JPH0212458B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () This invention relates to a method for producing a δ,ε-unsaturated ketone represented by In the above general formula (), R ¹ , R ² and R ³ are the same or different, each a hydrogen atom; methyl group, ethyl group, propyl group, butyl group, 3-methylbutyl group, pentyl group, hexyl group, heptyl group, Alkyl groups such as octyl group, 3,7-dimethyloctyl group; cyclopentyl group, cyclohexyl group,
Cycloalkyl group such as menthyl group; vinyl group,
1-propenyl group, allyl group, isopropenyl group, 2-methylallyl group, 1-butenyl group, 2-
butenyl group, prenyl group, 3-methyl-3-butenyl group, 2,3-dimethyl-2-butenyl group, 3
-Methyl-2-pentenyl group, 3-methyl-3-
Pentenyl group, 3,7-dimethyl-2-octenyl group, 3,7-dimethyl-6-octenyl group, geranyl group, neryl group, 3-ethyl-7-methyl-
It represents an alkenyl group such as a 2,6-nonadienyl group; or an aryl group such as a phenyl group, tolyl group, xylyl group, or naphthyl group. R ⁴ is a methyl group,
Ethyl group, propyl group, butyl group, 3-methylbutyl group, pentyl group, hexyl group, heptyl group,
Alkyl groups such as octyl group and 3,7-dimethyloctyl group; aryl groups such as phenyl group, tolyl group, xylyl group, and naphthyl group; or -CH=
Represents ⁷ CHR groups. Here, R ⁷ is a hydrogen atom; or a methyl group, ethyl group, propyl group, butyl group, 3
-Represents an alkyl group such as a methylbutyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, or a 3,7-dimethyloctyl group. The δ,ε-unsaturated ketone represented by the general formula () can not only be used as a fragrance itself, but also
It is also a useful compound as an intermediate in the production of fragrances, cosmetic base materials, medicines, agricultural chemicals, etc. Conventionally, δ, ε-unsaturated ketones are produced by reacting mesityl oxide with halogenated hydrocarbons in the presence of an alkaline condensing agent to produce β, γ-unsaturated ketones with α-positions substituted with hydrocarbon groups. It is produced by reacting with a vinyl Grignard reagent or ethynylation reaction followed by partial hydrogenation to obtain an allyl type alcohol, and then heating and isomerizing the allyl type alcohol (JP-A-52-1999)
(See No. 83409). This conventional method is excellent as an industrial method for producing δ,ε-unsaturated ketones because it uses cheap mesityl oxide as a raw material and is easy to operate. The δ,ε-unsaturated ketones produced by this method are limited to those having a methyl group at the δ position of the basic skeleton and one hydrocarbon group at the ε position, and are therefore diverse. It is not suitable for the production of δ, ε-unsaturated ketones. The present inventors have made intensive studies to solve the above-mentioned problems in the conventional method using mesityl oxide as a raw material. We have discovered a method for producing it, leading to the present invention. That is, according to the present invention, the general formula () [In the formula, R ₁ , R ² and R ₃ have the same meanings as in the general formula (), R ⁵ represents an alkyl group or an aryl group, and R ⁶ represents an alkyl group, an aryl group or

[Formula] represents a group. Here, R ⁷ represents a hydrogen atom or an alkyl group, and R ₈ represents an alkyl group or an aryl group. ) The δ,ε-unsaturated ketone represented by the general formula () can be produced by oxidizing the sulfur-containing homoallylic alcohol represented by the formula () to the corresponding sulfoxide, and then reacting the sulfoxide under heating. . In addition, the sulfur-containing homoallylic alcohol represented by the general formula () has the general formula () [In the formula, R ¹ , R ² and R ³ have the same meanings as in the general formula (), and X represents a chlorine atom, a bromine atom or an iodine atom. ] Allyl Grignard reagent and general formula () [In the formula, R ⁵ and R ⁶ have the same meanings as in the general formula (). ] It can be obtained in high yield by reacting with the α-thioketone shown below. The corresponding sulfoxide can be obtained by oxidizing the sulfur-containing homoallylic alcohol represented by the general formula (). This oxidation reaction can be carried out according to ordinary oxidation methods, including performic acid, peracetic acid, perpropionic acid, perphthalic acid, perbenzoic acid,
This can be easily carried out by a method known per se, which involves treatment with an organic peracid such as m-chloroperbenzoic acid or a suitable oxidizing agent such as hydrogen peroxide. As the oxidizing agent, m-chloroperbenzoic acid is particularly preferred from the viewpoint of ease of handling and selectivity to the target sulfoxide.
[D. Heissler, Tetrahedron Letters 487 (1976)
reference〕. The optimum amount of the oxidizing agent to be used is approximately 1 equivalent for sulfur-containing homoallylic alcohols in ^which R ⁶ in the general formula () is an alkyl group or an aryl group;

Approximately 2 equivalents is optimal for the sulfur-containing homoallylic alcohol which is the group [Formula].
The reaction temperature is suitably in the range of -30°C to +50°C.
Further, this oxidation reaction is preferably carried out in the presence of a solvent, and inert solvents such as chloroform, methylene chloride, carbon tetrachloride, diethyl ether, benzene, and toluene are used as the solvent. After the reaction is completed, the organic acid produced from the reaction mixture and the unreacted oxidizing agent are neutralized with a base and then removed, and then the solvent is distilled off to obtain a sulfoxide. This sulfoxide can be subjected to the next reaction under heating without being purified. In a preferred embodiment when m-chloroperbenzoic acid is used as the oxidizing agent, in a methylene chloride solution in which a sulfur-containing homoallylic alcohol represented by the general formula () is dissolved, the sulfur-containing homoallylic alcohol is When this sulfur-containing homoallylic alcohol is one in which R ⁶ is an alkyl group or an aryl group in the general formula (), approximately 1 equivalent of m-chloroperbenzoic acid in a methylene chloride solution ^is added; but

In the case of the group [Formula], approximately 2 equivalents of a methylene chloride solution of m-chloroperbenzoic acid is added dropwise at 0 to 5°C, followed by stirring at room temperature for about 1 hour to carry out the reaction. After the reaction is complete, a 10% aqueous potassium hydroxide solution is added to the reaction mixture in an amount approximately three times the molar amount of the m-chloroperbenzoic acid used, and the m-chlorobenzoic acid produced and the unreacted m
- Neutralizes chlorperbenzoic acid. After this mixed solution is washed with water and dried, methylene chloride is distilled off from it under reduced pressure, and the resulting residue containing sulfoxide is subjected to the next reaction under heating. Obtaining the δ,ε-unsaturated ketone represented by the general formula () by reacting the sulfoxide corresponding to the sulfur-containing homoallylic alcohol represented by the general formula () obtained by the above oxidation reaction under heating. Can be done. This reaction can be carried out in the liquid phase or gas phase by heating at a temperature of about 100 to 600°C, but from the viewpoint of reaction rate and selectivity, the reaction is carried out at a temperature of about 130 to 250°C, preferably 150 to 230°C. It is practical to do this in parallel. Although there are no particular restrictions on the atmosphere of the reaction system, an atmosphere of an inert gas such as nitrogen or helium is generally preferred. Although this reaction can be carried out in the absence of a solvent, it is preferably carried out in the presence of a solvent. N as a solvent,
N-dimethylformamide, ε-caprolactam, N-methyl-2-pyrrolidone, N-ethyl-
Nitrogen-containing compounds such as 2-pyrrolidone are particularly preferably used. The reaction time is greatly influenced by the reaction temperature, but when the reaction is carried out at a temperature of 165° C. in a liquid phase system using N-methyl-2-pyrrolidone as a solvent, the reaction is completed in about 6 hours. This reaction under heating is thought to proceed through a two-step reaction as shown in the following formula, but the reaction mechanism is not particularly limited. [In the above formula, R ¹ , R ² , R ³ , R ⁵ , R ⁷ and R ⁸ have the same meanings as in the general formula (), and R ⁶ ' represents an alkyl group or an aryl group. ] In addition, during the above reaction, the α′ position

[Formula] The reaction in which the group is eliminated with the hydrogen atom at the β' position is

The reaction is carried out under the same conditions as described above for the reaction in which the group [formula] is eliminated with a hydrogen atom in the β position. After the reaction is complete, in the case of a reaction mixture obtained in the absence of a solvent, it can be distilled as it is, or in the case of a reaction mixture obtained in the presence of a solvent, it can be poured into water and diluted with, for example, hexane. The δ,ε-unsaturated ketone represented by the general formula () can be isolated by distilling the extract or subjecting it to column chromatography. The allyl Grignard reagent represented by the general formula () is prepared by mixing the corresponding allyl halide and magnesium metal in an ether solvent such as tetrahydrofuran or diethyl ether in an inert gas atmosphere such as nitrogen or helium at -30°C to 50°C. It can be prepared by reacting at a temperature of preferably -5°C to 30°C. The time required for this reaction is considerably influenced by the type of allyl halide and the reaction temperature, but is usually about 1 hour. α-thioketone represented by the general formula () is added to this reaction system.
The reaction mixture containing the sulfur-containing homoallylic alcohol represented by the general formula () is prepared by adding dropwise at a temperature of 30°C to 50°C, preferably -10°C to 30°C, and stirring for about 1 hour at that temperature or at room temperature. can get. The amount of α-thioketone represented by the general formula () to be used is about 0.3 to 1 equivalent, preferably about 0.5 equivalent to the allyl Grignard reagent represented by the general formula ().
~0.9 equivalent. The sulfur-containing homoallylic alcohol can be separated and recovered from the reaction mixture by a conventional method. For example, add ammonium chloride aqueous solution to the reaction mixture, then extract with diethyl ether, hexane, etc., wash the extract with water,
After drying, the solvent is distilled off to obtain a sulfur-containing homoallylic alcohol represented by the general formula (). This sulfur-containing homoallylic alcohol can be subjected to the next oxidation reaction without being purified, but there is no problem in subjecting a sulfur-containing homoallylic alcohol that has been further purified by distillation or column chromatography to the oxidation reaction. do not have. α- shown by the general formula () used as a raw material
Thioketone has the general formula () [In the formula, R ⁶ has the same meaning as in the general formula (). ] Ketone represented by the general formula () R ⁵ S-SR ⁵ ... () [wherein R ⁵ has the same meaning as in the general formula (). ] Disulfide represented by the general formula () R ⁵ S-Y ... () [wherein R ⁵ has the same meaning as in the general formula (), and Y represents a halogen atom. ] It can be easily produced by reacting the sulfenyl halide represented by the following in the presence of a base such as sodium hydride, potassium hydride, or n-butyllithium. Examples of the ketone represented by the general formula () include methyl ethyl ketone, diethyl ketone, ethyl phenyl ketone, and α-methylthiodiethyl ketone.
Preferred examples of the disulfide represented by the general formula () include dimethyl disulfide, diethyl disulfide, diphenyl disulfide, etc. Preferable examples of the sulfenyl halide represented by the general formula () include Examples include methylsulfenyl chloride, ethylsulfenyl chloride, and phenylsulfenyl bromide. Hereinafter, the present invention will be specifically explained with reference to Examples. Example 1 1-(1-methylthio)ethyl-1,2,2-
Synthesis of trimethyl-3-buten-1-ol Metal magnesium in a 100ml three-necked flask
Take 0.95g and 45ml of dry tetrahydrofuran,
Under a nitrogen gas atmosphere, 4.1 g of prenyl chloride was gradually added dropwise while maintaining the internal temperature at about 20° C. to prepare a Grignard reagent. Next, add 3-methylthio-2-butanone (93.4% purity) to this Grignard reagent.
Add 3.79g of 15ml tetrahydrofuran solution to an internal temperature of 20~
It was added dropwise at 23°C. After stirring for 1 hour at room temperature,
The reaction mixture was poured into a large amount of aqueous ammonium chloride solution, and extracted with diethyl ether. After washing the extract with water several times, it was dried over anhydrous sodium sulfate. After distilling off the ether under reduced pressure, the residue was distilled under reduced pressure to obtain bp.62.0
~63.5℃/0.7~0.75mmHg fraction 5.66g (purity 99.6
%) was obtained. Yield 100%. As a result of gas chromatography analysis (filling material: OV-1, 1 m, column temperature: 80 to 140°C), this product was found to be a diastereomer with a ratio of approximately 1:4. This product is H ¹ −
1-(1-methylthio)ethyl-1,2,2-trimethyl-3-buten-1-ol was confirmed by NMR analysis and IR analysis. Representative signals are listed below. ^H1 -NMR ( _CDCl3 , ppm): 1.15 (6H, S)

【formula】 1.23 (3H, s)

【formula】 1.37 (3H, d)

[Formula] 2.08 (3H, s) - SCH ₃ 2.66 ~ 3.10 (1H, m))

【formula】 4.85~5.15 (2H, m)

【formula】 5.90~6.35 (1H, m)

[Formula] IR (cm ^-1 ): 3480, 3080, 2980, 1635, 1375,
1090,910 Synthesis of 7-methyl-6-octen-2-one 1-(1-methylthio)ethyl-1,2,2-
3.0 g of trimethyl-3-buten-1-ol was dissolved in 45 ml of methylene chloride and cooled to about 0°C. Next, add m-chloroperbenzoic acid (purity 80%) to this solution.
A solution of 3.6 g in 45 ml methylene chloride was added dropwise at the same temperature. Then, the temperature was returned to room temperature and stirred for 1 hour. A 10% aqueous potassium hydroxide solution in an amount of three times the amount of m-chloroperbenzoic acid used was added to the reaction mixture, and the mixture was stirred for 1 hour. The methylene chloride layer was separated, and the aqueous layer was further extracted with methylene chloride. The methylene chloride layer and the methylene chloride extract were combined, and the mixture was washed with water and then dried over anhydrous sodium sulfate. Methylene chloride was distilled off under reduced pressure.
The residue was dissolved in 4.8 g of N-methyl-2-pyrrolidone and heated under a nitrogen atmosphere at a bath temperature of 175±2° C. for 6 hours. Next, the reaction mixture was poured into a large amount of water and extracted with hexane. The hexane layer was washed with water and dried over anhydrous sodium sulfate. After distilling off hexane under reduced pressure, the residue was subjected to silica gel chromatography (eluent: ethyl acetate-hexane system).
By refining with
1.22 g of octen-2-one was obtained. Yield 55%. Characteristic fragments in the GC-Mass spectrum of the product are shown below. GC conditions: column packing material PEG20M, column length
2m, temperature 120℃ Mass spectrum m/e: [M] ⁺ 140, 122, 82,
67, 47 Examples 2 to 5 Various allyl Grignard reagents () and α-thioketone () were reacted under the same conditions as in Example 1, and the sulfur-containing homoallylic alcohol () was obtained by separating and recovering. Then, the sulfur-containing homoallylic alcohol () was heated and reacted under the same conditions as in Example 1, and was separated and purified to obtain a δ,ε-unsaturated ketone (). The result is the first
As shown in the table.

【table】

[Table] Examples 6 to 11 Various allyl Grignard reagents () and α-thioketone () were reacted under the same conditions as in Example 1, separated and recovered to obtain sulfur-containing homoallylic alcohols (), and then The sulfur-containing homoallylic alcohol () is subjected to a heating reaction under the same conditions as in Example 1, and is separated and purified to obtain δ,
ε-unsaturated ketone () was obtained. The results are shown in Table 2.

【table】

【table】

Claims (1)

[Claims] 1 General formula () (In the formula, R ¹ , R ² and R ³ are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group or an aryl group, R ⁵ represents an alkyl group or an aryl group, and R ⁶ represents an alkyl group. basis,
Represents an aryl group or a [formula] group. Here, R ⁷ represents a hydrogen atom or an alkyl group,
R ⁸ represents an alkyl group or an aryl group. ) The sulfur-containing homoallylic alcohol represented by formula () is oxidized to form the corresponding sulfoxide, and then the sulfoxide is reacted under heating. [In the formula, R ¹ , R ² and R ³ have the same meanings as in the general formula (), and R ⁴ is R ⁶ when R ⁶ is an alkyl group or an aryl group in the general formula ()
represents the same group as , and when R ⁶ is a [formula] group -CH=CHR ⁷ represents a group. Here, R ⁷ and R ⁸
has the same meaning as in general formula (). ] A method for producing a δ,ε-unsaturated ketone represented by 2 General formula () (In the formula, R ¹ , R ² and R ³ are the same or different,
Each hydrogen atom, alkyl group, cycloalkyl group,
It represents an alkenyl group or an aryl group, and X represents a chlorine atom, a bromine atom or an iodine atom. ) Allyl Grignard reagent and general formula () (In the formula, R ⁵ represents an alkyl group or an aryl group, R ⁶ represents an alkyl group, an aryl group, or a [formula] group. Here, R ⁷ represents a hydrogen atom or an alkyl group, and R ⁸ represents an alkyl group. or an aryl group) is reacted with an α-thioketone represented by the general formula (). [In the formula, R ¹ , R ² and R ³ have the same meanings as in the general formula (), and R ⁵ and R ⁶ have the same meaning as in the general formula ()
has the same meaning as in. ] A sulfur-containing homoallylic alcohol is obtained,
General formula () characterized in that the sulfur-containing homoallylic alcohol is oxidized to the corresponding sulfoxide, and then the sulfoxide is reacted under heating. [In the formula, R ¹ , R ² and R ³ have the same meanings as in the general formula (), and R ⁴ is R ⁶ when R ⁶ is an alkyl group or an aryl group in the general formula ()
represents the same group as , and when R ⁶ is a [formula] group, it represents a --CH=CHR ⁷ group. here,
R ⁷ and R ⁸ have the same meanings as in general formula (). ] A method for producing a δ,ε-unsaturated ketone represented by