JPS6316379B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing trifluoromethylbenzene derivatives, and more particularly, the present invention relates to a method for producing trifluoromethylbenzene derivatives, which comprises reacting trifluoromethylhalogenobenzene with copper cyanide in a specific solvent in the presence of copper bromide or copper iodide. Concerning a method for producing benzonitrile. In recent years, there has been a great deal of interest in the synthesis of physiologically active fluorine-containing organic compounds. This is because the introduction of a small number of fluorine atoms into a molecule often produces strong and selective physiological effects, and it has attracted particular attention in the fields of agrochemical and pharmaceutical synthesis. However, the reality is that the number of commercially available fluorine-containing compounds useful as synthetic blocks is extremely limited. By the way, aromatic halogen compounds have significantly lower reactivity than aliphatic halogen compounds, and do not undergo the usual S _N Ar type nucleophilic substitution reaction unless activated with an appropriate electron-withdrawing group. The trifluoromethyl group is known to act as an electron-withdrawing group exhibiting -I and -E effects due to the electronegativity of the fluorine atom and the contribution of negative hyperconjugation, but it is not susceptible to nucleophilic attack. The degree of activation of aromatic rings is relatively small. Therefore, when trying to introduce a cyano group into trifluoromethylhalogenobenzene, even if an alkali cyanide is used directly, the reaction is more likely to occur on the trifluoromethyl side chain than on the aromatic ring. , it is difficult to obtain benzonitrile derivatives as expected. The Rosenmund-von Braun reaction is well known as a method for obtaining a corresponding nitrile from an aromatic halogen compound. This reaction involves heating an aromatic bromine compound and copper cyanide to a high temperature of 250 to 260°C to replace the bromine atom with a cyano group.
However, since it requires extreme reaction conditions, it has the disadvantage of being accompanied by side reactions. Recently, a method of reacting in the presence of a palladium salt or a palladium-phosphine complex has been proposed, but this method is not suitable for industrial production. The present inventors have conducted extensive research to develop a simple and efficient method for obtaining the corresponding nitrile from trifluoromethylhalogenobenzene and its derivatives, and which does not involve side reactions. The inventors have discovered that a cyano group can be efficiently introduced into an aromatic ring by reacting copper cyanide with copper bromide or copper iodide in a specific solvent, and have completed the present invention. That is, the gist of the present invention is that the formula: [In the formula, X represents a halogen, and Y represents hydrogen, a lower alkoxy group, or a nitro group. ] Trifluoromethylhalogenobenzene shown by is reacted with copper cyanide to form the formula: [In the formula, Y has the same meaning as above. ] A method for producing a trifluoromethylbenzene derivative, characterized by obtaining trifluoromethylbenzonitrile represented by the following. Examples of trifluoromethylhalogenobenzenes () used as starting materials in the present invention include o-chlorobenzotrifluoride, m-chloro-benzotrifluoride, p-chlorobenzotrifluoride, o-, p- or m- Bromobenzotrifluoride, o-, p- or m-iodobenzotrifluoride, 2-chloro-5-nitrobenzotrifluoride, 2-nitro-5-chlorobenzotrifluoride, 3-nitro-4-chlorobenzotrifluoride , 2-nitro-5-bromobenzotrifluoride, 3-methoxy-4-chlorobenzotrifluoride, and the like. The proportion of copper cyanide used is at least 1 mol, preferably at least 2 mol, for example 2 mol, per 1 mol of trifluoromethylhalogenobenzene ().
~3 moles. It is also possible to use alkali cyanides, such as potassium or sodium cyanide, in combination with copper cyanide. Copper bromide or copper iodide is 0.1 to 5 times the molar amount of trifluoromethylhalogenobenzene (),
Preferably 0.5 to 2 times the mole, more preferably 0.8 to 2 times the mole
Used at 1.2 times the mole. As the solvent, aprotic polar solvents such as hexamethylphosphoric acid triamide (hereinafter referred to as HMPA) and N-methylpyrrolidone are used. When using a starting material that has a halogen atom at a position where a strong electron-withdrawing group represented by a nitro group and the electron effect of a trifluoromethyl group act synergistically, N-methylpyrrolidone is used as a solvent rather than HMPA. may be desirable. The reaction is usually carried out at normal pressure and at a temperature of 100 to 250°C, preferably 150 to 200°C, particularly 190 to 200°C. The reaction time is generally 1 to 10 hours. By hydrolyzing trifluoromethylbenzonitrile () obtained in this way,
It can be converted into benzoic acid and its derivatives or phthalic acid and its derivatives. Hydrolysis can be carried out by either acid or base hydrolysis. Hydrolysis with dilute or weak acids produces benzoic acid and its derivatives, although the reaction rate is very slow. On the other hand, when hydrolysis is performed with a strong acid, not only the cyano group but also the trifluoromethyl group is hydrolyzed to produce phthalic acid and its derivatives. When hydrolyzed with a base, the corresponding monocarboxylic acid is usually produced, but o-trifluoromethylbenzonitrile produces the corresponding acid amide, and when calcium hydroxide or barium hydroxide is used as a base, the corresponding monocarboxylic acid is produced. A mixture of amide and carboxylic acid is formed. This acid amide can be easily converted into a carboxylic acid by a nitrosation reaction. Next, examples and comparative examples will be shown to specifically explain the present invention. Example 1 3.61 g (20 mmol) of o-chlorobenzotrifluoride, 3.58 g (40 mmol) of copper cyanide and HMPA (10 ml) were charged into a flask, and then 1.91 g (10 mmol) of copper iodide was added and the mixture was stirred. was kept at 150-160 °C on an oil bath for 10 hours. The reaction mixture was subjected to gas chromatography (carrier: SE-30),
Yield of o-trifluoromethylbenzonitrile: 54
I confirmed that it was generated in %. Note that the yield was corrected using n-dodecane as an internal standard. Examples 2 to 3 and Comparative Example 1 A reaction was carried out in the same manner as in Example 1 using the amounts of each compound used, the type of copper halide, the reaction temperature, and the reaction time as shown in Table 1. The yield is the first
It was as shown in the table.

[Table] Examples 4 to 7 and Comparative Example 2 m-chlorobenzotrifluoride (m-chlorobenzotrifluoride (m
-CBTF) or p-chlorobenzotrifluoride (p-CBTF), the reaction was carried out in the same manner as in Example 1 under the conditions shown in Table 2. The yield was as shown in Table 2.

[Table] Example 8 A reaction was carried out in the same manner as in Example 4 except that N-methylpyrrolidone was used as the solvent and the reaction was carried out at reflux temperature. The yield after 9 hours was 39%. Examples 9-25 Trifluoromethylbenzonitrile (1 mmol) was added to an aqueous solution of the acid or base shown in Table 3 (1 mmol).
ml) and heated to reflux. For acid hydrolysis,
The reaction mixture was extracted with ethyl acetate, the solvent was distilled off from the extract, and the composition of the residue and the yield of carboxylic acid were determined by spectroscopy. For base hydrolysis, unreacted trifluoromethylbenzonitrile and acid amide were extracted from the reaction mixture with ethyl acetate, the aqueous phase was separated and made weakly acidic with hydrochloric acid, and the carboxylic acid to be separated was extracted with ether. . The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the remaining acid was quantified. The results are shown in Table 3.

【table】

[Table] Note 1) Trifluoromethylbenzonitrile
2) Trifluoromethylbenzoic acid Example 26 o-trifluoromethylbenzamide 178.8mg
(0.942 mmol), sodium nitrite 400 mg (5.80
mmol) and 3 ml of water were mixed and stirred, and 3 ml of concentrated sulfuric acid was added dropwise little by little while cooling on ice. Nitrogen gas was immediately observed. After the addition was complete, stirring was continued and the reaction mixture was heated to about 80° C. for about 20 minutes.
After cooling to room temperature, the precipitate was collected. The liquid was extracted with ethyl acetate, and the solvent was distilled off from the extract. The residue was combined with the precipitate obtained earlier and recrystallized from water/ethanol to obtain o-trifluoromethylbenzoic acid.
158.2mg was obtained. Melting point 109-110℃. Yield 88%. Example 27 3-nitro-4-chlorobenzotrifluoride
4.5 g (20 mmol) (boiling point 94.5°C/10 mmHg) [Journal of American Chemical Society (hereinafter referred to as JACS) 74 , 3011 (1952),
JACS, 75 , 1997 (1953) and JACS, 76 , 3936
(1954)], copper cyanide 3.58 g (40 mmol)
and HMPA (20 ml) were charged into a flask, and then 1.91 g (10 mmol) of copper iodide was added, and the mixture was kept at 150-160° C. for 15 hours in an oil solution with stirring. The reaction mixture was subjected to gas chromatography (carrier: SE-30), and it was confirmed that 2-nitro-4-trifluoromethylbenzonitrile was produced in a yield of 68%. Melting point: 47-8°C. Example 28 3-nitro-4-chlorobenzotrifluoride
4.2 g (20 mmol) of 3-methoxy-4-chlorobenzotrifluoride instead of 4.5 g (boiling point: 100
The reaction was carried out according to the procedure of Example 27, except that the reaction temperature was 1°C/38mmHg (see JACS, 73 , 3470 (1951)). The reaction mixture was subjected to gas chromatography, and it was confirmed that 2-methoxy-4-trifluoromethylbenzonitrile was produced in a yield of 60%. Melting point: 64-5°C.

Claims (1)

[Claims] 1 In the presence of copper bromide or copper iodide in at least one solvent selected from hexamethylphosphoric triamide and N-methylpyrrolidone, the formula: By reacting trifluoromethylhalogenobenzene represented by with copper cyanide, the formula: A method for producing a trifluoromethylbenzene derivative, characterized by obtaining trifluoromethylbenzonitrile represented by: [In the formula, X represents a halogen, and Y represents hydrogen, a lower alkoxy group, or a nitro group. ]. 2. The manufacturing method according to claim 1, in which copper bromide or copper iodide is used in an amount of 0.5 to 2 moles relative to trifluoromethylhalogenobenzene. 3 Reaction temperature 100-250℃, preferably 150-200℃
The manufacturing method according to any one of claims 1 to 3. 4 In the presence of copper bromide or copper iodide in at least one solvent selected from hexamethylphosphoric triamide and N-methylpyrrolidone, the formula: [In the formula, X represents a halogen. ] The formula obtained by reacting trifluoromethylhalogenobenzene with copper cyanide: A method for producing trifluoromethylbenzene monocarboxylic acid, which comprises hydrolyzing trifluoromethylbenzonitrile represented by: