JPH0611721B2 - Method for producing 2-methylene-6,6-dimethyl or 5,6,6-trimethylcyclohexylcarbaldehyde - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to γ-iron, which has a high value as a flavoring substance having an iris-like odor, and γ-ionone and rose-like, which have a high value as a flavoring substance having a violet-like flavor. For details of a novel process for producing a compound represented by the following formula (1), which is useful as a synthetic intermediate for γ-damascon, which is highly valuable as a fragrant substance having an odor, the present invention provides the following formula (1). However, in the formula, R represents a hydrogen atom or a methyl group, wherein 2-methylene-6,6-dimethyl or 5,
It relates to a method for producing 6,6-trimethylcyclohexylcarbaldehyde.

More specifically, the present invention includes the following formula (1) -1 included in the above formula (1) which is useful as a synthetic intermediate for γ-ionone and γ-damascenone. 2-methylene-6,6-dimethylcyclohexylcarbaldehyde (hereinafter referred to as γ-cyclocitral) represented by the formula (1) and the following formula (1) included in the above formula (1) useful as a synthetic intermediate for γ-iron. -2 And a novel process for producing 2-methylene-5,6,6-trimethylcyclohexylcarbaldehyde (hereinafter referred to as γ-methylcyclocitral).

(B) Prior Art Conventionally, γ of the above formula (1) -1 included in the above formula (1).
-The following proposals are known regarding the method for producing cyclocitral. [Tetrahedron Letter: Tetrah
edron Letter 25, (32) 3457-3
458 (1984)] According to this proposal, 2- (2
-Methylene-6,6-dimethylcyclohexan-1-yl) -N, N-dimethylacetonitrile is reacted with silver nitrate in water-diethyl ether-tetrahydrofuran to synthesize γ-cyclocitral of the above formula (b). The method is described.

(C) Problems to be Solved by the Invention The silver nitrate used in the above conventional proposals is a very expensive reagent and is unsuitable for industrial production methods. In addition, silver nitrate is not suitable for an industrial method because it may be polluted and care must be taken when handling it.

(D) Means for Solving the Problems The inventors of the present invention have earnestly conducted research on a catalyst to replace silver nitrate, which has the above-mentioned drawbacks or disadvantages.

As a result, the following formula (2) However, in the formula, R represents a hydrogen atom or a methyl group, R1 and R2 each represent a lower alkyl group, or R1 and R2 together represent a lower alkylene group, 2- (2-methylene) -6,6-dimethyl or 5,6,6-trimethylcyclohexan-1-yl)
-N, N-dialkyl or alkyleneacetonitrile is reacted with an organic acid by catalytic reaction (1) However, in the formula, R represents a hydrogen atom or a methyl group, wherein 2-methylene-6,6-dimethyl or 5,
It has been discovered that it can be easily converted to 6,6-trimethylcyclohexylcarbaldehyde.

And the compound of the above formula (2) is, for example, the following formula (4) However, in the formula, R represents a hydrogen atom or a methyl group, and is represented by: 1- (3,3-dimethyl or 3,3,4-trimethyl-1-cyclohexene-
1-yl) methyl alcohol can be formed by reacting it with a halogenating agent, a mesylating agent or a tosylating agent in the presence of a base in an organic solvent. However, in the formula, X is halogen such as Br, Cl, I, mesyloxy group (OMs) or tosyloxy (OT).
s) and R is as defined above, 1- (3,3-dimethyl or 3,3,6-
Trimethyl-1-cyclohexen-1-yl) methylene halide or mesylate or tosylate can be easily obtained by reacting with N, N-dilower alkyl or lower alkylene-aminoacetonitrile in an organic solvent in the presence of a base. it can.

Therefore, the object of the present invention is to provide a highly valuable γ as a perfume substance.
-To provide a method for producing the compound of the formula (1), which is useful as a synthetic intermediate of -ionone, γ-iron and γ-damascon, without the above-mentioned disadvantages or drawbacks.

These and many other objects and advantages of the present invention will become more apparent from the description below.

One embodiment of the synthesis example of the compound of the above formula (1) can be represented as follows when shown in a process diagram.

Taking the above embodiment as an example, the synthesis of the compound of formula (1) will be described in more detail.

1- (3,3-dimethyl or 3,3,4 of the above formula (3)
-Trimethyl-1-cyclohexen-1-yl) methylene halide or mesylate or tosylate can be synthesized by 1- (3,3-dimethyl or 3,3) of the above formula (4).
3,4-trimethyl-1-cyclohexen-1-yl)
It can be easily carried out by reacting methyl alcohol with a halogenating agent, mesylating agent or tosylating agent, preferably in an organic solvent in the presence of a base.

The reaction can be preferably carried out, for example, under a temperature condition of about −78 ° to about + 150 ° C., for a reaction time of about 1 to about 5 hours.

Specific examples of the organic solvent used in the reaction include ethers such as ether and tetrahydrofuran. The amount of these organic solvents used is
There is no particular restriction and it may be appropriately selected. For example, a use amount in the range of about 1 to about 10 times by weight with respect to the compound of the formula (4) can be preferably exemplified. Examples of the halogenating agent, mesylating agent and tosylating agent used in the reaction include phosphorus tribromide, phosphorus trichloride, methanesulfonyl chloride, P-toluenesulfonyl chloride and the like. In the example of the above process chart, an example using phosphorus tribromide as the halogenating agent is shown. The amount of these agents used can be appropriately selected and changed, but for example, the amount used can be preferably exemplified in the range of about 1 to about 3 mol relative to the compound of the above formula (4). Furthermore, examples of the base include organic bases such as pyridine and triethylamine. In the example of the above process diagram, an example using pyridine is shown. The use amount of these bases may be appropriately selected, and for example, the use amount in the range of about 1 to about 5 mol can be preferably mentioned with respect to the compound of the formula (4). After completion of the reaction, for example, the organic layer is subjected to post-treatment such as washing with water and neutralization, the solvent is distilled off, and the compound is then purified using a means such as distillation or column chromatography to easily obtain the compound of formula (3). You can

For example, 2- (2-) represented by the above formula (2) from the compound of the above formula (3) that can be synthesized as described above.
To synthesize methylene-6,6-dimethyl or 5,6,6-trimethylcyclohexan-1-yl) -N, N-dialkyl or alkyleneacetonitrile, for example, the compound of formula (3) is added to an organic solvent of calcium carbonate. , Sodium carbonate, lithium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide and the like, and easily synthesized by reacting with N, N-di-lower alkyl or lower alkylene-aminoacetonitrile in the presence of a base. .

The reaction can be preferably carried out, for example, under a temperature condition in the range of about -78 ° to about + 200 ° C, for a reaction time of about 0.5 to 48 hours.

The amount of N, N-dilower alkyl or lower alkylene-aminoacetonitrile used in the above reaction is, for example, about 1 to about the compound of the above formula (3).
The amount used may be preferably in the range of about 2 mol. The amount of the base used is preferably, for example, about 0.1 mol to about 10 mol with respect to the compound of the above formula (3). Examples of the organic solvent include dimethylformaldehyde, tetrahydrofuran, acetonitrile, dimethylsulfoxide, toluene, ether, dioxane and the like. The amount of these organic solvents used is not particularly limited and may be appropriately selected. For example, an amount of about 1 to about 100 times by weight the amount of the compound of the formula (3) is preferably exemplified. it can. After completion of the reaction, for example, the reaction product may be extracted with an organic solvent such as hexane and ether, washed with water, dried, and then subjected to the next hydrolysis as it is, or purified by a means such as column chromatography and distillation. Thus, the compound of formula (2) can be easily obtained.

The γ-cyclocitral or γ-methylcyclocitral represented by the formula (1) of the present invention is easily synthesized, for example, by bringing the compound of the formula (2) obtainable as described above into contact with an organic acid. can do.

The reaction is preferably carried out in a solvent, and a solvent such as water, tetrahydrofuran, ether or the like can be preferably used. These solvents can be mixed and used at an arbitrary ratio. The reaction temperature and reaction time can be appropriately selected depending on the solvent used, for example,
A reaction temperature of about 0 ° to about 100 ° C. and a reaction time of about 0.5 to about 48 hours can be exemplified. The amount of the organic solvent used is preferably, for example, about 1 to about 100 times by weight the amount of the compound of the formula (2).

Examples of the organic acid used in the above reaction include oxalic acid,
Formic acid and the like can be preferably mentioned. The amount of these organic acids used is preferably in the range of, for example, about 1 to about 5 mol relative to the compound of the formula (2).

After completion of the reaction, the organic layer is washed with saline, the solvent is distilled off, and the compound of the formula (1) can be easily synthesized by purification by means such as distillation and column chromatography.

For example, equation (1) that can be synthesized as described above.
An example of a method for synthesizing γ-ionone and γ-damascon using a compound can be represented as follows, for example, in a manufacturing process chart.

According to the above process chart, γ-
Ionone and γ-damascenone can be easily synthesized.

Next, several examples of the method of the present invention will be described in more detail with reference to examples. For reference, a production example of the compound of formula (2) is also described.

(E) Example Synthesis of γ-cyclocitral and γ-methylcyclocitral.

(1) 1- (3,3-dimethyl-1-cyclohexene-
1-yl) methylene bromide Synthesis of formula (3).

14 g (0.1 mol) of 1- (3,3-dimethyl-1-cyclohexen-1-yl) methyl alcohol formula (4) are charged together with 1 g of pyridine in 100 ml of dry ether. The inside temperature of cooling is kept at about 10 to about 15 ° C with an ice water bath. At the same temperature, 10.8 g (0.04 mol) of phosphorus tribromide is added dropwise. After completion of the dropping, stirring is continued for 1 hour and left overnight.

The reaction solution is poured into ice water, the ether layer is separated, washed with brine, neutralized with sodium bicarbonate water, dried over magnesium sulfate, and concentrated. Purify by silica gel column chromatography.

Rf = 0.729 (n-hexane / ethyl acetate = 3/1 Wakogel-200) 16 g, yield 70%.

(2) Synthesis of 2- (2-methylene-6,6-dimethylcyclohexan-1-yl) N, N-dimethylacetonitrile formula (2).

2.1 g (10 mmol) of the formula (3), 0.84 g (10 mmol) of N, N-dimethylaminoacetonitrile and 2.2 g (16 mmol) of calcium carbonate were added to 12 ml of DMF.
Along with this, the mixture is placed in a 50 ml flask and reacted under stirring at room temperature for 24 hours under argon. After completion n-hexane 100m
l is added and washed with water. Rf = by drying over magnesium sulfate, concentrating and purifying by silica gel chromatography
1.22 g of formula (2) having 0.600 (n-hexane / ethyl acetate = 3/1) was obtained. Yield: 80%.

(3) Synthesis of 1- (3,3,4-trimethyl-1-cyclohexen-1-yl) methylene bromide of formula (3).

The procedure of Example (1) was repeated except that 1- (3,3,4-trimethyl-1-cyclohexen-1-yl) methyl alcohol was used as the alcohol of the formula (4) to obtain the compound of the formula (3 compound). 18.3 g was obtained with a yield of 80%.

(4) Synthesis of 2- (2-methylene-5,6,6-trimethylcyclohexen-1-yl) -N, N-dimethylacetonitrile formula (3).

The procedure is the same as in Example (2) except that 1- (3,3,4-trimethyl-1-cyclohexen-1-yl) methylene bromide is used as the bromide of the formula (3) to obtain the formula (2). 1.8 g of the compound was obtained. Yield; 82%.

(5) Synthesis of γ-cyclocitral formula (1) -1.

2- (2-methylene-6,6-dimethylcyclohexen-1-yl) -N, N-dimethylacetonitrile 10.3 g (0.05 mol), 98% formic acid 9.2 g in a flask.
(0.2 mol), water 31 g, tetrahydrofuran 31 g
Was stirred for 30 minutes at room temperature, then heated and stirred at 70 ° C (reflux) for 20 minutes, cooled, extracted with ether, and the organic layer was washed with brine, sodium bicarbonate water, and brine, and dried over magnesium nitrate. After treatment, the ether was distilled off and the residue was distilled under reduced pressure to obtain 4.9 g of the compound of formula (1) -1 having a boiling point of 80 to 85 ° C. Yield: 64%.

(6) Synthesis of γ-cyclocitral formula (1) -1.

In the same manner as in Example (5) except that oxalic acid was used in place of formic acid in Example (5), 6.1 g of the compound of formula (1) -1 was obtained. Yield; 82%.

Synthesis of γ-methylcyclocitral Formula 1-2.

2- (2-Methylene-5,6,6-trimethylcyclohexan-1-yl) -N, N-dimethylacetonitrile was used, and the procedure of Example (5) was repeated to obtain formula (1)-
6.9 g of two compounds were obtained. Yield; 83%.

(7) Synthesis of γ-methylcyclocitral formula (1) -2.

In the same manner as in Example (5) except that oxalic acid was used in place of formic acid in Example (5), 7 g of the compound of formula (1) -2 was obtained. Yield: 85%.

(F) Reference Example (1) Synthesis of γ-ionone.

Acetylidene triphenylphosphorane in flask 20.
9 g (65.8 mmol) and 150 g of toluene are charged and distilled off. 5 g of γ-cyclocitral (32.9
Mmol) is added and the reaction is continued for another 18 hours. Then, it cools gradually and it cools to 10-15 degreeC. Phosphorane is filtered off, the crystals are washed with toluene, toluene is recovered from the filtrate and the washing solution by an evaporator, hexane is added to the residue to crystallize phosphine oxide, and then filtered. The crystals are
Wash with hexane, combine the filtrates, and collect the solvent with an evaporator. The obtained crude product was purified by silica gel column chromatography (hexane / ether = 3/1) to obtain 4.2 g of γ-ionone. Yield: 66%.

(2) Synthesis of γ-damaskone.

Synthesis of (2) -11- (6,6-dimethyl-2-methylenecyclohexan-1-yl) -3-buten-1-ol.

A Grignard reagent is prepared from 1.2 g (49.3 mmol) of magnesium metal, 3.02 g (39.5 mmol) of allyl chloride and 20 ml of dry tetrahydrofuran. 5 g (32.9 mmol) of γ-cyclocitral was added dropwise thereto at a reaction temperature of 10 to 12 ° C. (Dripping time 15 minutes) After completion of dropping, stirring is continued for 1 hour at room temperature to complete the reaction. The reaction solution is poured into a saturated aqueous ammonia solution, the organic layer is separated, and the aqueous layer is extracted with ether and combined with the organic layer.
After washing with water and drying over magnesium sulfate, the solvent was distilled off to obtain 5.7 g of the target compound. Crude yield; 89%.

(2) -2 Synthesis of 1- (6,6-dimethyl-2-methylenecyclohexan-1-yl) -3-buten-1-one.

5 g (25.8) of the alcohol obtained in Reference Example (2) -1
Mmole, 5.7 g of Diones reagent in 45 g of acetone.
While maintaining g at a temperature of 20 to 25 ° C, the solution is added dropwise over 10 minutes. After the dropping is completed, the reaction is continued for another 30 minutes at the same temperature.
Excess hexavalent chromium is reduced with isopropyl alcohol. Then, the sulfuric acid is neutralized with an alkali to remove the solid matter, and the acetone is distilled off. Ether is added to the residual liquid, washed with brine and dried over magnesium sulfate, and the ether is distilled off.
The crude product was purified by silica gel column chromatography (hexane / ether = 3/1) to obtain 3 g of the target compound. Yield: 60%.

(2) -3 Synthesis of γ-damaskone.

1.3 g (6.7 mmol) of the ketone obtained in Reference Example (2) -2, 0.1 g of P-toluenesulfonic acid and 50 ml of toluene are charged, and the mixture is heated to 80 ° C. and reacted for 1 hour.
The reaction solution was neutralized with alkali, dried over magnesium sulfate, and concentrated to obtain 1.6 g of crude product. The crude product was purified by silica gel column chromatography (hexane / ether = 3/1) to obtain 1.28 g of γ-damaskone. Yield: 87
%.

(G) Effect 2- (2-methylene-) conventionally included in the above formula (2)
6,6-Dimethylcyclohexan-1-yl) -N, N
From dimethylacetonitrile, the above formula (1) of the present invention
In the method for synthesizing γ-cyclocitral of the above formula (1) -1 included in (1), silver nitrate is used as a reagent.

This silver nitrate is extremely expensive and is not suitable for an industrial production method, and in addition, there is a risk of pollution, and there are disadvantages and drawbacks that the compound of the above formula (1) cannot be industrially produced inexpensively and easily.

However, by using an organic acid in place of the silver nitrate according to the method of the present inventors, it is possible to eliminate the above disadvantages and defects.

Claims (1)

[Claims] 1. The following formula (2) However, in the formula, R represents a hydrogen atom or a methyl group, R1 and R2 each represent a lower alkyl group, or R1 and R2 together represent a lower alkylene group, 2- (2-methylene) -6,6-dimethyl or 5,6,6-trimethylcyclohexan-1-yl)
-N, N-dialkyl- or -alkyleneacetonitrile is reacted with an organic acid in a catalytic reaction, the following formula (1): However, in the formula, R represents a hydrogen atom or a methyl group, wherein 2-methylene-6,6-dimethyl or 5,
A method for producing 6,6-trimethylcyclohexylcarbaldehyde.