JP3191114B2 - Method for producing 4-alkylidene-3,5,5-trimethyl-2-cyclohexen-1-one - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 4-alkylidene-3, which has high value as a flavoring agent for foods and drinks, cosmetics, tobacco and the like.
The present invention relates to a method for producing 5,5-trimethyl-2-cyclohexen-1-one.

[0002]

2. Description of the Related Art Conventionally, the following method has been proposed for producing 4-alkylidene-3,5,5-trimethyl-2-cyclohexen-1-ones. For example, "J.
Org. chem. 135, 1053 (1970)
Year) is

[0003]

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[0004] A method for synthesizing 4-methylene-3,5,5-trimethyl-2-cyclohexen-1-one in accordance with the above is disclosed. However, this method has the disadvantage that the reaction step is long and generates a large amount of by-products.

[0005] Also, "Liebigs Ann. Che.
m. Volume 1, page 19 (1991) states that

[0006]

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According to 4-alkylidene-3,5,5-
A method for synthesizing trimethyl-2-cyclohexen-1-one is disclosed. However, this process has the disadvantage that the Burgess reagent, which requires expensive and complicated operations to prepare, must be used.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide a process for producing 4-alkylidene-2-cyclohexen-1-one which is industrially advantageous by overcoming the disadvantages or deficiencies of the conventional processes described above. It is in.

[0009]

Means for Solving the Problems The present inventors have the general formula

[0010]

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Wherein R ² represents hydrogen or a methyl group, R ³ represents an alkyl or alkylene group having 1 to 6 carbon atoms, and X represents a halogen atom. Reaction with hydrogen hydride

[0012]

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(Wherein R ¹ represents hydrogen or an alkyl group or alkylene group having 1 to 5 carbon atoms), and the diene acetal is hydrolyzed with an acid to obtain a compound represented by the general formula

[0014]

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(Wherein R ¹ represents hydrogen or an alkyl or alkylene group having 1 to 5 carbon atoms)
The present inventors have found that alkylidene-3,5,5-trimethyl-2-cyclohexen-1-one can be easily obtained in a high yield, and have completed the present invention.

The allyl halide derivative [II], which is a starting material used in the present invention, is easily and in high yield by the following steps.

[0017]

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Specific examples of the allyl halide derivative [I] include, for example, 6-bromo-7,8,9,9-tetramethyl-1,4-dioxaspiro- [4,5] -dec-7-
Ene, 6-bromo-8-ethyl-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7-
Ene, 6-bromo-8-propyl-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7
-Ene, 6-bromo-8-isopropyl-7,9,9-
Trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6-bromo-8-butyl-7,9,9-
Trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6-bromo-8-pentyl-7,9,9
-Trimethyl-1,4-dioxaspiro- [4,5]-
Dec-7-ene, 6-bromo-8-hexyl-7,9,
9-trimethyl-1,4-dioxaspiro- [4,5]
-Dec-7-ene, 6-bromo-2,7,8,9,9-
Pentamethyl-1,4-dioxaspiro- [4,5]-
Dec-7-ene, 6-bromo-8-ethyl-2,7,
9,9-tetramethyl-1,4-dioxaspiro-
[4,5] -dec-7-ene, 6-bromo-8-propyl-2,7,9,9-tetramethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6 -Bromo-8
-Isopropyl-2,7,9,9-tetramethyl-1,
4-dioxaspiro- [4,5] -dec-7-ene, 6
-Bromo-8-butyl-2,7,9,9-tetramethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6-bromo-8-pentyl-2,7,9, 9-tetramethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6-bromo-8-hexyl-2,7,9,
9-tetramethyl-1,4-dioxaspiro- [4,
5] -dec-7-ene, 6-bromo-8- (3-butenyl) -7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6-bromo -8-
(1-butenyl) -7,9,9-trimethyl-1,4-
Dioxaspiro- [4,5] -dec-7-ene, 6-bromo-8- (3-butenyl) -2,7,9,9-tetramethyl-1,4-dioxaspiro- [4,5] -deca −
7-ene, 6-bromo-8- (1-butenyl) -2,
7,9,9-tetramethyl-1,4-dioxaspiro-
[4,5] -dec-7-ene, 6-chloro-7,8,
9,9-tetramethyl-1,4-dioxaspiro-
[4,5] -Deca-7-ene, 6-chloro-8-ethyl-7,9,9-trimethyl-1,4-dioxaspiro-
[4,5] -dec-7-ene, 6-chloro-8-propyl-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6-chloro- 8-isopropyl-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6-chloro-8
-Propyl-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 8-butyl-
6-chloro-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6-chloro-
8-pentyl-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6-chloro-8-hexyl-7,9,9-trimethyl-1,4- Dioxaspiro- [4,5] -dec-7-ene, 8 (3-
(Butenyl) -6-chloro-7,9,9-trimethyl-
1,4-dioxaspiro- [4,5] -dec-7-ene, 8 (1-butenyl) -6-chloro-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -deca -7-ene, 6-iodo-7,8,9,9-tetramethyl-1,4-dioxaspiro- [4,5] -dec-7-
Ene, 8-ethyl-6-iodo-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7-
Ene, 6-iodo-8-propyl-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7
-Ene, 6-iodo-8-isopropyl-7,9,9-
Trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 8-butyl-6-iodo-7,9,9-
Trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 6-iodo-8-pentyl-7,9,9
-Trimethyl-1,4-dioxaspiro- [4,5]-
Deca-7-ene, 8-hexyl-6-iodo-7,9,
9-trimethyl-1,4-dioxaspiro- [4,5]
-Dec-7-ene, 8 (3-butenyl) -6-iodo-
7,9,9-trimethyl-1,4-dioxaspiro-
[4,5] -dec-7-ene, 8 (1-butenyl) -6
-Iodo-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene; and the like.

The dehydrohalogenation reaction in the first step is suitably carried out by using an organic base. As the organic base, for example, 1,8-diazabicyclo- [5,4,0]
-Undec-7-ene, 1,5-diazabicyclo-
[4,3,0] -H-5-ene, 1,4-diazabicyclo- [2,2,0] -octane, 4,5-dihydro-
N, N-dimethyl-3H-pyrrol-2-amine is exemplified. The amount used is allyl halide derivative [I] 1
The molar amount is preferably 0.5 to 5 times, particularly 1 to 2 times the mole. The dehydrohalogenation reaction can be carried out using only an organic base, but is preferably carried out in the presence of another solvent. Examples of the reaction solvent include hydrocarbon solvents such as hexane, cyclohexane, benzene, toluene, and xylene; ether solvents such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and tetrahydropyran; and mixed solvents containing any combination of these. Can be

The reaction time is 0.5 to 15 hours, especially 1 to 5 hours.
Time is preferred. The reaction temperature is 25 to 200 ° C, especially 10
0-150 ° C is preferred.

After completion of the reaction, for example, the reaction solution is poured into a large excess of water and a suitable extraction solvent such as benzene, toluene,
The diene acetal [II] can be obtained by extracting with carbon tetrachloride, chloroform-ethyl acetate, etc., washing with water, drying with, for example, sodium sulfate and distilling the solvent. The diene acetal can be purified, if necessary, by means such as distillation under reduced pressure and column chromatography.
Of course, it may be subjected to the next step without going through these separation and purification steps.

Examples of the acid in the hydrolysis reaction in the next step include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and perchloric acid, organic acids such as paratoluenesulfonic acid, oxalic acid and acetic acid and pyridine salts of paratoluenesulfonic acid And organic salts of organic acids. The acid remains
Alternatively, an aqueous solution can be used, but an aqueous solution is preferred. The concentration of the aqueous solution is 0.1 to 95% by weight, especially 5
-20% by weight is preferred. The amount of the aqueous acid solution used is 0.1 to 50 times, preferably 1 to 50 times the amount of the diene acetal [II].
The amount is preferably 10 to 10 times. The reaction can be carried out in the presence of an aqueous acid solution, but is preferably carried out in the presence of another solvent.

Examples of the reaction solvent include ether solvents such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; alcohol solvents such as methanol, ethanol, propanol and butanol; and ketone solvents such as acetone, diethyl ketone and methyl ethyl ketone. The reaction time is preferably 0.1 to 15 hours, particularly preferably 1 to 3 hours. The reaction temperature is -5 ° C to 100 ° C, especially 20 to 50 ° C.
C is preferred. After completion of the reaction, for example, after distilling off the solvent, the reaction solution is poured into a large excess aqueous solution of sodium carbonate, potassium carbonate, or sodium hydrogen carbonate, and extracted using an appropriate extraction solvent such as benzene, toluene, carbon tetrachloride, or ethyl acetate. Washing with water and drying with, for example, sodium sulfate and removing the solvent to give 4-alkylidene-3,5,5-trimethyl-2.
-Cyclohexen-1-one [III] can be obtained. 4-alkylidene-3,5,5-trimethyl-2
-Cyclohexen-1-one [III] can be purified, if necessary, by means such as distillation under reduced pressure and column chromatography. Thus, 4-alkylidene-3, 4-alkylidene-3,
5,5-trimethyl-2-cyclohexen-1-one [III] can be obtained.

[0024]

EXAMPLES Examples will be specifically described below with reference to examples. Example-1: 455 mg (1.57 mmol) of 6-bromo-8-ethyl-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-7-ene, 1,8
263 mg (1.73 mmol) of -diazabicyclo- [5,4,0] -undec-7-ene was dissolved in 4 ml of toluene, and the mixture was refluxed with stirring for 3 hours. After cooling to room temperature, 1
The mixture was extracted with 50 ml of water and 50 ml of ethyl acetate. The organic layer was washed with 5 ml of saturated saline and dried over anhydrous magnesium sulfate. Next, after removing the solvent, silica gel chromatography was performed to obtain 262 mg of a fraction. The product was analyzed by gas chromatography to find that the cis-form (a) and trans-form of 8-ethylidene-7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-6-ene were obtained. b) was contained 49% and 51%, respectively. (Reaction yield = 80%)

[0025]

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[0026]

(Equation 1)

Next, 232 mg (1.12 mmol) of this fraction
l) 1.4 ml of 5 wt% aqueous hydrochloric acid, 3.6 ml of THF
And stirred at 25 ° C. for 1 hour. After the THF was distilled off under reduced pressure, 20 ml of ethyl acetate was added, and the mixture was added twice with 2 ml of a saturated aqueous sodium hydrogen carbonate solution and once with 2 ml of a saturated saline solution.
Washed twice. After drying over anhydrous magnesium sulfate, the solvent was removed and the residue was subjected to silica gel column chromatography.
9 mg of a fraction was obtained. The product was analyzed by gas chromatography to find that it contained 49% and 51% of the cis-form (c) and the trans-form (d) of 4-ethylidene-3,5,5-trimethyl-2-cyclohexen-1-one, respectively. Was. (Reaction yield = 92%) The cis form (c) and the trans form (d) were isolated by silica gel chromatography.

[0028]

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[0029]

(Equation 2)

[0030]

(Equation 3)

Example 2 6-bromo-8-butyl-7,9,9-trimethyl-
498 mg (1.57 mmol) of 1,4-dioxaspiro- [4,5] -dec-7-ene, 1,8-diazabicyclo- [5,4,0] -undec-7-ene 263
mg (1.73 mmol) was dissolved in 5 ml of toluene and refluxed with stirring for 4 hours. 1 ml of water after cooling to room temperature,
50 ml of ethyl acetate was added for extraction. 5 ml of organic layer
, And dried over anhydrous magnesium sulfate. Next, after removing the solvent, silica gel chromatography was performed to obtain 293 mg of a fraction. This was analyzed by gas chromatography to find that 8-butylidene-
7,9,9-trimethyl-1,4-dioxaspiro-
The cis form (e) and trans form (f) of [4,5] -dec-6-ene were contained in 60% and 40%, respectively. (Reaction yield = 79%)

[0032]

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[0033]

(Equation 4)

Next, 192 mg of this fraction (0.814 mm
ol) 1.4 ml of 5 wt% hydrochloric acid aqueous solution, THF 3.6 m
and stirred at 30 ° C. for 1 hour. After THF was distilled off under reduced pressure, 20 ml of ethyl acetate was added, and the mixture was washed twice with 2 ml of a saturated aqueous sodium hydrogen carbonate solution and once with 2 ml of a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was removed and the residue was subjected to silica gel column chromatography.
7 mg of a fraction was obtained. The product was analyzed by gas chromatography. As a result, it was found that the cis form (g) and the trans form (h) of 4-butylidene-3,5,5-trimethyl-2-cyclohexen-1-one contained 64% and 36%, respectively. Was. (Reaction yield = 81%) The cis form (g) and the trans form (h) were isolated by silica gel column chromatography.

[0035]

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[0036]

(Equation 5)

[0037]

(Equation 6)

Example 3 6-Bromo-8- (3-butenyl) -7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -deca-
495 mg (1.57 mmol) of 7-ene, 1,8-
263 mg (1.73 mmol) of diazabicyclo- [5,4,0] -undec-7-ene was dissolved in 5 ml of toluene, and the mixture was refluxed with stirring for 5 hours. 1 ml after cooling to room temperature
Of water and 50 ml of ethyl acetate were added for extraction. The organic layer was washed with 5 ml of saturated saline and dried over anhydrous magnesium sulfate. Next, after removing the solvent, silica gel chromatography was performed to obtain a 300 mg fraction. The product was analyzed by gas chromatography to find that the cis and trans mixture of 8- (3-butenylidene) -7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-6-ene ( i) and the four geometric isomers (j) of 8 (2-butenylidene) -7,9,9-trimethyl-1,4-dioxaspiro- [4,5] -dec-6-ene by 53% and 21%, respectively. %. (Reaction yield = 60%)

[0039]

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Next, 198 mg of this fraction (0.621 mm
ol) 5% hydrochloric acid aqueous solution 1.4 ml, THF 3.6 ml
And stirred at 30 ° C. for 1 hour. After the THF was distilled off under reduced pressure, 20 ml of ethyl acetate was added, and the mixture was added twice with 2 ml of a saturated aqueous sodium hydrogen carbonate solution and once with 2 ml of a saturated saline solution.
Washed twice. After drying over anhydrous magnesium sulfate, the solvent was removed, and silica gel column chromatography was performed.
7 mg of a fraction was obtained. This was analyzed by gas chromatography, and as a result, 4 (3-butenylidene) -3,5,5
A cis and trans mixture of 5-trimethyl-2-cyclohexen-1-one (k) and four isomers of 4 (2-butenylidene) -3,5,5-trimethyl-2-cyclohexen-1-one (1) Is 51%,
It contained 25%. (Reaction yield = 82%)

[0041]

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Continuation of front page (56) References JP-A-3-2139 (JP, A) US Patent 3,268,589 (US, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 49/647

Claims (1)

(57) [Claims] 1. A compound of the general formula (Wherein R ² represents hydrogen or a methyl group and R ³ has 1 carbon atom)
And X is a halogen atom, X is a halogen atom), and an allyl halide derivative represented by the general formula: (Wherein R ¹ represents hydrogen or an alkyl or alkylene group having 1 to 5 carbon atoms), and a diene acetal is then hydrolyzed with an acid. 3] (Wherein R ¹ represents hydrogen or an alkyl or alkylene group having 1 to 5 carbon atoms) 4-alkylidene-3,5,5-trimethyl-2-cyclohexene-1-
On recipe.