JPH0158173B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 3,5,5-trimethyl-2-cyclohexen-1-one derivatives. More specifically, the present invention relates to the general formula (However, R ¹ and R ² are hydrogen atoms or have 1 to 1 carbon atoms.
5 represents an aliphatic hydrocarbon group, and Y is

[Formula] or -CN, R ³ , R ⁵ and R ⁶ are hydrogen atoms or have 1 to 1 carbon atoms
5 represents an aliphatic hydrocarbon group, and R ⁴ has 1 to 1 carbon atoms.
3, which represents an aliphatic hydrocarbon group in 5)
5,5-trimethyl-2-cyclohexene-1-
The present invention relates to a method for producing on (hereinafter referred to as isophorone) derivatives. Isophorone derivatives are compounds found in various plant essential oils, and are highly valued as aroma components in foods, drinks, cosmetics, tobacco, etc.
It is also a useful compound as an intermediate for carotenoids, fragrances, pharmaceuticals, etc. As one method for producing such isophorone derivatives, a 4-substituted isophorone derivative is produced from isophorone and a dienophile compound according to the following formula.
Reported in Tetrahedron Letters, 19 , 1965, (1970). However, this method has the disadvantage that intermediate products are unstable and difficult to handle, and large amounts of by-products that are difficult to separate are produced. The inventors of the present invention have conducted intensive studies to develop a method for producing isophorone derivatives having the above-mentioned usefulness in a short process with simple operations and in high yield, and as a result, they have arrived at the present invention, which has remarkable effects. did. That is, the present invention is based on the general formula 3,5,5-trimethyl-2-cyclohexene- (where X represents a halogen atom)
1-one magnesium enolate and general formula (However, R ¹ and R ² are hydrogen atoms or have 1 to 1 carbon atoms.
5 represents an aliphatic hydrocarbon group, and Y is

[Formula] or -CN, R ³ , R ⁵ and R ⁶ are hydrogen atoms or have 1 to 1 carbon atoms
5 represents an aliphatic hydrocarbon group, and R ⁴ has 1 to 1 carbon atoms.
5) representing an aliphatic hydrocarbon group, and hydrolyzing the product,
The general formula is then optionally treated with an acid or base. The present invention provides a method for producing a 3,5,5-trimethyl-2-cyclohexen-1-one derivative represented by (where R ¹ , R ² and Y are as described above). The magnesium enolate of isophorone represented by the general formula (1) used in the method of the present invention can be produced by any known method. For example, a method in which methyl Grignard reagent is reacted with a catalytic amount of iron chloride () and then reacted with isophorone [J.
Am.Chem.Soc., 63 , 2308-2315 (1941)] is one of the preferred methods. As the reaction solvent used in this reaction, a solvent used in ordinary Grignard reagent synthesis can be appropriately used. The thus obtained isophorone magnesium enolate 1 is usually subjected to a reaction with an olefinic compound represented by the general formula (2) in the same solvent. As the olefinic compound, essentially any compound can be used as long as it satisfies the general formula (2), but the aliphatic hydrocarbon group in the general formula includes methyl, ethyl,
Alkyl groups such as propyl, butyl, pentyl and the like are commonly used. Such olefinic compounds include α,β unsaturated aldehydes such as acrolein, methacrolein, crotonaldehyde, 2-pentenal, 2-hexenal, 3-buten-2-one, 1-penten-3-one, 1- hexene-3-one, 1-heptene-3-one, 1-
Octen-3-one, 3-methyl-3-butene-
α, β unsaturated ketones such as 2-one, acrylic acid methyl ester, acrylic acid ethyl ester,
α, β unsaturated esters such as propyl acrylate, butyl acrylate, methyl methacrylate, acrylamide, acrylonitrile, N,N dimethylacrylamide,
Examples include N,N diethylacrylamide. The amount of the olefin compound to be used is preferably 0.1 to 10 mol, particularly 1 to 1.5 mol, per 1 mol of isophorone magnesium enolate. The reaction temperature is -
80 to 100°C, especially -20 to 5°C is preferred. The reaction product is then demagnetized by hydrolysis similar to conventional Grignard reagent demagnesization. Specifically, the reaction mixture is added to, for example, a saturated ammonium chloride aqueous solution, extracted using an appropriate extraction solvent such as benzene, toluene, carbon tetrachloride, chloroform, ethyl acetate, etc., and the solvent layer is collected. By washing with water, drying with, for example, Glauber's salt, and recovering the solvent by distillation, the general formula
The isophorone derivative represented by (3) can be obtained. Note that depending on the type of olefinic compound used in the reaction between isophorone magnesium enolate 1 and olefinic compound 2, isophorone derivative 3 may not be obtained directly, and the general formula A bicyclooctene compound shown in may be obtained. In this case, the bicyclooctene compound once produced can be easily converted into an isophorone derivative by subjecting it to a so-called reverse aldol condensation type reaction. This reaction is carried out by treating the bicyclooctene compound 4 with an acid or base. Specifically, the bicyclooctene compound 4 is treated with an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, or with an acid such as sodium hydride, potassium hydride, sodium methylate, sodium ethylate, potassium tertiary butoxide, or sodium hydroxide. , a base such as potassium hydroxide and an ethereal solvent such as diethyl ether, dibutyl ether, tetrahydrofuran, diisopropyl ether, dioxane, mono- or diethylene glycol dimethyl ether, mono- or diethylene glycol diethyl ether, tetrahydropyran,
The reaction is carried out in a solvent such as a hydrocarbon solvent such as benzene, toluene, or hexane, or an alcohol solvent such as methanol, ethanol, or tertiary butyl alcohol. Reaction temperature is usually 0℃ to 150℃
However, a temperature of 40°C to 90°C is particularly preferable for reactions with acids, and a temperature around room temperature is particularly preferable for reactions with bases. The olefinic compound that produces the bicyclooctene compound 4 is usually a compound in general formula (2) in which Y is ester, amide, or nitrile. After the reaction is complete, for example, pour the reaction solution into a large excess of ice water,
Neutralize and extract using a suitable extraction solvent such as benzene, toluene, carbon tetrachloride, chloroform, ethyl acetate, etc., collect the solvent layer, wash with saturated brine, dry with sodium sulfate, and remove the solvent. Isophorone derivative 4 can be obtained by distilling and recovering. Isophorone derivative 4 can be purified by vacuum distillation, column chromatography, or the like, if necessary. In this way, isophorone derivatives can be obtained in a short process and in high yield through simple operations. Next, the present invention will be explained based on examples. Example 1 Magnesium 5.1g (0.21mol), anhydrous ether
A mixture of 19.9 g (0.21 mol) of methyl bromide and 20 ml of anhydrous ether was added dropwise to 210 ml to prepare methylmagnesium bromide, and the mixture was cooled to -5°C and 0.35 g of ferric chloride was added. After stirring for 15 minutes at −5°C, 24 g (0.17 mol) of isophorone and anhydrous ether were added.
Add 45 ml of the solution dropwise over a period of 1 hour at -5°C to -2°C. After stirring at the same temperature for 2 hours, 12.2 g (0.17 mol) of 3-buten-2-one and 20 g of anhydrous ether were added.
Add ml of the mixture dropwise over 10 seconds. Next, stir at -2℃ to 0℃ for 30 minutes, return to room temperature, and then stir for 1 hour.
Stir for an hour. After the reaction, the reaction mixture is poured into 600 ml of saturated ammonium chloride aqueous solution, then 400 ml of ethyl acetate is added and extracted, and the organic phase is washed three times with water and dried over anhydrous sodium sulfate. After collecting ethyl acetate,
Distill under reduced pressure to obtain a fraction with a boiling point of 120℃~125℃/2mmHg
19.9 (55% yield) was obtained. As a result of gas chromatography analysis, this product contained 90% of 3,5,5-trimethyl-4(3-oxobutyl)-2-cyclohexen-1-one. IR: 1670, 1720 cm ^-1 NMR: (δTMS ppm in CCl ₄ ) 1.01 (s, 3H) 1.11 (s, 3H) 1.77 (m,
2H) 1.99 (d, 3H) 2.08 (s, 3H) 2.0
~2.5 (m, 5H) 5.71 (s, 1H) Example 2 1-Hydroxy-3,3,5-trimethyl-7
Synthesis of (2-methoxycarbonylethyl)-bicyclo-[2,2,2]-oct-5-ene 1.45 g (59.6 m mol) of magnesium, 5.66 g (59.6 m mol) of methyl bromide and anhydrous in 60 ml of anhydrous ether Methylmagnesium bromide was prepared by dropping a mixture of 20 ml of ether, then cooled to 0°C, and 125 mg of ferric chloride was added. After stirring at the same temperature for 15 minutes, a mixed solution of 6.9 g (50 mmol) of isophorone and 15 ml of anhydrous ether was added dropwise at -2°C to 0°C over 30 minutes. After stirring at the same temperature for 1 hour, a mixture of 4.3 g (50 mmol) of acrylic acid methyl ester and 10 ml of anhydrous ether was added dropwise over 5 seconds. Next, after stirring at -2°C to 0°C for 1 hour, the mixture was returned to room temperature and stirred for an additional 30 minutes. After the reaction, the reaction mixture
Pour 120ml into 200ml saturated ammonium chloride solution
of ethyl acetate was added, extracted, and the organic layer was washed three times with water and dried over anhydrous sodium sulfate. After collecting ethyl acetate, distill it under reduced pressure to obtain a fraction with a boiling point of 107℃/3mmHg.
8.96g (80% yield) was obtained. This product is 1-hydroxy-3,3,5-trimethyl-7(2-methoxycarbonylethyl)-bicyclo-[2,2,2], which shows a single peak in gas chromatography.
-Octo-5- It was on. IR: 3510, 1740 cm ^-1 NMR: (δTMS ppm in CCl ₄ ) 0.95 (s, 3H) 1.15 (s, 3H) 1.34 (s,
2H) 1.45~1.55 (m, 1H) 1.5~2.5 (bγs,
1H) 1.8 (m, 1H) 1.88 (d, 3H) 2.0
~2.7 (m, 2H) 3.69 (s, 3H) 5.69
(bγs, 1H) 3,5,5-trimethyl-4(2-methoxycarbonylethyl)-2-cyclohexene-1-
Synthesis of 1-hydroxy-3,3,5-trimethyl-
7(2-methoxycarbonylethyl)-bicyclo-[2,2,2]-oct-5-ene 790mg
(3.53m mol), methanol 8ml, 35% hydrochloric acid 8ml
After mixing, heat at 90 °C for 30 minutes. Next, the reaction mixture was cooled from 0°C to 5°C, neutralized with 2N aqueous sodium hydroxide solution, extracted with 400ml of ethyl acetate, and the organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. do. After recovering ethyl acetate
654 mg of oil was obtained. This was further purified by applying it to a silica gel column using a solution of ethyl acetate:hexane=1:9 to obtain a fraction of 635 mg (80% yield). This product is 3,5,5-trimethyl-4(2-methoxycarbonylethyl)- which forms a single peak in gas chromatography.
It was 2-cyclohexen-1-one. 2 1-hydroxy-3,5,5-trimethyl-
7(2-methoxycarbonylethyl)-bicyclo-[2,2,2]-oct-5-ene 9.4g
(42m mol) in a mixture of 154ml of anhydrous methanol.
Add 7.7 ml of 28% sodium methylate solution dropwise over 3 minutes at room temperature. Next, after stirring at the same temperature for 2 hours, the reaction solution was added to 500 ml of ice water and neutralized with 10% acetic acid. Add ethyl acetate 1 and extract.
The organic layer was washed three times with saturated brine and then dried over anhydrous sodium sulfate. After collecting ethyl acetate, it was distilled under reduced pressure to obtain 6.77g (72%) of a fraction with a boiling point of 130-135℃/2mmHg
Yield) was obtained. This fraction showed a single peak in gas chromatography, 3,5,5-trimethyl-4(2-methoxycarbonylethyl)-2
-Cyclohexene-1-one. IR: 1740, 1685 cm ^-1 NMR: (δTMS, ppm, in CCl ₄ ) 1.02 (s, 3H) 1.08 (s, 3H) 1.5 to 2.5
(m, 7H) 1.98 (d, 3H) 3.60 (s, 3H)
5.70 (bγS, 1H) Example 3 Methylmagnesium bromide was prepared by dropping a solution of 5.66 g (59.6 m mol) of methyl bromide and anhydrous ether into 1.45 g (59.6 m mol) of magnesium and 60 ml of anhydrous ether. Cool to ℃ and add 125 mg of ferric chloride. After stirring at the same temperature for 15 minutes, a solution of 6.9 g (50 mmol) of isophorone and 15 ml of anhydrous ether was added dropwise at 0 to 3° C. over 30 minutes. After stirring at the same temperature for 1 hour, 3.15 g of acrolein (50 m
mol) of anhydrous ether dropwise over 10 seconds. Next, after stirring for 30 minutes at -2°C to 0°C,
Return to room temperature, pour the reaction mixture into 200 ml of saturated ammonium chloride aqueous solution, add 120 ml of ethyl acetate,
After extraction, the organic layer was washed three times with saturated brine and dried over anhydrous sodium sulfate. After recovering the ethyl acetate, 11.2 g of a sticky oil was obtained. Add this to ethyl acetate:
The product was purified by applying it to a silica gel column using a 2:98 hexane solution to obtain 5.6 g (56% yield) of a fraction. This product has a single peak in gas chromatography, 3,5,5-trimethyl-4-(3
-oxopropyl)-2-cyclohexene-1-
It was on and hot. IR: 1685, 1730 cm ^-1 NMR: (δTMS, ppm, in CCl ₄ ) 1.03 (s, 3H) 1.08 (s, 3H) 1.99 (d,
3H) 1.5~2.8 (m, 7H) 5.75 (bγs, 1H)
9.78 (bγs, 1H) Example 4 After preparing magnesium enolate of isophorone in the same manner as in Example 3, a mixture of 3.5 g (50 mmol) of crotonaldehyde and 15 ml of anhydrous ether was added under stirring at 0 to 3°C. Drop for 10 seconds. Next -
After stirring for 1 hour at 2°C to 0°C, the reaction mixture was returned to room temperature, poured into 200ml of saturated ammonium chloride aqueous solution, extracted with 200ml of ethyl acetate, and the organic layer was washed twice with saturated brine and then diluted with anhydrous sodium sulfate. dry. After recovering the ethyl acetate, 9.5 g of a sticky oil was obtained. This is further ethyl acetate:hexane=
A 2:98 solution was purified by applying it to a silica gel column to obtain 5.4 g (52% yield) of a fraction. Furthermore, this is the result of gas chromatography analysis.
3,5,5-trimethyl-4-(1-methyl-3
-oxopropyl)-2-cyclohexene-1-
It contained 89% on. IR: 1723, 1680 cm ^-1 NMR: (δTMS, ppm, in CCl ₄ ) 0.92 (d, 3H) 1.05 (s, 3H) 1.15 (s,
3H) 1.98 (d, 3H) 1.5-2.8 (m, 6H)
5.88 (bγs, 1H) 9.77 (s, 1H) Example 5 1-Hydroxy-3,3,5-trimethyl-7
Synthesis of (2-ethoxycarbonylethyl)-bicyclo-[2,2,2]-oct-5-ene Magnesium enolate of isophorone was prepared in the same manner as in Example 2, and acrylic acid methyl ester was replaced with acrylic acid methyl ester. Acid ethyl ester 5.0g
(50 mmol) was reacted, and after the reaction treatment, the product was distilled under reduced pressure to obtain 9.3 g (78% yield) of a fraction with a boiling point of 118°C/3 mmHg. This substance shows a single peak in gas chromatography, 1-hydroxy-3,3,5-trimethyl-7(2-ethoxycarbonylethyl)-bicyclo-[2,2,
2]-Octo-5-en. Synthesis of 3,5,5-trimethyl-4(2-ethoxycarbonylethyl)-2-cyclohexen-1-one 1-Hydroxy-
805 mg (3.38 mmol) of 3,3,5-trimethyl-7(2-ethoxycarbonylethyl)-bicyclo-[2,2,2]-oct-5-ene was reacted,
After the reaction treatment, the product was purified by applying it to a silica gel column to obtain 670 mg (83% yield) of 3,5,
5-trimethyl-4(2-ethoxycarbonylethyl)-2-cyclohexen-1-one was obtained. Example 6 Magnesium enolate of isophorone was prepared in the same manner as in Example 2, and 2.65 g (50 m
mol) was added and 9.4 g of oily substance was obtained after reaction treatment. This oily substance contains 1-hydroxy-3,
3,5-trimethyl-7(2-cyanoethyl)-
The presence of bicyclo-[2,2,2]-oct-5-ene was confirmed. Next, without refining 9.4g of oily substance, t-BuOK0.9g, t-BuOH70
ml of the mixture and after stirring for 1 hour at room temperature.
Add 200 ml of ice water, extract with benzene, and wash the organic layer with saturated saline. Thereafter, it was dried over anhydrous sodium sulfate and the ether was distilled off to obtain 8.5 g of an oily substance. The presence of 3,5,5-trimethyl-4-(2-cyanoethyl)-2-cyclohexen-1-one was confirmed in this oily substance. Example 7 Magnesium enolate of isophorone was prepared in the same manner as in Example 2, and 4.2 g of 1-penten-3-one was used instead of acrylic acid methyl ester.
(50m mol), and after the reaction treatment, the product was distilled under reduced pressure to a boiling point of 138℃/3mm
6.0 g (54% yield) of Hg fraction was obtained. As a result of gas chromatography analysis, this item was 3,5,5
-Trimethyl-4(3-oxopentyl)-2-
It contained 88% cyclohexen-1-one.

Claims (1)

[Claims] 1. General formula 3,5,5-trimethyl-2-cyclohexene- (where X represents a halogen atom)
1-one magnesium enolate and general formula (However, R ¹ and R ² are hydrogen atoms or have 1 to 1 carbon atoms.
5 represents an aliphatic hydrocarbon group, Y represents [Formula] or -CN, and R ³ , R ⁵ and R ⁶ are hydrogen atoms or a group having 1 to 1 carbon atoms.
5 represents an aliphatic hydrocarbon group, and R ⁴ has 1 to 1 carbon atoms.
5) representing an aliphatic hydrocarbon group, and hydrolyzing the product,
A general formula characterized in that it is then optionally treated with an acid or a base. A method for producing a 3,5,5-trimethyl-2-cyclohexen-1-one derivative represented by (where R ¹ , R ² and Y are as described above).