JP2008143880A - New synthesis method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for synthesizing an α,β-unsaturated ketone bearing a hydroxy group on its γ-site. <P>SOLUTION: As a result of zealously studying the method for synthesizing an α,β-unsaturated ketone bearing a hydroxy group on its γ-site represented by formula (1): -COCH=CHCHOH-, it has been found that the problem can be solved by reacting a carboxylic acid and a basic substance with an epoxy-bearing compound represented by formula (2): -COCH<SB>2</SB>-epoxy-. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for synthesizing an α, β-unsaturated ketone having a hydroxyl group at the γ-position.

As a method for synthesizing α, β-unsaturated ketones,
An aldehyde and an alkali metal salt of acetoacetic acid are represented by the following formula (6) by reacting in a mixed solvent of different solvents of water and a poorly water-soluble organic solvent in the presence of an aliphatic secondary amine as a catalyst. A method for synthesizing α, β-unsaturated ketones is known (see, for example, Patent Document 1).
R · CH = CHCO-CH ₃ (6)
(In the formula (6), R is a linear or branched alkyl group having 1 to 9 carbon atoms, an alkylthioalkyl group, an alkylsulfonylalkyl group, a phenylthiosubstituted alkyl group, a substituted phenylthiosubstituted alkyl group, a phenylsulfonyl group. Represents a substituted alkyl group or a substituted phenylsulfonyl-substituted alkyl group.)
The thing using 3-azabicyclo [3, 2, 2] nonane etc. is known as said aliphatic secondary amine (for example, refer patent document 2).
A method of synthesizing α, β-unsaturated ketones by Carol reaction of a corresponding α, β-unsaturated alcohol and alkyl acetoacetate is known (for example, see Patent Document 3).

  1-Phenyl-4-hydroxy-2-buten-1-one, which is one of α, β-unsaturated ketone compounds, has been reported to be synthesized using a special oxidizing agent (Non-patent Document 1). . However, there is no known production method using a general-purpose carboxylic acid peroxide from a compound that is easily available.

JP 57-4930 A Japanese Patent Laid-Open No. 3-161456 JP 2000-159721 A R. Badri, H. Shalbaf, M.A. Heidary, Synthetic Communications, 31 (22), 3473-3479 (2001).

  The present invention provides a method for synthesizing α, β-unsaturated ketones having a hydroxyl group at the γ-position.

As a result of intensive studies to provide a method for synthesizing an α, β-unsaturated ketone having a hydroxyl group at the γ position represented by the following formula (1), the present inventor has found an epoxy represented by the following formula (2) (three The present inventors have found that the problem can be solved by allowing a carboxylic acid and a basic substance to act on those having a (membered ring).
-COCH = CHCHOH- (1)
-COCH ₂ - epoxy - (2)
That is, the present invention
<1> In a method for synthesizing a group represented by the above formula (1), a carboxylic acid and a basic substance are allowed to act on a compound having an epoxy represented by the above formula (2). Yes,
<2> The method according to 1 above, wherein the compound having an epoxy group represented by the formula (2) is obtained by epoxidizing the following formula (3) with a carboxylic acid peroxide,
_{A-COCH 2 CH = CH-} R (3)
(In Formula (3), A is an aryl group or an alkyl group which may have a substituent, and R is a hydrogen atom or an alkyl group which may have a substituent.)
<3> The method according to 1 above, wherein the compound having a group represented by the formula (1) is the following formula (4):

In (formula (4), R ¹ is a hydrogen atom or a hydrocarbon group having a carbon number of 1 to 11,, R ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or 1 to 6 carbon atoms, An alkoxy group, and m is an integer of 1 to 3.)
<4> The method of formula (4), wherein the carboxylic acid and basic substance are allowed to act after epoxidizing the following formula (5) with a carboxylic acid peroxide.

In (formula (5), R ¹ is a hydrogen atom or a hydrocarbon group having a carbon number of 1 to 11, R ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms, And m is an integer of 1 to 3.)

  By using the production method of the present invention, a hydroxyl group can be easily introduced at the γ position of the α, β-unsaturated ketone. Therefore, a compound having an α, β-unsaturated ketone having a hydroxyl group at the γ position can be easily synthesized.

The production method of an α, β-unsaturated ketone having a hydroxyl group at the γ position represented by the above formula (1) of the present invention will be described in detail.
The production method of the present invention can be easily synthesized by allowing a carboxylic acid and a basic substance to act on a compound having an epoxy group represented by the above formula (2).
In the compound represented by the formula (2), asymmetry can be introduced at the bonding position of the hydroxyl group as long as it has an asymmetric epoxy group. In other words, by applying the production method of the present invention to a compound having an asymmetric epoxy group, asymmetry can be introduced at the bonding position of the hydroxyl group.

In the production method of the present invention, the compound represented by formula (2) preferably has an aryl group next to the carbonyl group from the viewpoint of the synthesis yield.
Examples of the aryl group include a phenyl group, a naphthyl group, and an anthranyl group, and these may have a substituent such as an alkyl group or an alkoxy group.

  In the present invention, the compound having an epoxy group represented by the above formula (2) is epoxidized using a carboxylic acid peroxide such as peracetic acid to the compound represented by the above formula (3). Can be synthesized.

  As an example of the production method of the present invention, a double bond in a compound represented by the formula (3) is epoxidized by reaction with a carboxylic acid peroxide (epoxy compound), for example. Reduced to carboxylic acid. A basic substance is allowed to act on the mixture to cause an addition reaction between the epoxy compound and the carboxylic acid to produce an ester compound. The ester compound can be converted into a compound represented by the general formula (1) by forming a balanced mixture under the action of a basic substance and then removing the carboxylic acid.

  In the production method of the present invention, the first epoxidation reaction and the subsequent reaction may be carried out continuously, or the epoxy compound may be extracted and then the subsequent reaction may be carried out.

In the production method of the present invention, the carboxylic acid peroxide is not particularly limited, and examples thereof include peracetic acid, perbenzoic acid, and 3-chloroperbenzoic acid. Perbenzoic acid can be preferably used.
In the production method of the present invention, the amount of peroxide of carboxylic acid is basically a stoichiometric amount with respect to the double bond in the compound represented by the formula (3), taking into account the reactivity and the like. Thus, it is preferable to use 0.5 to 2.0 times, preferably 0.8 to 1.2 times the stoichiometric amount. If the amount of the carboxylic acid peroxide used is too small, the progress of the reaction is insufficient, and if the amount used is too large, the cost increases and the side reaction tends to proceed, which is not preferable.

The production method of the present invention is preferably carried out in a solvent, a halogen-based solvent such as dichloromethane and carbon tetrachloride, an aromatic solvent such as toluene and xylene, ethyl acetate, acetone, water, and a mixed solvent thereof. Can be used.
In the production method of the present invention, the temperature for reacting with the peroxide of carboxylic acid varies depending on the peroxide used and the amount used, but can be -20 ° C to 90 ° C, preferably 10 ° C to 60 ° C. is there. When the reaction temperature is too low, the progress of the reaction is slow, and when it is too high, the side reaction tends to proceed, which is not preferable.
In the production method of the present invention, the reaction time of the carboxylic acid with the peroxide is usually several hours to several tens of hours, although it varies depending on the conditions.

In the production method of the present invention, the double bond in the compound represented by the formula (3) is epoxidized, and then converted into the epoxy compound represented by the formula (2) by acting a basic substance. Examples of the basic substance include sodium carbonate and potassium carbonate. Examples include inorganic basic substances such as sodium hydroxide, organic amines such as triethylamine and diisopropylethylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide. Organic amines such as triethylamine and diisopropylethylamine are preferably used. can do.
In the production method of the present invention, the amount of the basic substance is 0.1 to 3 equivalents, preferably 0.3 to 1.2 equivalents, relative to the carboxylic acid peroxide. If the amount of the basic substance is too small, the progress of the reaction becomes insufficient, and if the amount used is too large, the cost increases, which is not preferable.

  In the production method of the present invention, the reaction temperature with the basic substance is −20 ° C. to 90 ° C., preferably 10 ° C. to 60 ° C., although it varies depending on the product used and the amount used. If the reaction temperature is too low, the progress of the reaction is slow, and if it is too high, the side reaction tends to proceed, which is not preferable. The reaction time varies depending on conditions, but is usually from several hours to several tens of hours.

  In the production method of the present invention, after completion of the reaction, the compound represented by the general formula (1) can be separated and purified by a conventionally known method such as solvent extraction, column chromatography, or crystallization method.

<Example>
EXAMPLES Next, the present invention will be described more specifically with reference to examples, but the production method of the present invention is not limited thereto.

<Synthesis Example 1>
-Synthesis of 1-phenyl-3-buten-1-one
To a 2.0 M allylmagnesium chloride / tetrahydrofuran solution (400 ml) was added dropwise a tetrahydrofuran solution (450 ml) of benzylaldehyde (380 mmol) under ice cooling. After stirring at the same temperature for 15 minutes, 3 N hydrochloric acid (300 ml) was added to stop the reaction. Ethyl acetate (300 ml) was added and partitioned, and the organic layer was collected. The organic layer was washed with saturated brine (300 ml), and the solvent was evaporated under reduced pressure.
The resulting residue was then dissolved in acetone (1500 ml) and cooled. Jones reagent (a solution in which 75.0 g of chromic anhydride was dissolved in 225 ml of 47% sulfuric acid and distilled water was added to make a total volume of 300 ml) was adjusted so that the temperature of the reaction solution was in the range of -5 to 20 ° C. Added in minutes. After stirring for 10 minutes, isopropyl alcohol (50 ml) was added. After stirring for 10 minutes, the insoluble material was filtered off, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate (400 ml) and washed successively with distilled water (300 ml) and saturated brine (150 ml × 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain 1-phenyl-3-buten-1-one.
1-phenyl-3-buten-1-one should be synthesized using the synthesis method described in Adam Shih-Yuan Lee, Li-Shin Lin, Tetrahedron Lett., 41, 8803-8806 (2000). You can also.

-Synthesis of 1-phenyl-4-hydroxy-2-buten-1-one (Compound 1) (Part 1)
3-Chloroperbenzoic acid (377 mmol) was added to a solution of 1-phenyl-3-buten-1-one (317 mmol) in dichloromethane (1000 ml). After heating under reflux for 18 hours, the mixture was allowed to cool, and 10% aqueous sodium thiosulfate solution (500 ml) was added to stop the reaction. The organic layer was separated, and the aqueous layer was extracted twice with chloroform (200 ml). The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
Next, the obtained residue was dissolved in acetone (600 ml), triethylamine (187 mmol) was added, and the mixture was heated to reflux. After 3 hours, the mixture was allowed to cool and the solvent was distilled off under reduced pressure. The residue was partitioned by adding ethyl acetate (500 ml) and 20% aqueous sodium carbonate (400 ml). The organic layer was collected and washed with saturated brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain pale yellow crystalline compound 1 (the following formula (6)) (24.2 g, yield 47%).

-Physicochemical properties of Compound 1
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 2.59 (1H, br), 4.73 (2H, s), 7.11-7.17 (1H, m), 7.21-
7.28 (1H, m), 7.44-7.49 (2H, m), 7.55-7.96 (1H, m), 7.97 (2H, d, J = 7.6Hz).

-Synthesis of Compound 1 (Part 2)
3-Chloroperbenzoic acid (70.0 g, 264 mmol) was added to a solution of 1-phenyl-3-buten-1-one (260 mmol) in dichloromethane (1300 ml). After stirring at room temperature for 20 hours, 10% aqueous sodium thiosulfate solution (300 ml) was added and stirred for 15 minutes. Next, triethylamine (273 mmol) was added and stirred. After 5 hours, the organic layer was separated, and the aqueous layer was extracted twice with chloroform (150 ml). The combined organic layers were concentrated under reduced pressure. Next, the concentrated residue was dissolved in acetic acid ethyl ester (300 ml), and washed successively with 10% aqueous sodium carbonate solution (100 ml × 2) and saturated brine (100 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain pale yellow crystalline Compound 1 (8.00 g, yield 19%).

-Synthesis of compound 2
A tetrahydrofuran solution (450 ml) of isophthalaldehyde (51.0 g, 380 mmol) was added dropwise to a 2.0 M allylmagnesium chloride / tetrahydrofuran solution (400 ml) under ice-cooling. After stirring at the same temperature for 15 minutes, 3 N hydrochloric acid (300 ml) was added to stop the reaction. Ethyl acetate (300 ml) was added and partitioned, and the organic layer was collected. The organic layer was washed with saturated brine (300 ml), and the solvent was evaporated under reduced pressure.
The resulting residue was then dissolved in acetone (1500 ml) and cooled. Jones reagent (a solution in which 75.0 g of chromic anhydride was dissolved in 225 ml of 47% sulfuric acid and distilled water was added to make a total volume of 300 ml) was adjusted so that the temperature of the reaction solution was in the range of -5 to 20 ° C. Added in minutes. After stirring for 10 minutes, isopropyl alcohol (50 ml) was added. After stirring for 10 minutes, the insoluble material was filtered off, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate (400 ml) and washed successively with distilled water (300 ml) and saturated brine (150 ml × 2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography to obtain pale yellow liquid compound 2 (the following formula (7)) (yield 30.1 g). .

-Physicochemical properties of Compound 2
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 3.81 (4H, d, J = 6.8 Hz), 5.22-5.28 (4H, m), 6.04-6.14
(2H, m), 7.57-7.62 (1H, m), 8.15-8.18 (2H, m), 8.54 (1H, s).

Synthesis of Compound 3 3-Chloroperbenzoic acid (124 mmol) was added to a solution of compound 2 (61.6 mmol) in dichloromethane (500 ml). After stirring at room temperature for 20 hours, 10% aqueous sodium thiosulfate solution (200 ml) was added and stirred for 15 minutes. The organic layer was separated, and the aqueous layer was extracted twice with chloroform (150 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
Next, the concentrated residue was dissolved in acetone (150 ml), triethylamine (5.20 ml, 37.3 mmol) was added, and the mixture was heated to reflux. After 3 hours, the mixture was allowed to cool and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain pale yellow liquid compound 3 (the following formula (8)) (1.80 g, yield 12%).

-Physicochemical properties of Compound 3
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 3.00-3.41 (2H, br), 4.48 (4H, q, J = 4.0 Hz), 7.13-7.28
(4H, m), 7.53 (1H, t, J = 7.6Hz), 8.10 (2H, dd, J = 4.0 and 7.6Hz), 8.44 (1H, s).

-Synthesis of 1- (4-methylphenyl) -4-hydroxy-2-buten-1-one (compound 4)
To a solution of 1- (4-methylphenyl) -3-buten-1-one (173 mmol) in dichloromethane (600 ml) was added 3-chloroperbenzoic acid (222 mmol). After heating at reflux for 3 hours, the mixture was allowed to cool. The organic layer was washed sequentially with a 10% aqueous sodium thiosulfate solution (200 ml) and a 10% aqueous sodium carbonate solution (300 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
Next, the obtained residue was dissolved in acetone (200 ml), a solution prepared by previously dissolving triethylamine (87.6 mmol) and acetic acid (175 mmol) in acetone (200 ml) was added, and the mixture was stirred at 50 ° C. After 1 hour, the mixture was allowed to cool and the solvent was distilled off under reduced pressure. The residue was partitioned by adding chloroform (200 ml) and 10% aqueous sodium carbonate (150 ml). The organic layer was collected and the aqueous layer was extracted 3 times with chloroform (50 ml). The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and recrystallized from toluene to obtain colorless plate crystal compound 4 (the following formula (9)) (12.7 g, yield 42%).

○ Physicochemical properties of Compound 4 Melting point 61.7-62.6 ℃
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 1.90 (1H, t, J = 6.0 Hz), 2.42 (3H, s), 4.74 (2H, m), 7.12 (1H, dt, J = 3.6 and 15.6 Hz ), 7.22 (1H, d, J = 15.6 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.89 (2H, d, J = 8.0 Hz).

  By using the production method of the present invention, a compound having a hydroxyl group at the γ-position of an α, β-unsaturated ketone can be easily provided.

Claims (4)

A process for synthesizing a group represented by the following formula (1), wherein a carboxylic acid and a basic substance are allowed to act on a compound having an epoxy represented by the following formula (2).
-COCH = CHCHOH- (1)
-COCH ₂ - epoxy - (2) The method according to claim 1, wherein the compound having an epoxy group represented by the formula (2) is obtained by epoxidizing the following formula (3) with a peroxide of carboxylic acid.
_{A-COCH 2 CH = CH-} R (3)
(In Formula (3), A is an aryl group or an alkyl group which may have a substituent, and R is a hydrogen atom or an alkyl group which may have a substituent.) The production method according to claim 1, wherein the compound having a group represented by the formula (1) is the following formula (4).

In (formula (4), R ¹ is a hydrogen atom or a hydrocarbon group having a carbon number of 1 to 11,, R ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or 1 to 6 carbon atoms, An alkoxy group, and m is an integer of 1 to 3.) The method of formula (4) according to claim 3, wherein the carboxylic acid and a basic substance are allowed to act after epoxidizing the following formula (5) with a carboxylic acid peroxide.

In (formula (5), R ¹ is a hydrogen atom or a hydrocarbon group having a carbon number of 1 to 11, R ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms, And m is an integer of 1 to 3.)