JPH0680616A - Production of 3,3-difluoro-2-propenamide derivative - Google Patents

Abstract

(57) [Summary] [Purpose] It is useful as a synthetic raw material for medicines and agricultural chemicals.
Provided is a novel method for producing a difluoro-2-propenamide derivative in a high yield by a simple operation. [Structure] A monovalent copper salt is added to a solution of 1-R ¹ -2,2-difluorovinylborane in an aprotic polar solvent, and then an isocyanate represented by R ² -NCO is reacted. The following formula (I): A method for producing a 3,3-difluoro-2-propenamide derivative represented by:

Description

Detailed Description of the Invention

[0001]

The present invention relates to 3,3-difluoro-
The present invention relates to a novel method for producing a 2-propenamide derivative.

[0002]

2. Description of the Related Art Fluorine-containing organic compounds, which show unique properties not found in other compounds, have recently attracted attention in various fields ranging from pharmaceuticals and agrochemicals to functional materials. Therefore, the development of a method for efficiently introducing the fluorine-containing carbon unit into the molecular structure is currently an important issue in synthetic chemistry. Among them, gem-difluoroolefins have a carbon-carbon double bond active for nucleophilic reaction and radical reaction, and can be a useful building block when synthesizing various fluorine-containing organic compounds and fluoropolymers. Therefore, establishment of a general synthetic method thereof is strongly desired.

Further, as conventional gem-difluorovinylamides, 3,3-difluoro-2-propenamide derivative N, N-diethyl-3,3-difluoro-2- has been used.
A method of synthesizing methyl-2-propenamide by a photochemical reaction of an inamine and a perhaloalkane is known [Tetrahedron Lett. , 22 , 340
5 (1981)].

[0004]

However, the above-mentioned method based on the photochemical reaction of an inamine and a perhaloalkane has many problems such as a low yield and the need to prepare an appropriately substituted inamine as a starting material. Yes, ge
The development of a useful synthetic method for m-difluorovinylamides has been an issue.

Therefore, the present invention provides 3,3-difluoro-2.
-An object of the present invention is to provide a novel production method by which a propene amide derivative can be obtained in a high yield by a simple operation.

[0006]

The present inventors can easily introduce various substituents derived from tri-substituted borane 1-
The present invention has been completed by finding that the above object can be achieved by a method for producing a 3,3-difluoro-2-propenamide derivative from a substituted-2,2-difluorovinylborane and an isocyanate.

That is, the present invention provides 1-R ^{1-2, 2} -difluorovinylborane (wherein R ¹ is a C ₁ -C ₁₀ alkyl group or alkenyl group, or an aryl group, a cycloalkyl group or a cycloalkenyl group). After adding a monovalent copper salt to the aprotic polar solvent solution of (shown), R ² —NCO (wherein R ² is an alkylbenzenesulfonyl group, a C ₁ -C ₁₀ alkyl or alkenyl group, or an aryl group). , Which represents a cycloalkyl group or a cycloalkenyl group) is reacted with an isocyanate represented by the following formula (I):

[0008]

[Chemical 2] Is a method for producing a 3,3-difluoro-2-propenamide derivative represented by: 3,3-difluoro-of the present invention
^1-R 1-2,2-difluoro-vinyl borane First a starting material in the production method of 2-propenamide derivative known methods [Ichikawa, other Tetrahedron L
ett. , 30 , 1641 (1989), etc.]. For example, 2,2,2-trifluoroethyl p in tetrahydrofuran (THF) solvent
-Toluenesulfonate is added, the temperature is cooled to about -78 ° C, and a hexane solution of butyllithium is added dropwise to this and stirred. Then, T of tri-substituted borane [(R ¹ ) ₃ B]
It can be obtained by adding an HF solution and reacting at a temperature of about −78 ° C. to room temperature. Examples of the tri-substituted borane [(R ¹ ) ₃ B] used in this case include an alkyl group or an alkenyl group in which R ¹ is C _{1 to} C ₁₀ , an aryl group, a cycloalkyl group or a cycloalkenyl group (these groups are alkyl groups). , Aryl and / or cycloalkyl groups) may be included. Therefore, the ^1-R 1-2,2-difluoro-vinyl boranes R ¹
The group is derived from tri-substituted borane [(R ¹ ) ₃ B] to give various R ¹ -substituted compounds. For example, dibutyl (1-butyl-2,2-difluorovinyl) borane can be obtained from tributylborane.

Therefore, 1-R ¹ -obtained as described above
An aprotic polar solvent is added to 2,2-difluorovinylborane, a monovalent copper salt is added thereto, and the mixture is stirred at a temperature of about 0 ° C. or lower within about 1 hour, preferably within 30 minutes. Then, an isocyanate (R ² —NCO) is added and the reaction is carried out at room temperature for about 1 hour or less, preferably 30 minutes or less.
2-as a difluoro-2-propenamide derivative
Can be obtained R ¹ -N-R ² -3,3- difluoro-2-propenamide. At this time, for example, dibutyl (1
When 2-butyl-2,2-difluorovinyl) borane and p-toluenesulfonyl isocyanate are used, 2-butyl-3,3-difluoro-N-tosyl-2-propenamide is obtained.

Examples of the aprotic polar solvent used in the above-mentioned production method of the present invention include hexamethylphosphoric triamide (HMPA), dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile and the like. Further, as the monovalent copper salt, CuC
1, CuBr, CuI, CuCN and the like and their complexes are used.

The amount of monovalent copper salt used is 1-R ^1-2, 2-
The amount is usually about twice the molar amount of difluorovinylborane, and the amount of the aprotic polar solvent used is appropriately 6 to 15 times the molar amount.

Next, as the isocyanate (R ² —NCO), for example, R ² is an alkylbenzenesulfonyl group,
C ₁ -C alkyl or alkenyl group having ₁₀ or an aryl group, and various isocyanate is a cycloalkyl group or cycloalkenyl group can be used. 1-R
^The ratio of 1-2,2-difluorovinylborane to isocyanate is usually 1: 0.2 to 1: 5, preferably 1: 0.5 to 1.5. When the amount of the isocyanate (R ² —NCO) used exceeds 5 times the molar amount of 1-R ¹ -2,2-difluorovinylborane, it is produced by reacting with 1 molecule of the isocyanate. The compound of formula I was further reacted with isocyanate,
If the amount is less than 2 times the molar amount, the yield is lowered, which is not preferable.

Further, the compound of the formula I of the present invention is prepared by adding a phosphate buffer to the product solution after the reaction to adjust the pH to 6 to 8 and adding hydrogen peroxide and stirring, and then adding a solvent such as ethyl acetate. And can be separated and purified.

Further, in the method for producing the compound of formula I according to the present invention, trifluoromethanesulfonyl isocyanate (CF ₃ SO 4) is used as the isocyanate (R ² —NCO).
_2- NCO), the following formula (I
I): A compound represented by CF ₂ ═C (R ¹ ) CONH ₂ is obtained. This is a compound of formula I CF ₂ ═C (R ¹ ) C
It is considered that after the ONH-SO ₂ CF ₃ is once formed, the trifluoromethanesulfonyl group is immediately eliminated due to the instability of this compound to form the compound of the formula II.

[0015]

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited thereto.

[0016]

Example 1 Preparation of 2-Butyl-3,3-difluoro-N-tosyl-2-propenamide THF2.
Put 4 ml and 127 mg (0.500 mmol) of 2,2,2-trifluoroethyl p-toluenesulfonate, cool to -78 ° C, and add 0.66 ml of butyllithium.
(1.05 mmol, 1.59 M / hexane solution) was added dropwise over about 10 minutes. After stirring for 30 minutes, 0.55 ml of tributylborane (0.550 mmol, 1.0 M / THF)
Solution) was added, and the mixture was stirred at −78 ° C. for 1 hour and further stirred at room temperature for 3 hours to cause a reaction to obtain a solution of 1-butyl-2,2-difluorovinylborane. The solution is then cooled to 0 ° C,
HMPA 0.6 ml and cuprous iodide 190 mg (1.0
0 mmol) was added and stirred for 30 minutes. Then p at room temperature
-Toluenesulfonyl isocyanate 76 μl (0.5
(00 mmol) was added and stirred for 30 minutes. Phosphate buffer (pH 6.86) was added to the reaction solution, 0.70 ml of 30% hydrogen peroxide solution was added at 0 ° C., and the mixture was stirred at room temperature for 15 minutes, the organic matter was extracted with ethyl acetate, and the organic layer was sulfuric acid. Dry with sodium. After evaporation of the solvent, silica gel column chromatography (developing solvent hexane: ethyl acetate = 1: 1)
A colorless liquid was isolated according to 1). The yield is 105 mg
(0.331 mmol), the yield was 66%. This product was analyzed by NMR, IR, MS and HRMS.
It was identified as 2-butyl-3,3-difluoro-N-tosyl-2-propenamide as follows.

FT-59.8 MHz ¹ H-NMR (T
MS / CDCl ₃ -CCl ₄ ): δ / ppm 0.85 (3H, m), 1.02-1.56 (4H,
m), 1.86-2.38 (2H, m), 2.45 (3)
H, s), 7.32 (2H, dm, J = 8.5 Hz),
7.96 (2H, dm, J = 8.5Hz), 8.10-
8.70 (1H, s) FT-93.7MHz ¹⁹ F-NMR (C ₆ F ₆ / CD
Cl ₃ -CCl ₄ ): δ / ppm 85.2 (1F, d, J = 22 Hz), 89.6 (1
F, d, J = 22 Hz) FT-67.5 MHz ¹³ C-NMR (TMS / CDC
l ₃ ): δ / ppm 13.6, 21.7, 22.1, 23.9, 30.3
(T, J _CF = 2 Hz), 91.0 (dd, J _CF = 21H
z, 7 Hz), 128.7, 129.6, 135.3,
145.3, 158.6 (t, J _CF = 300 Hz), 1
61.0 (dd, J _CF = 12 Hz, 6 Hz) IR (neat / NaCl): cm ⁻¹ 3230, 2950, 2860, 1710, 1600,
1440, 1350, 1165, 1090, 1020,
870, 810, 705, 665 MS (70 eV) m / Z (relative intensity) 317 (M
⁺ : 1), 253 (36), 155 (24), 108
(100), 91 (47) HRMS measured value m / Z 317.0881 calculated value: C ₁₄ H ₁₇ NO ₃ SF ₂ 317.0896

[0018]

Example 2 3,3-Difluoro-2- (4-phenylbutyl) -N
-Preparation of Tosyl-2-propenamide THF3.
5 ml and 191 mg (0.75 mmol) of 2,2,2-trifluoroethyl p-toluenesulfonate were added, cooled to -78 ° C, and 0.98 ml of butyllithium.
(1.58 mmol, 1.61 M / hexane solution) was added dropwise over about 10 minutes and stirred for 30 minutes (referred to as solution A). In a separate 10 ml two-necked eggplant flask, 327 mg (2.48 mmol) of 4-phenyl-1-butene in a THF solution (2
ml), and borane-THF complex (BH ₃ · T
HF) 0.83 ml (0.83 mmol, 1.0 M / T)
HF solution) was added dropwise at 0 ° C. and stirred at room temperature for 1 hour, and tris (4-phenylbutyl) borane (0.83 mmol,
THF solution), which was further added to the above solution A-7
The mixture was stirred at 8 ° C. for 1 hour and further at room temperature for 3 hours to react with each other to obtain a solution of 2,2-difluoro-1- (4-phenylbutyl) -vinylborane. The solution is cooled to 0 ° C., H
MPA 1.7 ml and cuprous iodide 286 mg (1.50
(mmol) and stirred for 30 minutes. Then at room temperature p-
Toluenesulfonyl isocyanate 148 mg (0.7
5 mmol) in THF (0.7 ml) and added 30
Stir for minutes. Phosphate buffer solution (pH 6.86) in the reaction solution
Was added, 0.75 ml of 30% hydrogen peroxide solution was added at 0 ° C., and the mixture was stirred at room temperature for 15 minutes, the organic matter was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After evaporation of the solvent, a colorless liquid was isolated by silica gel column chromatography (developing solvent: hexane: ethyl acetate = 3: 1). The yield was 124 mg (0.315 mmol), and the yield was 42%.

[0019]

Example 3 Preparation of 2-Butyl-3,3-difluoro-N-tosyl-2-propenamide THF2.
4 ml and 125 mg (0.49 mmol) of 2,2,2-trifluoroethyl p-toluenesulfonate were added, cooled to -78 ° C, and 0.63 ml of butyl lithium.
(1.03 mmol, 1.64 M / hexane solution) was added dropwise over about 10 minutes. After stirring for 30 minutes, 0.54 ml of tributylborane (0.54 mmol, 1.0 M / THF solution) was added, and the mixture was stirred at -78 ° C for 1 hour and further stirred at room temperature for 3 hours to react them with 1-butyl-2,2-difluorovinyl. A solution of borane was obtained. The solution is then cooled to 0 ° C. and H 2
MPA (0.6 ml) and cuprous bromide dimethyl sulfide complex (202 mg, 0.98 mmol) were added, and the mixture was stirred for 30 minutes. Then, at room temperature, a solution of 97 mg (0.49 mmol) of p-toluenesulfonyl isocyanate in THF (0.
5 ml) was added and stirred for 30 minutes. Phosphate buffer (pH 6.86) was added to the reaction solution, 0.20 ml of 30% hydrogen peroxide solution was added at 0 ° C., and the mixture was stirred at room temperature for 15 minutes, the organic matter was extracted with ethyl acetate, and the organic layer was sulfuric acid. Dry with sodium. After the solvent was distilled off, a colorless liquid was isolated by silica gel column chromatography (developing solvent: hexane: ethyl acetate = 1: 1). The yield was 92 mg (0.29
mmol) and the yield was 59%.

[0020]

Example 4 Preparation of 2-Butyl-3,3-difluoro-N-tosyl-2-propenamide THF2.
4 ml and 127 mg (0.50 mmol) of 2,2,2-trifluoroethyl p-toluenesulfonate were added, cooled to −78 ° C., and 0.69 ml of butyllithium
(1.05 mmol, 1.53 M / hexane solution) was added dropwise over about 10 minutes. After stirring for 30 minutes, 0.55 ml (0.55 mmol, 1.0M / THF solution) of tributylborane was added, and the mixture was stirred at -78 ° C for 1 hour and further stirred at room temperature for 3 hours to cause reaction, and 1-butyl-2,2-difluorovinyl was added. A solution of borane was obtained. The solution is then cooled to 0 ° C. and H 2
MPA 0.6 ml and cuprous iodide 190 mg (1.00
(mmol) and stirred for 30 minutes. Then at room temperature p-
90 μl of toluenesulfonyl isocyanate (0.59
(mmol) and then stirred at room temperature for 30 minutes. Add phosphate buffer (pH 6.86) to the reaction solution,
After adding 0.35 ml of 0% hydrogen peroxide solution,
The mixture was stirred for 1 minute, the organic matter was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After the solvent was distilled off, a colorless liquid was isolated by silica gel column chromatography (developing solvent: hexane: ethyl acetate = 1: 1). The yield is 97
mg (0.31 mmol), the yield was 61%.

[0021]

Example 5 Preparation of 2-Butyl-3,3-difluoro-N-tosyl-2-propenamide THF2.
Put 4 ml and 127 mg (0.50 mmol) of 2,2,2-trifluoroethyl p-toluenesulfonate, cool to -78 ° C, and add 0.66 ml of butyllithium.
(1.05 mmol, 1.59 M / hexane solution) was added dropwise over about 10 minutes. After stirring for 30 minutes, 0.55 ml (0.55 mmol, 1.0M / THF solution) of tributylborane was added, and the mixture was stirred at -78 ° C for 1 hour and further stirred at room temperature for 3 hours to cause reaction, and 1-butyl-2,2-difluorovinyl was added. A solution of borane was obtained. Next, 0.6 ml of HMPA and 83 μl of p-toluenesulfonyl isocyanate (0.55 m
mol), and 190 mg of cuprous iodide (1.00 m
(mol) was added rapidly in this order and stirred for 45 minutes. Phosphate buffer (pH 6.86) was added to the reaction solution, and 0.70 ml of 30% hydrogen peroxide solution was added at 0 ° C., and then 1 at room temperature.
The mixture was stirred for 5 minutes, the organic matter was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After the solvent was distilled off, a colorless liquid was isolated by silica gel column chromatography (developing solvent: hexane: ethyl acetate = 1: 1). The yield is 5
The yield was 9 mg (0.186 mmol) and 37%.

[0022]

According to the novel manufacturing method of the present invention, 3,3-
The difluoro-2-propenamide derivative can be obtained in high yield and by a simple one-pot operation. In addition, the compound is useful as a raw material for synthetic chemicals such as medicines and agricultural chemicals as a kind of gem-difluoroolefins.

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[Procedure amendment]

[Submission date] October 1, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0014

[Correction method] Delete

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07C 233/08 7106-4H 233/10 7106-4H 317/14 7419-4H // C07B 61/00 300 (72) Inventor Minami Minami 11-15-5 Jiyugaoka, Munakata City, Fukuoka Prefecture

Claims (1)

[Claims] 1. R ¹ -2,2-difluorovinylborane (wherein R ¹ represents a C ₁ -C ₁₀ alkyl group or alkenyl group, or an aryl group, a cycloalkyl group or a cycloalkenyl group) After adding a monovalent copper salt to the aprotic polar solvent solution, R ² -NCO was added.
(However, R ² is an alkylbenzenesulfonyl group, C ₁
To C ₁₀ alkyl group or alkenyl group, or an aryl group, a cycloalkyl group or a cycloalkenyl group), represented by the following formula (I): A method for producing a 3,3-difluoro-2-propenamide derivative represented by: