JP5581091B2 - 4-Cyclopentylcyclohexanone derivative and method for producing the same - Google Patents

Description

  The present invention relates to a 4-cyclopentylcyclohexanone derivative useful as a production intermediate of a liquid crystal compound and a production method thereof.

  A 4-cyclopentylcyclohexanecarboxylic acid derivative is useful as a liquid crystal compound (Patent Document 1). It is known that cyclohexanecarboxylic acid derivatives can be easily prepared from cyclohexanone derivatives (Patent Document 2). However, a 4-cyclopentylcyclohexanone derivative which is an intermediate for producing a 4-cyclopentylcyclohexanecarboxylic acid derivative and a production method thereof have not been reported at all.

German Patent Application No. 3918884 International Publication No. 2005/005456

  An object of the present invention is to provide a 4-cyclopentylcyclohexanone derivative that is a production intermediate of a 4-cyclopentylcyclohexanecarboxylic acid derivative that is a liquid crystal compound, and a method for producing the same.

  As a result of intensive studies in view of the above problems, the present inventors have found that 4-cyclopentylcyclohexanone derivatives can be easily produced by catalytic hydrogenation of 4- (cyclopentenyl) cyclohexenone derivatives, and the present invention. It came to complete.

  That is, the present invention relates to the general formula (5)

（式中、Ｒ^１は、炭素数３から４のアルキル基を表す。）で表される４−シクロペンチルシクロヘキサノン誘導体に関する。

(Wherein R ¹ represents an alkyl group having 3 to 4 carbon atoms ).

  The present invention also provides a general formula (4)

（式中、Ｒ^１は前記と同じ意味を表す。）で表される４−（シクロペンテニル）シクロヘキセノン誘導体を、接触水素化反応させることを特徴とする、一般式（５）

(Wherein R ¹ represents the same meaning as described above), a 4- (cyclopentenyl) cyclohexenone derivative represented by the general formula (5)

（式中、Ｒ^１は前記と同じ意味を表す）で表される４−シクロペンチルシクロヘキサノン誘導体の製造方法に関するものである。

(Wherein R ¹ represents the same meaning as described above), and relates to a method for producing a 4-cyclopentylcyclohexanone derivative.

  According to the present invention, a 4-cyclopentylcyclohexanone derivative (5), which is a production intermediate of a 4-cyclopentylcyclohexanecarboxylic acid derivative that is a liquid crystal compound, can be easily produced.

  The present invention is described in detail below.

R ¹ represents an alkyl group having 3 to 4 carbon atoms .

The alkyl group having 3 to 4 carbon atoms represented by R ¹ may be linear or branched, and is a propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert- A butyl group etc. can be illustrated. These alkyl groups having 3 to 4 carbon atoms may be substituted with a halogen atom or an alkoxy group having 1 to 4 carbon atoms. Specifically, a 3-fluoropropyl group etc. can be illustrated.

R ¹ is preferably a propyl group in terms of easy preparation.

  Next, the production method of the present invention will be described in detail.

  The production method of the 4- (cyclopentenyl) cyclohexenone derivative (4) which is the raw material of the present invention and the production method of the 4-cyclopentylcyclohexanone derivative (5) of the present invention using the same are as shown in the following scheme.

（式中、Ｒ^１は前記と同じ意味を表し、Ｒ^２は水素原子、置換されていてもよいシクロヘキシル基、置換されていてもよいフェニル基、またはコレステリル基を表す。）

(Wherein R ¹ represents the same meaning as described above, and R ² represents a hydrogen atom, an optionally substituted cyclohexyl group, an optionally substituted phenyl group, or a cholesteryl group.)

  Step 1 is a step for producing an aldehyde derivative (2) by oxidizing the alcohol derivative (1).

  The alcohol derivative (1) which is the raw material of Step 1 can be synthesized by a method described in the literature (for example, Bioorganic & Medicinal Chemistry, Vol. 5, pages 2173-2183, 1997).

  Examples of the oxidizing agent that can be used in Step 1 include chromic acid, dimethyl sulfoxide / oxalyl chloride / triethylamine mixed oxidant, dimethyl sulfoxide / sulfur trioxide-pyridine complex / triethylamine mixed oxidant, dimethyl sulfoxide / N, N- Dicyclohexylcarbodiimide mixed oxidizer, dimethyl sulfide / N-chlorinated succinimide / triethylamine mixed oxidizer, Dess-Martin reagent, 2-iodoxybenzoic acid, sulfur trioxide / pyridine mixed oxidizer, aluminum triisopropoxide, dioxide dioxide Examples include manganese, 2,2,6,6-tetramethylpiperidine = 1-oxyl = free radical, 4-methoxy-2,2,6,6-tetramethylpiperidine = 1-oxyl = free radical, and the like. .

  The solvent that can be used in step 1 may be any solvent that does not inhibit the reaction. Specifically, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, hydrocarbon solvents such as hexane, pentane, cyclohexane, Aromatic hydrocarbon solvents such as benzene, toluene, xylene, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetone, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N-methyl Examples include 2-pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, water, and the like. Two or more of these solvents may be mixed and used.

  The molar ratio of the alcohol derivative (1) and the oxidizing agent is not particularly limited, but is usually 1: 1 to 1: 5. Among these, 1: 1 to 1: 3 is more preferable in terms of a good yield.

  Although the reaction temperature is not particularly limited, it can usually be carried out at a temperature appropriately selected from the range of −78 ° C. to solvent reflux temperature.

  The method for isolating the desired product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.

  Step 2 is a step of producing a ketone derivative (3) by reacting the aldehyde derivative (2) with methyl vinyl ketone (6).

  In step 2, it is essential to use a base. Examples of bases that can be used include metal alkoxide bases such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, pyrrolidine, piperidine, proline, N, N Examples include amines such as -diethyl-N- (trimethylsilyl) amine, hydroxides such as potassium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide, and tetramethylammonium hydroxide. From the viewpoint of good reaction yield, amines are preferably used, and N, N-diethyl-N- (trimethylsilyl) amine is more preferably used.

  The solvent that can be used in step 2 may be any solvent that does not inhibit the reaction. Specifically, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, hydrocarbon solvents such as hexane, pentane, cyclohexane, Aromatic hydrocarbon solvents such as benzene, toluene, xylene, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2 -Pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, methanol, ethanol, water and the like can be exemplified. Two or more of these solvents may be mixed and used. Acetonitrile is preferably used because the reaction yield is good.

  The molar ratio of the aldehyde derivative (1) and methyl vinyl ketone (6) is not particularly limited, but is usually preferably 1: 1 to 1: 5. Among these, 1: 1 to 1: 3 is more preferable in terms of a good yield.

  The molar ratio of the aldehyde derivative (1) and the base is not particularly limited, but is usually preferably from 1: 3 to 1: 0.1.

  Although the reaction temperature is not particularly limited, it can usually be carried out at a temperature appropriately selected from the range of −78 ° C. to solvent reflux temperature.

  The method for isolating the desired product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.

  Step 3 is a step of producing a 4- (cyclopentenyl) cyclohexenone derivative (4) by reacting the ketone derivative (3) in the presence of an auxiliary agent.

  In step 3, it is essential to use an auxiliary agent. Examples of auxiliary agents that can be used include lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperazide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide. Metal amide, sodium methoxide, potassium methoxide, metal alkoxide such as sodium ethoxide, potassium ethoxide, pyrrolidine, piperidine, proline, amines such as N, N-diethyl-N- (trimethylsilyl) amine, potassium hydroxide, Brenstein such as sodium hydroxide, tetrabutylammonium hydroxide, tetramethylammonium hydroxide and the like, trifluoroacetic acid, acetic acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, etc. De acid, titanium tetrachloride, boron trifluoride ether complex, can be exemplified such as a Lewis acid such as aluminum chloride. From the viewpoint of good yield, amines, metal alkoxides, hydroxides, Bronsted acids are preferably used, and proline, potassium hydroxide, tetrabutylammonium hydroxide, sodium methoxide, p-toluenesulfonic acid or trifluoro More preferably, acetic acid is used.

  The solvent that can be used in step 3 may be any solvent that does not inhibit the reaction. Specifically, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, hydrocarbon solvents such as hexane, pentane, cyclohexane, Aromatic hydrocarbon solvents such as benzene, toluene, xylene, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, N-methyl-2 -Pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, methanol, ethanol, water and the like can be exemplified. Two or more of these solvents may be mixed and used.

  The molar ratio between the ketone derivative (3) and the auxiliary agent is not particularly limited, but is usually preferably from 1: 3 to 1: 0.1.

  Although the reaction temperature is not particularly limited, it can usually be carried out at a temperature appropriately selected from the range of −78 ° C. to solvent reflux temperature.

  The method for isolating the desired product from the solution after the reaction is not particularly limited. For example, the desired product can be obtained by a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation.

  Further, after completion of the reaction in Step 2, Step 3 is continuously performed without isolating the product ketone derivative (3) from the reaction system, and 4- (cyclopentenyl) cyclohexenone derivative (4) is obtained. There is no problem even if it is manufactured in the same reaction vessel.

  Step 4 is a step of producing 4-cyclopentylcyclohexanone derivative (5) by catalytic hydrogenation of 4- (cyclopentenyl) cyclohexenone derivative (4).

  It is essential to perform step 4 in the presence of a metal catalyst, in a hydrogen gas atmosphere, or in the presence of a hydrogen donor. Examples of hydrogen donors include cyclohexene, 1,4-cyclohexadiene, formic acid, decalin, ammonium formate, and the like. It is preferable to perform in a hydrogen gas atmosphere in terms of a good yield.

  Examples of the metal catalyst include palladium carbon, palladium black, palladium alumina, palladium chloride, palladium hydroxide, Raney nickel, rhodium alumina, and the like. It is preferable to use palladium carbon in terms of good yield.

  The solvent that can be used in step 4 may be any solvent that does not inhibit the reaction. Specifically, the reaction can be carried out in a solvent such as toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, methanol, ethanol, acetic acid, water, or a mixed solvent thereof.

The addition amount of the metal catalyst may be a so-called catalyst amount, and it is sufficient to use about 0.1 to 1 mol% with respect to the 4- (cyclopentenyl) cyclohexenone derivative (4).
The pressure of the hydrogen gas is not particularly limited, and the reaction can be performed at a low pressure of about 10 to 10 atm. When the hydrogen donor is used in an equivalent amount or more with respect to the 4- (cyclopentenyl) cyclohexenone derivative (4), the 4-cyclopentylcyclohexanone derivative (5) can be obtained with good yield. There is no restriction | limiting in particular in reaction temperature, It can implement at the temperature selected suitably from room temperature to 100 degreeC.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but may be a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  The 4-cyclopentylcyclohexanone derivative (5) obtained in Step 4 can be easily converted into a 4-cyclopentylcyclohexanecarboxylic acid derivative (7) which is a liquid crystal compound by the method described in the literature (for example, International Publication No. 2005/005456). Can be converted to

  Next, the present invention will be described in detail by experimental examples, but the present invention is not limited thereto.

  Regarding Experimental Examples 1 to 12, Experimental Example 1 is Step 1, Experimental Examples 2 to 3 are Step 2, Experimental Examples 4 to 8 are Step 3, Experimental Examples 9 to 11 are Steps 2 to 3, and Experimental Example 12 is Step 4 Indicates.

２−（トランス−４−プロピル−２−シクロペンテニル）エタノール（４９．６ｍｇ、０．３２２ｍｍｏｌ）のジメチルスルホキシド溶液（１．０ｍＬ）に、アルゴン雰囲気下、２−ヨードキシ安息香酸（１５１ｍｇ、０．５３９ｍｍｏｌ）を加え、室温にて２時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液（１．０ｍＬ）、水（１．０ｍＬ）およびアセトン（１．０ｍＬ）を加え、室温にて５分間攪拌し、ジエチルエーテル（３．０ｍＬｘ３）で抽出した。あわせた有機層を、飽和炭酸水素ナトリウム水溶液（２．０ｍＬ）および飽和食塩水（２．０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた油状物を中圧カラムクロマトグラフィー［シリカゲル（２８ｇ）、ヘキサン―酢酸エチル（４：１）］により精製することで、２−（トランス−４−プロピル−２−シクロペンテニル）アセトアルデヒド（２６．０ｍｇ、収率５３％）を無色油状物として得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ９．７７（ｂｒｓ，１Ｈ），５．７４（ｂｒｄ，Ｊ＝５．６Ｈｚ，１Ｈ），５．６５（ｂｒｄ，Ｊ＝５．６Ｈｚ，１Ｈ），３．１７（ｍ，１Ｈ），２．７０（ｍ，１Ｈ），２．４９（ｂｒｄｄｄ，Ｊ＝１６，６．３，６．３Ｈｚ，１Ｈ），２．４１（ｂｒｄｄｄ，Ｊ＝１６，７．７，７．７Ｈｚ，１Ｈ），１．７５（ｍ，１Ｈ），１．６６（ｍ，１Ｈ），１．４３−１．１７（ｍ，４Ｈ），０．９０（ｔ，Ｊ＝６．７Ｈｚ，３Ｈ）． Experimental example-1

2-Iodoxybenzoic acid (151 mg, 0.539 mmol) was added to a solution of 2- (trans-4-propyl-2-cyclopentenyl) ethanol (49.6 mg, 0.322 mmol) in dimethyl sulfoxide (1.0 mL) under an argon atmosphere. ) And stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution (1.0 mL), water (1.0 mL) and acetone (1.0 mL) were added to the reaction mixture, stirred at room temperature for 5 minutes, and extracted with diethyl ether (3.0 mL × 3). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (4: 1)] to give 2- (trans-4-propyl-2-cyclopentenyl) acetaldehyde (26 0.0 mg, 53% yield) was obtained as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.77 (brs, 1H), 5.74 (brd, J = 5.6 Hz, 1H), 5.65 (brd, J = 5.6 Hz, 1H), 3 .17 (m, 1H), 2.70 (m, 1H), 2.49 (brdddd, J = 16, 6.3, 6.3 Hz, 1H), 2.41 (brdddd, J = 16,7. 7, 7.7 Hz, 1 H), 1.75 (m, 1 H), 1.66 (m, 1 H), 1.43-1.17 (m, 4 H), 0.90 (t, J = 6. 7Hz, 3H).

２−（トランス−４−プロピル−２−シクロペンテニル）アセトアルデヒド（１０６ｍｇ、０．７０２ｍｍｏｌ）のアセトニトリル溶液（２．０ｍＬ）に、アルゴン雰囲気下室温にて、メチルビニルケトン（０．１７ｍＬ、２．１０ｍｍｏｌ）およびＮ，Ｎ−ジエチル−Ｎ−（トリメチルシリル）アミン（０．２６ｍＬ，１．４ｍｍｏＬ）を加え、９０℃にて１５時間攪拌した。反応混合物を減圧濃縮後、得られた油状物を中圧カラムクロマトグラフィー［シリカゲル（２８ｇ）、ヘキサン―酢酸エチル（６：１）］により精製することで、２−（トランス−４−プロピル−２−シクロペンテニル）−５−オキソヘキサナール（１３０ｍｇ、収率７７％）を無色油状物として得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ９．６１（ｄ，Ｊ＝２．７Ｈｚ，０．５Ｈ），９．６０（ｄ，Ｊ＝２．５Ｈｚ，０．５Ｈ），５．７９（ｄｄｄ，Ｊ＝５．７，２．０，２．０Ｈｚ，０．５Ｈ），５．７９（ｄｄｄ，Ｊ＝５．７，２．０，２．０Ｈｚ，０．５Ｈ），５．６７（ｄｄｄ，Ｊ＝５．７，２．２，２．２Ｈｚ，０．５Ｈ），５．６２（ｄｄｄ，Ｊ＝５．７，２．１，２．１Ｈｚ，０．５Ｈ），３．０４（ｍ，１Ｈ），２．６６（ｍ，１Ｈ），２．５０（ｍ，１Ｈ），２．３９（ｍ，１Ｈ），２．２５（ｍ，１Ｈ），２．１２（ｓ，３Ｈ），１．９３−１．７０（ｍ，３Ｈ），１．６４（ｍ，１Ｈ），１．３９−１．２１（ｍ，４Ｈ），０．９０（ｔ，Ｊ＝７．０Ｈｚ，１．５Ｈ），０．８９（ｔ，Ｊ＝７．０Ｈｚ，１．５Ｈ）． Experimental example-2

To a solution of 2- (trans-4-propyl-2-cyclopentenyl) acetaldehyde (106 mg, 0.702 mmol) in acetonitrile (2.0 mL) at room temperature under argon atmosphere, methyl vinyl ketone (0.17 mL, 2.10 mmol). ) And N, N-diethyl-N- (trimethylsilyl) amine (0.26 mL, 1.4 mmol) were added and stirred at 90 ° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (6: 1)] to give 2- (trans-4-propyl-2 -Cyclopentenyl) -5-oxohexanal (130 mg, 77% yield) was obtained as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.61 (d, J = 2.7 Hz, 0.5H), 9.60 (d, J = 2.5 Hz, 0.5H), 5.79 (ddd, J = 5.7, 2.0, 2.0 Hz, 0.5H), 5.79 (ddd, J = 5.7, 2.0, 2.0 Hz, 0.5H), 5.67 (ddd, J = 5.7, 2.2, 2.2 Hz, 0.5H), 5.62 (ddd, J = 5.7, 2.1, 2.1 Hz, 0.5H), 3.04 (m, 1H), 2.66 (m, 1H), 2.50 (m, 1H), 2.39 (m, 1H), 2.25 (m, 1H), 2.12 (s, 3H), 1. 93-1.70 (m, 3H), 1.64 (m, 1H), 1.39-1.21 (m, 4H), 0.90 (t, J = 7.0 Hz, 1.5H), 0.89 (t, J = 7.0 Hz, .5H).

Experimental Example-3
To a solution of 2- (trans-4-propyl-2-cyclopentenyl) acetaldehyde (150 mg, 0.99 mmol) in acetonitrile (5.0 mL) at room temperature under argon atmosphere, methyl vinyl ketone (110 mg, 1.57 mmol) and N, N-diethyl-N- (trimethylsilyl) amine (70 mg, 0.48 mmol) was added, and the mixture was stirred at 80 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, and the obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (6: 1)] to give 2- (trans-4-propyl-2 -Cyclopentenyl) -5-oxohexanal (204 mg, 93% yield) was obtained as a colorless oil.

２−（トランス−４−プロピル−２−シクロペンテニル）−５−オキソヘキサナール（１２０ｍｇ、０．５４１ｍｍｏｌ）のテトラヒドロフラン溶液（６．０ｍＬ）に、室温にて、５％水酸化カリウム水溶液（２．０ｍＬ）と水酸化テトラブチルアンモニウムの０．５Ｍテトラヒドロフラン溶液（０．１０ｍＬ、０．０５ｍｍｏｌ）を加え、７０℃にて２時間攪拌した。反応混合物を室温に放冷後、ジエチルエーテル（２．０ｍＬｘ２）で抽出した。あわせた有機層を、飽和塩化アンモニウム水溶液（２．０ｍＬ）および飽和食塩水（２．０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた油状物を中圧カラムクロマトグラフィー［シリカゲル（２８ｇ）、ヘキサン―酢酸エチル（６：１）］により精製することで、４−（トランス−４−プロピル−２−シクロペンテニル）−２−シクロヘキセノン（２０．１ｍｇ、収率１８％）を無色油状物として得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ６．８７（ｍ，０．５Ｈ），６．８４（ｍ，０．５Ｈ），６．０３（ｄｄｄ，Ｊ＝５．８，２．６，０．８Ｈｚ，０．５Ｈ），６．０１（ｄｄｄ，Ｊ＝５．７，２．６，０．８Ｈｚ，０．５Ｈ），５．８３（ｄｄｄ，Ｊ＝５．７，２．１，２．１Ｈｚ，０．５Ｈ），５．８１（ｄｄｄ，Ｊ＝５．７，２．１，２．１Ｈｚ，０．５Ｈ），５．６７（ｄｄｄ，Ｊ＝５．７，２．１，２．１Ｈｚ，０．５Ｈ），５．６２（ｄｄｄ，Ｊ＝５．７，２．１，２．１Ｈｚ，０．５Ｈ），２．８８（ｍ，１Ｈ），２．６８（ｍ，１Ｈ），２．５４−２．３０（ｍ，３Ｈ），２．０５（ｍ，１Ｈ），１．７５−１．５９（ｍ，３Ｈ），１．４１−１．２２（ｍ，４Ｈ），０．９０８（ｔ，Ｊ＝７．０Ｈｚ，１．５Ｈ），０．９０６（ｔ，Ｊ＝７．０Ｈｚ，１．５Ｈ）． Experimental Example-4

To a tetrahydrofuran solution (6.0 mL) of 2- (trans-4-propyl-2-cyclopentenyl) -5-oxohexanal (120 mg, 0.541 mmol) at room temperature was added a 5% aqueous potassium hydroxide solution (2.0 mL). ) And a 0.5 M tetrahydrofuran solution (0.10 mL, 0.05 mmol) of tetrabutylammonium hydroxide, and the mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and extracted with diethyl ether (2.0 mL × 2). The combined organic layers were washed with saturated aqueous ammonium chloride solution (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (6: 1)] to give 4- (trans-4-propyl-2-cyclopentenyl) -2- Cyclohexenone (20.1 mg, 18% yield) was obtained as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.87 (m, 0.5 H), 6.84 (m, 0.5 H), 6.03 (ddd, J = 5.8, 2.6, 0. 8 Hz, 0.5 H), 6.01 (ddd, J = 5.7, 2.6, 0.8 Hz, 0.5 H), 5.83 (ddd, J = 5.7, 2.1, 2.. 1 Hz, 0.5 H), 5.81 (ddd, J = 5.7, 2.1, 2.1 Hz, 0.5 H), 5.67 (ddd, J = 5.7, 2.1, 2. 1 Hz, 0.5H), 5.62 (ddd, J = 5.7, 2.1, 2.1 Hz, 0.5H), 2.88 (m, 1H), 2.68 (m, 1H), 2.54-2.30 (m, 3H), 2.05 (m, 1H), 1.75-1.59 (m, 3H), 1.41-1.22 (m, 4H), 0. 908 (t, J = 7.0 Hz, 1. H), 0.906 (t, J = 7.0Hz, 1.5H).

Experimental example-5
Methanol solution of sodium methoxide in methanol solution (5.0 mL) of 2- (trans-4-propyl-2-cyclopentenyl) -5-oxohexanal (220 mg, 0.99 mmol) at −10 ° C. under argon atmosphere (28%, 960 mg, 4.98 mmol) was added and stirred for 2 hours. Water (4.0 mL) was added to the reaction mixture, stirred at room temperature for 5 minutes, and extracted with diisopropyl ether (3.0 mL × 3). The combined organic layers were washed with saturated aqueous ammonium chloride solution (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (6: 1)] to give 4- (trans-4-propyl-2-cyclopentenyl) -2- Cyclohexenone (81 mg, 40% yield) was obtained as a colorless oil.

Experimental example-6
To a dimethyl sulfoxide solution (4.0 mL) of 2- (trans-4-propyl-2-cyclopentenyl) -5-oxohexanal (110 mg, 0.49 mmol) was added proline (29 mg, 0.25 mmol) at room temperature under an argon atmosphere. ) And stirred at 30 ° C. for 4 hours. Water (4.0 mL) was added to the reaction mixture, stirred at room temperature for 5 minutes, and extracted with diisopropyl ether (3.0 mL × 3). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (6: 1)] to give 4- (trans-4-propyl-2-cyclopentenyl) -2- Cyclohexenone (76 mg, 75% yield) was obtained as a colorless oil.

Experimental example-7
To a solution of 2- (trans-4-propyl-2-cyclopentenyl) -5-oxohexanal (220 mg, 0.99 mmol) in acetonitrile (5.0 mL) in trifluoroacetic acid (460 mg, 4. 03 mmol) was added and the mixture was stirred at 60 ° C. for 27 hours. Water (4.0 mL) was added to the reaction mixture, stirred at room temperature for 5 minutes, and extracted with diisopropyl ether (3.0 mL × 3). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (6: 1)] to give 4- (trans-4-propyl-2-cyclopentenyl) -2- Cyclohexenone (172 mg, 85% yield) was obtained as a colorless oil.

Experimental Example-8
P-Toluenesulfonic acid monohydrate in 2- (trans-4-propyl-2-cyclopentenyl) -5-oxohexanal (220 mg, 0.99 mmol) in acetonitrile (5.0 mL) under argon atmosphere at room temperature The product (380 mg, 2.00 mmol) was added and stirred at 20 ° C. for 31 hours. Water (4.0 mL) was added to the reaction mixture, stirred at room temperature for 5 minutes, and extracted with diisopropyl ether (3.0 mL × 3). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (6: 1)] to give 4- (trans-4-propyl-2-cyclopentenyl) -2- Cyclohexenone (158 mg, 78% yield) was obtained as a colorless oil.

２−（トランス−４−プロピル−２−シクロペンテニル）アセトアルデヒド（１５０ｍｇ、０．９９ｍｍｏｌ）のアセトニトリル溶液（５．０ｍＬ）に、アルゴン雰囲気下室温にて、メチルビニルケトン（１１０ｍｇ、１．５７ｍｍｏｌ）およびＮ，Ｎ−ジエチル−Ｎ−（トリメチルシリル）アミン（７０ｍｇ、０．４８ｍｍｏｌ）を加え、８０℃にて８時間攪拌した。２０℃まで降温後、トリフルオロ酢酸（３４０ｍｇ、２．９８ｍｍｏｌ）を加え、６０℃で２７時間撹拌した。反応混合物に水（４．０ｍＬ）を加え、室温にて５分間攪拌し、ジイソプロピルエーテル（３．０ｍＬｘ３）で抽出した。あわせた有機層を、飽和炭酸水素ナトリウム水溶液（２．０ｍＬ）および飽和食塩水（２．０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた油状物を中圧カラムクロマトグラフィー［シリカゲル（２８ｇ）、ヘキサン―酢酸エチル（６：１）］により精製することで、４−（トランス−４−プロピル−２−シクロペンテニル）−２−シクロヘキセノン（１５１ｍｇ、収率７５％）を無色油状物として得た。 Experimental example-9

To a solution of 2- (trans-4-propyl-2-cyclopentenyl) acetaldehyde (150 mg, 0.99 mmol) in acetonitrile (5.0 mL) at room temperature under argon atmosphere, methyl vinyl ketone (110 mg, 1.57 mmol) and N, N-diethyl-N- (trimethylsilyl) amine (70 mg, 0.48 mmol) was added, and the mixture was stirred at 80 ° C. for 8 hours. After cooling to 20 ° C., trifluoroacetic acid (340 mg, 2.98 mmol) was added, and the mixture was stirred at 60 ° C. for 27 hours. Water (4.0 mL) was added to the reaction mixture, stirred at room temperature for 5 minutes, and extracted with diisopropyl ether (3.0 mL × 3). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (6: 1)] to give 4- (trans-4-propyl-2-cyclopentenyl) -2- Cyclohexenone (151 mg, 75% yield) was obtained as a colorless oil.

Experimental example-10
To a solution of 2- (trans-4-propyl-2-cyclopentenyl) acetaldehyde (150 mg, 0.99 mmol) in acetonitrile (5.0 mL) at room temperature under argon atmosphere, methyl vinyl ketone (110 mg, 1.57 mmol) and N, N-diethyl-N- (trimethylsilyl) amine (70 mg, 0.48 mmol) was added, and the mixture was stirred at 80 ° C. for 8 hours. After the temperature was lowered to 0 ° C., p-toluenesulfonic acid monohydrate (300 mg, 1.58 mmol) was added, and the mixture was stirred at 20 ° C. for 31 hours. Water (4.0 mL) was added to the reaction mixture, stirred at room temperature for 5 minutes, and extracted with diisopropyl ether (3.0 mL × 3). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (6: 1)] to give 4- (trans-4-propyl-2-cyclopentenyl) -2- Cyclohexenone (141 mg, 70% yield) was obtained as a colorless oil.

Experimental example-11
To a solution of 2- (trans-4-propyl-2-cyclopentenyl) acetaldehyde (36.8 mg, 0.242 mmol) in dimethyl sulfoxide (1.0 mL) at room temperature under an argon atmosphere, methyl vinyl ketone (22.5 mg, 0.321 mmol) and proline (27.9 mg, 0.242 mmol) were added, and the mixture was stirred at room temperature for 27 hours. Water (2.0 mL) and diethyl ether (3.0 mL) were added to the reaction mixture, stirred at room temperature for 10 minutes, and extracted with diethyl ether (3.0 mL × 3). The combined organic layers were washed with water (2.0 mL) and saturated brine (2.0 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The resulting oil was purified by preparative thin phase chromatography [silica gel (250 × 250 × 0.50 mm), hexane-ethyl acetate (8: 1)] to give 4- (trans-4-propyl-2-cyclopentenyl) 2-Cyclohexenone (1.0 mg, 2.0% yield) was obtained as a colorless oil.

４−（トランス−４−プロピル−２−シクロペンテニル）−２−シクロヘキセノン（１６．４ｍｇ、０．０８０ｍｍｏｌ）の酢酸エチル溶液に、１０ｗｔ％Ｐｄ／Ｃ（１．６ｍｇ）を加え、水素雰囲気下、室温にて１５時間攪拌した。反応混合物をろ過し、減圧濃縮した。得られた油状物を中圧カラムクロマトグラフィー［シリカゲル（２８ｇ）、ヘキサン―酢酸エチル（８：１）］により精製することで、４−（トランス−４−プロピルシクロペンチル）シクロヘキサノン（１５．５ｍｇ、収率９３％）を無色油状物として得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ２．４０−２．２６（ｍ，４Ｈ），２．１２−２．０４（ｍ，２Ｈ），１．９８−１．６２（ｍ，４Ｈ），１．５６−１．０３（ｍ，１１Ｈ），０．８９（ｔ，Ｊ＝７．０Ｈｚ，３Ｈ）． Experimental example-12

To a solution of 4- (trans-4-propyl-2-cyclopentenyl) -2-cyclohexenone (16.4 mg, 0.080 mmol) in ethyl acetate, 10 wt% Pd / C (1.6 mg) was added, and hydrogen atmosphere was added. And stirred at room temperature for 15 hours. The reaction mixture was filtered and concentrated under reduced pressure. The obtained oil was purified by medium pressure column chromatography [silica gel (28 g), hexane-ethyl acetate (8: 1)] to give 4- (trans-4-propylcyclopentyl) cyclohexanone (15.5 mg, yield). 93%) was obtained as a colorless oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.40-2.26 (m, 4H), 2.12-2.04 (m, 2H), 1.98-1.62 (m, 4H), 1 .56-1.03 (m, 11H), 0.89 (t, J = 7.0 Hz, 3H).

  The 4-cyclopentylcyclohexanone derivative (5) of the present invention can be used for producing a 4-cyclopentylcyclohexanecarboxylic acid derivative useful as a liquid crystal compound.

Claims (6)

General formula (5)

(Wherein R ¹ represents an alkyl group having 3 to 4 carbon atoms ), a 4-cyclopentylcyclohexanone derivative represented by: 4- cyclopentyl cyclohexanone derivative according to claim 1 R ¹ is a propyl group. General formula (4)

(Wherein R ¹ represents an alkyl group having 3 to 4 carbon atoms ) and a catalytic hydrogenation reaction of a 4- (cyclopentenyl) cyclohexenone derivative represented by the general formula (5 )

(Wherein R ¹ represents the same meaning as described above), and a method for producing a 4-cyclopentylcyclohexanone derivative. R ¹ The production method according to claim 3, wherein is a propyl group. The production method according to claim 3 or 4 , wherein the catalytic hydrogenation reaction is carried out in a hydrogen gas atmosphere in the presence of a metal catalyst. The production method according to claim 5 , wherein the metal catalyst is palladium carbon.