KR101254538B1 - Preparation method of α, β-ynoate derivatives - Google Patents

Abstract

[화학식 2]

[화학식 3]

[상기 화학식 1, 2 및 3에서 R¹, R², Ar 및 X은 각각 발명의 상세한 설명에서 정의한 바와 같다.]The present invention relates to a method for preparing α, β-ynoate derivative represented by the following formula (1). More specifically, the present invention relates to a method of preparing α, β-inoate derivatives through a cross-coupling reaction of an aryl halide derivative represented by the following Chemical Formula 2 with an organoindium reagent represented by the following Chemical Formula 3 under a palladium catalyst.
[Formula 1]

(2)

(3)

[In Formulas 1, 2 and 3, R ¹ , R ² , Ar, and X are as defined in the detailed description of the invention, respectively.]

Description

Preparation method of α, β-inoate derivatives {Preparation method of α, β-ynoate derivatives}

The present invention relates to a method for producing α, β-inoate derivatives. More specifically, the α, β-inoate derivatives are prepared through a cross-coupling reaction between an organic indium reagent derived from alkane having an substituent such as an alkoxy carbonyl, which is attracted in the presence of a palladium catalyst, and an aryl halide. It is about how to.

Organic chemistry is the study of carbon-containing compounds, and this depends on how efficiently the carbon bonds are formed and cleaved. A representative of the methods for generating the carbon-to-carbon bonds reported so far is cross-coupling. This reaction is a carbon-to-carbon bond formation reaction between aryl halides or similar electrophiles and organometallic compounds in the presence of transition metals. , Negishi, Heck, Trost-Tsuji, etc.). Sonogashira reaction using Cu is a representative method for introducing alkane into aryl halides. However, the reaction does not proceed well with alkane having a functional group that attracts electrons. Therefore, research is needed to solve this problem. ( Synthesis 1986 , 320; Synthesis 1992 , 746; Tetrahedron Lett . 1995 , 36 , 4525; Bioorg . Med . Chem . Lett . 1996 , 6 , 2859; Synth . Commun. 1998 , 28 , 327; Russ . Chem . Bull . 1998 , 47 , 2256; Eur . J. Org . Chem . 2000 , 3085; Org . Lett . 2001 , 3 , 859; Chem . ReV . 1993 , 93, 2023; Synlett 1995 , 1087; Tetrahedron 1996 , 52, 5643; Organic Reactions in Aqueous Media Wiley : New York , 1997; Tetrahedron 1999 , 55, 11149; Aldrichimica Acta 2000 , 33, 16; J. Chem . Soc , Perkin Trans . 1 2000 , 3015; Org . Chem . 2002 , 6, 715; Synthesis 2003 , 633.)

However, in the Sonogashira reaction, a method of preparing α, β-inoate through cross-coupling reaction from reaction with organic indium reagent when electrons are deficient due to the introduction of a substituent that attracts electrons to alkane has been reported in any literature so far. There is no bar.

An object of the present invention is to provide a method for preparing α, β-inoate derivatives through the cross-coupling reaction of alkane (alkyne) and an aryl halide derivative containing an electron pulling group using a palladium catalyst and an organic indium reagent. have.

The present invention relates to a method for preparing α, β-ynoate derivative represented by the following formula (1). More specifically, the present invention relates to a method of preparing α, β-inoate derivatives through a cross-coupling reaction of an aryl halide derivative represented by the following Chemical Formula 2 with an organoindium reagent represented by the following Chemical Formula 3 under a palladium catalyst.

[Formula 1]

[Formula 2]

(3)

[In Formulas 1 to 3,

이고;R ¹ is hydrogen, (C ¹ -C 7) alkyl, (C 1 -C 7) alkoxy, halogen, (C 1 -C 7) alkoxycarbonyl, (C 1 -C 7) alkylcarbonyl or

ego;

R ² And R ³ are each (C1-C7) alkyl;

으로 이루어진 군으로부터 선택되는 하나 이상으로 더 치환될 수 있고;Ar is (C6-C20) arylene or (C3-C20) heteroarylene, wherein the arylene and heteroarylene are (C1-C7) alkyl, (C1-C7) alkoxy, halogen, (C1-C7) alkoxy Carbonyl, (C1-C7) alkylcarbonyl or

It may be further substituted with one or more selected from the group consisting of;

X is halogen.]

Ar is selected from the following structures.

이고; R³은 (C1-C7)알킬이다.]
[R ¹¹ to R ¹⁵ is hydrogen, (C1-C7) alkyl, (C1-C7) alkoxy, halogen, (C1-C7) alkoxycarbonyl, (C1-C7) alkylcarbonyl or

ego; R ³ is (C1-C7) alkyl.]

Specifically, R ¹ is hydrogen, ethoxycarbonyl, methoxy, acetyl, methyl, bromine, n-butyl or ethoxycarbonylethynyl, Ar is phenylene, thiophenylene, naphthylene or pyridinylene And R ² is methyl, ethyl, i-propyl, n-propyl or n-butyl.

More specific structure of the α, β-inoate derivative of Formula 1 is as follows.

In addition, the organic indium reagent represented by Formula 3 is prepared by treating the alkane derivative of Formula 4 with n-butyllithium, which is a base, and then treating with indium trichloride (InCl ₃ ) to react in-situ. It is done.

 [Formula 4]

[In Formula 4, R ² is (C1-C7) alkyl.]

The n-butyllithium: alkane derivative of the general formula (4): indium trichloride (InCl ₃ ) is preferably used in a molar ratio of 1: 1: 0.2 to 0.25.

Alkaine derivatives having an electron-pulling group are known to have no sonogashira reaction due to a decrease in the electron density of alkane, and also because the nucleophiles, which are ligands bound to the metal, are not transferred to the electrophiles, the reaction was inefficient. In the case of the organic indium reagent of Formula 3, even though it has an electron-pulling group, all four ligands bound to indium are transferred to the electrophile so that a cross-coupling reaction occurs very effectively.

The reaction vessel used in the production method of the present invention is preferably selected from the group consisting of a round bottom flask, a test tube and a V-vial, more preferably using a test tube.

The palladium catalyst used in the preparation method of the present invention is one or more mixtures selected from the group consisting of Pd ₂ dba ₃ CHCl ₃ , Pd (PPh ₃ ) ₄ and Pd (dppf) Cl, and Pd ₂ dba ₃ CHCl ₃ is used. More preferably used as a catalyst. In addition, the phosphine ligands used in the preparation method of the present invention are triphenylphosphine (PPh ₃ ), (tris ( p -trifluoromethyl) phenyl) phosphine (P [ p -CF ₃ (C ₆ H ₄ ) ₃ ]), Tris ( p -methoxyphenyl) phosphine (P ( p -CH ₃ OC ₆ H ₄ ) ₃ ), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos ), Bis (2-diphenylphosphinophenyl) ether (DPEphos) and 1,3-bis (diphenylphosphino) propane (DPPP), one or two or more mixtures selected from the group consisting of 4,5-bis It is more preferable to use (diphenylphosphino) -9,9-dimethylxanthene (Xantphos).

The amount of the palladium catalyst used in the preparation method of the present invention is preferably used 1 to 5 mol%, more preferably 2 mol% based on the aryl halide derivative represented by the formula (2). In addition, the amount of the phosphine ligand used in the preparation method of the present invention is preferably used 1 to 16 mol% based on the aryl halide derivative represented by the formula (2), more preferably 8 mol%.

The solvent used in the production method of the present invention is a conventional organic solvent, it is preferable to use tetrahydrofuran (THF) as a solvent.

Reaction temperature is 25 The reaction is carried out at a temperature of from 70 ° C. to reflux (70 ° C.), more preferably at reflux. The reaction time may vary depending on the reactants, the type of solvent, and the amount of the solvent. After confirming that the starting material aryl halide derivative is completely consumed through TLC, the reaction is completed. After the reaction is completed, the solvent may be distilled off under reduced pressure after the extraction process, and the desired product may be separated and purified through a conventional method such as column chromatography.

To date, cross-coupling reactions using a large number of transition metals have been reported and used to synthesize various compounds. However, each reaction has some effects, and new reactions are being studied to compensate for the shortcomings. In order for cross-coupling reactions to have important meanings, the preparation of organometallic compounds It should be easy and all nucleophiles used should be transferred to the electrophile. Therefore, through the present invention, not only sp - sp ² bonds can be formed through the cross-coupling reaction between the organic indium reagent and the aryl halide derivatives using the palladium catalyst, but also sp -in the conventional Sonogashira reaction. In sp ² binding, it was possible to overcome the limitations of the specific functional groups.

In addition, the method for producing α, β-inoate derivatives according to the present invention has the advantage of producing α, β-inoate derivatives in high yield through the cross-coupling reaction of the organic indium reagent in the presence of an aryl halide derivative and a palladium catalyst. Has

In addition, the reaction according to the present invention is superior to conventional reactions in terms of efficiency as well as economics, it is possible to develop a new reaction using indium.

Hereinafter, the structure of the present invention will be described in more detail with reference to Examples, but the following Examples are provided to assist in understanding the present invention, and the scope of the present invention is not limited thereto.

[Example 1] Preparation of ethyl 4- (3-ethoxy-3-oxo-1-propynyl) benzoate (Ethyl 4- (3-ethoxy-3-oxoprop-1-ynyl) benzoate)

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, ethyl 4-iodobenzoate (50.5 mL, 0.3 mmol) and THF (0.5 mL) were added, stirred at room temperature for 10 minutes, and then the organic It was added to the reaction test tube containing the indium reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 4-(3-에톡시-3-옥소-1-프로피닐)벤조에이트 (65 mg, 88%)를 얻었다. The reaction was then stirred at reflux for 3 hours and then terminated. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 4- (3-ethoxy-3-oxo-1-propynyl) benzoate (65 mg, 88%).

¹ H NMR (400 MHz CDCl ₃ , 25 ° C., TMS): δ 8.05 (d, J = 8.37 Hz, 2H), 7.65 (d, J = 8.36 Hz, 2H), 4.39 (q, J = 7.10 Hz, 2H ), 4.32 (q, J = 7.16 Hz, 2H), 1.42-1.35 (m, 6H)

[Example 2] Preparation of ethyl 3- (3-ethoxy-3-oxo-1-propynyl) benzoate (Ethyl 3- (3-ethoxy-3-oxoprop-1-ynyl) benzoate)

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, ethyl 3-iodobenzoate (50.5 mL, 0.3 mmol) and THF (0.5 mL) were added, stirred at room temperature for 10 minutes, and then the organic It was added to the reaction test tube containing the indium reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(3-에톡시-3-옥소-1-프로피닐)벤조에이트 (61 mg, 82%)를 얻었다.The reaction was then terminated after stirring for 2 hours at reflux. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (3-ethoxy-3-oxo-1-propynyl) benzoate (61 mg, 82%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 8.27 (s, 1H), 8.12 (dt, J = 7.91, 1.38 Hz, 1H), 7.75 (dt, J = 7.66, 1.22 Hz, 1H ), 7.47 (t, J = 7.8 Hz, 1H), 4.39 (q, J = 7.12 Hz, 2H), 4.32 (q, J = 7.16 Hz, 2H), 1.43-1.35 (m, 6H)

[Example 3] Preparation of ethyl 2- (3-ethoxy-3-oxo-1-propynyl) benzoate (Ethyl 2- (3-ethoxy-3-oxoprop-1-ynyl) benzoate)

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, ethyl 2-iodobenzoate (50.5 mL, 0.3 mmol) and THF (0.5 mL) were added, stirred at room temperature for 10 minutes, and then the organic It was added to the reaction test tube containing the indium reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 2-(3-에톡시-3-옥소-1-프로피닐)벤조에이트 (63 mg, 85%)를 얻었다.The reaction was then stirred at reflux for 4 hours and then terminated. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 2- (3-ethoxy-3-oxo-1-propynyl) benzoate (63 mg, 85%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 8.05-8.02 (m, 1H), 7.70-7.67 (m, 1H), 7.56-7.49 (m, 2H), 4.43 (q, J = 7.17 Hz, 2H), 4.31 (q, J = 7.10 Hz, 2H), 1.44 (t, J = 7.08 Hz, 3H), 1.36 (t, J = 7.15 Hz, 3H)

Example 4 Preparation of Ethyl 3- (4-methoxyphenyl) propiolate

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, 4-iodo anisole (70.2 mg, 0.3 mmol) and THF (0.5 mL) were added, stirred at room temperature for 10 minutes, and then the organic indium It was added to the reaction test tube containing the reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(4-메톡시페닐)프로피올레이트 (52 mg, 85%)를 얻었다.The reaction was then stirred at reflux for 2.5 hours and then terminated. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (4-methoxyphenyl) propiolate (52 mg, 85%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 7.54 (dt, J = 9.52, 2.29 Hz, 2H), 6.88 (dt, J = 9.33, 2.35 Hz, 2H), 4.29 (q, J = 7.16 Hz, 2H), 3.83 (s, 3H), 1.35 (t, J = 7.12 Hz, 3H)

Example 5 Preparation of Ethyl 3- (3-methoxyphenyl) propiolate

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, 3-iodo anisole (70.2 mg, 0.3 mmol) and THF (0.5 mL) were added, stirred at room temperature for 10 minutes, and then the organic It was added to the reaction test tube containing the indium reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(3-메톡시페닐)프로피올레이트 (50 mg, 82%)를 얻었다.The reaction was then stirred at reflux for 2.5 hours and then terminated. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (3-methoxyphenyl) propiolate (50 mg, 82%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C, TMS): δ 7.27 (t, J = 7.94 Hz, 1H), 7.18 (d, J = 7.56 Hz, 1H), 7.09 (dd, J = 2.5, 1.34 Hz, 1H), 7.01-6.98 (m, 1H), 4.30 (q, J = 7.16 Hz, 2H), 3.80 (s, 3H), 1.35 (t, J = 7.11 Hz, 3H)

Example 6 Preparation of Ethyl 3- (2-methoxyphenyl) propiolate

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, 2-iodo anisole (70.2 mg, 0.3 mmol) and THF (0.5 mL) were added, stirred at room temperature for 10 minutes, and then the organic indium It was added to the reaction test tube containing the reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(2-메톡시페닐)프로피올레이트 (55 mg, 89%)를 얻었다.The reaction was then stirred at reflux for 1.5 hours and then terminated. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (2-methoxyphenyl) propiolate (55 mg, 89%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 7.52 (dd, J = 7.63, 1.71 Hz, 1H), 7.43-7.38 (m, 1H), 6.96-6.89 (m, 2H), 4.30 (q, J = 7.09 Hz, 2H), 3.90 (s, 3H), 1.35 (t, J = 7.21 Hz, 3H)

Example 7 Preparation of Ethyl 3-phenylpropiolate

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When the cooling vessel is removed from the reaction, iodobenzene (61.2 mg, 0.3 mmol) and THF (0.5 mL) are added, stirred at room temperature for 10 minutes, and then for reaction containing the organoindium reagent. Was added to the test tube.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-페닐프로피올레이트 (43 mg, 83%)를 얻었다.The reaction was then terminated after stirring for 3 hours at reflux. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3-phenylpropiolate (43 mg, 83%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 7.60-7.57 (m, 2H), 7.47-7.42 (m, 1H), 7.39-7.35 (m, 2H), 4.30 (q, J = 7.11 Hz, 2H), 1.36 (t, J = 7.09 Hz, 3H)

Example 8 Preparation of Ethyl 3- (4-acetylphenyl) propiolate

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, 1- (4-iodophenyl) ethanone (7 (3.8 mg, 0.3 mmol) and THF (0.5 mL) were added followed by 10 at room temperature. After stirring for minutes, it was then added to the reaction test tube containing the organoindium reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(4-아세틸페닐)프로피올레이트 (52 mg, 80%)를 얻었다.The reaction was then stirred at reflux for 4 hours and then terminated. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (4-acetylphenyl) propiolate (52 mg, 80%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C, TMS): δ 7.96 (d, J = 8.28 Hz, 2H), 7.68 (d, J = 8.31 Hz, 2H), 4.32 (q, J = 7.11 Hz, 2H), 2.62 (s, 3H), 1.37 (t, J = 7.18 Hz, 3H)

Example 9 Ethyl 3- o - tolyl production of propionic oleate (Ethyl 3- o -tolylpropiolate)

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, 2-iodotoluene (65.4 mg, 0.3 mmol) and THF (0.5 mL) were added, stirred at room temperature for 10 minutes, and then the organic indium It was added to the reaction test tube containing the reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-o-톨릴프로피올레이트 (51 mg, 90%)를 얻었다.The reaction was then stirred at reflux for 1.5 hours and then terminated. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- o -tolylpropiolate (51 mg, 90%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 7.54 (d, J = 7.61 Hz, 1H), 7.33 (td, J = 7.58, 1.2 Hz, 1H), 7.23 (d, J = 7.72 Hz, 1H), 7.18 (t, J = 7.55 Hz, 1H), 4.30 (q, J = 7.15 Hz, 2H), 2.49 (s, 3H), 1.36 (t, J = 7.20 Hz, 3H)

Example 10 Preparation of ethyl 3- (2-pyridinyl) propiolate (ethyl 3- (pyridine-2-yl) propiolate)

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, add iodopyridine (61.5 mg, 0.3 mmol) and THF (0.5 mL), stir at room temperature for 10 minutes, and then contain the organoindium reagent. It was added to the reaction test tube.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(2-피리딘일)프로피올레이트 (40 mg, 75%)를 얻었다.The reaction was then terminated after stirring for 2 hours at reflux. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (2-pyridinyl) propiolate (40 mg, 75%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 8.66 (d, J = 5.12 Hz, 1H), 7.73 (td, J = 7.56, 1.62 Hz, 1H), 7.60 (dd, J = 6.77 , 0.91 Hz, 1H), 7.38-7.34 (m, 1H), 4.32 (q, J = 7.15 Hz, 2H), 1.35 (t, J = 7.20 Hz, 3H)

 Example 11 Preparation of ethyl 3- (2-thiophenyl) propiolate (ethyl 3- (thiophen-2-yl) propiolate)

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When the cooling vessel was removed from the reaction, iodothiophene (63 mg, 0.3 mmol) and THF (0.5 mL) were added, followed by stirring at room temperature for 10 minutes, and then containing the organoindium reagent. It was added to the reaction test tube.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(2-싸이오페닐)프로피올레이트 (47 mg, 86%)를 얻었다.The reaction was then terminated after stirring for 2 hours at reflux. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (2-thiophenyl) propiolate (47 mg, 86%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 7.49 (dd, J = 3.57, 0.96 Hz, 1H), 7.46 (dd, J = 5.04, 0.94 Hz, 1H), 7.05 (dd, J = 5.10, 3.75 Hz, 1H), 4.30 (q, J = 7.13 Hz, 2H), 1.35 (t, J = 7.19 Hz, 3H)

Example 12 Preparation of ethyl 3- (5-naphthalenyl) propiolate (Ethyl 3- (naphthalene-5-yl) propiolate)

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When the cooling vessel was removed from the reaction, 1-iodonaphthalene (76.2 mg, 0.3 mmol) and THF (0.5 mL) were added, followed by stirring at room temperature for 10 minutes, and then the organic indium It was added to the reaction test tube containing the reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(5-나프탈레닐)프로피올레이트 (55 mg, 82%)를 얻었다.The reaction was then stirred at reflux for 4 hours and then terminated. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (5-naphthalenyl) propiolate (55 mg, 82%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 8.34 (d, J = 8.44 Hz, 1H), 7.94 (d, J = 8.35 Hz, 1H), 7.86 (t, J = 8.61 Hz, 2H), 7.65-7.61 (m, 1H), 7.56 (td, J = 8.06, 1.08 Hz, 1H), 7.46 (dd, J = 8.07, 7.44 Hz, 1H), 4.36 (q, J = 7.12 Hz, 2H ), 1.40 (t, J = 7.10 Hz, 3H)

Example 13 Preparation of Ethyl 3- (3,5-dimethylphenyl) propiolate

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, 1-iodo-3,5-dimethylbenzene (69.6 mg, 0.3 mmol) and THF (0.5 mL) were added followed by room temperature. After stirring for 10 minutes, it was then added to the reaction test tube containing the organoindium reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(3,5-디메틸페닐)프로피올레이트 (52 mg, 85%)를 얻었다.The reaction was then stirred at reflux for 1.5 hours and then terminated. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (3,5-dimethylphenyl) propiolate (52 mg, 85%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 7.21 (s, 2H), 7.07 (s, 2H), 4.29 (q, J = 7.16 Hz, 2H), 2.30 (s, 6H), 1.35 (t, J = 7.18 Hz, 3H)

Example 14 Preparation of Ethyl 3- (4-bromophenyl) propiolate

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, 1-bromo-4-iodobenzene (84.8 mg, 0.3 mmol) and THF (0.5 mL) are added and at room temperature for 10 minutes After stirring, it was then added to the reaction test tube containing the organoindium reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(4-브로모페닐)프로피올레이트 (62 mg, 82%)를 얻었다.The reaction was then terminated after stirring for 2 hours at reflux. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (4-bromophenyl) propiolate (62 mg, 82%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 7.52 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 4.30 (q, J = 7.16 Hz, 2H), 1.36 (t, J = 7.16 Hz, 3H)

Example 15 Preparation of Ethyl 3- (4-butylphenyl) propiolate

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was added dissolved in THF (0.5 mL) and then stirred at −78 ° C. for 10 minutes. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, 1-butyl-4-iodobenzene (78 mg, 0.3 mmol) and THF (0.5 mL) were added and stirred at room temperature for 10 minutes. Then, it was added to the reaction test tube containing the organoindium reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 에틸 3-(4-부틸페닐)프로피올레이트 (58 mg, 84%)를 얻었다.The reaction was then terminated after stirring at reflux for 1 hour. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and then separated by column chromatography to give the title compound ethyl 3- (4-butylphenyl) propiolate (58 mg, 84%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 7.50 (d, J = 8.21 Hz, 2H), 7.18 (d, J = 8.16 Hz, 2H), 4.29 (q, J = 7.12 Hz, 2H), 2.62 (t, J = 7.73 Hz, 2H), 1.63-1.55 (m, 2H), 1.37-1.31 (m, 5H), 0.92 (t, J = 7.33 Hz, 3H)

Example 16 Preparation of Diethyl 3,3 '-(1,4-phenylene) dipropiolate (Diethyl 3,3'-(1,4-phenylene) dipropiolate)

Ethyl propiolate (0.42 mmol , 43 in a test tube for reaction under nitrogen atmosphere) mL) and THF (0.5 mL) were added and the temperature was reduced to -78 ° C. N- BuLi (0.43 mmol, 1.6 M in Hexane) was slowly added thereto, followed by stirring at -78 ° C. After 10 minutes InCl ₃ (23.3 mg, 0.105 mmol) was dissolved in THF (0.5 mL) and added and then stirred for 10 minutes at -78 ° C. The cooling vessel was then removed and stirred for 10 minutes at room temperature to prepare an organoindium reagent.

Simultaneously with this reaction, Pd ₂ dba ₃ CHCl ₃ (6.2 mg, 2 mol%) and Xantphos (14 mg, 8 mol%) were added to a separate reaction test tube under a nitrogen atmosphere, and the organic indium reagent (Indate) synthesis was performed. When removing the cooling vessel from the reaction, 1,4-diiodobenzene (98.9 mg, 0.3 mmol) and THF (0.5 mL) were added, stirred at room temperature for 10 minutes, and then Next, it was added to the reaction test tube containing the organoindium reagent.

20 mL)로 추출하였다. 추출한 유기물을 무수 MgSO₄로 건조하고 여과하였다. 용매를 제거한 후 관 크로마토그래피로 분리하여 표제 화합물 디에틸 3,3'-(1,4-페닐렌)디프로피올레이트 (69 mg, 85%)를 얻었다. The reaction was then stirred at reflux for 1.5 hours and then terminated. Wash with saturated NH ₄ Cl (20 mL) and brine (20 mL), CH ₂ Cl ₂ (3

20 mL). The extracted organics were dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to give the title compound diethyl 3,3 '-(1,4-phenylene) dipropiolate (69 mg, 85%).

¹ H NMR (400 MHz, CDCl ₃ , 25 ° C., TMS): δ 7.58 (s, 4H), 4.31 (q, J = 7.12 Hz, 4H), 1.36 (t, J = 7.09 Hz, 6H)

Claims (10)

In the presence of Pd ₂ dba ₃ CHCl ₃ and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos), an aryl halide derivative represented by the following formula (2) and an organic represented by the following formula (3) A method of producing an α, β-ynoate derivative, characterized by preparing an α, β-ynoate derivative represented by the following Chemical Formula 1 by cross-reacting an indium reagent.
[Formula 1]

(2)

(3)

[In Formulas 1 to 3,
R ¹ is hydrogen, (C ¹ -C 7) alkyl, (C 1 -C 7) alkoxy, halogen, (C 1 -C 7) alkoxycarbonyl, (C 1 -C 7) alkylcarbonyl or

ego;
R ² and R ³ are each (C 1 -C 7) alkyl;
Ar is (C6-C20) arylene, pyridinylene or thiophenylene, and the arylene, pyridinylene and thiophenylene are (C1-C7) alkyl, (C1-C7) alkoxy, halogen, ( C1-C7) alkoxycarbonyl, (C1-C7) alkylcarbonyl or

It may be further substituted with one or more selected from the group consisting of;
X is halogen.]
The method of claim 1,
Ar is selected from the following structures.

[R ¹¹ to R ¹⁵ is hydrogen, (C1-C7) alkyl, (C1-C7) alkoxy, halogen, (C1-C7) alkoxycarbonyl, (C1-C7) alkylcarbonyl or

ego; R ³ is (C1-C7) alkyl.]
The method of claim 2,
The α, β-inoate derivatives are selected from the following compounds.

The method of claim 1,
The organoindium reagent represented by Formula ₃ may be prepared by treating an alkyne derivative of Formula 4 with n-butyllithium, which is a base, followed by indium trichloride (InCl ₃ ) to react in-situ. Manufacturing method.
(3)

[Chemical Formula 4]

[In Formulas 3 and 4, R ² is (C1-C7) alkyl.]
5. The method of claim 4,
The n-butyllithium: alkane derivative of the general formula (4): Indium trichloride (InCl ₃ ) is a manufacturing method characterized in that used in a molar ratio of 1: 1: 0.2 ~ 0.25.
delete delete The method of claim 1,
The Pd ₂ dba ₃ CHCl ₃ is characterized in that 1 to 5 mol% based on the aryl halide derivative represented by the formula (2).
The method of claim 1,
The 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos) is used in an amount of 1 to 16 mol% based on the aryl halide derivative represented by Formula 2 above. .
The method of claim 1,
The cross-coupling reaction is characterized in that the tetrahydrofuran (THF) is carried out at 25 to 70 ℃ as a solvent.