyloxy group And propionyloxy group, isopropyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, and pivaloyloxy group.

Specific examples of the halogen atom represented by R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ in the general formula (2) include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Adjacent R ¹¹ and R ¹² , or R ¹² and R ¹³ may form a benzene ring together with the carbon atoms to be bonded, and specifically, (2a) and (2b) shown below. Can be illustrated.

(In the formula, R ¹³ , R ¹⁴ , R ¹⁵ , M and X have the same contents as described above.)

(In the formula, R ¹¹ , R ¹⁴ , R ¹⁵ , M and X have the same contents as described above.)

  X in the general formula (2) is preferably a bromine atom or an iodine atom in terms of good yield when M is a magnesium atom. When M is a zinc atom, a chlorine atom is preferred in terms of good yield and easy availability of raw materials. In addition, when M is a zinc atom, N, N, N ′, N′-tetramethylethylenediamine (TMEDA) in terms of good yield as described in, for example, Palladium Reagents and Catalysis, Wiley, pp. 327-335, 2004. ) Are preferably present together.

  The aryl metal species (2) can be easily obtained as a commercial product, but can also be synthesized, for example, by the method described in JP2010-116363A.

  Specific examples of the halogen atom represented by Y in the general formula (3) include a chlorine atom, a bromine atom, and an iodine atom. From the viewpoint of good yield, a bromine atom or an iodine atom is preferable.

  The fluoroalkyl group represented by Rf in the general formula (3) may be linear or branched, and specifically, 1,2,2,2-tetrafluoroethyl group, 1,1,2,2- Tetrafluoroethyl group, 2,2,2-trifluoroethyl group, 1,2,2-trifluoroethyl group, 1,1,2-trifluoroethyl group, 2,2-difluoroethyl group, 1,1- Difluoroethyl group, 1,2-difluoroethyl group, 2-fluoroethyl group, 1-fluoroethyl group, 1,1,2,2,2-pentafluoroethyl group, 1,1,1,3,3,3 -Hexafluoroisopropyl group, 2,2,3,3,3-pentafluoropropyl group, 2,2,3,3-tetrafluoropropyl group, 1,1,1-trifluoroisopropyl group, 1,1,1 , 2,3,3,3-heptafluo It can be exemplified isopropyl group.

  A 1,1-difluoroethyl group is preferred because it is useful as a pharmaceutical synthesis intermediate.

  (Fluoroalkyl) halide (3) is easily available as a commercial product. For example, 1,1-difluoro-1-iodoethane, which is not commercially available, is Journal of Chemical Research (S), p. 122, 1998. It can also be synthesized by a method using trifluoromethanesulfonic acid and vinylidene fluoride as raw materials according to the method described in 1).

The alkyl group having 1 to 4 carbon atoms represented by R ²¹ and R ²² in the general formula (5) may be linear, branched or cyclic, and specifically includes a methyl group, an ethyl group, a propyl group, and isopropyl. Examples thereof include a group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.
A methyl group or an ethyl group is preferable in terms of easy availability and a good yield.

  Next, the manufacturing method of this invention is demonstrated.

  Examples of the cobalt compound that can be used in this reaction include cobalt (II) iodide, cobalt bromide (II), cobalt chloride (II), cobalt acetate (II), acetylacetonato cobalt (II) and the like (II) ) Salt, cobalt (III) salt such as cobalt acetate (III) and acetylacetonatocobalt (III). From the viewpoint of good yield and easy availability, cobalt (II) iodide, cobalt (II) bromide, and cobalt (II) chloride are more preferable.

  The concentration of the cobalt compound is preferably 1 to 100 mmol / L, more preferably 10 to 50 mmol / L in terms of good yield.

  The molar ratio of the ethylenediamine derivative (1) and the cobalt compound is preferably 1: 0.1 to 1:10, and more preferably 1: 0.5 to 1: 5 in terms of a good yield.

  The molar ratio of the aryl metal species (2) and the cobalt compound is preferably 1: 1 to 500: 1, and more preferably 5: 1 to 100: 1 in terms of good yield.

  The molar ratio of (fluoroalkyl) halide (3) to cobalt compound is preferably from 0.1: 1 to 50000: 1, and more preferably from 1: 1 to 200: 1 in terms of good yield.

  The production method of the present invention can use a solvent that does not harm the reaction. Specific examples include ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether and cyclopentyl methyl ether, aromatic hydrocarbons such as toluene and xylene, and aliphatic hydrocarbons such as hexane and heptane. Ether is preferable and tetrahydrofuran is more preferable in terms of good yield.

  In the production method of the present invention, the yield may be improved by adding the polyether (5). Examples of the polyether that can be used include ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, diethylene glycol diethyl ether, and triethylene glycol diethyl ether. From the viewpoint of good yield, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether are preferable.

The molar ratio of the polyether (5) to the cobalt compound is preferably 5: 1 to 500: 1, and more preferably 20: 1 to 200: 1 in terms of good yield.
The reaction temperature can be carried out at a temperature appropriately selected from the range of −50 ° C. to 100 ° C. -30 ° C to 50 ° C is preferable in terms of good yield.

  The reaction can be carried out under a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. The atmosphere at that time is preferably an inert gas such as argon or nitrogen.

  When the (fluoroalkyl) halide (3) is a gas at normal temperature and pressure, it may be used as it is, and in that case, diluted with an inert gas such as argon or nitrogen to obtain a (fluoroalkyl) halide (3) Can be used as a mixed gas having a molar fraction of 1% or more. Alternatively, (fluoroalkyl) halide (3) or a mixed gas thereof with an inert gas may be bubbled and introduced into the reaction solution. The introduction rate of the (fluoroalkyl) halide (3) or the mixed gas at that time depends on the scale of the reaction, the amount of catalyst, the reaction temperature, and the molar fraction of the (fluoroalkyl) halide (3) in the mixed gas, A speed selected from the range of 1 mL to 200 mL per minute is sufficient.

  (Fluoroalkyl) halide (3) may be dissolved in the above reaction solvent and used as a solution. Tetrahydrofuran is preferred from the viewpoint of high solubility of (fluoroalkyl) halide (3) and convenience. The concentration at that time is preferably 0.05 to 5 mol / L, and more preferably 0.1 to 2 mol / L.

  Although there is no restriction | limiting in particular in reaction time, A target object can be obtained with a sufficient yield by performing for 0.5 hour or more.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but may be a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  The present invention is effective as a method for efficiently producing (fluoroalkyl) arene, which is an important compound as a raw material for synthesizing drugs and functional materials.

  EXAMPLES Next, although an Example and a comparative example demonstrate this invention in detail, this invention is not limited to these.

Example-1

In a reaction vessel, 1.0 mL of a 1 mol / L tetrahydrofuran solution of 1-bromo-1,1-difluoroethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, trans-1,2-bis (dimethylamino) cyclohexane 17.0 mg (0.10 mmol) and 1.87 g (14.0 mmol) of diethylene glycol dimethyl ether were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 2 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. Then, saturated ammonium chloride aqueous solution: water (1: 1) was added, and diethyl ether was further added for extraction operation. Benzotrifluoride was added as an internal standard substance to the diethyl ether layer, and by ¹⁹ F-NMR, 92% of 4- (1,1-difluoroethyl) anisole was produced relative to 1-bromo-1,1-difluoroethane. It was confirmed. The diethyl ether layer was washed with saturated brine and then dehydrated with anhydrous sodium sulfate. Then, filtration, concentration and purification by silica gel column chromatography gave 4- (1,1-difluoroethyl) anisole as a colorless oily liquid (0.105 g, 61%).
¹ H NMR (CDCl ₃ ) δ 1.91 (3H, t, J _HF = 18.1 Hz), 3.83 (3H, s), 6.92 (2H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.4 Hz).
¹⁹ F NMR (CDCl ₃ ) δ-85.5 (2F, q, J _FH = 18.1 Hz).

Example-2
In a reaction vessel, 1.0 mL of a 1.0 mol / L tetrahydrofuran solution of 1-bromo-1,1-difluoroethane, 6.5 mg (0.05 mmol) of cobalt (II) chloride, trans-1,2-bis (dimethylamino) cyclohexane 8.5 mg (0.05 mmol) and 2.0 mL of tetrahydrofuran were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at 40 ° C. over 4 hours. After completion of dropping, the mixture was further stirred at 40 ° C. for 1 hour. After the reaction, the same ¹⁹ F-NMR analysis as in Example 1 confirmed that 70% of 4- (1,1-difluoroethyl) anisole was formed relative to 1-bromo-1,1-difluoroethane. did.

Example-3
In a reaction vessel, 1.0 mL of a 1 mol / L tetrahydrofuran solution of 1-bromo-1,1-difluoroethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, trans-1,2-bis (dimethylamino) cyclohexane 17.0 mg (0.10 mmol) and 2.0 mL of tetrahydrofuran were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 2 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. After the reaction, it was confirmed by ¹⁹ F-NMR analysis similar to Example-1 that 62% of 4- (1,1-difluoroethyl) anisole was formed with respect to 1-bromo-1,1-difluoroethane. did.

Example-4
The amount used of 13.0 mg (0.10 mmol) of cobalt (II) chloride and 17.0 mg (0.10 mmol) of trans-1,2-bis (dimethylamino) cyclohexane was 6.5 mg (0.05 mmol) and 8. Except for 5 mg (0.05 mmol), the same operation as in Example 3 was carried out to produce 52% of 4- (1,1-difluoroethyl) anisole with respect to 1-bromo-1,1-difluoroethane. I confirmed.

Example-5
The same operation as in Example 3 was performed except that cobalt bromide (II) was changed to 21.9 mg (0.1 mmol) instead of cobalt chloride (II), and 4- (1,1-difluoroethyl) anisole was It was confirmed that 67% of 1-bromo-1,1-difluoroethane was produced.

Example-6
In place of cobalt chloride (II), 10.9 mg (0.05 mmol) of cobalt bromide (II) was used, and 17.0 mg (0.10 mmol) of trans-1,2-bis (dimethylamino) cyclohexane was used. The same operation as in Example 3 was performed except that 5 mg (0.05 mmol) was made, and 54% of 4- (1,1-difluoroethyl) anisole was formed with respect to 1-bromo-1,1-difluoroethane. I confirmed.

Example-7
The same operation as in Example 3 was performed except that cobalt iodide (II) was changed to 31.3 mg (0.1 mmol) in place of cobalt chloride (II), and 4- (1,1-difluoroethyl) anisole was obtained. It was confirmed that 79% of 1-bromo-1,1-difluoroethane was produced.

Example-8
In place of cobalt chloride (II), cobalt iodide (II) was changed to 15.6 mg (0.05 mmol), and the amount of trans-1,2-bis (dimethylamino) cyclohexane 17.0 mg (0.10 mmol) used was 8. The same operation as in Example 3 was carried out except that 5 mg (0.05 mmol) was made, and 74% of 4- (1,1-difluoroethyl) anisole was formed relative to 1-bromo-1,1-difluoroethane. I confirmed.

Example-9
The same operation as in Example 3 was carried out except that 17.7 mg (0.1 mmol) of cobalt acetate (II) was used instead of cobalt chloride (II), and 4- (1,1-difluoroethyl) anisole was 1 It was confirmed that 55% of bromo-1,1-difluoroethane was produced.

Example-10
The same procedure as in Example 3 was performed except that 25.7 mg (0.1 mmol) of bis (acetylacetonato) cobalt (II) was used instead of cobalt (II) chloride, and 4- (1,1-difluoro It was confirmed that 58% of ethyl) anisole was produced with respect to 1-bromo-1,1-difluoroethane.

Example-11
The same operation as in Example 3 was performed except that tris (acetylacetonato) cobalt (III) was 35.6 mg (0.1 mmol) instead of cobalt (II) chloride, and 4- (1,1-difluoro It was confirmed that 40% of ethyl) anisole was produced with respect to 1-bromo-1,1-difluoroethane.

Example-12
In a reaction vessel, 1.0 mL of a 1 mol / L tetrahydrofuran solution of 1-bromo-1,1-difluoroethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, trans-1,2-bis (dimethylamino) cyclohexane 17.0 mg (0.10 mmol) and 1.97 g (11.1 mmol) of triethylene glycol dimethyl ether were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 2 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. After the reaction, the same ¹⁹ F-NMR analysis as in Example 1 confirmed that 67% of 4- (1,1-difluoroethyl) anisole was formed relative to 1-bromo-1,1-difluoroethane. did.

Example-13
The same operation as in Example 2 was carried out except that 1.87 g (14.0 mmol) of diethylene glycol dimethyl ether was used instead of 2.0 mL of tetrahydrofuran, and 4- (1,1-difluoroethyl) anisole was 1-bromo- It was confirmed that 89% of 1,1-difluoroethane was produced.

Example-14
In place of 2.0 mL of tetrahydrofuran, 1.87 g (14.0 mmol) of diethylene glycol dimethyl ether was used, and 6.5 mg (0.05 mmol) of cobalt (II) chloride and 8.5 mg of trans-1,2-bis (dimethylamino) cyclohexane were used. (0.05 mmol) was used in the same manner as in Example 2, except that the amount used was 3.9 mg (0.03 mmol) and 5.1 mg (0.03 mmol), respectively. 4- (1,1-difluoro It was confirmed that 85% of ethyl) anisole was produced with respect to 1-bromo-1,1-difluoroethane.

Example-15
In a reaction vessel, 1.0 mL of a 1.0 mol / L tetrahydrofuran solution of 1-bromo-1,1-difluoroethane, 9.4 mg (0.03 mmol) of cobalt (II) iodide, trans-1,2-bis (dimethylamino) Cyclohexane 5.1 mg (0.03 mmol) and diethylene glycol dimethyl ether 1.87 g (14.0 mmol) were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the resulting mixture, a 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 4 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. After the reaction, it was confirmed by ¹⁹ F-NMR analysis similar to that in Example-1 that 4- (1,1-difluoroethyl) anisole was produced at 75% of 1-bromo-1,1-difluoroethane. did.

Example-16
In place of trans-1,2-bis (dimethylamino) cyclohexane, 14.4 mg (0.10 mmol) of N, N, N ′, N ′, 2-pentamethyl-1,2-propanediamine was used. The same operation as in Example 3 was performed, and it was confirmed that 89% of 4- (1,1-difluoroethyl) anisole was produced with respect to 1-bromo-1,1-difluoroethane.

Example-17
Other than using N, N, N ′, N ′, 3,3-hexamethyl-1,2-butanediamine 17.2 mg (0.10 mmol) instead of trans-1,2-bis (dimethylamino) cyclohexane The same operation as in Example 3 was carried out, and it was confirmed that 4- (1,1-difluoroethyl) anisole was produced at 21% with respect to 1-bromo-1,1-difluoroethane.

Example-18
In place of trans-1,2-bis (dimethylamino) cyclohexane, 20.5 mg (0.10 mmol) of N, N, N ′, N′-tetramethyl-2-phenyl-1,2-propanediamine was used. Except for the above, the same operation as in Example 3 was performed, and it was confirmed that 4- (1,1-difluoroethyl) anisole was produced at 22% with respect to 1-bromo-1,1-difluoroethane.

Example-19
except that trans-N, N, N ′, N′-tetramethyl-1,2-diphenylethylenediamine 26.8 mg (0.10 mmol) was used instead of trans-1,2-bis (dimethylamino) cyclohexane. Then, the same operation as in Example 3 was performed, and it was confirmed that 57% of 4- (1,1-difluoroethyl) anisole was generated with respect to 1-bromo-1,1-difluoroethane.

Example-20
Example-3, except that 19.2 mg (0.10 mmol) of N, N, N ′, N′-tetramethyl (phenyl) ethylenediamine was used in place of trans-1,2-bis (dimethylamino) cyclohexane The same operation was performed, and it was confirmed that 33% of 4- (1,1-difluoroethyl) anisole was formed relative to 1-bromo-1,1-difluoroethane.

Example-21
Example-3 except that in place of trans-1,2-bis (dimethylamino) cyclohexane, 14.2 mg (0.10 mmol) of 2- (N, N-dimethylamino) -1-methylpyrrolidine was used. The same operation was performed, and it was confirmed that 26% of 4- (1,1-difluoroethyl) anisole was formed with respect to 1-bromo-1,1-difluoroethane.

Example-22
In place of trans-1,2-bis (dimethylamino) cyclohexane, 29.6 mg (0.10 mmol) of trans-9,10-dihydro-11,12-bis (dimethylamino) -9,10-ethanoanthracene was used. Except that, 4- (1,1-difluoroethyl) anisole was confirmed to be 29% produced with respect to 1-bromo-1,1-difluoroethane.

Example-23
In a reaction vessel, 1.0 mL of a 1 mol / L tetrahydrofuran solution of 1-bromo-1,1-difluoroethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, N, N, N ′, N ′, 2- Pentamethyl-1,2-propanediamine (14.4 mg, 0.10 mmol) and ethylene glycol dimethyl ether (1.74 g, 19.3 mmol) were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 2 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. After the reaction, the same ¹⁹ F-NMR analysis as in Example 1 confirmed that 80% of 4- (1,1-difluoroethyl) anisole was formed relative to 1-bromo-1,1-difluoroethane. did.

Example-24
In a reaction vessel, 192 mg of 1,1-difluoro-1-iodoethane, 6.5 mg (0.05 mmol) of cobalt (II) chloride, 8.5 mg (0.05 mmol) of trans-1,2-bis (dimethylamino) cyclohexane and tetrahydrofuran 3.0 mL was added and stirred for 15 minutes at room temperature in argon. To the resulting mixture, a 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 1 hour. After completion of the dropwise addition, the mixture was further stirred at room temperature for 0.5 hour. After the reaction, the same ¹⁹ F-NMR analysis as in Example 1 confirmed that 80% of 4- (1,1-difluoroethyl) anisole was formed relative to 1-bromo-1,1-difluoroethane. did.

Example-25
The same operation as in Example-24, except that 5.8 mg (0.05 mmol) of N, N, N ', N'-tetramethylethylenediamine was used instead of trans-1,2-bis (dimethylamino) cyclohexane. It was confirmed that 40% of 4- (1,1-difluoroethyl) anisole was produced with respect to 1-bromo-1,1-difluoroethane.

Example-26
The same operation as in Example-24, except that 11.6 mg (0.10 mmol) of N, N, N ', N'-tetramethylethylenediamine was used instead of trans-1,2-bis (dimethylamino) cyclohexane. Then, it was confirmed that 37% of 4- (1,1-difluoroethyl) anisole was formed with respect to 1-bromo-1,1-difluoroethane.

Example-27
Implementation was carried out except that 13.0 mg (0.10 mmol) of N, N, N ′, N′-tetramethyl-1,2-propanediamine was used in place of trans-1,2-bis (dimethylamino) cyclohexane. The same operation as in Example-24 was performed, and it was confirmed that 41% of 4- (1,1-difluoroethyl) anisole was formed with respect to 1-bromo-1,1-difluoroethane.

Example-28
Example-24 except that 18.2 mg (0.10 mmol) of 1-[(1-methylpyrrolidin-2-yl) methyl] piperidine was used in place of trans-1,2-bis (dimethylamino) cyclohexane. The same operation was performed, and it was confirmed that 31% of 4- (1,1-difluoroethyl) anisole was produced with respect to 1-bromo-1,1-difluoroethane.

Example-29
Instead of trans-1,2-bis (dimethylamino) cyclohexane, 21.6 mg (0.10 mmol) of 2,3-dihydro-2-[(1-methylpyrrolidin-2-yl) methyl] -1H-isoindole Except that was used, the same operation as in Example-24 was performed, and it was confirmed that 4- (1,1-difluoroethyl) anisole was produced in an amount of 29% with respect to 1-bromo-1,1-difluoroethane. .

Example-30
In a reaction vessel, 2.0 mL of a 1.0 mol / L tetrahydrofuran solution of 1-bromo-1,1-difluoroethane, 6.5 mg (0.05 mmol) of cobalt (II) chloride, trans-1,2-bis (dimethylamino) cyclohexane 8.5 mg (0.05 mmol) and 2.0 mL of tetrahydrofuran were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36 mol / L tetrahydrofuran solution (2.8 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 3 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. After the reaction, it was confirmed by ¹⁹ F-NMR analysis similar to Example-1 that 37% of 4- (1,1-difluoroethyl) anisole was formed with respect to (4-methoxyphenyl) magnesium bromide. did.

Example-31
The same procedure as in Example-30 was performed except that 1.87 g (14.0 mmol) of diethylene glycol dimethyl ether was used instead of 2.0 mL of tetrahydrofuran, and 4- (1,1-difluoroethyl) anisole was brominated (4- It was confirmed that 61% of methoxyphenyl) magnesium was formed.

Example-32
Implemented except that N, N, N ′, N ′, 2-pentamethyl-1,2-propanediamine (14.4 mg, 0.10 mmol) was used instead of trans-1,2-bis (dimethylamino) cyclohexane. The same operation as in Example-30 was performed, and it was confirmed that 58% of 4- (1,1-difluoroethyl) anisole was formed with respect to (4-methoxyphenyl) magnesium bromide.

Example-33

In a reaction vessel, 0.67 mL of a 1.5 mol / L tetrahydrofuran solution of 1-chloro-1,1-difluoroethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, trans-1,2-bis (dimethylamino) cyclohexane 17.0 mg (0.10 mmol), 0.33 mL of tetrahydrofuran and 1.87 g (14.0 mmol) of diethylene glycol dimethyl ether were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at 40 ° C. over 4 hours. After completion of dropping, the mixture was further stirred at 40 ° C. for 1 hour. After the reaction, the same ¹⁹ F-NMR analysis as in Example 1 confirmed that 60% of 4- (1,1-difluoroethyl) anisole was formed relative to 1-chloro-1,1-difluoroethane. did.

Example-34

Except that the 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was replaced with a 1.07 mol / L tetrahydrofuran solution (1.4 mL) of (phenyl) magnesium bromide, Example -1 was carried out, and ¹⁹ F-NMR analysis confirmed that 86% (1,1-difluoroethyl) benzene was produced relative to 1-bromo-1,1-difluoroethane. Further, the same isolation operation as in Example 1 was performed to obtain (1,1-difluoroethyl) benzene as a colorless oily liquid (0.040 g, 28%).
¹ H NMR (CDCl ₃ ) δ 1.92 (3H, t, J _HF = 18.1 Hz), 7.39-7.45 (3H, m), 7.48-7.54 (2H, m).
¹⁹ F NMR (CDCl ₃ ) δ-87.6 (2F, q, J _FH = 18.1 Hz).

Example-35
In a reaction vessel, 1.0 mL of a 1 mol / L tetrahydrofuran solution of 1-bromo-1,1-difluoroethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, trans-1,2-bis (dimethylamino) cyclohexane 17.0 mg (0.10 mmol) and 2.0 mL of tetrahydrofuran were added, and the mixture was stirred in argon at room temperature for 15 minutes. A 1.07 mol / L tetrahydrofuran solution (1.4 mL) of (phenyl) magnesium bromide was added dropwise to the resulting mixture at room temperature over 2 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. After the reaction, the same ¹⁹ F-NMR analysis as in Example 1 confirmed that 81% of (1,1-difluoroethyl) benzene was produced relative to 1-bromo-1,1-difluoroethane.

Example-36

  Same as Example-35 except that 1.07 mol / L tetrahydrofuran solution (1.4 mL) of (phenyl) magnesium bromide was replaced with 1.97 mol / L tetrahydrofuran solution (0.75 mL) of (phenyl) magnesium chloride. Operation was performed, and it was confirmed that (1,1-difluoroethyl) benzene was produced in an amount of 35% with respect to 1-bromo-1,1-difluoroethane.

Example-37

A 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was replaced with a 1.12 mol / L tetrahydrofuran solution (1.3 mL) of (3-methoxyphenyl) magnesium bromide. The same operation as in Example 1 was performed, and ¹⁹ F-NMR analysis showed that 74% of 3- (1,1-difluoroethyl) anisole was produced relative to 1-bromo-1,1-difluoroethane. confirmed. Further, the same isolation operation as in Example 1 was performed to obtain 3- (1,1-difluoroethyl) anisole as a colorless oily liquid (0.084 g, 49%).
¹ H NMR (CDCl ₃ ) δ 1.91 (3H, t, J _HF = 18.1 Hz), 3.84 (3H, s), 6.93-6.98 (1H, m), 7.02-7 .05 (1H, m), 7.06-7.11 (1H, m), 7.30-7.36 (1H, m).
¹⁹ F NMR (CDCl ₃ ) δ-87.6 (2F, q, J _FH = 18.1 Hz).

Example-38

A 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was replaced with a 1.06 mol / L tetrahydrofuran solution (1.4 mL) of (2-methoxyphenyl) magnesium bromide. The same operation as in Example 1 was carried out, and it was confirmed by ¹⁹ F-NMR analysis that 2- (1,1-difluoroethyl) anisole was produced 21% with respect to 1-bromo-1,1-difluoroethane. confirmed. Further, the same isolation operation as in Example 1 was performed to obtain 2- (1,1-difluoroethyl) anisole as a colorless oily liquid (0.014 g, 8%).
¹ H NMR (CDCl ₃ ) δ 2.00 (3H, t, J _HF = 18.7 Hz), 3.88 (3H, s), 6.94-7.01 (2H, m), 7.36-7 .42 (1H, m), 7.50-7.54 (1H, m).
¹⁹ F NMR (CDCl ₃ ) δ-87.2 (2F, q, J _FH = 18.7 Hz).

Example-39

Except that the 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was replaced with a 0.96 mol / L tetrahydrofuran solution (1.6 mL) of (p-tolyl) magnesium bromide, The same operation as in Example 1 was carried out, and (1,1-difluoroethyl) -4-methylbenzene was produced 75% of 1-bromo-1,1-difluoroethane by ¹⁹ F-NMR analysis. It was confirmed. Furthermore, the same isolation operation as in Example 1 was performed to obtain (1,1-difluoroethyl) -4-methylbenzene as a colorless oily liquid (0.060 g, 38%).
¹ H NMR (CDCl ₃ ) δ 1.91 (3H, t, J _HF = 18.1 Hz), 2.38 (3H, s), 7.22 (2H, d, J = 8.0 Hz), 7.39 (2H, d, J = 8.0 Hz).
¹⁹ F NMR (CDCl ₃ ) δ-86.9 (2F, q, J _FH = 18.1 Hz).

Example-40

A 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was replaced with a 0.53 mol / L tetrahydrofuran solution (2.8 mL) of (biphenyl-4-yl) magnesium bromide. The same operation as in Example 1 was carried out, and 96% generation of 4- (1,1-difluoroethyl) biphenyl with respect to 1-bromo-1,1-difluoroethane was confirmed by ¹⁹ F-NMR analysis. It was confirmed. Further, the same isolation operation as in Example 1 was performed to obtain 4- (1,1-difluoroethyl) biphenyl as a colorless solid (0.203 g, 93%).
¹ H NMR (CDCl ₃ ) δ 1.96 (3H, t, J _HF = 18.1 Hz), 7.35-7.41 (1H, m), 7.43-7.49 (2H, m), 7 .56-7.61 (4H, m), 7.62-7.66 (2H, m).
¹⁹ F NMR (CDCl ₃ ) δ-87.3 (2F, q, J _FH = 18.1 Hz).

Example-41

Except that the 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was replaced with a 0.25 mol / L tetrahydrofuran solution (6.0 mL) of (naphthyl-1-yl) magnesium bromide. The same operation as in Example 1 was conducted, and by ¹⁹ F-NMR analysis, 50% of 1- (1,1-difluoroethyl) naphthalene was produced relative to 1-bromo-1,1-difluoroethane. It was confirmed. Further, the same isolation operation as in Example 1 was performed to obtain 1- (1,1-difluoroethyl) naphthalene as a colorless oily liquid (0.079 g, 41%).
¹ H NMR (CDCl ₃ ) δ 2.15 (3H, t, J _HF = 18.3 Hz), 7.45-7.60 (3H, m), 7.70-7.74 (1H, m), 7 .88-7.94 (2H, m), 8.24-8.29 (1H, m).
¹⁹ F NMR (CDCl ₃ ) δ-83.5 (2F, q, J _FH = 18.3 Hz).

Example-42

A 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added to a 0.60 mol / L tetrahydrofuran solution (2.5 mL) of [4- (trifluoromethyl) phenyl] magnesium bromide. The same operation as in Example-1 was performed except that the internal standard substance was changed from benzotrifluoride to 2,2,2-trifluoroethanol, and the same ¹⁹ F-NMR analysis as in Example-1 was performed. 1- (1,1-difluoroethyl) -4- (trifluoromethyl) benzene was confirmed to be 77% produced relative to 1-bromo-1,1-difluoroethane. Furthermore, the isolation operation similar to Example-1 was performed, and 1- (1,1-difluoroethyl) -4- (trifluoromethyl) benzene was obtained as a colorless oily liquid (0.042 g, 20%).
¹ H NMR (CDCl ₃ ) δ 1.93 (3H, t, J _HF = 18.2 Hz), 7.63 (2H, d, J = 8.2 Hz), 7.70 (2H, d, J = 8. 2 Hz).
¹⁹ F NMR (CDCl ₃ ) δ-62.9 (3F, s), -88.7 (2F, q, J _FH = 18.2 Hz).

Example-43

A 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was replaced with a 0.91 mol / L tetrahydrofuran solution (1.65 mL) of (4-fluorophenyl) magnesium bromide. The same operation as in Example 1 was performed, and ¹⁹ F-NMR analysis showed that 1- (1,1-difluoroethyl) -4-fluorobenzene was 60% of 1-bromo-1,1-difluoroethane. Confirmed that. Furthermore, the isolation operation similar to Example-1 was performed, and 1- (1,1-difluoroethyl) -4-fluorobenzene was obtained as a colorless oily liquid (0.053 g, 33%).
¹ H NMR (CDCl ₃ ) δ 1.91 (3H, t, J _HF = 18.1 Hz), 7.07-7.13 (2H, m), 7.46-7.52 (2H, m).
¹⁹ F NMR (CDCl ₃ ) δ-86.45 to −86.64 (2F, m), −111.45 to −11.56 (1F, m).

Example-44

In a reaction vessel, 192 mg of 1,1-difluoro-1-iodoethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, 17.0 mg (0.10 mmol) of trans-1,2-bis (dimethylamino) cyclohexane, tetrahydrofuran 1.0 mL and 1.87 g (14.0 mmol) of diethylene glycol dimethyl ether were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.8 mol / L tetrahydrofuran solution (2.5 mL) of (phenyl) zinc chloride · TMEDA was further added. Thereafter, the mixture was further stirred at 40 ° C. for 15 hours. After the reaction, 1-methoxy-3- (1,1-difluoroethyl) benzene was found to form 74% of 1,1-difluoro-1-iodoethane by ¹⁹ F-NMR analysis similar to Example-1. I confirmed.

Example-45

In a reaction vessel, 192 mg of 1,1-difluoro-1-iodoethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, 17.0 mg (0.10 mmol) of trans-1,2-bis (dimethylamino) cyclohexane, tetrahydrofuran 1.0 mL and 1.87 g (14.0 mmol) of diethylene glycol dimethyl ether were added, and the mixture was stirred at room temperature for 30 minutes in argon. To the obtained mixture, a 0.5 mol / L tetrahydrofuran solution (4.0 mL) of [4- (ethoxycarbonyl) phenyl] zinc chloride · TMEDA was further added. Thereafter, the mixture was further stirred at 50 ° C. for 15 hours. After the reaction, the same ¹⁹ F-NMR analysis as in Example 1 revealed that 58% ethyl 4- (1,1-difluoroethyl) benzoate was formed relative to 1,1-difluoro-1-iodoethane. It was confirmed. Furthermore, the same isolation operation as in Example 1 was performed to obtain ethyl 4- (1,1-difluoroethyl) benzoate as a colorless oily liquid (0.114 g, 53%).
¹ H NMR (CDCl ₃ ) δ 1.41 (3H, t, J = 7.1 Hz), 1.93 (3H, t, J _HF = 18.2 Hz), 4.40 (2H, q, J = 7. 1 Hz), 7.58 (2H, d, J = 8.6 Hz), 8.10 (2H, d, J = 8.6 Hz).
¹⁹ F NMR (CDCl ₃ ) δ-88.7 (2F, q, J _FH = 18.2 Hz).

Example-46

Instead of [4- (ethoxycarbonyl) phenyl] zinc chloride / TMEDA in 0.5 mol / L tetrahydrofuran solution (4.0 mL), a solution of [4-cyanophenyl] zinc chloride · TMEDA in 0.5 mol / L tetrahydrofuran (4 mL) 0.0 mL), and the reaction temperature was changed to 40 ° C., and the same operation as in Example-45 was performed. According to ¹⁹ F-NMR analysis, 4- (1,1-difluoroethyl) benzonitrile was 1-bromo-1 , 1-difluoroethane was confirmed to be 28% produced. Further, the same isolation operation as in Example 1 was performed to obtain 4- (1,1-difluoroethyl) benzonitrile as a colorless oily liquid (0.035 g, 21%).
¹ H NMR (CDCl ₃ ) δ 1.93 (3H, t, J _HF = 18.2 Hz), 7.63 (2H, d, J = 8.1 Hz), 7.74 (2H, d, J = 8. 1 Hz).
¹⁹ F NMR (CDCl ₃ ) -89.3 (2F, q, J _FH = 18.2 Hz).

Example-47

In a reaction vessel, 1-iodo-2,2,2-trifluoroethane 210 mg (1.0 mmol), cobalt (II) chloride 13.0 mg (0.10 mmol), N, N, N ′, N ′, 2-pentamethyl -1,2-Propanediamine (14.4 mg, 0.10 mmol) and tetrahydrofuran (3.0 mL) were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 2 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. Then, saturated ammonium chloride aqueous solution: water (1: 1) was added, and diethyl ether was further added for extraction operation. Benzotrifluoride was added to the diethyl ether layer as an internal standard substance, and 4- (2,2,2-trifluoroethyl) anisole was compared with 1-iodo-2,2,2-trifluoroethane by ¹⁹ F-NMR. , 39% was confirmed to be produced. The diethyl ether layer was washed with saturated brine and then dehydrated with anhydrous sodium sulfate. Thereafter, the mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 4- (2,2,2-trifluoroethyl) anisole as a colorless oily liquid (0.042 g, 22%).
¹ H NMR (CDCl ₃ ) δ 3.30 (2H, q, J _HF = 10.9 Hz), 3.81 (3H, s), 6.88 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz).
¹⁹ F NMR (CDCl ₃ ) δ-66.4 (3F, t, J _FH = 10.9 Hz).

Example-48
In a reaction vessel, 210 mg (1.0 mmol) of 1-iodo-2,2,2-trifluoroethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, trans-1,2-bis (dimethylamino) cyclohexane 17 0.0 mg (0.10 mmol) and 3.0 mL of tetrahydrofuran were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at 0 ° C. over 2 hours. After completion of dropping, the mixture was further stirred at 0 ° C. for 1 hour. Then, saturated ammonium chloride aqueous solution: water (1: 1) was added, and diethyl ether was further added for extraction operation. Benzotrifluoride was added to the diethyl ether layer as an internal standard substance, and 4- (2,2,2-trifluoroethyl) anisole was compared with 1-iodo-2,2,2-trifluoroethane by ¹⁹ F-NMR. , 92% was confirmed.

Example-49
The same procedure as in Example 48, except that a 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at −20 ° C., followed by further stirring at −20 ° C. for 1 hour. Then, it was confirmed that 88% of 4- (2,2,2-trifluoroethyl) anisole was formed relative to 1-iodo-2,2,2-trifluoroethane.

Example-50

In a reaction vessel, 192 mg (1.0 mmol) of 1-iodo-2,2-difluoroethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, N, N, N ′, N ′, 2-pentamethyl-1,2 -Propanediamine 14.4 mg (0.10 mmol) and tetrahydrofuran 3.0mL were added, and it stirred at room temperature for 15 minutes in argon. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 2 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. Then, saturated ammonium chloride aqueous solution: water (1: 1) was added, and diethyl ether was further added for extraction operation. Benzotrifluoride was added as an internal standard substance to the diethyl ether layer, and by ¹⁹ F-NMR, 79% of 4- (2,2-difluoroethyl) anisole was formed relative to 1-iodo-2,2-trifluoroethane. Confirmed that. The diethyl ether layer was washed with saturated brine and then dehydrated with anhydrous sodium sulfate. Thereafter, the mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 4- (2,2-difluoroethyl) anisole as a colorless oily liquid (0.060 g, 35%).
¹ H NMR (CDCl ₃ ) δ 3.07 (2H, dt, J = 4.6 Hz, J _HF = 17.4 Hz), 3.80 (3H, s), 5.87 (1H, tt, J = 4. 6 Hz, J _HF = 56.7 Hz), 6.87 (2H, d, J = 8.7 Hz), 7.17 (2H, d, J = 8.7 Hz).
¹⁹ F NMR (CDCl ₃ ) δ-115.0 (2F, dt, J _FH = 56.7, 17.4 Hz).

Example-51
N, N, N ′, N ′, 2-pentamethyl-1,2-propanediamine 14.4 mg (0.10 mmol) instead of 1-[(1-methylpyrrolidin-2-yl) methyl] piperidine 18.2 mg (0.10 mmol) was used, except that a 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at 0 ° C. and then stirred at 0 ° C. for 1 hour. The same operation as in Example-50 was carried out, and ¹⁹ F-NMR confirmed that 94% of 4- (2,2-difluoroethyl) anisole was formed relative to 1-iodo-2,2-trifluoroethane. did.

Example-52

In a reaction vessel, 1-iodo-2,2,3,3-tetrafluoropropane 242 mg (1.0 mmol), cobalt (II) chloride 13.0 mg (0.10 mmol), N, N, N ′, N ′, 2 -Pentamethyl-1,2-propanediamine (14.4 mg, 0.10 mmol) and tetrahydrofuran (3.0 mL) were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 2 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. Then, saturated ammonium chloride aqueous solution: water (1: 1) was added, and diethyl ether was further added for extraction operation. Benzotrifluoride was added as an internal standard substance to the diethyl ether layer, and 4- (2,2,3,3-tetrafluoropropyl) anisole was converted to 1-iodo-2,2,3,3-tetra by ¹⁹ F-NMR. It was confirmed that 55% of fluoropropane was produced. The diethyl ether layer was washed with saturated brine and then dehydrated with anhydrous sodium sulfate. Thereafter, the mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 4- (2,2,3,3-tetrafluoropropyl) anisole as a colorless oily liquid (0.069 g, 31%).
¹ H NMR (CDCl ₃ ) δ 3.22 (2H, t, J _HF = 17.9 Hz), 3.81 (3H, s), 5.68 (1 H, tt, J _HF = 3.4, 53.7 Hz) ), 6.88 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz).
¹⁹ F NMR (CDCl ₃ ) δ-115.9 (2F, dt, J _FH = 3.4, 17.9 Hz), -136.5 (2F, d, J _FH = 53.7 Hz).

Example-53
N, N, N ′, N ′, 2-pentamethyl-1,2-propanediamine 14.4 mg (0.10 mmol) instead of trans-1,2-bis (dimethylamino) cyclohexane 17.0 mg (0.10 mmol) ), A 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at 0 ° C., and the mixture was further stirred at 0 ° C. for 1 hour. The same operation was performed, and ¹⁹ F-NMR produced 96% of 4- (2,2,3,3-tetrafluoropropyl) anisole with respect to 1-iodo-2,2,3,3-tetrafluoropropane. Confirmed that.

Example-54

In a reaction vessel, 1-iodo-2,2,3,3,3-pentafluoropropane 260 mg (1.0 mmol), cobalt (II) chloride 13.0 mg (0.10 mmol), N, N, N ′, N ′ , 2-pentamethyl-1,2-propanediamine (14.4 mg, 0.10 mmol) and tetrahydrofuran (3.0 mL) were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 2 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. Then, saturated ammonium chloride aqueous solution: water (1: 1) was added, and diethyl ether was further added for extraction operation. Benzotrifluoride was added as an internal standard substance to the diethyl ether layer, and 4- (2,2,3,3,3-pentafluoropropyl) anisole was converted to 1-iodo-2,2,3,3 by ¹⁹ F-NMR. , 3-pentafluoropropane was confirmed to be 31% produced. The diethyl ether layer was washed with saturated brine and then dehydrated with anhydrous sodium sulfate. Thereafter, the mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 4- (2,2,3,3-tetrafluoropropyl) anisole as a colorless oily liquid (0.0269 g, 11%).
¹ H NMR (CDCl ₃ ) δ 3.26 (2H, t, J _HF = 18.3 Hz), 3.81 (3H, s), 6.89 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz).
¹⁹ F NMR (CDCl ₃ ) δ-84.6 (3F, s), -117.2 (2F, t, J _FH = 18.3 Hz).

Example-55
N, N, N ′, N ′, 2-pentamethyl-1,2-propanediamine 14.4 mg (0.10 mmol) instead of trans-1,2-bis (dimethylamino) cyclohexane 17.0 mg (0.10 mmol) Example 4-54, except that a 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at 0 ° C. and then stirred at 0 ° C. for 1 hour. The same operation was performed, and ^{19 (} F) NMR showed that 4- (2,2,3,3,3-pentafluoropropyl) anisole was 1-iodo-2,2,3,3,3-pentafluoropropane, It was confirmed that 75% was produced.

Example-56

In a reaction vessel, 1-iodo-2,2,2-trifluoroethane 210 mg (1.0 mmol), cobalt (II) chloride 13.0 mg (0.10 mmol), N, N, N ′, N ′, 2-pentamethyl -1,2-Propanediamine (14.4 mg, 0.10 mmol) and tetrahydrofuran (3.0 mL) were added, and the mixture was stirred in argon at room temperature for 15 minutes. A 0.58 mol / L tetrahydrofuran solution (2.6 mL) of [4- (N, N-dimethylaminophenyl)] magnesium bromide in (4-methoxyphenyl) magnesium bromide was added to the resulting mixture at room temperature for 2 hours. It was dripped over. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. Then, saturated ammonium chloride aqueous solution: water (1: 1) was added, and diethyl ether was further added for extraction operation. Benzotrifluoride was added as an internal standard substance to the diethyl ether layer, and 4- (2,2,2-trifluoroethyl) -N, N-dimethylaniline was converted to 1-iodo-2,2,2 by ¹⁹ F-NMR. -It confirmed that 41% was produced | generated with respect to the trifluoroethane. The diethyl ether layer was washed with saturated brine and then dehydrated with anhydrous sodium sulfate. Thereafter, the mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 4- (2,2,2-trifluoroethyl) -N, N-dimethylaniline as a colorless oily liquid (0.059 g, 29%). .
¹ H NMR (CDCl ₃ ) δ 2.95 (6H, s), 3.25 (2H, q, J _HF = 10.9 Hz), 6.70 (2H, d, J = 8.7 Hz), 7.15 (2H, d, J = 8.7 Hz).
¹⁹ F NMR (CDCl ₃ ) δ-66.5 (3F, t, J _FH = 10.9 Hz).

Example-57
N, N, N ′, N ′, 2-pentamethyl-1,2-propanediamine 14.4 mg (0.10 mmol) instead of trans-1,2-bis (dimethylamino) cyclohexane 17.0 mg (0.10 mmol) ), A 0.58 mol / L tetrahydrofuran solution (2.6 mL) of [4- (N, N-dimethylaminophenyl)] magnesium bromide was added dropwise at 0 ° C., and the mixture was further stirred at 0 ° C. for 1 hour. Was the same as in Example-56, and ¹⁹ F-NMR showed that 4- (2,2,2-trifluoroethyl) -N, N-dimethylaniline was converted to 1-iodo-2,2,2-trimethyl. It was confirmed that 86% of the fluoroethane was produced.

Example-58

In a reaction vessel, 210 mg (1.0 mmol) of 1-iodo-2,2,2-trifluoroethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, trans-1,2-bis (dimethylamino) cyclohexane 17 0.0 mg (0.10 mmol) and 3.0 mL of tetrahydrofuran were added, and the mixture was stirred in argon at room temperature for 15 minutes. The obtained mixture was cooled to 0 ° C., and a 1.07 mol / L tetrahydrofuran solution (1.4 mL) of phenylmagnesium bromide was added dropwise at 0 ° C. over 2 hours. After completion of dropping, the mixture was further stirred at 0 ° C. for 1 hour. Then, saturated ammonium chloride aqueous solution: water (1: 1) was added, and diethyl ether was further added for extraction operation. Benzotrifluoride was added as an internal standard substance to the diethyl ether layer, and (2,2,2-trifluoroethyl) benzene was compared with 1-iodo-2,2,2-trifluoroethane by ¹⁹ F-NMR. % Production was confirmed. The diethyl ether layer was washed with saturated brine and then dehydrated with anhydrous sodium sulfate. Thereafter, the mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain (2,2,2-trifluoroethyl) benzene as a colorless oily liquid (0.040 g, 25%).
_{^{1 H NMR (CDCl 3) δ3.37}} (2H, q, J HF = 10.8Hz), 7.27-7.40 (5H, m).
¹⁹ F NMR (CDCl ₃ ) δ-65.9 (3F, t, J _FH = 10.8 Hz).

Example-59

Example -58 except that the 1.07 mol / L tetrahydrofuran solution (1.4 mL) of phenylmagnesium bromide was replaced with a 0.96 mol / L tetrahydrofuran solution (1.6 mL) of (p-tolyl) magnesium bromide. The same operation was performed, and ¹⁹ F-NMR analysis showed that 75% of (2,2,2-trifluoroethyl) -4-methylbenzene was produced relative to 1-iodo-2,2,2-trifluoroethane. I confirmed. Furthermore, the isolation operation similar to Example-58 was performed, and (2,2,2-trifluoroethyl) -4-methylbenzene was obtained as a colorless oily liquid (0.052 g, 30%).
_{^{1 H NMR (CDCl 3) δ2.35}} (3H, s), 3.32 (2H, q, J HF = 10.9Hz), 7.14-7.21 (4H, m).
¹⁹ F NMR (CDCl ₃ ) δ-66.1 (3F, t, J _FH = 10.9 Hz).

Example-60

Example-58, except that a 1.07 mol / L tetrahydrofuran solution (1.4 mL) of phenylmagnesium bromide was replaced with a 0.91 mol / L tetrahydrofuran solution (1.65 mL) of (4-fluorophenyl) magnesium bromide. In the ¹⁹ F-NMR analysis, 77% of (2,2,2-trifluoroethyl) -4-fluorobenzene was produced with respect to 1-iodo-2,2,2-trifluoroethane. Confirmed that. Furthermore, the isolation operation similar to Example-58 was performed, and (2,2,2-trifluoroethyl) -4-fluorobenzene was obtained as a colorless oily liquid (0.057 g, 32%).
_{^{1 H NMR (CDCl 3) δ3.34}} (2H, q, J HF = 10.7Hz), 7.01-7.09 (2H, m), 7.23-7.30 (2H, m).
¹⁹ F NMR (CDCl ₃ ) δ-66.3 (3F, t, J _FH = 10.7 Hz), −114.0 to −114.2 (1F, m).

Example-61

Example-58, except that a 1.07 mol / L tetrahydrofuran solution (1.4 mL) of phenylmagnesium bromide was replaced with a 1.12 mol / L tetrahydrofuran solution (1.3 mL) of (3-methoxyphenyl) magnesium bromide. , And ¹⁹ F-NMR analysis revealed that 71% of 3- (2,2,2-trifluoroethyl) anisole was produced relative to 1-iodo-2,2,2-trifluoroethane. It was confirmed. Furthermore, the isolation operation similar to Example-58 was performed, and 3- (2,2,2-trifluoroethyl) anisole was obtained as a colorless oily liquid (0.078 g, 41%).
¹ H NMR (CDCl ₃ ) δ 3.34 (2H, q, J _HF = 10.8 Hz), 3.81 (3H, s), 6.82-6.85 (1H, m), 6.86-6 .90 (2H, m), 7.24-7.30 (1H, m).
¹⁹ F NMR (CDCl ₃ ) δ-65.7 (3F, t, J _FH = 10.8 Hz).

Example-62

In a reaction vessel, a 1.6 mol / L tetrahydrofuran solution (0.63 mL) of 1-chloro-2,2,2-trifluoroethane, 13.0 mg (0.10 mmol) of cobalt (II) chloride, trans-1,2- Bis (dimethylamino) cyclohexane (17.0 mg, 0.10 mmol) and tetrahydrofuran (2.4 mL) were added, and the mixture was stirred in argon at room temperature for 15 minutes. To the obtained mixture, a 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added dropwise at room temperature over 2 hours. After completion of dropping, the mixture was further stirred at room temperature for 1 hour. Then, saturated ammonium chloride aqueous solution: water (1: 1) was added, and diethyl ether was further added for extraction operation. Benzotrifluoride was added to the diethyl ether layer as an internal standard substance, and 4- (2,2,2-trifluoroethyl) anisole was compared with 1-chloro-2,2,2-trifluoroethane by ¹⁹ F-NMR. , 91% was confirmed to be produced.

Example-63

A 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was added to a 0.58 mol / L tetrahydrofuran solution (2.N) of (4- (N, N-dimethylaminophenyl)) magnesium bromide. 6-mL) except that 4- (2,2,2-trifluoroethyl) -N, N-dimethylaniline was converted to 1-chloro- by ¹⁹ F-NMR analysis. It was confirmed that 78% of 2,2,2-trifluoroethane was produced.

Example-64

The same operation as Example -62 was carried out, except that the 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was replaced with a 1.07 mol / L tetrahydrofuran solution (1.4 mL). , ¹⁹ F-NMR analysis confirmed that 83% of (2,2,2-trifluoroethyl) benzene was produced relative to 1-chloro-2,2,2-trifluoroethane.

Example-65

Except that the 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was replaced with a 0.96 mol / L tetrahydrofuran solution (1.6 mL) of (p-tolyl) magnesium bromide, The same operation as in Example-62 was performed, and (2,2,2-trifluoroethyl) -4-methylbenzene was compared with 1-chloro-2,2,2-trifluoroethane by ¹⁹ F-NMR analysis. It was confirmed that 69% was produced.

Example-66

A 0.36 mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide was replaced with a 0.91 mol / L tetrahydrofuran solution (1.65 mL) of (4-fluorophenyl) magnesium bromide. The same operation as in Example-62 was performed, and (2,2,2-trifluoroethyl) -4-fluorobenzene was compared with 1-chloro-2,2,2-trifluoroethane by ¹⁹ F-NMR analysis. , 71% was confirmed.

Example-67

Except for changing the 0.36-mol / L tetrahydrofuran solution (4.2 mL) of (4-methoxyphenyl) magnesium bromide to the 1.12 mol / L tetrahydrofuran solution (1.3 mL) of (3-methoxyphenyl) magnesium, The same operation as in Example-62 was conducted, and ¹⁹ F-NMR analysis showed that 3- (2,2,2-trifluoroethyl) anisole was 65% of 1-chloro-2,2,2-trifluoroethane. It was confirmed that it was generated.

Claims (7)

Cobalt compounds and general formula (1)

(Wherein R ¹ , R ² , R ³ and R ⁴ each independently represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a phenyl group. R ⁵ , R ⁶ , R ⁷ and R ⁸ are each Independently, it represents an alkyl group having 1 to 8 carbon atoms, and R ² and R ³ together represent a tetramethylene-1,4-diyl group or 9,10-dihydro-9,10-ethanoanthracene-11, R ¹ and R ⁵ may be combined to form a trimethylene-1,3-diyl group or a tetramethylene-1,4-diyl group, and R ⁵ and R ⁶ may be a 12-diyl group. May be combined to form a tetramethylene-1,4-diyl group or a benzo [b] butane-1,4-diyl group, and R ⁷ and R ⁸ are combined to form tetramethylene-1, 4-diyl group or benzo [b] butane-1,4-diyl May become .R ⁵ and R ⁸ are bonded may .R ⁶ and R ⁷ may become an ethylene group and is bonded to the ethylene diamine derivative represented by may be a ethylene group.) In the presence of general formula (2)

(Wherein R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are each independently substituted with a hydrogen atom or a C 1-4 alkyl group optionally substituted with a halogen atom, or a halogen atom. C2-C4 alkenyl group, C1-C6 alkoxy group, (C1-C4 alkoxy) carbonyl group, C2-C5 acyl group, C2-C5 acyloxy A group, a halogen atom, a cyano group, or a phenyl group, R ¹¹ and R ¹² may be combined with a carbon atom to form a benzene ring, and R ¹² and R ¹³ may be A benzene ring may be formed together, M represents a magnesium atom or a zinc atom, X represents a chlorine atom, a bromine atom or an iodine atom.) And a general formula (3 )

(Wherein Y represents a chlorine atom, a bromine atom or an iodine atom, Rf represents a fluoroalkyl group having 2 or 3 carbon atoms), and a (fluoroalkyl) halide represented by General formula (4)

(Wherein R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and Rf have the same contents as described above). The production method according to claim 1, wherein Rf of (fluoroalkyl) halide (3) is a 1,1-difluoroethyl group. The ethylenediamine derivative (1) is N, N, N ′, N ′, 2-pentamethyl-1,2-propanediamine, 1,2-bis (dimethylamino) cyclohexane or 1-[(1-methylpyrrolidine-2- Yl) methyl] piperidine. The production method according to claim 1 or 2. The production method according to any one of claims 1 to 3, wherein X of the aryl metal species (2) is a chlorine atom or a bromine atom. The production method according to any one of claims 1 to 4, wherein the cobalt compound is cobalt (II) chloride, cobalt (II) bromide or cobalt (II) iodide. General formula (5)

(Wherein R ²¹ and R ²² each independently represents an alkyl group having 1 to 4 carbon atoms, m represents an integer of 1 to 3), and the reaction is carried out in the presence of a polyether represented by The manufacturing method according to claim 1, wherein: The production method according to claim 6, wherein R ²¹ and R ²² are methyl groups.