JPH11292810A - Production of cis-form unsaturated alcohol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject compound in high yield by reacting a cyclic vinyl ether with a Grignard reagent in the presence of a tiarylphosphine and a specific amount of a nickel compound. SOLUTION: (A) A cyclic vinyl ether represented by formula I [(n) is 1 or 2; R<1> is H or methyl] (e.g. 2,3-dihydrofuran) is reacted with (B) a Grignard reagent represented by the formula R<2> MgX (R<2> is a <=10C aralkyl or the like; X is Cl, Br or I) in the presence of (C) a triarylphosphine (e.g. triphenylphosphine) and (D) a nickel compound in an amount of <=0.05 mol based on 1 mol cyclic vinyl ether represented by formula I [e.g. tetrakis (triphenylphosphine) nickel (0)], preferably at 30-100 deg.C for 30 min to 10 h to thereby produce the objective compound represented by formula II. The amount of the component C used is preferably usually 0.1-3,000 mol based on 1 mol Ni atom in the component D.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to the following formula (1):

[0002]

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(Wherein, R ¹ represents a hydrogen atom or a methyl group, and R ² represents an alkyl group having 10 or less carbon atoms, an alkenyl group having 10 or less carbon atoms, an aralkyl group having 10 or less carbon atoms, or an aryl group. And n represents 1 or 2
Represents )). The cis-type unsaturated alcohol obtained by the production method of the present invention is useful as a raw material for fragrances, pharmaceuticals and the like. Among them, cis-3-hexen-1-ol (a compound in the case where R ¹ is a hydrogen atom, R ² is an ethyl group, and n is 1 in the formula (1)) is called green leaf alcohol. It is used industrially as a fragrance.

[0004]

2. Description of the Related Art As a method for synthesizing a compound represented by the above formula (1), a cyclic vinyl ether selected from the group consisting of 2,3-dihydrofuran and 3,4-dihydro-2H-pyran is used. A Grignard reagent such as methylmagnesium bromide or phenylmagnesium bromide for 20 hours or in the presence of a catalyst comprising a nickel complex having a phosphorus compound as a ligand (0.1 mol relative to 1 mol of the cyclic vinyl ether) 15-48
Methods for reacting for a predetermined time within a time range have been reported [J. Org. Chem., 49 , 4894 (1984), J. Am. Chem. S.
oc., 101 , 2246 (1979)].

[0005]

In the above synthesis method,
When 3,4-dihydro-2H-pyran is used as a raw material, the yield of the cis-type unsaturated alcohol represented by the formula (1) is at most 80%. In addition, the above formula (1) depends on the reaction conditions.
In addition to the cis-type unsaturated alcohol (hereinafter sometimes abbreviated as a cis-form), isomers having a carbon-carbon double bond in a trans-configuration (hereinafter abbreviated as a trans-form) May be produced, and when the trans form is the largest, the ratio of the cis form to the trans form is 76/24. On the other hand, when 2,3-dihydrofuran is used as a raw material, the desired formula (1)
The yield of the cis unsaturated alcohol represented by
%. In addition, a trans form may be produced depending on the reaction conditions. In the case where the trans form is most frequently used, the ratio of the cis form and the trans form is 33/67. Therefore, if the cis-type unsaturated alcohol represented by the formula (1) is industrially and advantageously obtained with high purity by utilizing the above reaction, the production of the trans form is suppressed and the cis-formula represented by the formula (1) is suppressed. It is desired to improve the reaction results such as the yield of type unsaturated alcohol.

The present invention has been made in view of such prior art, and provides a method for industrially advantageously obtaining a cis-type unsaturated alcohol represented by the above formula (1) with a high purity. That is the task.

[0007]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, they have been used as a catalyst in reacting a cyclic vinyl ether represented by the formula (2) with a Grignard reagent. When the amount of the nickel compound is reduced, not only the generation of the trans form is suppressed, but also the cis-type unsaturated compound represented by the formula (1) can be obtained by shortening the reaction time set to 15 hours or more in the above literature. Have found that alcohol can be obtained in good yields,
As a result of further studies, the present invention has been completed.

That is, the present invention provides the following formula (2)

[0009]

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Wherein R ¹ and n are as defined above, and a cyclic vinyl ether of the formula (3) R ² MgX (3) wherein R ² is as defined above; Represents a chlorine atom, a bromine atom or an iodine atom) with a Grignard reagent represented by the formula (1) per 0.1 mol of triarylphosphine and 1 mol of the cyclic vinyl ether represented by the formula (2).
Reacting in the presence of not more than 05 mol of a nickel compound, formula (1)

[0011]

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(Wherein R ¹ , R ² and n are as defined above).

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The cyclic vinyl ether represented by the formula (2) used as a starting material in the present invention is, specifically, 2,3-dihydrofuran (n = 1, R ¹ = hydrogen atom), 3-methyl-2,3-dihydrofuran (n =
1, R ¹ = methyl group), 3,4-dihydro-2H-pyran (n = 2, R ¹ = hydrogen atom), 4-methyl-3,4-
Dihydro-2H-pyran (n = 2, R ¹ = methyl group), a commercially available product may be used, or a product prepared by a method described in the literature may be used.

The cyclic vinyl ether represented by the formula (2) is used in an amount of usually 0.8 to 5 mol, preferably 0.8 to 1 mol, per mol of the Grignard reagent represented by the following formula (3).
Used in molar proportions.

In the formula (3) representing the Grignard reagent used in the present invention, the number of carbon atoms represented by R ² is 1
Examples of the alkyl group of 0 or less include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group,
-Butyl group, n-hexyl group, 2-ethylhexyl group,
Examples of the alkenyl group having 10 or less carbon atoms include a vinyl group, a 2-propenyl group, a 1-propenyl group, a 1-butenyl group, a 2-butenyl group, and a 3-methyl-2 group. -Butenyl group, 1-octenyl group and the like. Examples of the aralkyl group having 10 or less carbon atoms represented by R ² include, for example, a benzyl group and a phenethyl group. Examples of the aryl group include:
Examples include a phenyl group and a tolyl group. Among them, R ² is preferably a methyl group or a phenyl group.

The Grignard reagent represented by the formula (3) is
A commercially available solution of diethyl ether or tetrahydrofuran may be used, or a compound represented by the formula R ² X (where R ² and X are as defined above) in diethyl ether or tetrahydrofuran according to a conventional method. A compound prepared by reacting the compound represented by with metal magnesium may be used. In addition, from the viewpoint of the reaction rate, the diethyl ether or tetrahydrofuran should be removed as much as possible before the reaction of the Grignard reagent represented by the formula (3) with the cyclic vinyl ether represented by the formula (2). Is preferred.
As a method for removing diethyl ether or tetrahydrofuran, for example, a known method such as a method of evaporating under reduced pressure and a method of substituting a solvent described below can be used.

The nickel compound used in the present invention includes, for example, nickel chloride (II), nickel bromide (I
I), nickel (II) acetate tetrahydrate, nickel (II)
Divalent nickel compounds such as acetylacetonate dihydrate and dichlorobis (triphenylphosphine) nickel (II); bis (1,5-cyclooctadiene) nickel (0), tetrakis (triphenylphosphine) nickel ( Examples thereof include a zero-valent nickel compound such as 0), and a nickel complex having a ligand such as triphenylphosphine is preferable. The amount of the nickel compound used is 0.05 mol or less per 1 mol of the cyclic vinyl ether represented by the general formula (2). If the amount of the nickel compound is more than 0.05 mol per 1 mol of the cyclic vinyl ether represented by the general formula (2), no improvement in the reaction results is observed. The amount of the nickel compound to be used is usually 0.1 to 1 mol of the cyclic vinyl ether represented by the general formula (2).
Although it is within the range of 00001 to 0.05 mol, the use amount of the nickel compound is preferably small from the viewpoint of lowering the production amount of the trans form, and the amount per mol of the cyclic vinyl ether represented by the general formula (2) is better. , Preferably 0.0
It is in the range of 0001 to 0.02 mol, more preferably in the range of 0.0001 to 0.01 mol.

According to the present invention, the amount of nickel catalyst used (2,3-dihydrofuran or 3,3
(0.1 mol per 1 mol of 4-dihydro-2H-pyran). As described above, since the amount of the expensive nickel compound used can be reduced, the production method of the present invention can be said to be an industrially advantageous method in combination with the improvement of the reaction results.

The triarylphosphine used in the present invention includes, for example, triphenylphosphine, tris (p-tolylphenyl) phosphine, tris (2,
Examples thereof include 4-dimethylphenyl) phosphine, and industrially inexpensive triphenylphosphine is preferred. The amount of the triarylphosphine to be used is generally 0.1 mol per mol of nickel atom in the above nickel compound.
The amount is in the range of 1 to 3000 mol, but from the viewpoint of increasing the reaction rate and the selectivity to the cis-form, it is better to use a large amount of triarylphosphine, and it is 2 to 2000 mol per mol of nickel atom. Preferably, the amount is in the range. Depending on the type of nickel compound used, triarylphosphine may be incorporated as a ligand into the nickel compound in the reaction system. In this case, it is preferable to increase the amount of the triarylphosphine used in consideration of the amount incorporated as a ligand.

The reaction according to the invention is usually carried out in the presence of a solvent. Examples of usable solvents include those that do not adversely affect the reaction of aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene; ether-based solvents such as t-butyl methyl ether, which have a small coordination force to nickel, and the like. No. The amount of the solvent to be used is not particularly limited, and is preferably in a range that does not adversely affect the reaction. In the reaction according to the present invention, it is also possible to use a large amount of the cyclic vinyl ether represented by the formula (2) used as a raw material instead of the above-mentioned solvent, and also to function as a solvent.

The reaction according to the present invention is usually carried out at 30 to 100
C., preferably at a temperature in the range of 50 to 90.degree. The reaction time is usually in the range of 30 minutes to 10 hours.

The reaction according to the present invention is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

After completion of the reaction, the cis-unsaturated alcohol represented by the formula (1) is prepared by, for example, charging the reaction mixture into an aqueous solution of ammonium chloride, dilute hydrochloric acid, etc.
Extraction with an organic solvent such as a hydrocarbon solvent such as benzene or toluene; an ether solvent such as diethyl ether; an ester solvent such as ethyl acetate; a halogenated hydrocarbon solvent such as dichloromethane; Can be separated and obtained according to a conventional method such as a method of distilling off.

The purity of the thus obtained cis-type unsaturated alcohol represented by the formula (1) can be further increased, if necessary, by known means such as distillation and column chromatography.

[0025]

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 2.88 g of dichlorobis (triphenylphosphine) nickel (II) was placed in a two-liter three-necked flask.
(4.4 mmol, 4-methyl-2,3-dihydro-2
0.51 mol% based on H-pyran), 2.31 g of triphenylphosphine (8.8 mmol, 2 mol per mol of nickel atom) and 1000 ml of toluene were charged, and the mixture was charged under a nitrogen atmosphere. 400 ml of methylmagnesium bromide in diethyl ether at room temperature
(Concentration: 2.2 mol / l, containing 0.88 mol of methyl magnesium bromide) and stirred for 15 minutes. Thereafter, about 400 ml of diethyl ether was distilled off at a temperature of 25 ° C. or less and about 1 mmHg, and then 200 ml of toluene was added. The resulting mixture was added to 4-methyl-2,3-dihydro-2H- at 20 ° C. under a nitrogen atmosphere.
82.6 g (0.84 mol) of pyrane were added dropwise over 5 minutes. The temperature of the obtained reaction mixture was raised to 50 ° C., and the mixture was stirred at the same temperature for 4 hours and further at 70 ° C. for 6 hours. After cooling the obtained reaction mixture to room temperature, it was poured into 4 liters of a saturated aqueous solution of ammonium chloride and allowed to stand to separate into two layers. The organic layer and the aqueous layer are separated, and the aqueous layer is
Washed twice with 0 ml. When the organic layer and the toluene layer were combined and analyzed by gas chromatography, 90.97 g of 3-methyl-cis-4-hexen-1-ol was obtained.
(800 mmol, yield: 95.2%), 3-methyl-
0.78 g of trans-4-hexen-1-ol (7
Mmol, yield: 0.8%) (cis-isomer / trans-isomer = 99.1 / 0.9).

Gas Chromatography Analysis Conditions Column: PEG-HT (5%, 80/100 mesh, Chromsolve WAW DMCS: Gaschrom Industry Co., Ltd., length: 4 m) Column temperature: After holding at 80 ° C. for 8 minutes The temperature is raised to 230 ° C. at a rate of 5 ° C./min. Injection temperature: 230 ° C Detector: FID Carrier gas: Nitrogen

By distilling the above organic layer and the toluene layer into one under reduced pressure, 3-methyl-cis-
4-hexen-1-ol (boiling point: 62 ° C./9 mmH
g, purity: 98.5%). The physical properties of this product are shown below.

¹ H-NMR (300 MHz, CDCl ₃ ,
TMS) δ (ppm): 0.97 (d, 3H), 1.63
(D, 3H), 1.41 to 1.67 (m, 2H), 2.
59-2.70 (m, 1H), 3.55-3.69
(M, 2H), 5.14 to 5.23 (m, 1H), 5.
38 to 5.48 (m, 1H)

Example 2 3.2 mg of dichlorobis (triphenylphosphine) nickel (II) was placed in a 100 ml three-necked flask.
(0.005 mmol, 0.02 mol% based on 2,3-dihydrofuran), 2.623 g of triphenylphosphine (10 mmol, 2000 mol per mol of nickel atom) and toluene 30ml
Charged, 11.8 ml of a diethyl ether solution of methylmagnesium bromide at room temperature under a nitrogen atmosphere (concentration: 2.
37 mol / l, containing 28 mmol of methyl magnesium bromide) and stirred for 15 minutes. Thereafter, about 10 ml of diethyl ether is distilled off at a temperature of 25 ° C. or less and about 1 mmHg, and then toluene 10 m
1 was added. The obtained mixture is added at 20 ° C. under a nitrogen atmosphere.
Then, 1.73 g (24.7 mmol) of 2,3-dihydrofuran was added dropwise over 5 minutes. The temperature of the resulting reaction mixture was raised to 50 ° C.,
Stirring was performed for hours. After cooling the obtained reaction mixture to room temperature, it was poured into 120 ml of a saturated aqueous solution of ammonium chloride and allowed to stand to separate into two layers. The organic layer and the aqueous layer were separated, and the aqueous layer was washed twice with 20 ml of toluene. When the organic layer and the toluene layer were combined into one and analyzed by gas chromatography under the same analysis conditions as in Example 1, cis-3-
It was found that penten-1-ol contained 2.03 g (23.6 mmol, yield: 95.5%).
No peak corresponding to trans-3-penten-1-ol was observed (cis-form / trans-form = 10).
0/0)

30 g of the above-mentioned organic layer and toluene layer were combined and purified by silica gel column chromatography to give 3-methyl-cis-4-hexen-1-ol (boiling point: 53 ° C./17 mmHg). I got The physical properties of this product are shown below.

¹ H-NMR (300 MHz, CDCl ₃ ,
TMS) δ (ppm): 1.64 to 1.67 (m, 3H),
2.34 (q, 2H), 3.65 (t, 2H), 5.3
5 to 5.45 (m, 1H), 5.59 to 5.69 (m, 1H)
1H)

Example 3 In Example 2, the amounts of dichlorobis (triphenylphosphine) nickel (II) and triphenylphosphine used were 163.6 mg (0.25 mmol,
To 1 mol% based on 2,3-dihydrofuran) and 2.625 g (10 mmol, 40 mol per mol of nickel atom), and to 11.8 ml of a diethyl ether solution of methylmagnesium bromide. Instead, 13.9 ml of a solution of ethyl magnesium bromide in diethyl ether (concentration: 2.13 mol / l, 29.
(Including 6 mmol of ethyl magnesium bromide), and the same operation as in Example 2 was carried out except that stirring of the reaction mixture was carried out at 50 ° C. for 3 hours, and the resulting reaction mixture was cooled to room temperature. The solution was poured into 120 ml of a saturated aqueous solution of ammonium chloride, allowed to stand, and separated into two layers.
The organic layer and the aqueous layer were separated, and the aqueous layer was washed twice with 20 ml of toluene. When the organic layer and the toluene layer were combined and analyzed by gas chromatography under the same analysis conditions as in Example 1, cis-3-hexen-1-ol (green leaf alcohol) was 0.71 g (7.1 mmol, Yield: 29.0
%), Trans-3-hexen-1-ol is 0.02%
g (0.2 mmol, yield: 0.8%). (Cis-form / trans-form = 97.3 / 2.
7)

Example 4 In Example 2, the amounts of dichlorobis (triphenylphosphine) nickel (II) and triphenylphosphine used were 81.8 mg (0.125 mmol,
0.5 mol% based on 2,3-dihydrofuran) and 655.8 mg (2.5 mmol, 20 mol per mol of nickel atom), and a solution of methylmagnesium bromide in diethyl ether. 11.
Except that 28.9 ml of a diethyl ether solution of phenylmagnesium bromide (concentration 0.90 mol / l, containing 26 mmol of phenylmagnesium bromide) was used instead of 8 ml, and the reaction mixture was stirred at 50 ° C. for 2 hours. After the same operation as in Example 2 was performed, the obtained reaction mixture was cooled to room temperature, poured into a saturated ammonium chloride aqueous solution (120 ml), and allowed to stand to separate into two layers. The organic layer and the aqueous layer are separated, and the aqueous layer is
Washed twice with ml. Combine the organic layer and the toluene layer,
When analyzed by gas chromatography under the same analysis conditions as in Example 1, cis-4-phenyl-3-butene-1 was obtained.
2.59 g (17.5 mmol, yield: 7)
1.0%). No peak corresponding to trans-4-phenyl-3-buten-1-ol was observed (cis-form / trans-form = 10).
0/0).

Comparative Example 1 In Example 2, the amount of dichlorobis (triphenylphosphine) nickel (II) used was 1.616 g (2.4).
7 mmol, 10 mol% with respect to 2,3-dihydrofuran), and the same operation as in Example 2 was carried out except that triphenylphosphine was not used. After cooling, the mixture was poured into a saturated aqueous ammonium chloride solution (120 ml), allowed to stand, and separated into two layers. The organic layer and the aqueous layer were separated, and the aqueous layer was washed twice with 20 ml of toluene. The organic layer and the toluene layer were combined and analyzed by gas chromatography under the same analysis conditions as in Example 1. As a result, 1.72 g (20.0 mmol, yield: 81) of cis-3-penten-1-ol was obtained. .0
%), 0.30 of trans-3-penten-1-ol
g (3.5 mmol, yield: 14.0%) (cis-isomer / trans-isomer = 85.3 / 1).
4.7).

[0036]

According to the present invention, the cis-type unsaturated alcohol represented by the formula (1) can be industrially advantageously produced with high purity.

Claims (2)

[Claims] (1) Formula (2) (Wherein n represents 1 or 2, R ¹ represents a hydrogen atom or a methyl group) and a cyclic vinyl ether represented by the formula (3) R ² MgX (3) (wherein R ² has 10 carbon atoms). A Grignard reagent represented by the following alkyl group, an alkenyl group having 10 or less carbon atoms, an aralkyl group having 10 or less carbon atoms, or an aryl group, and X represents a chlorine atom, a bromine atom or an iodine atom), The reaction is carried out in the presence of a triarylphosphine and 0.05 mol or less of a nickel compound per 1 mol of the cyclic vinyl ether represented by the formula (2). (Wherein R ¹ , R ² and n are as defined above)
A method for producing a cis-type unsaturated alcohol represented by the formula: 2. The production method according to claim 1, wherein the amount of the triarylphosphine used is 0.1 to 3000 mol per mol of nickel atom.