JP2007153772A - METHOD FOR PRODUCING 3-SUBSTITUTED alpha,beta-UNSATURATED CARBOXYLIC ESTER - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new method for producing a 3-substituted α,β-unsaturated carboxylic ester useful as an intermediate for pharmaceuticals and agrochemicals. <P>SOLUTION: The method for producing the 3-substituted α,β-unsaturated carboxylic ester of formula(3) comprises making a cross coupling of an enol derivative of formula(1) and a Grignard reagent of formula(2) in an organic solvent such as an ether or hydrocarbon in the presence of an iron catalyst or rhodium catalyst. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a process for producing 3-substituted-α, β-unsaturated carboxylic acid esters that can be important intermediates for pharmaceuticals and agricultural chemicals.

  Conventionally, as a method for producing 2-substituted-1-cycloalkenecarboxylic acid esters, i) enol tosylate obtained by treating cyclic β-ketoester with tosylic anhydride or tosyl chloride and arylboronic acid under palladium catalyst Suzuki-Miyaura coupling method (Non-patent document 1), and ii) Cross coupling reaction of enol triflate obtained by treating cyclic β-ketoester with anhydrous triflate and aryl zinc bromide under palladium catalyst ( Non-patent document 2), iii) Similarly, coupling reaction of enol triflate with vinyltributyltin in the presence of a palladium catalyst (Non-patent document 3), iv) Enol nonaflate obtained by treating cyclic β-ketoester with anhydrous nonaflate And arylzinc chloride and palladium-catalyzed cross-coupling And reaction (Non-Patent Document 4) is known.

  However, in these production methods, expensive fluorinated alkyl sulfonates and palladium catalysts need to be used, and after the completion of the reaction, there is a problem that palladium contamination from waste and silica gel purification are essential. This makes it difficult to convert to a larger production scale, and an improvement has been desired.

Synlett, 471 (1999). Tetrahedron Lett., 38, 8067 (1997). Tetrahedron Lett., 32, 6675 (1991). Tetrahedron, 55,2103 (1999).

  It is an object of the present invention to provide a novel process for producing 3-substituted-α, β-unsaturated carboxylic acid esters in which the above problems are solved.

（式中、Ｒ^１は不飽和結合を有することもある炭素数が１〜８のアルキル基、アリール基、アラルキル基である。Ｒ^２およびＲ^３は不飽和結合を有することもある直鎖または分岐鎖の炭素数１〜８のアルキル基であり、この場合Ｒ^２とＲ^３が結合して環を形成していてもよい。Ｒ^４は、炭素数１〜４のアルキル基もしくはフェニル基で置換されたシリル基またはスルホニル基を意味する。）
で表されるエノール誘導体と、一般式（２）

（式中、Ｒ^５は非置換もしくは炭素数１〜４のアルキル基（アルキル基に存在する水素の１つ以上がハロゲン原子で置換されていてもよい）置換フェニル基、非置換もしくは炭素数１〜４のアルキル基（アルキル基に存在する水素の１つ以上がハロゲン原子で置換されていてもよい）置換ヘテロアリール基、非置換もしくは１つ以上の水素が炭素数１〜４のアルキル基に置換されたアミノ基置換フェニル基、または非置換もしくは１つ以上の水素が炭素数１〜４のアルキル基に置換されたアミノ基置換ヘテロアリール基を意味する。Ｘはハロゲン原子を意味する。）
で表されるグリニャール試薬を溶媒中、ニッケル触媒、鉄触媒またはロジウム触媒の存在下にクロスカップリングさせることを特徴とする一般式（３）

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５は前記と同じ。）
で表される３−置換−α，β−不飽和カルボン酸エステル類の製造法に関する。 The above problems have been solved by developing the manufacturing method shown below.
That is, the general formula (1)

(In the formula, R ¹ is an alkyl group having 1 to 8 carbon atoms, an aryl group or an aralkyl group which may have an unsaturated bond. R ² and R ³ may be a straight chain or an unsaturated bond. A branched chain alkyl group having 1 to 8 carbon atoms, in which case R ² and R ³ may be combined to form a ring, and R ⁴ is an alkyl group having 1 to 4 carbon atoms or a phenyl group; (This means a substituted silyl group or sulfonyl group.)
An enol derivative represented by the general formula (2)

(Wherein R ⁵ is unsubstituted or an alkyl group having 1 to 4 carbon atoms (one or more of hydrogens present in the alkyl group may be substituted with a halogen atom), a substituted phenyl group, unsubstituted or 1 carbon atom; -4 alkyl group (one or more hydrogen atoms present in the alkyl group may be substituted with a halogen atom) substituted heteroaryl group, unsubstituted or one or more hydrogen atoms in the alkyl group having 1 to 4 carbon atoms A substituted amino group-substituted phenyl group, or an amino group-substituted heteroaryl group in which one or more hydrogen atoms are substituted with an alkyl group having 1 to 4 carbon atoms, and X represents a halogen atom.
The Grignard reagent represented by the general formula (3) is cross-coupled in a solvent in the presence of a nickel catalyst, an iron catalyst or a rhodium catalyst.

(In the formula, R ¹ , R ² , R ³ and R ⁵ are the same as above.)
The present invention relates to a process for producing 3-substituted-α, β-unsaturated carboxylic acid esters represented by the formula:

  According to the present invention, process costs can be reduced by using cheap and easily available silyl enol ether and tosyl enolate as raw materials, using cheap and easily available catalysts compared to conventional methods. The problem of environmental pollution caused by waste materials, which was a difficult point of palladium-based catalysts, has been solved, and after the reaction is completed, silica gel purification is not required, and the target product can be obtained by extraction alone, simplifying post-treatment. Is done.

As specific examples of the enol derivative represented by the general formula (1), R ¹ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, A pentyl group, a hexyl group, a heptyl group, an octyl group, a vinyl group, an allyl group, a phenyl group, a benzyl group and the like can be mentioned, and a methyl group is particularly preferable. R ² and R ³ are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group. R ² and R ³ may be combined to form a methylene chain having 3 to 6 carbon atoms and bonded to form an unsaturated 5- to 8-membered ring as a whole. In particular, it is preferable to form a methylene chain having 4 carbon atoms and form a 6-membered ring as a whole. Examples of R ⁴ include trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, p-toluenesulfonyl group, m-nitrobenzenesulfonyl group, methanesulfonyl group and the like. When R ⁴ is a substituted silyl group, a trimethylsilyl group, a triethylsilyl group, or a tert-butyldimethylsilyl group is preferable, and a triethylsilyl group is particularly preferable. On the other hand, when R ⁴ is a substituted sulfonyl group, a p-toluenesulfonyl group, an m-nitrobenzenesulfonyl group, and a methanesulfonyl group are preferable, and a p-toluenesulfonyl group is particularly preferable.

Of the above general formula (1), when R ⁴ is a substituted silyl group, the silyl enol ether is, for example, β-ketoester in dichloromethane or N, N-dimethylformamide solvent, N, N-dimethylamino It can be obtained quantitatively by adding pyridine as a catalyst, using triethylamine as a base, and reacting with the corresponding halosilane.

Of the general formula (1), enol sulfonates when R ⁴ is a substituted sulfonyl group, for example, react β-ketoesters with the corresponding sulfonyl chloride using sodium hydride as a base in a tetrahydrofuran solvent. And can be easily obtained.

  Specific examples of the enol derivative represented by the general formula (1) include 2-triethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester, 2-trimethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester, Preferable examples include 2-tert-butyldimethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester and 2-p-toluenesulfonyloxy-1-cyclohexenecarboxylic acid ethyl ester. Particularly preferred is 2-triethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester.

The Grignard reagent represented by the general formula (2) is easily prepared, for example, by reacting an aryl halide and magnesium in a hydrocarbon solvent (for example, toluene) or an ether solvent (for example, tetrahydrofuran) in a nitrogen atmosphere. can do.
One kind of Grignard reagent may be used alone, or a plurality of kinds may be used in combination.

Specific examples of Grignard reagents include chlorobenzene, bromobenzene, iodobenzene, 4-chlorotoluene, 4-bromotoluene, 4-iodotoluene, 1-chloro-4-ethylbenzene, 1-bromo-4-ethylbenzene, 1-ethyl. -4-iodobenzene, 1-tert-butyl-4-chlorobenzene, 1-bromo-4-tert-butylbenzene, 1-tert-butyl-4-iodobenzene, 1-chloro-4-methoxybenzene, 1-bromo -4-methoxybenzene, 1-iodo-4-methoxybenzene, 1-chloro-4-ethoxybenzene, 1-bromo-4-ethoxybenzene, 1-ethoxy-4-iodobenzene, 4-tert-butoxy-1- Chlorobenzene, 1-bromo-4-tert-butoxybenzene, 4-ter -Butoxy-1-iodobenzene, 4-chloro-N, N-dimethylaniline, 4-bromo-N, N-dimethylaniline, 4-iodo-N, N-dimethylaniline, 1-chloro-4-fluorobenzene, 1-bromo-4-fluorobenzene, 1-fluoro-4-iodobenzene, 1-chloro-4- (trifluoromethyl) benzene, 1-bromo-4- (trifluoromethyl) benzene, 1-iodo-4- (Trifluoromethyl) benzene, 1-chloro-4- (trifluoromethoxy) benzene, 1-bromo-4- (trifluoromethoxy) benzene, 1-iodo-4- (trifluoromethoxy) benzene, 3-bromopyridine 4-bromopyridine, 2-amino-5-bromopyridine, 2-amino-6-bromopyridine, 3-amino-6-butyl Mopirijin, 2-amino-5-bromopyrimidine, and aromatic magnesium compound derived from aryl halides and magnesium, such as 2-amino-5-bromothiazole.
In this case, preferred aryl halides include chlorobenzene, bromobenzene, iodobenzene, 4-chlorotoluene, 4-bromotoluene, 4-iodotoluene, 1-bromo-4-ethylbenzene or 4-bromo-N, N-dimethylaniline. Particularly preferred is 4-bromotoluene, 1-bromo-4-ethylbenzene, 4-bromo-N, N-dimethylaniline or 1-bromo-4-methoxybenzene.

  Specific examples of the Grignard reagent include p-tolyl magnesium chloride, p-tolyl magnesium bromide, 4-ethylphenyl magnesium bromide, 4- (N, N-dimethylamino) phenyl magnesium bromide, and 4-methoxyphenyl magnesium bromide. The

  The amount of Grignard reagent used is not particularly limited, but it is preferably used in a ratio of 1 to 3 equivalents, particularly preferably 1.5 to 2 equivalents, relative to the enol derivative (1) as a raw material. Range.

  The nickel catalyst, iron catalyst or rhodium catalyst used in the cross-coupling reaction may be used alone or in combination of two or more.

Preferred nickel catalysts include nickel dichloride, nickel (II) acetylacetonate, bis (triphenylphosphine) nickel (II) dichloride, bis (triphenylphosphine) nickel (II) dibromide, bis (trin-butylphosphine) nickel. (II) dichloride, [1,2-bis (diphenylphosphino) ethane] nickel (II) dichloride, [1,3-bis (diphenylphosphino) propane] nickel (II) dichloride, tetrakis (triphenylphosphine) nickel (0), [1,1′-bis (diphenylphosphino) iron] nickel (II) dichloride is exemplified.
Preferred iron catalysts include iron (II) chloride, iron (III) chloride, iron (III) acetylacetonate, [1,2-bis (diphenylphosphino) ethane] iron (II) dichloride, tris (di- Examples thereof include benzoylmethanate) iron and iron (II) chloride.
Preferred rhodium catalysts include tris (triphenylphosphine) rhodium (I) chloride, tris (triphenylphosphine) rhodium (I) iodide, (1,5-cyclooctadiene) bis (triphenylphosphine) rhodium (I ) Is exemplified.

  Among these, particularly preferable catalysts include nickel (II) acetylacetonate, bis (triphenylphosphine) nickel (II) dichloride, [1,2-bis (diphenylphosphino) ethane] nickel (II) dichloride as nickel catalysts. As an iron catalyst, iron (III) acetylacetonate can be mentioned.

  Although the usage-amount of these catalysts is not specifically limited, It is preferable to use it in the ratio of 0.2-20 mol% with respect to the enol derivative represented by General formula (1), Most preferably It is in the range of 1 mol% to 5 mol%.

The solvent to be used may be any solvent that is generally used in organic reactions and complex synthesis, and organic solvents are particularly preferable and may be appropriately selected in consideration of the solubility of the metal catalyst and the reactivity of the Grignard reagent.
For example, ethers (eg, diethyl ether, dimethoxymethane, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, t-butyl methyl ether, etc.), hydrocarbons (eg, hexane, isohexane, heptane, cyclohexane, benzene, toluene, xylene, etc.) Amides (for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc.), nitriles (for example, acetonitrile, propionitrile, butyronitrile, etc.), and mixtures thereof.
Ethers, hydrocarbons, amides, and mixtures thereof are preferred, for example, dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, diisopropyl ether for ethers, hexane, heptane, cyclohexane, benzene, toluene, xylene for hydrocarbons Examples of amides include dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and hexamethylphosphoramide.
Ethers, hydrocarbons, and mixtures thereof are particularly preferred. Examples of ethers include dimethoxyethane and tetrahydrofuran, and examples of hydrocarbons include cyclohexane, benzene, toluene, and xylene.
Most preferred are tetrahydrofuran, dimethoxyethane, benzene, toluene, and mixtures thereof.

  Although there is no limitation in particular in the quantity of the solvent to be used, it is preferable to use by 5-30 times volume with respect to the enol derivative represented by General formula (1), Most preferably, it is 8-21 times volume.

  There are no particular limitations on the reaction conditions for the cross-coupling reaction, but the reaction is preferably carried out under an inert gas atmosphere such as nitrogen or argon at normal pressure, and the temperature range can be preferably from -78 ° C to the reflux temperature of the solvent. . Especially preferably, it is the range of 25 to 60 degreeC.

  There is no particular limitation on the order in which each reagent is charged into the reaction vessel, and any charging means can be used. For example, a method in which an enol derivative and a metal catalyst are mixed in a reaction vessel in advance and a Grignard reagent is added thereto, a Grignard reagent and a transition metal catalyst are mixed in a reaction vessel in advance, and an enol derivative is introduced therein. The method etc. to perform are mentioned preferably.

Examples are shown below, but the present invention is not limited to these Examples.
In the examples, TES means triethylsilyl group, TBDMS means tert-butyldimethylsilyl group, Ts means p-toluenesulfonyl group, Me means methyl group, and Et means ethyl group.

Production Example 1
[Synthesis of 2-triethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester (4)]
In a 1 L flask, 10 g (0.30 mol) of 2-cyclohexanone carboxylic acid ethyl ester was weighed in an argon atmosphere, 400 mL of N, N-dimethylformamide, 33.39 g (0.33 mol) of triethylamine, N, N-dimethylamino. 3.66 g (0.03 mol) of pyridine was added. While cooling to 0 ° C., 48.23 g (0.32 mol) of triethylsilyl chloride was added dropwise over 1 hour. After completion of dropping, the temperature was raised to 25 ° C., and the mixture was further stirred for 1.5 hours. After completion of the reaction, N, N-dimethylformamide was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, concentrated, and the target product, 2-triethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester. (4) 80.38 g (0.28 mol) was obtained with a yield of 93.3%.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３、２７０ＭＨｚ）：０．７１（６Ｈ，ｑ，Ｊ＝７．６Ｈｚ），０．９９（９Ｈ, ｔ，Ｊ＝７．６Ｈｚ），１．２８（３Ｈ，ｔ，Ｊ＝６．８Ｈｚ），１．５０−１．７１（４Ｈ，ｍ），２．１０−２．２０（２Ｈ，ｍ），２．２５−２．３５（２Ｈ，ｍ），４．１７（２Ｈ，ｑ，Ｊ＝６．８Ｈｚ）．

¹ H-NMR (CDCl ₃ , 270 MHz): 0.71 (6H, q, J = 7.6 Hz), 0.99 (9H, t, J = 7.6 Hz), 1.28 (3H, t, J = 6.8 Hz), 1.50-1.71 (4H, m), 2.10-2.20 (2H, m), 2.25-2.35 (2H, m), 4.17 (2H) , Q, J = 6.8 Hz).

Production Example 2
[Synthesis of 2-tert-butyldimethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester (5)]
In a 30 mL flask, 1 g (5.87 mmol) of 2-cyclohexanone carboxylic acid ethyl ester was weighed out under an argon atmosphere, 10 mL of N, N-dimethylformamide, 1.23 mL (8.805 mmol) of triethylamine, N, N-dimethylamino. 0.359 g (2.94 mmol) of pyridine was added. Under cooling to 0 ° C., 3.1 mL (8.805 mmol) of a toluene solution of tert-butyldimethylsilyl chloride was added dropwise. After completion of dropping, the mixture was stirred at 60 ° C. for 15 hours. After completion of the reaction, water was added and extracted twice with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried over magnesium sulfate, filtered, concentrated, and then the target 2-tert-butyldimethylsiloxy. -1-cyclohexenecarboxylic acid ethyl ester (5) (1.65 g, 5.800 mmol) was obtained in a yield of 99%.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３、２７０ＭＨｚ）：０．１８（６Ｈ，ｓ），０．９５（９Ｈ, ｔｓ），１．２８（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．５０−１．７０（４Ｈ，ｍ），２．１０−２．２０（２Ｈ，ｍ），２．２５−２．３５（２Ｈ，ｍ），４．１６（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ）．

¹ H-NMR (CDCl ₃ , 270 MHz): 0.18 (6H, s), 0.95 (9H, ts), 1.28 (3H, t, J = 7.3 Hz), 1.50-1. 70 (4H, m), 2.10-2.20 (2H, m), 2.25-2.35 (2H, m), 4.16 (2H, q, J = 7.3 Hz).

Production Example 3
[Synthesis of 2-p-toluenesulfonyloxy-1-cyclohexenecarboxylic acid ethyl ester (6)]
To a 300 mL flask, 2.59 g (64.62 mmol) of sodium hydride (60% oil suspension) and 120 mL of tetrahydrofuran were added under an argon atmosphere, cooled to 0 ° C., and 10 g (58.75 mmol) of 2-cyclohexanone carboxylic acid ethyl ester. Of tetrahydrofuran (20 mL) was added dropwise. After stirring at 0 ° C. for 30 minutes, a solution of 11.76 g (61.69 mmol) of p-toluenesulfanyl chloride in tetrahydrofuran (20 mL) was added dropwise. After stirring for 20 minutes, the temperature was raised to 25 ° C., and a saturated aqueous ammonium chloride solution was added to quench the reaction mixture. Further, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 10% aqueous potassium carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. 16.49 g (50.83 mmol) of oxy-1-cyclohexenecarboxylic acid ethyl ester (6) was obtained in a yield of 86.5%.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３、２７０ＭＨｚ）：１．２４（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．５０−１．６２（４Ｈ，ｍ），２．１５−２．２８（２Ｈ，ｍ），２．３０−２．４５（２Ｈ，ｍ），２．４５（３Ｈ，ｓ），４．０９（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），７．３３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．

¹ H-NMR (CDCl ₃ , 270 MHz): 1.24 (3H, t, J = 7.0 Hz), 1.50-1.62 (4H, m), 2.15-2.28 (2H, m ), 2.30-2.45 (2H, m), 2.45 (3H, s), 4.09 (2H, q, J = 7.0 Hz), 7.33 (2H, d, J = 7) .8 Hz), 7.83 (2H, d, J = 7.8 Hz).

Example 1
Under a nitrogen stream, 2.0 mL (2.0 mmol) of a tetrahydrofuran solution of p-tolylmagnesium bromide was weighed into a 50 mL flask, and 32.7 mg (0.05 mmol) of bis (triphenylphosphine) nickel (II) dichloride at 25 ° C. And stirred with a magnetic stirrer. A solution of 0.284 g (1.0 mmol) of 2-tert-butyldimethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester (5) prepared in Production Example 2 in tetrahydrofuran (2.0 mL) was added dropwise. The internal temperature was heated to 40 ° C. and stirred for 3 hours. After completion of the reaction, the internal temperature was cooled to 25 ° C., and 1N hydrochloric acid was added to quench the reaction. After extraction with ethyl acetate, the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over magnesium sulfate, filtration, and concentration, 0.105 g (0.429 mmol) of 2-p-tolyl-1-cyclohexenecarboxylic acid ethyl ester (7), which is the target product, is obtained in a yield of 42.9%. Obtained.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３、２７０ＭＨｚ）：０．８８（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．６０−１．８０（４Ｈ，ｍ），２．３０−２．４５（４Ｈ，ｍ），２．３３（３Ｈ，ｓ），３．８９（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），７．０２（２Ｈ，ｄ，Ｊ＝８．１Ｈｚ），７．１０（２Ｈ，ｄ，Ｊ＝８．１Ｈｚ）．

¹ H-NMR (CDCl ₃ , 270 MHz): 0.88 (3H, t, J = 7.0 Hz), 1.60-1.80 (4H, m), 2.30-2.45 (4H, m ), 2.33 (3H, s), 3.89 (2H, q, J = 7.0 Hz), 7.02 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

Example 2
Under a nitrogen stream, weigh out 0.284 g (1.0 mmol) of 2-triethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester (4) prepared in Production Example 1 and 2 mL of tetrahydrofuran in a 50 mL flask, and add nickel at 25 ° C. (II) 12.8 mg (0.05 mmol) of acetylacetonate was added and stirred with a magnetic stirrer. 2.0 mL (2.0 mmol) of a tetrahydrofuran solution of p-tolylmagnesium bromide was added dropwise, and after completion of the dropwise addition, the internal temperature was heated to 40 ° C. and stirred for 2 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1, and 0.155 g (0.634 mmol) of 2-p-tolyl-1-cyclohexenecarboxylic acid ethyl ester (7), which was the target product, was obtained in a yield of 63.4%. Obtained at a rate. The spectrum data of ¹ H-NMR was the same as that obtained in Example 1.

Example 3
Under a nitrogen stream, 0.284 g (1.0 mmol) of 2-triethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester (4) prepared in Production Example 1 and 2.0 mL of tetrahydrofuran were weighed into a 50 mL flask at 25 ° C. Then, 32.7 mg (0.05 mmol) of bis (triphenylphosphine) nickel (II) dichloride was added thereto and stirred with a magnetic stirrer. 2.0 mL (2.0 mmol) of a tetrahydrofuran solution of p-tolylmagnesium bromide was added dropwise, and after completion of the addition, the internal temperature was heated to 40 ° C. and stirred for 1.5 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 to obtain 0.168 g (0.687 mmol) of 2-p-tolyl-1-cyclohexenecarboxylic acid ethyl ester (7), which was the target product, in a yield of 68.7%. Obtained at a rate. The spectrum data of ¹ H-NMR was the same as that obtained in Example 1.

Example 4
Under a nitrogen stream, 0.284 g (1.0 mmol) of 2-triethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester (4) prepared in Production Example 1 and 2.0 mL of tetrahydrofuran were weighed into a 50 mL flask at 25 ° C. Then, 26.4 mg (0.05 mmol) of [1,2-bis (diphenylphosphino) ethane] nickel (II) dichloride was added and stirred with a magnetic stirrer. 2.0 mL (2.0 mmol) of a tetrahydrofuran solution of p-tolylmagnesium bromide was added dropwise, and after completion of the addition, the internal temperature was heated to 40 ° C. and stirred for 2.0 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 to obtain 0.128 g (0.526 mmol) of 2-p-tolyl-1-cyclohexenecarboxylic acid ethyl ester (7), which was the target product, in a yield of 52.6%. Obtained at a rate. The spectrum data of ¹ H-NMR was the same as that obtained in Example 1.

Example 5
[Preparation of Grignard reagent]
Under a nitrogen stream, 0.248 g (10.2 mmol) of magnesium and 2 mL of tetrahydrofuran are weighed into a 50 mL flask, and 1.85 g (10 mmol) of 4-bromo-ethylbenzene in tetrahydrofuran (4 mL) is stirred with a magnetic stirrer. Was added dropwise after confirming the exotherm. After completion of the dropwise addition, the internal temperature was heated to 40 ° C. After 1 hour, the mixture was cooled to 25 ° C. to obtain a tetrahydrofuran solution of 4-ethylphenylmagnesium bromide.
[Cross coupling reaction]
In a 50 mL flask under nitrogen flow, 1.424 g (5.0 mmol) of 2-triethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester (4) prepared in Production Example 1 and 7 mL of tetrahydrofuran were weighed and biscuated at 25 ° C. 0.163 g (0.25 mmol) of (triphenylphosphine) nickel (II) dichloride was added, and the mixture was stirred with a magnetic stirrer. The tetrahydrofuran solution of 4-ethylphenylmagnesium bromide prepared above was added dropwise, and after completion of the addition, the internal temperature was heated to 40 ° C. and stirred for 1.5 hours. After completion of the reaction, the same treatment as in Example 1 was carried out, and 62.8 of 0.812 g (3.14 mmol) of 2- (4-ethylphenyl) -1-cyclohexenecarboxylic acid ethyl ester (8) as the target product was obtained. % Yield.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３、２７０ＭＨｚ）：０．８３（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．２２（３Ｈ，ｔ，Ｊ＝７．６Ｈｚ），１．６２−１．８０（４Ｈ，ｍ），２．３０−２．４８（４Ｈ，ｍ），２．６３（２Ｈ，ｑ，Ｊ＝７．６Ｈｚ），３．８７（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），７．０５（２Ｈ，ｄ，Ｊ＝８．１Ｈｚ），７．１２（２Ｈ，ｄ，Ｊ＝８．１Ｈｚ）．

¹ H-NMR (CDCl ₃ , 270 MHz): 0.83 (3H, t, J = 7.3 Hz), 1.22 (3H, t, J = 7.6 Hz), 1.62-1.80 (4H M), 2.30-2.48 (4H, m), 2.63 (2H, q, J = 7.6 Hz), 3.87 (2H, q, J = 7.3 Hz), 7.05 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

Example 6
[Preparation of Grignard reagent]
Under a nitrogen stream, 0.248 g (10.2 mmol) of magnesium and 2 mL of tetrahydrofuran were weighed into a 50 mL flask, and while stirring with a magnetic stirrer, 2.0 g (10 mmol) of 4-bromo-N, N-dimethylaniline was added. 1.0 mL of tetrahydrofuran (4 mL) solution was added dropwise, and after confirming the exotherm, the rest was added dropwise. After completion of the dropwise addition, the internal temperature was heated to 40 ° C. After 1 hour, the mixture was cooled to 25 ° C. to obtain a tetrahydrofuran solution of 4- (N, N-dimethylamino) phenylmagnesium bromide.
[Cross coupling reaction]
In a 50 mL flask under nitrogen flow, 1.424 g (5.0 mmol) of 2-triethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester (4) prepared in Production Example 1 and 7 mL of tetrahydrofuran were weighed and biscuated at 25 ° C. 0.163 g (0.25 mmol) of (triphenylphosphine) nickel (II) dichloride was added and stirred with a magnetic stirrer. The tetrahydrofuran solution of 4- (N, N-dimethylamino) phenylmagnesium bromide prepared above was added dropwise, and after completion of the dropwise addition, the internal temperature was heated to 40 ° C. and stirred for 1.5 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1, and 0.489 g (1) of the target product, 2- [4- (N, N-dimethylamino) phenyl] -1-cyclohexenecarboxylic acid ethyl ester (9). .789 mmol) was obtained in a yield of 35.8%.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３、２７０ＭＨｚ）：０．９４（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．６５−１．８０（４Ｈ，ｍ），２．３０−２．４５（４Ｈ，ｍ），２．９３（６Ｈ，ｓ），３．９４（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），６．６６（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．０５（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ）．

¹ H-NMR (CDCl ₃ , 270 MHz): 0.94 (3H, t, J = 7.3 Hz), 1.65 to 1.80 (4H, m), 2.30-2.45 (4H, m ), 2.93 (6H, s), 3.94 (2H, q, J = 7.3 Hz), 6.66 (2H, d, J = 8.9 Hz), 7.05 (2H, d, J = 8.9 Hz).

Example 7
Under a nitrogen stream, take 0.284 g (1.0 mmol) of 2-triethylsiloxy-1-cyclohexenecarboxylic acid ethyl ester (4) prepared in Production Example 1 and 2 mL of tetrahydrofuran in a 50 mL flask, and bis ( 32.7 mg (0.05 mmol) of triphenylphosphine) nickel (II) dichloride was added and stirred with a magnetic stirrer. 4.0 mL (2.0 mmol) of tetrahydrofuran solution of 4-methoxyphenylmagnesium bromide was added dropwise, and after completion of the addition, the internal temperature was heated to 40 ° C. and stirred for 1.5 hours. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 to obtain 0.124 g (0.524 mmol) of 2- (4-methoxyphenyl) -1-cyclohexenecarboxylic acid ethyl ester (10), which is the target product, in 52.4. % Yield.

^１Ｈ−ＮＭＲ（ＣＤＣｌ_３、２７０ＭＨｚ）：０．９１（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．６５−１．８０（４Ｈ，ｍ），２．２８−２．４５（４Ｈ，ｍ），３．８０（３Ｈ，ｓ），３．９１（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），６．８３（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．０８（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ）．

¹ H-NMR (CDCl ₃ , 270 MHz): 0.91 (3H, t, J = 7.3 Hz), 1.65 to 1.80 (4H, m), 2.28-2.45 (4H, m ), 3.80 (3H, s), 3.91 (2H, q, J = 7.3 Hz), 6.83 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz).

Example 8
In a 50 mL flask under a nitrogen stream, 0.324 g (1.0 mmol) of 2-p-toluenesulfonyloxy-1-cyclohexenecarboxylic acid ethyl ester (6) prepared in Production Example 3 and 0.65 mL of N-methylpyrrolidone were prepared. Then, 3.0 mL of tetrahydrofuran was taken, 20 mg (0.057 mmol) of iron (III) acetylacetonate was added at 25 ° C., and the mixture was stirred with a magnetic stirrer. 1.5 mL (1.5 mmol) of a tetrahydrofuran solution of p-tolylmagnesium bromide was added dropwise, and the mixture was stirred for 1 hour after completion of the addition. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1, and 0.155 g (0.634 mmol) of 2-p-tolyl-1-cyclohexenecarboxylic acid ethyl ester (7), which was the target product, was obtained in a yield of 63.4%. Obtained at a rate.
The spectrum data of ¹ H-NMR was the same as that obtained in Example 1.

Claims (7)

General formula (1)

(In the formula, R ¹ is an alkyl group having 1 to 8 carbon atoms, an aryl group or an aralkyl group which may have an unsaturated bond. R ² and R ³ may be a straight chain or an unsaturated bond. A branched chain alkyl group having 1 to 8 carbon atoms, in which case R ² and R ³ may be combined to form a ring, and R ⁴ is an alkyl group having 1 to 4 carbon atoms or a phenyl group; (This means a substituted silyl group or sulfonyl group.)
An enol derivative represented by the general formula (2)

(In the formula, R ⁵ is unsubstituted or an alkyl group having 1 to 4 carbon atoms (one or more of hydrogens present in the alkyl group may be substituted with a halogen atom), a substituted phenyl group, unsubstituted or 1 carbon atom. -4 alkyl group (one or more hydrogen atoms present in the alkyl group may be substituted with a halogen atom) substituted heteroaryl group, unsubstituted or one or more hydrogen atoms in the alkyl group having 1 to 4 carbon atoms A substituted amino group-substituted phenyl group, or an amino group-substituted heteroaryl group in which one or more hydrogen atoms are substituted with an alkyl group having 1 to 4 carbon atoms, and X represents a halogen atom.
The Grignard reagent represented by the general formula (3) is cross-coupled in a solvent in the presence of a nickel catalyst, an iron catalyst or a rhodium catalyst.

(In the formula, R ¹ , R ² , R ³ and R ⁵ are the same as above.)
A process for producing 3-substituted-α, β-unsaturated carboxylic acid esters represented by the formula: The R ² and R ³ in the general formula (1) are combined to form a methylene chain having 3 to 6 carbon atoms, thereby forming an unsaturated 5- to 8-membered ring as a whole. A process for producing 3-substituted-α, β-unsaturated carboxylic acid esters of The method for producing 3-substituted-α, β-unsaturated carboxylic acid esters according to claim 1 or 2, wherein R ⁴ in the general formula (1) is a trimethylsilyl group, a triethylsilyl group, or a tert-butyldimethylsilyl group. . R ³ in the general formula (1) is a p-toluenesulfonyl group, an m-nitrobenzenesulfonyl group, or a methanesulfonyl group. The 3-substituted-α, β-unsaturated carboxylic acid esters according to claim 1 or 2, Manufacturing method.   The method for producing 3-substituted-α, β-unsaturated carboxylic acid esters according to any one of claims 1 to 4, wherein the catalyst is a nickel catalyst or an iron catalyst.   The catalyst is nickel (II) acetylacetonate, bis (triphenylphosphine) nickel (II) dichloride, or [1,2-bis (diphenylphosphino) ethane] nickel (II) dichloride. A process for producing a 3-substituted-α, β-unsaturated carboxylic acid ester according to claim 1. The method for producing 3-substituted-α, β-unsaturated carboxylic acid esters according to any one of claims 1 to 4, wherein the catalyst is iron (III) acetylacetonate.