JP3120409B2 - Method for producing optically active 1-alkenes - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION This invention relates to geranyl acetate
Carbon atoms adjacent to the terminal double bond of 3,7-dimethyl-1,6-octadiene or the like, which is useful as a terpene synthesis intermediate for pharmaceuticals, agricultural chemicals or fragrances, from substituted allyl alcohol derivatives such as glycerol or neryl acetate ; The present invention relates to a method for producing optically active 1-alkenes which are asymmetric carbon atoms.

[0002]

2. Description of the Related Art Conventionally, as a method for producing 1-alkenes, a method of reducing an ester of a substituted allyl alcohol in the presence of a palladium catalyst is known. In this case, 2-alkenes are produced as a by-product. There is a disadvantage of doing so.

[0003] Therefore, as a method for selectively producing 1-alkenes without by-producing 2-alkenes, tributylamine is used as a ligand by reacting triethylamine salt of formic acid in addition to a palladium catalyst. A method has been proposed in which 3,7-dimethyl-1,6-octadiene is obtained from geranyl acetate or neryl acetate (J. Tsuji et a.
1, Tetrahedron Letter, 101
7 (1984)).

[0004] 3,7-Speaking limited to the production of dimethyl-1,6-octadiene, a method for thermally isomerizing pinane obtained by hydrogenating pinene, 3,7-dimethyl-1-octene -7-ol is heated and dehydrated in the presence of an acid catalyst, and citral is reduced (Dan
ieski et al, Rocz. Chem. , 4
5 (5), 923 (1971)) and the like.

[0005]

By the way, in the case of compounds for medicines and fragrances, even if they have the same skeleton, there is often a great difference in their physiological activities depending on whether or not they have optical activity. It is known. Therefore, 3,7-dimethyl-, a kind of 1-alkenes
In producing 1,6-octadiene, it is required to introduce an asymmetric carbon atom at the 3-position.

However, the conventional method cannot directly and simply produce optically active 1-alkenes, particularly 3,7-dimethyl-1,6-octadiene having an asymmetric carbon atom at the 3-position. There was a problem.

The present invention is intended to solve such problems of the prior art, and 1-alkenes in which the carbon atom adjacent to the terminal double bond is an asymmetric carbon atom, particularly, an optically active 3-alkene. It is an object of the present invention to provide a method for easily obtaining 7,7-dimethyl-1,6-octadiene.

[0008]

Means for Solving the Problems The present inventors have found that substituted allyl alcohol derivative, such as esters thereof, the third in the presence of a palladium compound and an optically active phosphine compound
It has been found that the above-mentioned object of the present invention can be achieved by reacting with a secondary amine and formic acid, and the present invention has been completed.

That is, the present invention relates to a compound represented by the formula (1) R ₁ R ₂ C ＣCHCH ₂ X (1) wherein R ₁ and R ₂ are each independently an unsubstituted alkyl group ,
Alkyl substituted with a halogen atom or aryl group
Group, unsubstituted alkenyl group , halogen atom or aryl
An alkenyl group substituted with an aryl group , an unsubstituted aryl group , or
Although an aryl group substituted by a halogen atom, R ₁
And R ₂ are not the same and X is OCOR ₃ , OCO
₂ R ₄ , OCONR ₅ R ₆ (wherein R ₃ , R ₄ , R ₅ and R ₆ are
Each of which is a hydrogen atom, an alkyl group or an aryl group)
And a leaving group selected from the group consisting of a halogen atom and a tertiary amine and formic acid in the presence of a palladium compound and an optically active phosphine compound. (2) R ₁ R ₂ C ^* HCH ＝ CH ₂ (2) (wherein R ₁ and R ₂ are as described above, and C ^* is an asymmetric carbon atom). Provided is a method for producing an alkene.

In the present invention, R ₁ and R ₂ of the compound of the formula (1) as a starting material may not be the same group at the same time because the carbon atom to which they are commonly connected is an asymmetric carbon atom. is necessary. However, even when R ₁ and R ₂ are the same alkyl group, for example, when R ₁ is a methyl group and R ₂ is an ethyl group, they are not the same group.

[0011] The Contact Specific examples of the unsubstituted alkyl group, methyl, lower alkyl groups are exemplified preferably ethyl or the like, the alkyl group is a halogen atom or an aryl group as long as it does not inhibit the reaction between the tertiary amine and formic acid Replaced by
May be.

[0012] Also, specific examples of the unsubstituted alkenyl group, allyl, butenyl, lower alkenyl groups such as 4-methyl-3-pentenyl group are preferably exemplified, alkenyl
The group may also be substituted with a halogen atom or an aryl group as long as it does not inhibit the reaction with the tertiary amine and formic acid.

[0013] Also, specific examples of the unsubstituted aryl group, a phenyl group, or an aromatic hydrocarbon group such as a naphthyl group,
Examples include heterocyclic groups such as 2-pyridyl and 2-furanyl groups, and the aryl group may be substituted with a halogen atom as long as the reaction with a tertiary amine and formic acid is not inhibited.

[0014] X is Ri <br/> Ah at eliminated group capable under the reaction conditions of the present _{invention, O COR 3, OCO 2 R} 4, OCONR 5 R 6 ( _{wherein, R 3, R 4, R} 5 and R ₆ each represents a hydrogen atom, an alkyl group or an aryl group such as phenyl methyl and the like) 及
Fine chloro, bromo, the group consisting of a halogen atom, such as iodo
Is selected from

Examples of the more preferred groups of such R _1, R ₂ and X, R ₁ is a methyl group, R ₂ is 4-methyl-3-pentenyl group, X can be cited acetone preparative alkoxy group. Therefore,
As the compound of the formula (1), the following formula (3) which is easily available
Geranyl acetate represented by the following formula and neryl acetate represented by the formula (4) are preferably used.

[0016]

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The palladium compound used in this invention, rather than as a catalyst stay the same, but to react with an optically active phosphine compound to be described later, the complex is formed that optically active phosphine compound as a ligand, the complex Is believed to form optically active 1-alkenes after forming a π-allylpalladium intermediate with the substituted allyl alcohol derivative of formula (1).

[0018] Such as the palladium compound can be used various palladium compounds, for example, palladium acetyl acetate toner over preparative, .pi.-allyl palladium acetate, .pi.-allyl palladium chloride, palladium acetate, carbonate palladium, palladium nitrate, palladium chloride , Sodium chloroparadate, bisbenzonitrile palladium chloride, bis (1,5-cyclooctadiene) palladium, π-allyl palladium, tris (dibenzylideneacetone) dipalladium-monochloroform adduct [Pd ₂ (dba) _3. CHCl ₃ ] can be used.

The amount of the palladium compound used depends on the type of the palladium compound used and the like.
The amount is preferably from 0.1 to 100 mmol, more preferably from 1 to 10 mmol, per 1 mol of the substituted allyl alcohol derivative.

The optically active phosphine compound used in the present invention forms a complex with the ligand of the palladium compound as described above. Such optically active phosphine compound, (R) - (+) or (S) - (-) - 2- diphenylphosphino -2 '-R
₆ O-1,1'-binaphthyl (wherein R ₆ is a substituent such as lower alkyl such as methyl, benzyl, diphenylmethyl, etc.), (R)-(S) -PPFA [(R) -N, N-
Dimethyl-1-{(S) -2-diphenylphosphino)
Ferrocenyl @ ethylamine], (R)-(S) -PP
Monodentate compounds such as FOMe [(R) -1-{(S) -2- (diphenylphosphino) ferrocenyl} ethyl methyl ether] and (R) -BINAP [(R)
-2, 2'-bis (diphenylphosphino) -1, 1'
-Binaphthyl], (+)-DIOP [(+)-2,3-
O- isopropylidene -2, 3- dihydroxy-1,4
-Bis (diphenylphosphino ) butane ] , (S, S)
-Chiraphos [(2S, 3S)-(-)-bis (diphenyl
Ruphosphino) butane] , (R)-(S) -BPPFA
[(R) -N, N-dimethyl-{(2S, 3S) bis (diphenylphosphino) ferrocenyl} ethylamine]
And the like, and further, an optically active phosphine compound having a multidentate coordination can be used.
Among them, (R)-
(+) Or (S) - (-) - 2-diphenylphosphino-2 '- methoxy-1,1'-binaphthyl [(R) or (S) -MeO-MOP] is preferred.

[0021] The amount of such an optically active phosphine compound varies depending on its type or the like, to stabilize the palladium compound, palladium compound per mol of at least 2 molar than on, preferably 2-6 Mo Use the amount of le . This is because if the amount of the optically active phosphine compound is too small, palladium black is precipitated, and if it is too large, the reaction rate is too slow.

In the present invention, a tertiary amine and formic acid are used. These are components necessary for the rapid progress of the reaction according to the present invention .

The amount of formic acid used is at least 1 mole, preferably 1 to 1 mole, per mole of the compound of formula (1) as a starting material.
0 moles, more preferably 1.5 to 3 mol. The amount of the tertiary amine used is based on 1 mol of the compound of the formula (1).
It is used in an amount of not less than equimolar and not more than 1 mole of formic acid.

It is preferable to use a tertiary amine having a relatively high basic constant (pKa) from the viewpoint of accelerating the reaction rate. Examples thereof include trimethylamine, triethylamine, tri-n-butylamine and trioctylamine. , 1- (N, N-dimethylamino) -2
-Propanol, N, N-dimethyl-2-methoxyethylamine, N-methylmorpholine, N, N, N ', N'
-Tetramethylhexamethylenediamine, pyridine,
N, N-dimethylaniline and the like can be used.

In the present invention, generally, a palladium compound and an optically active phosphine compound are preferably dissolved in a solvent, and then a tertiary amine and formic acid are added in order while cooling the reaction system with ice, and then the formula (I) is added. 1) The compound of 1)
Was added at a temperature of 80 ° C., it can be carried out by reaction.

When a solvent is used in the present invention, it is necessary to use a solvent which is inert to the reaction with the tertiary amine and formic acid . Examples of such a solvent include diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, dioxolan, ethylene glycol dimethyl ether, ethers such as polyethylene glycol dimethyl ether having an average molecular weight of 200 to 20,000, alcohols such as methanol, ethanol, isopropanol and butanol; Glycols such as ethylene glycol and propylene glycol, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile, benzonitrile and propionitrile, acetamido, propionamide, N, N
- dimethylformamide, N, amides such as N- dimethylacetamide, sulfoxides such as dimethyl sulfoxide, scan Ruhoran, sulfolane and methyl sulfolane, phosphoric acid amides such as hexamethylphosphoramide Le amide,
Methyl acetate, ethyl acetate, methyl benzoate, esters such as ethylene carbonate, benzene, toluene, xylene, ethylbenzene, etc., blanking Tan, hexane, cyclohexane, cyclic or acyclic aliphatic such as methyl cyclohexane Hydrocarbons, any mixtures thereof, and the like can be used.

In the practice of the present invention, it is preferable to replace the atmosphere of the reaction system with an inert gas such as nitrogen or argon.

Separation and purification of the reaction product obtained as a result of the practice of the present invention can be performed by a conventional method. For example,
An extraction solvent such as pentane and water are added to the reaction solution to perform an extraction operation, and then an organic layer is separated. Then add 10 organic layers
The solution is washed once or twice with a 1% aqueous hydrochloric acid solution, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. After drying, a crude product can be obtained by removing the solvent. This conventional purification means, for example recrystallization, can be obtained an optically active 1-aralkyl Ke emissions such purified by means such as column chromatography.

[0029] Next, a stereoscopic configuration of the asymmetric carbon of the optically active 1-aralkyl Ke emissions such obtained when carrying out the present invention, a geranyl acetate (3) as the compound of formula (1) which is the starting material neryl using the acetate _{(4), P d 2 (} dba) 3 · CHCl 3 as a palladium compound,
(R) or (S) -M as an optically active phosphine compound
eO-MOP, triethylamine as a tertiary amine,
The case where formic acid is used will be described as an example.

The products from geranyl acetate (3) and neryl acetate (4) are both 3,7-dimethyl-1,6-octadienes as shown below.

[0031]

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However, when the optically active phosphine compound has the (R) configuration, geranyl acetate gives a product (5) in which the absolute configuration at the 3-position is the (S) configuration, whereas neryl acetate gives the (R) configuration. ) Configuration (6) is obtained.

Conversely, when the optically active phosphine compound is (S)
In the case of the configuration, geranyl acetate gives the product (6) with the absolute configuration at the 3-position (R), while neryl acetate gives the product (5) with the absolute configuration at the 3-position in the (S) configuration. ) Is obtained. Thus, by appropriately selecting a starting material and a reaction reagent in the present invention, an optically active 1-alkene having a desired configuration can be produced.

[0034]

SUMMARY OF] According to the present invention, the substituted allyl alcohol derivative having a leaving group at the terminal, in the presence of a palladium compound and an optically active phosphine compound, by reacting a tertiary amine with formic acid, elimination It is possible to remove the group, move the double bond to the terminal, and further make the carbon atom at the 3-position an asymmetric carbon.

[0035]

The present invention will be described in more detail with reference to the following examples.

Example 1 2.6 mg (0.0025 mm) of palladium compound
ol) of Pd ₂ (dba) ₃ .CHCl ₃ and 5.1 mg (0.011 mmol) of an optically active phosphine compound.
1) (S) -MeO-MOP was placed in a glass Schlenk tube and purged with nitrogen, and 0.5 ml of dry THF was further added to dissolve it.

Next, while the Schlenk tube was cooled on ice, 61 mg (0.60 mmol) of triethylamine and 50 mg (1.1 mmol) of formic acid were sequentially added thereto. Subsequently, at the same temperature, 98.4 mg (0.50 mmol)
Geranyl acetate was added, and the mixture was placed in a 40 ° C constant temperature bath.
Allowed to react for hours.

After confirming the disappearance of geranyl acetate by gas chromatography, 2 ml of water and 20 ml of geranyl acetate were added to the reaction mixture.
The reaction product was extracted by addition of pentane. The organic layer was separated, washed twice with 2 ml of a 10% aqueous hydrochloric acid solution, once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution.
After washing twice, the organic layer was dried over anhydrous sodium sulfate.

After drying, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using pentane as a developing solvent. As a result, 64.5 mg
(R) -3,7- (0.47 mmol, 94% yield)
Dimethyl-1,6-octadiene was obtained. The optical rotation of this product is [α] _D ²⁰ : −4.2 ° (c = 1.1,
It was CHCl _3).

The optical purity of this product was evaluated by oxidizing and then reacting with aniline to dianilide as shown below.

[0041]

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That is, 64.5 mg (0.47 mmol)
Of (R) -3,7-dimethyl-1,6-octadiene and 10 ml of t-butyl alcohol in a flask,
Furthermore, 6 ml of an aqueous solution of 390 mg (2.8 mmol) of potassium carbonate was added, followed by 1.5 g (7.1 mmol) of sodium metaperiodate and 186 mg (1.2 mmol) of potassium permanganate dissolved in 6 ml of water. .

The pH of the reaction solution was adjusted to about 8 with a 3N-NaOH aqueous solution, and the mixture was stirred for about 12 hours. After completion of the reaction, the pH of the reaction solution was adjusted to approximately 1 with concentrated hydrochloric acid, and then sodium sulfite was gradually added under ice cooling until the color tone of the reaction solution changed from reddish brown to yellow, and the reaction product was extracted with ether. did. The desired dicarboxylic acid of the formula (7) was extracted twice from the organic layer with a 1N-NaOH aqueous solution. The pH of the aqueous layer was adjusted to about 1 by adding concentrated hydrochloric acid, and then extracted again with ether. The ether layer was dried over anhydrous magnesium sulfate.

After drying, the solvent was distilled off under reduced pressure.
Dissolved in ml of benzene and transferred to a flask. Here, 0.89 g (9.4 mmol) of aniline and 0.30 g
N of (1.4 mmol), was added and N'- dicyclohexyl Cal <br/> Boji Lee bromide. After the mixture was stirred at room temperature for 2 hours, concentrated hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate.

After drying, the solvent was distilled off, and the obtained residue was purified by column chromatography on silica gel using a mixed solvent of hexane / ethyl acetate (1/3) as a developing solvent. As a result, 56 mg (0.19 mmol, 40% yield) N of the formula (8), is N'- diphenyl-2-methyl-1,5-pentanedioic acid diamide was obtained.

The optical purity of this diamide was measured using hexane / 1,2-dichloroethane / ethanol (5
HLPC using a mixed solvent of 0/15/1 (volume ratio)
(UV detection wavelength 254 nm, Sumic as column
OA-4100 (manufactured by Sumitomo Chemical Co., Ltd.) and found to be 55% ee.

Example 2 2.6 mg (0.0025 mm) of palladium compound
ol) of Pd ₂ (dba) ₃ .CHCl ₃ and 5.0 mg (0.011 mmol) as an optically active phosphine compound.
1) ( R ) -MeO-MOP was placed in a glass Schlenk tube and purged with nitrogen, and further 0.5 ml of dry dioxane was added to dissolve.

Next, while the Schlenk tube was cooled with ice, 61 mg (0.60 mmol) of triethylamine and 47 mg (1.0 mmol) of formic acid were sequentially added thereto. Subsequently, at the same temperature, 98.6 mg (0.50 mmol)
Geranyl acetate was added, and the mixture was placed in a thermostat at 20 ° C. for 1 hour.
The reaction was performed for 40 hours.

After confirming the disappearance of geranyl acetate by gas chromatography, 2 ml of water and 20 ml of water were added to the reaction mixture.
The reaction product was extracted by addition of pentane. The organic layer was separated, washed twice with 2 ml of a 10% aqueous hydrochloric acid solution, once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution.
After washing twice, the organic layer was dried over anhydrous sodium sulfate.

After drying, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel using pentane as a developing solvent. As a result, 42.1 mg
(S) -3,7- (0.30 mmol, 60% yield)
Dimethyl-1,6-octadiene was obtained. The optical purity of this product was determined in the same manner as in Example 1,
70% ee.

Example 3 2.5 mg (0.0024 mm) of palladium compound
ol) of Pd ₂ (dba) ₃ .CHCl ₃ and 4.9 mg (0.010 mmol) of an optically active phosphine compound.
1) ( R ) -MeO-MOP was placed in a glass Schlenk tube and purged with nitrogen, and further 0.5 ml of dry dioxane was added to dissolve.

Next, while the Schlenk tube was cooled with ice, 61 mg (0.60 mmol) of triethylamine and 52 mg (1.1 mmol) of formic acid were sequentially added thereto. Subsequently, at the same temperature, 94.5 mg (0.48 mmol)
Neryl acetate was added and placed in a thermostat at 20 ° C. for 11 hours.
The reaction was performed for 9 hours.

[0053] After confirming the disappearance of the neryl Asete <br/> preparative gas chromatography, water and 20m of 2ml reaction solution
The reaction product was extracted with 1 pentane. The organic layer was separated, washed twice with 2 ml of a 10% aqueous hydrochloric acid solution, once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution, and then dried over anhydrous sodium sulfate.

After drying, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel using pentane as a developing solvent. As a result, 27.0 mg
(R) -3,7- (0.20 mmol, yield 42%)
Dimethyl-1,6-octadiene was obtained. The optical purity of this product was determined in the same manner as in Example 1,
63% ee.

[0055]

According to the present invention, 1-alkenes wherein the carbon atom adjacent to the terminal double bond is an asymmetric carbon atom,
In particular, optically active 3,7-dimethyl-1,6-octadiene can be easily obtained.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI C07C 11/12 C07C 11/12 // C07B 61/00 300 C07B 61/00 300 (56) Reference Chem. Lett. , (1984) (6) p. 1017-p. 1020 Pure Appl. Chem. , 58 (6) (1986) p. 869-p. 878 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 1/213 C07C 1/30 C07C 11/02 C07C 11/12

Claims (3)

(57) [Claims] (1) R ₁ R ₂ C） CHCH ₂ X (1) (wherein R ₁ and R ₂ are each independently an unsubstituted alkyl group ,
Alkyl substituted with a halogen atom or aryl group
Group, unsubstituted alkenyl group , halogen atom or aryl
An alkenyl group substituted with an aryl group , an unsubstituted aryl group , or
Although an aryl group substituted by a halogen atom, R ₁
And R ₂ are not the same and X is OCOR ₃ , OCO
₂ R ₄ , OCONR ₅ R ₆ (wherein R ₃ , R ₄ , R ₅ and R ₆ are
Each of which is a hydrogen atom, an alkyl group or an aryl group)
And a leaving group selected from the group consisting of a halogen atom and a tertiary amine and formic acid in the presence of a palladium compound and an optically active phosphine compound. (2) R ₁ R ₂ C ^* HCH ＝ CH ₂ (2) (wherein R ₁ and R ₂ are as described above, and C ^* is an asymmetric carbon atom). A method for producing alkenes. 2. The compound of (1), wherein R ₁ is methyl, R ₂ is 4-methyl-3-pentenyl,
The method for producing an optically active 1-alkene according to claim 1, wherein is acetoxy. 3. The method according to claim 1, wherein the optically active phosphine compound is (S)-
The method for producing optically active 1-alkenes according to claim 1, which is (-) or (R)-(+)-2-diphenylphosphino-2'-methoxy-1,1'-binaphthyl.