WO2023157909A1 - Method for producing diarylacetylene derivative - Google Patents

Method for producing diarylacetylene derivative Download PDF

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WO2023157909A1
WO2023157909A1 PCT/JP2023/005415 JP2023005415W WO2023157909A1 WO 2023157909 A1 WO2023157909 A1 WO 2023157909A1 JP 2023005415 W JP2023005415 W JP 2023005415W WO 2023157909 A1 WO2023157909 A1 WO 2023157909A1
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浩一 松本
政史 小林
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関東電化工業株式会社
学校法人近畿大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/40—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals
    • C07C15/50—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals polycyclic non-condensed
    • C07C15/54—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals polycyclic non-condensed containing a group with formula
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/25—Preparation of halogenated hydrocarbons by splitting-off hydrogen halides from halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/24—Halogenated aromatic hydrocarbons with unsaturated side chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C5/00—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms

Definitions

  • the present invention relates to a novel method for producing diarylacetylene derivatives.
  • Diphenylacetylene and its derivatives are molecules with a ⁇ -electron conjugated system, and are important compounds as synthetic intermediates for pharmaceuticals, agricultural chemicals, and polymer materials.
  • gas separation membranes such as oxygen gas (Patent Document 1) and carbon dioxide gas (Patent Document 2, Non-Patent Document 1) are used as polymer materials, and liquid crystal materials (Patent Document 3) and stilbene are used as single molecules.
  • Patent Document 4 A system pharmaceutical intermediate (Patent Document 4) and the like have been reported.
  • the conventional method for producing diphenylacetylene is a reaction of phenylacetylene and benzene iodide using a palladium catalyst, a base, and a copper (I) halide salt, called the Sonogashira reaction (Patent Document 4, Non-Patent Document 2). It is well known that the purification is complicated, the catalyst cannot be completely removed, and the reaction must be carried out in an inert gas atmosphere. There is a drawback that it is necessary to obtain it in advance, and it cannot be said that it is necessarily a simple method.
  • JP 2018-167220 A JP 2010-214324 A Re-table 2019/116702 Japanese Patent Publication No. 2012-533600
  • the object of the present invention is to provide a novel method for producing diarylacetylene derivatives.
  • R1 to R5 may be the same or different and are hydrogen, a halogen element, a hydroxyl group, an amino group or a monovalent organic group, and two or more of R1 to R5 are combined to form a condensed ring.
  • a method for producing a diarylacetylene derivative represented by (a) the following formula (2): (Wherein, X represents a halogen element) and a tetrahalogenated ethylene represented by the following formula (3): (Wherein, R1 to R5 are as described above) is reacted with an arylboronic acid derivative represented by the following formula (4) in the presence of a catalyst and a base: (wherein R1 to R5 and X are as defined above) and a step of reacting the diaryldihalogenated ethylene represented by the formula (4) with an organic alkali metal to obtain the diarylacetylene derivative represented by the formula (1).
  • a method including [2] The method according to [1], wherein the monovalent organic group is selected from the group consisting of an alkoxy group, an alkylamino group, an alkylester group, and an acylamino group.
  • the condensed ring is a naphthalene ring or an anthracene ring.
  • the catalyst and base are selected from the group consisting of a combination of tetrakis(triphenylphosphine)palladium and KOH, and a combination of tetrakis(triphenylphosphine)palladium and K 3 PO 4 The method described in Crab.
  • R1 to R5 may be the same or different and are hydrogen, a halogen element, a hydroxyl group, an amino group or a monovalent organic group, and two or more of R1 to R5 are combined to form a condensed ring. may be.
  • a novel method for producing a novel diarylacetylene derivative is provided.
  • This method A series of reactions can be performed up to the target product in the presence of a catalyst in the reaction solution. the reaction can be carried out under atmospheric pressure, In order to obtain a product having a substituent, it is sufficient to prepare an aryl compound having a substituent. , and the diarylacetylene derivative can be easily produced.
  • the present invention relates to a method for producing a diarylacetylene derivative represented by formula (1), which is characterized by utilizing Suzuki coupling reaction instead of Sonogashira coupling reaction, which has been often used as a conventional method. . Since the production method of the present invention can use tetrachloroethylene, which is one type of tetrahalogenated ethylene, as a starting material, the starting material is easy to obtain and handle.
  • a catalyst especially a palladium catalyst
  • the arylboronic acid represented by the formula (3) is converted to the tetrahalogenated ethylene represented by the formula (2).
  • a derivative is reacted to produce a diaryldihalogenated ethylene represented by formula (4), and as a second step, the diaryldihalogenated ethylene represented by formula (4) is treated with an organic alkali metal to give a compound of formula (1 ) to produce a diarylacetylene derivative represented by
  • the first step and the second step can be performed continuously, and the target diarylacetylene derivative can be produced substantially in one step.
  • the role of the catalyst in the first step is to catalyze the coupling reaction between the tetrahalogenated ethylene and the arylboronic acid derivative, and the base plays a role of activating the tetrahalogenated ethylene and arylboronic acid.
  • arylboronic acid e.g., ArB(OH) 2 +OH ⁇ ⁇ Ar ⁇ +B(OH) 3 ; where Ar is an aryl group
  • the role of the organic alkali metal in the second step is alkali metalization of the reaction substrate by abstraction of the halogen element, followed by triple bond formation by dealkalization metal halide (for example, the organic alkali metal is n-butyllithium,
  • the reaction in the first step is a type of reaction called Suzuki coupling reaction, and various substituents can be relatively easily introduced onto the aromatic ring of arylboronic acid. Therefore, by using the production method of the present invention, it is possible to obtain a reaction substrate relatively easily and to select substituents on the aromatic ring of diarylacetylene with a very high degree of freedom. Furthermore, after the reaction in the first step, the organic alkali metal treatment in the second step can be performed in a state where the catalyst and the product are mixed without performing the separation operation of the reactants, so that the operation is simpler than the conventional method. can get the target.
  • First step In the first step, in the presence of a catalyst (especially a palladium catalyst) and a base, an ethylene tetrahalide is reacted with an arylboronic acid derivative represented by the formula (3) to obtain a diaryldihalogen represented by the formula (4). produces ethylene chloride.
  • a catalyst especially a palladium catalyst
  • an ethylene tetrahalide is reacted with an arylboronic acid derivative represented by the formula (3) to obtain a diaryldihalogen represented by the formula (4). produces ethylene chloride.
  • tetrahalogenated ethylene tetrafluoroethylene, tetrachloroethylene, tetrabromoethylene, tetraiodoethylene, etc. can be used, but tetrachlorethylene, tetrabromoethylene, and more preferably tetrachlorethylene can be used.
  • Tetrachlorethylene has been conventionally used as a raw material for synthesizing halogen-containing compounds, and is extremely easy to obtain.
  • Tetrabromoethylene can be synthesized from pentabromoethylene by the method of Non-Patent Document 3.
  • Aryl boronic acid derivative represented by formula (3) can be produced by methods well known in the art. For example, aryl magnesium halide (ArMgBr; where Ar is an aryl group) and trimethyl boronate (B(OMe) 3 ; where Me is a methyl group) are reacted to form dimethyl aryl boronate (ArB(OMe) 2 ). It can be produced by hydrolyzing it.
  • aryl magnesium halide ArMgBr; where Ar is an aryl group
  • B(OMe) 3 trimethyl boronate
  • Me is a methyl group
  • It can be produced by hydrolyzing it.
  • various substituents can be introduced onto the benzene ring. can be done.
  • R1 to R5 are independently hydrogen, a halogen element such as fluorine, chlorine, bromine, and iodine, a hydroxyl group, an amino group, or a monovalent organic group that does not affect the reaction. Two or more of R5 may be combined to form a condensed ring.
  • monovalent organic groups include alkyl groups, N-1 substituted amino groups, N,N-2 substituted amino groups, alkoxy groups, aryl groups, aryloxy groups, alkyl ester groups, acylamino groups and the like.
  • alkyl group examples include alkyl groups having 1 to 4 carbon atoms, particularly methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and t-butyl group.
  • the hydrogen of the alkyl group may be substituted with a halogen element
  • the halogenated alkyl group includes, for example, a halogenated alkyl group having 1 to 4 carbon atoms, particularly a perfluoroalkyl group having 1 to 4 carbon atoms, particularly trifluoromethyl group, pentafluoroethyl group, n-heptafluoropropyl group, iso-heptafluoropropyl group, n-nonafluorobutyl group, sec-nonafluorobutyl group, iso-nonafluorobutyl group, t-nonafluorobutyl group, and the like.
  • alkoxy groups include alkoxy groups having 1 to 4 carbon atoms, particularly methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, and the like. mentioned.
  • Aryl groups include, for example, phenyl, naphthyl, anthranyl, naphthacenyl, and pentacenyl groups.
  • aryloxy groups include phenyloxy, naphthyloxy, anthranyloxy, naphthacenyloxy, and pentacenyloxy groups.
  • N-1 substituted amino group examples include those in which one substituent such as the aforementioned alkyl group having 1 to 4 carbon atoms or an aryl group is bonded to the nitrogen of the amino group, and more specifically, , methylamino group, ethylamino group, propylamino group, isopropylamino group, and the like.
  • N,N-disubstituted amino group examples include those in which two substituents such as the aforementioned alkyl group having 1 to 4 carbon atoms or an aryl group are bonded to the nitrogen of the amino group. The substituents may be the same or different.
  • the alkyl ester group includes, for example, a carboxyl group protected with an alkyl group, such as a methyl ester group (ie --COOCH 3 ) and an ethyl ester group (ie --COOC 2 H 5 ).
  • the acylamino group includes, for example, an amino group protected with an acyl group, such as a formylamino group (ie —NHCHO), an acetylamino group (ie —NHCOCH 3 ), a benzoylamino group (ie —NHCOC 6 H 5 ).
  • a formylamino group ie —NHCHO
  • an acetylamino group ie —NHCOCH 3
  • a benzoylamino group ie —NHCOC 6 H 5
  • Two or more of R1 to R5 may be combined to form a fused ring with a benzene ring.
  • condensed rings include naphthalene ring, anthracene ring, phenanthrene ring, pyrene ring and the like, and halogen elements such as fluorine, hydroxyl group, amino group, monovalent organic You may have a group.
  • catalysts used in the first step include palladium catalysts, particularly tetrakis(triphenylphosphine)palladium, palladium acetate, dichlorobis(triphenylphosphine)palladium (II), dichloro(1,1′-bis(diphenylphosphine) phino)ferrocene)palladium(II), and more preferably tetrakis(triphenylphosphine)palladium. Since the palladium catalyst is weak against oxygen, it is preferable to carry out the reaction under an inert atmosphere. Gases that form the inert atmosphere include, for example, nitrogen and rare gases (helium, neon, argon, xenon, etc.).
  • the base used in the first step is intended to promote the reaction of the tetrahalogenated ethylene and the arylboronic acid derivative and convert the liberated halogen and boronic acid into stable by-products that do not affect the reaction.
  • Examples of the base used in the first step include alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal phosphates (e.g. potassium phosphate), quaternary ammonium salts (e.g.
  • tetrabutyl fluoride ammonium tertiary amines (eg triethylamine), strong organic bases (eg DBN (1,5-diazabicyclo[4.3.0]non-5-ene), MTBD (7-methyl-1,5,7-tri zabicyclo[4.4.0]dec-5-ene)), etc., preferably sodium hydroxide, potassium hydroxide, potassium phosphate, more preferably potassium hydroxide.
  • solvent examples include polar solvents, preferably water, tetrahydrofuran (THF), ethers such as diethyl ether, diglyme and triglyme, dimethylformamide (DMF), N-methylpyrrolidone (NMP ), dimethyl sulfoxide (DMSO), methanol, ethanol, propanol, and alcohols such as butanol.
  • polar solvents preferably water, tetrahydrofuran (THF), ethers such as diethyl ether, diglyme and triglyme, dimethylformamide (DMF), N-methylpyrrolidone (NMP ), dimethyl sulfoxide (DMSO), methanol, ethanol, propanol, and alcohols such as butanol.
  • THF tetrahydrofuran
  • ethers such as diethyl ether, diglyme and triglyme
  • DMF dimethylformamide
  • NMP N-methylpyrrolidone
  • reaction conditions for the first step The reaction temperature in the first step is preferably -100 to 200°C, more preferably 0 to 100°C, still more preferably 25 to 60°C.
  • the number of molar equivalents of the arylboronic acid derivative represented by formula (3) is 0.01 to 100 molar equivalents, preferably 0.1 to 10 molar equivalents, more preferably 5 molar equivalents relative to the tetrahalogenated ethylene. be.
  • the number of molar equivalents of the catalyst is 0.0001 to 1 molar equivalents, preferably 0.1 to 0.5 molar equivalents, more preferably 0.09 to 0.1 molar equivalents relative to the tetrahalogenated ethylene.
  • the base itself may be used for the reaction as it is, or it may be dissolved in water before use.
  • the number of molar equivalents of the base is 0.01 to 100 molar equivalents, preferably 0.1 to 10 molar equivalents, more preferably 0.5 to 1 molar equivalents relative to the tetrahalogenated ethylene.
  • the diaryldihalogenated ethylene represented by the formula (4) is obtained, and after it is isolated, it is treated with an organic alkali metal to carry out the halogen-lithium exchange reaction, which is the reaction in the second step.
  • the reaction of the second step which is the reaction of the second step, which is the reaction of treating with an organic alkali metal to perform the halogen-lithium exchange reaction, and then the reaction of releasing dehalogenated lithium, is performed.
  • a diarylacetylene represented by (1) is obtained.
  • the reaction can be stopped by adding water to quench the reaction solution.
  • the organic alkali metal in the second step can react with water, if the product in the first step is not purified, an operation is performed to remove water from the reaction mixture, and then the resulting crude product is treated in the second step.
  • the operation of removing water from the reaction mixture may be an operation commonly performed in the industry. For example, after washing the reaction solution with saturated saline, the organic layer is separated, and the organic layer is treated with sodium sulfate, magnesium sulfate, or the like. An operation of mixing with a desiccant and filtering the desiccant can be mentioned.
  • Organic alkali metal used in the second step forms a triple bond by alkali metalizing diaryldihalogenated ethylene through a halogen-lithium exchange reaction and then eliminating the alkali metal halide.
  • organic alkali metals include alkylalkali metals, especially alkyllithium, especially butyllithium such as n-butyllithium, s-butyllithium and t-butyllithium; alkali metal piperidides, especially lithium tetramethylpiperidiide; alkali metal diisopropylamide, especially lithium diisopropylamide; alkali metal hexamethyldisilazane, especially lithium hexamethyldisilazane; and the like, preferably alkyllithium, more preferably butyllithium, especially n - butyllithium.
  • the solvent in the second step may be any one that can be used for organic alkali metals.
  • examples include polar solvents, preferably tetrahydrofuran (THF), ethers such as diethyl ether, diglyme and triglyme, Methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and the like can be mentioned, and THF is more preferred.
  • THF tetrahydrofuran
  • NMP Methylpyrrolidone
  • DMSO dimethylsulfoxide
  • the reaction temperature in the second step is preferably -100 to 200°C, more preferably -100 to 25°C, still more preferably -78 to 25°C.
  • the reaction using alkyllithium, particularly n-butyllithium is preferably carried out at a low temperature because the intermediate (lithiated product) obtained by the reaction is unstable.
  • a halogen-lithium exchange reaction occurs at a low temperature, and when the temperature rises, the lithiated product decomposes to release lithium halide to form an acetylene compound.
  • the number of molar equivalents of the organic alkali metal is 0.1 to 10 molar equivalents, preferably 0.5 to 5 molar equivalents, more preferably 2 to 4 molar equivalents relative to the tetrahalogenated ethylene starting material.
  • reaction apparatus used for general organic synthesis can be used.
  • Example 1 Production of diphenylacetylene (1st step base: KOH) A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding phenylboronic acid (304.6 mg, 2.50 mmol) and Pd(PPh 3 ) 4 (57.8 mg, 0.05 mmol), THF (1.0 mL) was added and stirring was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (83.5 mg, 0.504 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer.
  • Example 7 p-(n-propyl) phenyl derivative Table 1
  • a glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding (p-(n-propyl)phenyl)boronic acid (409.8 mg, 2.50 mmol) and Pd(PPh 3 ) 4 (57.4 mg, 0.05 mmol), THF (1.0 mL) was added. Agitation was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (83.0 mg, 0.500 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer.
  • Example 8 p-(n-butyl) phenyl derivative Table 1
  • a glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding (p-(n-butyl)phenyl)boronic acid (444.1 mg, 2.49 mmol) and Pd(PPh 3 ) 4 (57.0 mg, 0.049 mmol), THF (1.0 mL) was added. Agitation was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (82.9 mg, 0.50 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer.
  • Example 9 p-(t-butyl) phenyl derivative Table 1
  • a glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding (p-(t-butyl)phenyl)boronic acid (444.5 mg, 2.50 mmol) and Pd(PPh 3 ) 4 (57.8 mg, 0.05 mmol), THF (1.0 mL) was added. Agitation was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (83.3 mg, 0.502 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer.

Abstract

Provided is a novel method for producing a diarylacetylene derivative.　An alkyne derivative having aryl substituents at both ends is provided by subjecting a tetrahalogenated ethylene and phenylboronic acid to a cross-coupling reaction and then conducting a treatment with a base.

Description

ジアリールアセチレン誘導体の製造方法Method for producing diarylacetylene derivative
　本発明は、ジアリールアセチレン誘導体の新規な製造方法に関する。 The present invention relates to a novel method for producing diarylacetylene derivatives.
　ジフェニルアセチレンおよびその誘導体は、π電子共役系を有する分子で、医農薬や高分子材料の合成中間体として重要な化合物である。その用途に関しては、たとえば、高分子材料として酸素ガス（特許文献１）、炭酸ガス（特許文献２、非特許文献１）などのガス分離膜や、単分子として液晶材料（特許文献３）、スチルベン系医薬中間体（特許文献４）などが報告されている。 Diphenylacetylene and its derivatives are molecules with a π-electron conjugated system, and are important compounds as synthetic intermediates for pharmaceuticals, agricultural chemicals, and polymer materials. With respect to its use, for example, gas separation membranes such as oxygen gas (Patent Document 1) and carbon dioxide gas (Patent Document 2, Non-Patent Document 1) are used as polymer materials, and liquid crystal materials (Patent Document 3) and stilbene are used as single molecules. A system pharmaceutical intermediate (Patent Document 4) and the like have been reported.
　従来法におけるジフェニルアセチレンの製造方法は、薗頭反応と呼ばれる、パラジウム触媒、塩基およびハロゲン化銅（Ｉ）塩を用いたフェニルアセチレンとヨウ化ベンゼンの反応（特許文献４、非特許文献２）が良く知られているが、精製が煩雑で触媒が完全に除去できない、反応を不活性ガス雰囲気下で行う必要がある、置換基を有する生成物を得るためには、置換基を有するアリールアセチレンをあらかじめ入手しておく必要がある、といった欠点が存在し、必ずしも簡便な方法とは言えない。 The conventional method for producing diphenylacetylene is a reaction of phenylacetylene and benzene iodide using a palladium catalyst, a base, and a copper (I) halide salt, called the Sonogashira reaction (Patent Document 4, Non-Patent Document 2). It is well known that the purification is complicated, the catalyst cannot be completely removed, and the reaction must be carried out in an inert gas atmosphere. There is a drawback that it is necessary to obtain it in advance, and it cannot be said that it is necessarily a simple method.
特開２０１８－１６７２２０号公報JP 2018-167220 A 特開２０１０－２１４３２４号公報JP 2010-214324 A 再表２０１９／１１６７０２Re-table 2019/116702 特表２０１２－５３３６００号公報Japanese Patent Publication No. 2012-533600
　以上のような従来の製造方法に鑑みて、本発明はジアリールアセチレン誘導体の新規な製造方法を提供することを目的とする。 In view of the conventional production methods as described above, the object of the present invention is to provide a novel method for producing diarylacetylene derivatives.
　本発明は以下の態様を提供する。
［１］
　下記式（１）：
Figure JPOXMLDOC01-appb-C000006
 （式中、Ｒ１からＲ５は、同一でも異なっていてもよく、水素、ハロゲン元素、水酸基、アミノ基又は１価の有機基であり、Ｒ１からＲ５の２つ以上が組み合わさって縮合環を形成していてもよい。）
で表されるジアリールアセチレン誘導体の製造方法であって、
（ａ）下記式（２）：
Figure JPOXMLDOC01-appb-C000007
 （式中、Ｘはハロゲン元素を表す）
で表されるテトラハロゲン化エチレンと、下記式（３）：
Figure JPOXMLDOC01-appb-C000008
 （式中、Ｒ１からＲ５は前記のとおりである）
で表されるアリールボロン酸誘導体とを、触媒及び塩基の存在下で反応させて、下記式（４）：
Figure JPOXMLDOC01-appb-C000009
 （式中、Ｒ１からＲ５、及びＸは前記の通りである）
で表されるジアリールジハロゲン化エチレンを得る工程、そして
　前記式（４）で表されるジアリールジハロゲン化エチレンに有機アルカリ金属を作用させて、前記式（１）で表されるジアリールアセチレン誘導体を得る工程を含む、方法。
［２］
　前記１価の有機基が、アルコキシ基、アルキルアミノ基、アルキルエステル基、及びアシルアミノ基からなる群から選ばれる、［１］に記載の方法。
［３］
　前記縮合環が、ナフタレン環又はアントラセン環である、［１］に記載の方法。
［４］
　前記触媒及び塩基が、テトラキス（トリフェニルホスフィン）パラジウム及びＫＯＨの組み合わせ、並びに、テトラキス（トリフェニルホスフィン）パラジウム及びＫ３ＰＯ４の組み合わせからなる群から選ばれる、［１］～［３］のいずれかに記載の方法。
［５］
　前記有機アルカリ金属が、アルキルリチウムである、［１］～［３］のいずれかに記載の方法。
［６］
　前記触媒及び塩基が、テトラキス（トリフェニルホスフィン）パラジウム及びＫＯＨの組み合わせ、並びに、テトラキス（トリフェニルホスフィン）パラジウム及びＫ３ＰＯ４の組み合わせからなる群から選ばれ、前記有機アルカリ金属が、アルキルリチウムである、［１］～［３］のいずれかに記載の方法。
［７］
　下記式（１）：
Figure JPOXMLDOC01-appb-C000010
 （式中、Ｒ１からＲ５は、同一でも異なっていてもよく、水素、ハロゲン元素、水酸基、アミノ基又は１価の有機基であり、Ｒ１からＲ５の２つ以上が組み合わさって縮合環を形成していてもよい。）
で表されるジアリールアセチレン誘導体。 The present invention provides the following aspects.
[1]
Formula (1) below:
Figure JPOXMLDOC01-appb-C000006
 (Wherein, R1 to R5 may be the same or different and are hydrogen, a halogen element, a hydroxyl group, an amino group or a monovalent organic group, and two or more of R1 to R5 are combined to form a condensed ring. may be.)
A method for producing a diarylacetylene derivative represented by
(a) the following formula (2):
Figure JPOXMLDOC01-appb-C000007
 (Wherein, X represents a halogen element)
and a tetrahalogenated ethylene represented by the following formula (3):
Figure JPOXMLDOC01-appb-C000008
 (Wherein, R1 to R5 are as described above)
is reacted with an arylboronic acid derivative represented by the following formula (4) in the presence of a catalyst and a base:
Figure JPOXMLDOC01-appb-C000009
 (wherein R1 to R5 and X are as defined above)
and a step of reacting the diaryldihalogenated ethylene represented by the formula (4) with an organic alkali metal to obtain the diarylacetylene derivative represented by the formula (1). A method, including
[2]
The method according to [1], wherein the monovalent organic group is selected from the group consisting of an alkoxy group, an alkylamino group, an alkylester group, and an acylamino group.
[3]
The method according to [1], wherein the condensed ring is a naphthalene ring or an anthracene ring.
[4]
Any of [1] to [3], wherein the catalyst and base are selected from the group consisting of a combination of tetrakis(triphenylphosphine)palladium and KOH, and a combination of tetrakis(triphenylphosphine)palladium and K 3 PO 4 The method described in Crab.
[5]
The method according to any one of [1] to [3], wherein the organic alkali metal is alkyllithium.
[6]
wherein said catalyst and base are selected from the group consisting of a combination of tetrakis(triphenylphosphine)palladium and KOH , and a combination of tetrakis(triphenylphosphine)palladium and K3PO4 , and said organic alkali metal is alkyllithium; The method according to any one of [1] to [3].
[7]
Formula (1) below:
Figure JPOXMLDOC01-appb-C000010
 (Wherein, R1 to R5 may be the same or different and are hydrogen, a halogen element, a hydroxyl group, an amino group or a monovalent organic group, and two or more of R1 to R5 are combined to form a condensed ring. may be.)
A diarylacetylene derivative represented by
　本発明によれば、新規なジアリールアセチレン誘導体の新規な製造方法が提供される。この方法は、
　反応液に触媒が存在した状態で、目的物まで一連の反応を行うことができる、
　反応を大気圧下で行うことができる、
　置換基を有する生成物を得るためには、置換基を有するアリール化合物を用意すればよく、従来法のように、アセチル基をあらかじめ反応基質に導入しておく必要がない、
といった利点があり、簡便にジアリールアセチレン誘導体を製造することができる。 According to the present invention, a novel method for producing a novel diarylacetylene derivative is provided. This method
A series of reactions can be performed up to the target product in the presence of a catalyst in the reaction solution.
the reaction can be carried out under atmospheric pressure,
In order to obtain a product having a substituent, it is sufficient to prepare an aryl compound having a substituent.
, and the diarylacetylene derivative can be easily produced.
［作用］
　本発明は、式（１）で表されるジアリールアセチレン誘導体の製造方法に関するが、従来法としてよく用いられてきた薗頭カップリング反応の替わりに、鈴木カップリング反応を利用することを特徴としている。本発明の製造方法は、テトラハロゲン化エチレンの1種であるテトラクロロエチレンを出発原料とすることができるので、出発原料の入手及び取り扱いが容易である。本発明の製造方法において、第１工程として、触媒（特に、パラジウム触媒）及び塩基存在下、式（２）で表されるテトラハロゲン化エチレンに対して式（３）で表されるアリールボロン酸誘導体を反応させて式（４）で表されるジアリールジハロゲン化エチレンを生成し、第２工程として、式（４）で表されるジアリールジハロゲン化エチレンを有機アルカリ金属で処理して、式（１）で表されるジアリールアセチレン誘導体を生成することを特徴とする。後述するように、第１工程と第２工程は連続的に行うことができ、実質的には１つの工程で目的物のジアリールアセチレン誘導体を製造することができる。第１工程における触媒の役割はテトラハロゲン化エチレンとアリールボロン酸誘導体のカップリング反応を触媒することであり、塩基は、テトラハロゲン化エチレンの活性化とアリールボロン酸の活性化の役割を果たす。すなわち、テトラハロゲン化エチレンからの脱ハロゲン化を促進（例えば、ＣＸ２＝ＣＸ２＋Ｋ＋→ＣＸ２＝Ｃ＋Ｘ＋ＫＸ；ここでＸは、フッ素、塩素、臭素、ヨウ素などのハロゲン元素）、及びアリールボロン酸からのホウ素官能基の脱離を促進（例えば、ＡｒＢ（ＯＨ）２＋ＯＨ－→Ａｒ－＋Ｂ（ＯＨ）３；ここでＡｒはアリール基）させることで、パラジウムの触媒反応を促進させることである。一方、第２工程における有機アルカリ金属の役割はハロゲン元素の引き抜きによる反応基質のアルカリ金属化、及び引き続き起こる脱アルカリ金属ハロゲン化物による三重結合形成である（例えば、有機アルカリ金属がｎ－ブチルリチウムである場合、ハロゲン元素をＸ、アリール基をＡｒ、ｎ－ブチル基をｎ－Ｂｕで表して、反応式は、
ＡｒＣＸ＝ＣＸＡｒ＋ｎ－ＢｕＬｉ→ＡｒＣＬｉ＝ＣＸＡｒ＋ｎ－ＢｕＸ、
ＡｒＣＬｉ＝ＣＸＡｒ→ＡｒＣ≡ＣＡｒ＋ＬｉＸ
となり、目的物とハロゲン化ｎ－ブチル及びハロゲン化リチウムが生成する。）。ＡｒＣＬｉ＝ＣＸＡｒは不安定な化合物であり、温度が上がるとハロゲン化リチウムを放出して目的物であるジアリールアセチレンに変換される。 [Action]
The present invention relates to a method for producing a diarylacetylene derivative represented by formula (1), which is characterized by utilizing Suzuki coupling reaction instead of Sonogashira coupling reaction, which has been often used as a conventional method. . Since the production method of the present invention can use tetrachloroethylene, which is one type of tetrahalogenated ethylene, as a starting material, the starting material is easy to obtain and handle. In the production method of the present invention, as the first step, in the presence of a catalyst (especially a palladium catalyst) and a base, the arylboronic acid represented by the formula (3) is converted to the tetrahalogenated ethylene represented by the formula (2). A derivative is reacted to produce a diaryldihalogenated ethylene represented by formula (4), and as a second step, the diaryldihalogenated ethylene represented by formula (4) is treated with an organic alkali metal to give a compound of formula (1 ) to produce a diarylacetylene derivative represented by As will be described later, the first step and the second step can be performed continuously, and the target diarylacetylene derivative can be produced substantially in one step. The role of the catalyst in the first step is to catalyze the coupling reaction between the tetrahalogenated ethylene and the arylboronic acid derivative, and the base plays a role of activating the tetrahalogenated ethylene and arylboronic acid. That is, promoting dehalogenation from tetrahalogenated ethylene (e.g., CX 2 = CX 2 + K + → CX 2 = C + X + KX; where X is a halogen element such as fluorine, chlorine, bromine, or iodine), and facilitating elimination of the boron functional group from the arylboronic acid (e.g., ArB(OH) 2 +OH − →Ar − +B(OH) 3 ; where Ar is an aryl group), thereby promoting palladium catalysis; That is. On the other hand, the role of the organic alkali metal in the second step is alkali metalization of the reaction substrate by abstraction of the halogen element, followed by triple bond formation by dealkalization metal halide (for example, the organic alkali metal is n-butyllithium, In some cases, the halogen element is represented by X, the aryl group by Ar, and the n-butyl group by n-Bu, and the reaction formula is as follows:
ArCX=CXAr+n-BuLi→ArCLi=CXAr+n-BuX,
ArCLi=CXAr→ArC≡CAr+LiX
As a result, the desired product, n-butyl halide and lithium halide are produced. ). ArCLi=CXAr is an unstable compound, and when the temperature rises, it releases lithium halide and is converted to the target diarylacetylene.
　第１工程の反応は、鈴木カップリング反応と呼ばれる反応の１種であり、アリールボロン酸の芳香環上には、様々な置換基を比較的容易に導入することができる。そのため、本発明の製法を用いることで、反応基質の入手が比較的容易であり、非常に高い自由度でジアリールアセチレンの芳香環上の置換基を選択することができる。さらには、第１工程の反応の後、反応物の分離操作を行うことなく、触媒と生成物が混在した状態で第２工程の有機アルカリ金属処理を行えるために、従来法よりも簡便な操作で目的物を得ることができる。 The reaction in the first step is a type of reaction called Suzuki coupling reaction, and various substituents can be relatively easily introduced onto the aromatic ring of arylboronic acid. Therefore, by using the production method of the present invention, it is possible to obtain a reaction substrate relatively easily and to select substituents on the aromatic ring of diarylacetylene with a very high degree of freedom. Furthermore, after the reaction in the first step, the organic alkali metal treatment in the second step can be performed in a state where the catalyst and the product are mixed without performing the separation operation of the reactants, so that the operation is simpler than the conventional method. can get the target.
［第１工程］
　第１工程では、触媒（特に、パラジウム触媒）及び塩基存在下、テトラハロゲン化エチレンに対して式（３）で表されるアリールボロン酸誘導体を反応させて式（４）で表されるジアリールジハロゲン化エチレンを生成する。テトラハロゲン化エチレンとしては、テトラフルオロエチレン、テトラクロロエチレン、テトラブロモエチレン、テトラヨードエチレンなどが使用できるが、好ましくはテトラクロロエチレン、テトラブロモエチレン、より好ましくはテトラクロロエチレンが使用できる。特に、テトラクロロエチレンはハロゲン含有化合物の合成原料として従来から使用されており、入手が極めて容易である。テトラブロモエチレンは非特許文献３の方法でペンタブロモエチレンから合成可能である。 [First step]
In the first step, in the presence of a catalyst (especially a palladium catalyst) and a base, an ethylene tetrahalide is reacted with an arylboronic acid derivative represented by the formula (3) to obtain a diaryldihalogen represented by the formula (4). produces ethylene chloride. As the tetrahalogenated ethylene, tetrafluoroethylene, tetrachloroethylene, tetrabromoethylene, tetraiodoethylene, etc. can be used, but tetrachlorethylene, tetrabromoethylene, and more preferably tetrachlorethylene can be used. In particular, tetrachlorethylene has been conventionally used as a raw material for synthesizing halogen-containing compounds, and is extremely easy to obtain. Tetrabromoethylene can be synthesized from pentabromoethylene by the method of Non-Patent Document 3.
［式（３）で表されるアリールボロン酸誘導体］
　式（３）で表されるアリールボロン酸誘導体は、当業界で周知の方法で製造できる。例えば、ハロゲン化アリールマグネシウム（ＡｒＭｇＢｒ；ここでＡｒはアリール基）とボロン酸トリメチル（Ｂ（ＯＭｅ）３；ここでＭｅはメチル基）を反応させてアリールボロン酸ジメチル（ＡｒＢ（ＯＭｅ）２）を製造し、これを加水分解して製造することができる。式（３）で表されるアリールボロン酸誘導体の製造方法において、使用するアリール化合物の官能基がボロン酸との反応に影響することがないので、ベンゼン環上に様々な置換基を導入することができる。
　式（３）において、Ｒ１からＲ５は、独立して、水素の他、フッ素、塩素、臭素、ヨウ素などのハロゲン元素、水酸基、アミノ基又は反応に影響しない１価の有機基であり、Ｒ１からＲ５の２つ以上が組み合わさって縮合環を形成してもよい。１価の有機基としては、例えば、アルキル基、Ｎ－１置換アミノ基、Ｎ，Ｎ－２置換アミノ基、アルコキシ基、アリール基、アリールオキシ基、アルキルエステル基、アシルアミノ基などが挙げられる。アルキル基としては、例えば、炭素数１～４のアルキル基、特に、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｔ－ブチル基、などが挙げられる。アルキル基の水素はハロゲン元素で置換されていてもよく、ハロゲン化アルキル基としては、例えば、炭素数１～４のハロゲン化アルキル基、特に、炭素数１～４のパーフルオロアルキル基、特に、トリフルオロメチル基、ペンタフルオロエチル基、ｎ－ヘプタフルオロプロピル基、ｉｓｏ－ヘプタフルオロプロピル基、ｎ－ノナフルオロブチル基、ｓｅｃ－ノナフルオロブチル基、ｉｓｏ－ノナフルオロブチル基、ｔ－ノナフルオロブチル基、などが挙げられる。アルコキシ基としては、例えば、炭素数１～４のアルコキシ基、特に、メトキシ基、エトキシ基、ｎ－プロピルオキシ基、イソプロピルオキシ基、ｎ－ブチルオキシ基、イソブチルオキシ基、ｔ－ブチルオキシ基、などが挙げられる。アリール基としては、例えば、フェニル基、ナフチル基、アントラニル基、ナフタセニル基、ペンタセニル基などが挙げられる。アリールオキシ基としては、例えば、フェニルオキシ基、ナフチルオキシ基、アントラニルオキシ基、ナフタセニルオキシ基、ペンタセニルオキシ基などが挙げられる。Ｎ－１置換アミノ基としては、例えば、アミノ基の窒素上に前述した炭素数１～４のアルキル基、アリール基、などの置換基が１つ結合したものが挙げられ、より具体的には、メチルアミノ基、エチルアミノ基、プロピルアミノ基、イソプロピルアミノ基、などが挙げられる。Ｎ，Ｎ－２置換アミノ基としては、例えば、アミノ基の窒素上に前述した炭素数１～４のアルキル基、アリール基、などの置換基が２つ結合したものが挙げられ、これら２つの置換基は同じものであってよく、違うものであってもよい。より具体的には、ジメチルアミノ基、ジエチルアミノ基、エチルメチルアミノ基、ジイソプロピルアミノ基、などが挙げられる。アルキルエステル基としては、例えば、カルボキシル基をアルキル基で保護したもの、例えば、メチルエステル基（即ち、－ＣＯＯＣＨ３）、エチルエステル基（即ち、－ＣＯＯＣ２Ｈ５）、などが挙げられる。アシルアミノ基としては、例えば、アミノ基をアシル基で保護したもの、例えば、ホルミルアミノ基（即ち、－ＮＨＣＨＯ）、アセチルアミノ基（即ち、－ＮＨＣＯＣＨ３）、ベンゾイルアミノ基（即ち、－ＮＨＣＯＣ６Ｈ５）などがあげられる。Ｒ１からＲ５の２つ以上が組み合わさってベンゼン環と縮合環を形成しても良い。そのような縮合環としては、例えば、ナフタレン環、アントラセン環、フェナントレン環、ピレン環などが挙げられ、さらにその縮合環上にフッ素などのハロゲン元素や、水酸基、アミノ基、前述した１価の有機基を有していても良い。 [Aryl boronic acid derivative represented by formula (3)]
Arylboronic acid derivatives represented by formula (3) can be produced by methods well known in the art. For example, aryl magnesium halide (ArMgBr; where Ar is an aryl group) and trimethyl boronate (B(OMe) 3 ; where Me is a methyl group) are reacted to form dimethyl aryl boronate (ArB(OMe) 2 ). It can be produced by hydrolyzing it. In the method for producing the arylboronic acid derivative represented by formula (3), since the functional group of the aryl compound used does not affect the reaction with boronic acid, various substituents can be introduced onto the benzene ring. can be done.
In formula (3), R1 to R5 are independently hydrogen, a halogen element such as fluorine, chlorine, bromine, and iodine, a hydroxyl group, an amino group, or a monovalent organic group that does not affect the reaction. Two or more of R5 may be combined to form a condensed ring. Examples of monovalent organic groups include alkyl groups, N-1 substituted amino groups, N,N-2 substituted amino groups, alkoxy groups, aryl groups, aryloxy groups, alkyl ester groups, acylamino groups and the like. Examples of the alkyl group include alkyl groups having 1 to 4 carbon atoms, particularly methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and t-butyl group. The hydrogen of the alkyl group may be substituted with a halogen element, and the halogenated alkyl group includes, for example, a halogenated alkyl group having 1 to 4 carbon atoms, particularly a perfluoroalkyl group having 1 to 4 carbon atoms, particularly trifluoromethyl group, pentafluoroethyl group, n-heptafluoropropyl group, iso-heptafluoropropyl group, n-nonafluorobutyl group, sec-nonafluorobutyl group, iso-nonafluorobutyl group, t-nonafluorobutyl group, and the like. Examples of alkoxy groups include alkoxy groups having 1 to 4 carbon atoms, particularly methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, and the like. mentioned. Aryl groups include, for example, phenyl, naphthyl, anthranyl, naphthacenyl, and pentacenyl groups. Examples of aryloxy groups include phenyloxy, naphthyloxy, anthranyloxy, naphthacenyloxy, and pentacenyloxy groups. Examples of the N-1 substituted amino group include those in which one substituent such as the aforementioned alkyl group having 1 to 4 carbon atoms or an aryl group is bonded to the nitrogen of the amino group, and more specifically, , methylamino group, ethylamino group, propylamino group, isopropylamino group, and the like. Examples of the N,N-disubstituted amino group include those in which two substituents such as the aforementioned alkyl group having 1 to 4 carbon atoms or an aryl group are bonded to the nitrogen of the amino group. The substituents may be the same or different. More specific examples include dimethylamino group, diethylamino group, ethylmethylamino group, diisopropylamino group, and the like. The alkyl ester group includes, for example, a carboxyl group protected with an alkyl group, such as a methyl ester group (ie --COOCH 3 ) and an ethyl ester group (ie --COOC 2 H 5 ). The acylamino group includes, for example, an amino group protected with an acyl group, such as a formylamino group (ie —NHCHO), an acetylamino group (ie —NHCOCH 3 ), a benzoylamino group (ie —NHCOC 6 H 5 ). Two or more of R1 to R5 may be combined to form a fused ring with a benzene ring. Examples of such condensed rings include naphthalene ring, anthracene ring, phenanthrene ring, pyrene ring and the like, and halogen elements such as fluorine, hydroxyl group, amino group, monovalent organic You may have a group.
［触媒］
　第１工程で使用する触媒としては、例えば、パラジウム触媒、特に、テトラキス（トリフェニルホスフィン）パラジウム、酢酸パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）、ジクロロ（１，１’－ビス（ジフェニルホスフィノ）フェロセン）パラジウム（ＩＩ）などが挙げられ、より好ましくは、テトラキス（トリフェニルホスフィン）パラジウムである。パラジウム触媒は、酸素に弱いので、不活性雰囲気下で反応を行うことが好ましい。不活性雰囲気を形成するガスとしては、例えば、窒素、希ガス（ヘリウム、ネオン、アルゴン、キセノン、など）などが挙げられる。 [catalyst]
Examples of catalysts used in the first step include palladium catalysts, particularly tetrakis(triphenylphosphine)palladium, palladium acetate, dichlorobis(triphenylphosphine)palladium (II), dichloro(1,1′-bis(diphenylphosphine) phino)ferrocene)palladium(II), and more preferably tetrakis(triphenylphosphine)palladium. Since the palladium catalyst is weak against oxygen, it is preferable to carry out the reaction under an inert atmosphere. Gases that form the inert atmosphere include, for example, nitrogen and rare gases (helium, neon, argon, xenon, etc.).
［塩基］
　第１工程で使用する塩基は、テトラハロゲン化エチレン及びアリールボロン酸誘導体の反応を促進するとともに遊離するハロゲン及びボロン酸を、反応に影響を与えない安定な副生物へと変換することを目的として上記触媒とともに作用する。
　第１工程で使用する塩基としては、例えば、アルカリ金属水酸化物（例えば水酸化ナトリウム、水酸化カリウム）、アルカリ金属リン酸塩（例えばリン酸カリウム）、４級アンモニウム塩（例えばフッ化テトラブチルアンモニウム）、３級アミン（例えばトリエチルアミン）、有機強塩基（例えばＤＢＮ（１，５－ジアザビシクロ［４．３．０］ノナ－５－エン）、ＭＴＢＤ（７－メチル－１，５，７―トリアザビシクロ［４．４．０］デカ－５－エン））、などが挙げられ、好ましくは、水酸化ナトリウム、水酸化カリウム、リン酸カリウム、より好ましくは水酸化カリウムである。 [base]
The base used in the first step is intended to promote the reaction of the tetrahalogenated ethylene and the arylboronic acid derivative and convert the liberated halogen and boronic acid into stable by-products that do not affect the reaction. Works with the above catalyst.
Examples of the base used in the first step include alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal phosphates (e.g. potassium phosphate), quaternary ammonium salts (e.g. tetrabutyl fluoride ammonium), tertiary amines (eg triethylamine), strong organic bases (eg DBN (1,5-diazabicyclo[4.3.0]non-5-ene), MTBD (7-methyl-1,5,7-tri zabicyclo[4.4.0]dec-5-ene)), etc., preferably sodium hydroxide, potassium hydroxide, potassium phosphate, more preferably potassium hydroxide.
［溶媒］
　第１工程で使用する溶媒としては、例えば、極性溶媒が挙げられ、好ましくは、水、テトラヒドロフラン（ＴＨＦ）、ジエチルエーテル、ジグライム、トリグライムなどのエーテル、ジメチルホルムアミド（ＤＭＦ）、Ｎ－メチルピロリドン（ＮＭＰ）、ジメチルスルホキシド（ＤＭＳＯ）、メタノール、エタノール、プロパノール、ブタノールなどのアルコールであるが、それらを単独で用いても良いし、混合して用いても良く、より好ましくは、ＴＨＦ又はＴＨＦと水の混合物である。 [solvent]
Examples of the solvent used in the first step include polar solvents, preferably water, tetrahydrofuran (THF), ethers such as diethyl ether, diglyme and triglyme, dimethylformamide (DMF), N-methylpyrrolidone (NMP ), dimethyl sulfoxide (DMSO), methanol, ethanol, propanol, and alcohols such as butanol. A mixture.
［第１工程の反応条件］
　第１工程の反応温度は、好ましくは、－１００～２００℃、より好ましくは、０～１００℃、さらに好ましくは、２５～６０℃である。 [Reaction conditions for the first step]
The reaction temperature in the first step is preferably -100 to 200°C, more preferably 0 to 100°C, still more preferably 25 to 60°C.
　式（３）で表されるアリールボロン酸誘導体のモル当量数は、テトラハロゲン化エチレンに対して０．０１～１００モル当量、好ましくは０．１～１０モル当量、より好ましくは５モル当量である。触媒のモル当量数はテトラハロゲン化エチレンに対して０．０００１～１モル当量、好ましくは０．１～０．５モル当量、より好ましくは０．０９～０．１モル当量である。塩基は、それ自身をそのまま反応に使用しても良く、あらかじめ水に溶かした状態で用いてもよい。塩基のモル当量数は、テトラハロゲン化エチレンに対して０．０１～１００モル当量、好ましくは０．１～１０モル当量、より好ましくは０．５～１モル当量である。 The number of molar equivalents of the arylboronic acid derivative represented by formula (3) is 0.01 to 100 molar equivalents, preferably 0.1 to 10 molar equivalents, more preferably 5 molar equivalents relative to the tetrahalogenated ethylene. be. The number of molar equivalents of the catalyst is 0.0001 to 1 molar equivalents, preferably 0.1 to 0.5 molar equivalents, more preferably 0.09 to 0.1 molar equivalents relative to the tetrahalogenated ethylene. The base itself may be used for the reaction as it is, or it may be dissolved in water before use. The number of molar equivalents of the base is 0.01 to 100 molar equivalents, preferably 0.1 to 10 molar equivalents, more preferably 0.5 to 1 molar equivalents relative to the tetrahalogenated ethylene.
［第２工程］
　第１工程で式（４）で表されるジアリールジハロゲン化エチレンが得られ、これを単離してから第２工程の反応である、有機アルカリ金属で処理してハロゲン―リチウム交換反応を行わせるか、又は単離精製操作を行うことなく、第２工程の反応である、有機アルカリ金属で処理してハロゲン―リチウム交換反応を行った後に脱ハロゲン化リチウムを放出する反応を行わせることにより、式（１）で表されるジアリールアセチレンが得られる。第１工程では、反応液に水を加えてクエンチすることで反応を停止させることができる。第２工程の有機アルカリ金属は水と反応しうるので、第１工程の生成物の精製を行わない場合、反応混合物から水を取り除く操作を行ってから、得られた粗生成物を第２工程に利用することができる。反応混合物から水を取り除く操作は、当業界で通常行われている操作でよく、例えば、反応液を飽和食塩水で洗浄後、有機層を分液し、有機層を硫酸ナトリウム、硫酸マグネシウムなどの乾燥剤と混合し、乾燥剤をろ過する操作が挙げられる。 [Second step]
In the first step, the diaryldihalogenated ethylene represented by the formula (4) is obtained, and after it is isolated, it is treated with an organic alkali metal to carry out the halogen-lithium exchange reaction, which is the reaction in the second step. Alternatively, without performing the isolation and purification operation, the reaction of the second step, which is the reaction of the second step, which is the reaction of treating with an organic alkali metal to perform the halogen-lithium exchange reaction, and then the reaction of releasing dehalogenated lithium, is performed. A diarylacetylene represented by (1) is obtained. In the first step, the reaction can be stopped by adding water to quench the reaction solution. Since the organic alkali metal in the second step can react with water, if the product in the first step is not purified, an operation is performed to remove water from the reaction mixture, and then the resulting crude product is treated in the second step. can be used for The operation of removing water from the reaction mixture may be an operation commonly performed in the industry. For example, after washing the reaction solution with saturated saline, the organic layer is separated, and the organic layer is treated with sodium sulfate, magnesium sulfate, or the like. An operation of mixing with a desiccant and filtering the desiccant can be mentioned.
［有機アルカリ金属］
　第２工程で使用する有機アルカリ金属は、ジアリールジハロゲン化エチレンをハロゲン―リチウム交換反応により、アルカリ金属化し、次いでアルカリ金属ハロゲン化物を脱離することにより、三重結合を形成する。有機アルカリ金属としては、例えば、アルキルアルカリ金属、特に、アルキルリチウム、特に、ｎ－ブチルリチウム、ｓ－ブチルリチウム、ｔ－ブチルリチウム、などのブチルリチウム；アルカリ金属ピペリジド、特に、リチウムテトラメチルピペリジド；アルカリ金属ジイソプロピルアミド、特に、リチウムジイソプロピルアミド；アルカリ金属ヘキサメチルジシラザン、特に、リチウムヘキサメチルジシラザン；などが挙げられるが、好ましくは、アルキルリチウム、より好ましくは、ブチルリチウム、特に、ｎ－ブチルリチウムである。 [Organic alkali metal]
The organic alkali metal used in the second step forms a triple bond by alkali metalizing diaryldihalogenated ethylene through a halogen-lithium exchange reaction and then eliminating the alkali metal halide. Examples of organic alkali metals include alkylalkali metals, especially alkyllithium, especially butyllithium such as n-butyllithium, s-butyllithium and t-butyllithium; alkali metal piperidides, especially lithium tetramethylpiperidiide; alkali metal diisopropylamide, especially lithium diisopropylamide; alkali metal hexamethyldisilazane, especially lithium hexamethyldisilazane; and the like, preferably alkyllithium, more preferably butyllithium, especially n - butyllithium.
［第２工程の反応条件］
　第２工程の溶媒は、有機アルカリ金属に使用できるものであればよく、例えば、極性溶媒、好ましくは、テトラヒドロフラン（ＴＨＦ）、ジエチルエーテル、ジグライム、トリグライムなどのエーテル、ジメチルホルムアミド（ＤＭＦ）、Ｎ－メチルピロリドン（ＮＭＰ）、ジメチルスルホキシド（ＤＭＳＯ）などが挙げられるが、より好ましくは、ＴＨＦである。
　第２工程の反応温度は、好ましくは、－１００～２００℃、より好ましくは、－１００～２５℃、さらにより好ましくは、－７８～２５℃である。アルキルリチウム、特にｎ－ブチルリチウムを用いた反応は、反応して得られる中間体（リチオ化体）が不安定なため、低温で行うことが好ましい。この場合、第２工程の反応においては、低温でハロゲン―リチウム交換反応が起こり、昇温する際に、このリチオ化体が分解してハロゲン化リチウムを放出することによりアセチレン化合物が生成する。
　有機アルカリ金属のモル当量数は、出発原料のテトラハロゲン化エチレンに対して０．１～１０モル当量、好ましくは０．５～５モル当量、より好ましくは２～４モル当量である。 [Reaction conditions for the second step]
The solvent in the second step may be any one that can be used for organic alkali metals. Examples include polar solvents, preferably tetrahydrofuran (THF), ethers such as diethyl ether, diglyme and triglyme, Methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and the like can be mentioned, and THF is more preferred.
The reaction temperature in the second step is preferably -100 to 200°C, more preferably -100 to 25°C, still more preferably -78 to 25°C. The reaction using alkyllithium, particularly n-butyllithium, is preferably carried out at a low temperature because the intermediate (lithiated product) obtained by the reaction is unstable. In this case, in the reaction of the second step, a halogen-lithium exchange reaction occurs at a low temperature, and when the temperature rises, the lithiated product decomposes to release lithium halide to form an acetylene compound.
The number of molar equivalents of the organic alkali metal is 0.1 to 10 molar equivalents, preferably 0.5 to 5 molar equivalents, more preferably 2 to 4 molar equivalents relative to the tetrahalogenated ethylene starting material.
［反応装置］
　反応装置は一般の有機合成に用いられるものが使用できる。 [Reactor]
A reaction apparatus used for general organic synthesis can be used.
　以下、実施例に基づいて本発明を具体的に説明するが、本発明の範囲はこれら例に限定されるものではない。以下に示す実施例において用いた試薬のうち、テトラクロロエチレンは関東電化工業株式会社製のものを使用した。その他の試薬や溶媒は、アルドリッチ、東京化成、富士フイルム和光純薬、佐々木化学薬品、ナカライテスク、関東化学などの化学品製造会社から入手した。リサイクル型分取ＨＰＬＣは日本分析工業社のＪＡＩＧＥＬ－１ＨとＪＡＩＧＥＬ－２Ｈを装着したＬＣ－９２０１、ＬＣ－９１１０ＮＥＸＴ、またはＬＣ－９２１０ＮＥＸＴを使用した。分析はＨＲＭＳ（Ｔｈｅｒｍｏ Ｆｉｓｈｅｒ Ｓｃｉｅｎｔｉｆｉｃ ＥＸＡＣＴＩＶＥ Ｐｌｕｓ）、ＮＭＲ（バリアン社製ＭＥＲＣＵＲＹ　３００と日本電子社製ＪＮＭ－ＥＣＳ ４００）、およびＧＣ－ＭＳ（アジレント社製５９７３Ｎ）を使用した。 The present invention will be specifically described below based on examples, but the scope of the present invention is not limited to these examples. Among the reagents used in the examples below, tetrachlorethylene manufactured by Kanto Denka Kogyo Co., Ltd. was used. Other reagents and solvents were obtained from chemical manufacturers such as Aldrich, Tokyo Kasei, Fujifilm Wako Pure Chemical, Sasaki Chemical, Nacalai Tesque, and Kanto Kagaku. Recycling type preparative HPLC used LC-9201, LC-9110NEXT, or LC-9210NEXT equipped with JAIGEL-1H and JAIGEL-2H manufactured by Japan Analytical Industry Co., Ltd. Analysis used HRMS (Thermo Fisher Scientific EXACTIVE Plus), NMR (Varian MERCURY 300 and JEOL JNM-ECS 400), and GC-MS (Agilent 5973N).
（実施例１、実施例２）ジフェニルアセチレンの製造
　以下の反応スキームに従って製造した。
Figure JPOXMLDOC01-appb-C000011
 　第１工程の粗生成物のＧＣ－ＭＳを行ったところ、１，２－ジクロロ－１，２－ジフェニルエチレンとジフェニルアセチレンの存在を示唆する質量分析結果が得られた。 (Examples 1 and 2) Production of diphenylacetylene It was produced according to the following reaction scheme.
Figure JPOXMLDOC01-appb-C000011
 GC-MS of the first step crude product gave mass spectrometric results suggesting the presence of 1,2-dichloro-1,2-diphenylethylene and diphenylacetylene.
（実施例１）ジフェニルアセチレンの製造（第１工程の塩基：ＫＯＨ）
Figure JPOXMLDOC01-appb-C000012
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。フェニルボロン酸（３０４．６ｍｇ、２．５０ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．８ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８３．５ｍｇ、０．５０４ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 1) Production of diphenylacetylene (1st step base: KOH)
Figure JPOXMLDOC01-appb-C000012
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding phenylboronic acid (304.6 mg, 2.50 mmol) and Pd(PPh 3 ) 4 (57.8 mg, 0.05 mmol), THF (1.0 mL) was added and stirring was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (83.5 mg, 0.504 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に浸漬して撹拌をした。このナスフラスコに、ｎ－ブチルリチウム（ｎ－ＢｕＬｉ）（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。ジエチルエーテル（Ｅｔ２Ｏ）（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、ジフェニルアセチレン（６３．５ｍｇ、０．３５６ｍｍｏｌ）を収率７１％で得た。ジフェニルアセチレンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 7.30-7.40 (m, 6H), 7.48-7.58 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 89.3, 123.2, 128.2, 128.3, 131.6 ppm; HRMS (ESI) calculated for C14H11 ([M+H]+): 179.0855, found 179.0857. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added for dissolution, and the eggplant flask was immersed in a constant temperature bath at -78°C and stirred. n-Butyllithium (n-BuLi) (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with diethyl ether (Et 2 O) (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The resulting crude product was purified with a preparative GPC column attached to a recycling HPLC to obtain diphenylacetylene (63.5 mg, 0.356 mmol) with a yield of 71%. The identity of diphenylacetylene was judged from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ= 7.30-7.40 (m, 6H), 7.48-7.58 (m, 4H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ= 89.3, 123.2, 128.2 , 128.3, 131.6 ppm; HRMS (ESI) calculated for C 14 H 11 ([M+H] + ): 179.0855, found 179.0857.
（実施例２）ジフェニルアセチレンの製造（第１工程の塩基：Ｋ３ＰＯ４）
Figure JPOXMLDOC01-appb-C000013
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。フェニルボロン酸（３０４．６ｍｇ、２．５０ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．９ｍｇ、０．０５ｍｍｏｌ）を加えた後、Ｋ３ＰＯ４（５２９．９ｍｇ、２．５０ｍｍｏｌ）を加えた。これにＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。テトラクロロエチレン（８３．７ｍｇ、０．５０５ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 ( Example 2) Production of diphenylacetylene (1st step base: K3PO4 )
Figure JPOXMLDOC01-appb-C000013
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. Phenylboronic acid (304.6 mg, 2.50 mmol) and Pd( PPh3 ) 4 (57.9 mg, 0.05 mmol) were added followed by K3PO4 ( 529.9 mg, 2.50 mmol). THF (1.0 mL) was added thereto and stirring was started. After adding tetrachlorethylene (83.7 mg, 0.505 mmol), stirring was continued with an aluminum block stirrer at 60° C. for 18 hours. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きの後、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、ジフェニルアセチレン（３２．４ｍｇ、０．１８２ｍｍｏｌ）を収率３６％で得た。ジフェニルアセチレンの同定は、実施例１のスペクトルとの比較で行った。 After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. After cotton plug filtration and concentration, the crude product was obtained after drawing a vacuum. The resulting crude product was purified with a preparative GPC column attached to a recycling HPLC to obtain diphenylacetylene (32.4 mg, 0.182 mmol) with a yield of 36%. Identification of diphenylacetylene was performed by comparison with the spectrum of Example 1.
（実施例３）ｐ－メチルフェニル誘導体　表１
Figure JPOXMLDOC01-appb-C000014
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。ｐ－トリルボロン酸（３３８．２ｍｇ、２．４９ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．５ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８３．０ｍｇ、０．５０１ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 3) p-methylphenyl derivative Table 1
Figure JPOXMLDOC01-appb-C000014
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding p-tolylboronic acid (338.2 mg, 2.49 mmol) and Pd(PPh 3 ) 4 (57.5 mg, 0.05 mmol), THF (1.0 mL) was added and stirring was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (83.0 mg, 0.501 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ジ－ｐ－トリルエチン（５４．４ｍｇ、０．２６４ｍｍｏｌ）を収率５３％で得た。１，２－ジ－ｐ－トリルエチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 2.36 (s, 6H), 7.15 (d, J = 8.2 Hz, 4H), 7.42(d, J = 8.2 Hz, 4H) ppm;13C NMR (100 MHz, CDCl3): δ = 21.4, 88.8, 120.3, 129.1, 131.4, 138.2 ppm; HRMS (ESI) calculated for C16H15([M+H]+): 207.1168, found 207.1168. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The resulting crude product was purified by a preparative GPC column attached to a recycling HPLC to obtain 1,2-di-p-tolylethine (54.4 mg, 0.264 mmol) with a yield of 53%. The identity of 1,2-di-p-tolylethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ = 2.36 (s, 6H), 7.15 (d, J = 8.2 Hz, 4H), 7.42 (d, J = 8.2 Hz, 4H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ = 21.4, 88.8, 120.3, 129.1, 131.4, 138.2 ppm; HRMS (ESI) calculated for C 16 H 15 ([M+H] + ): 207.1168, found 207.1168.
（実施例４）ｍ－メチルフェニル誘導体　表１
Figure JPOXMLDOC01-appb-C000015
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。ｍ－トリルボロン酸（３４０．０ｍｇ、２．５０ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．５ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８３．１ｍｇ、０．５０１ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 4) m-methylphenyl derivative Table 1
Figure JPOXMLDOC01-appb-C000015
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding m-tolylboronic acid (340.0 mg, 2.50 mmol) and Pd(PPh 3 ) 4 (57.5 mg, 0.05 mmol), THF (1.0 mL) was added and stirring was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (83.1 mg, 0.501 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ジ－ｍ－トリルエチン（４３．１ｍｇ、０．２０９ｍｍｏｌ）を収率４２％で得た。１，２－ジ－ｍ－トリルエチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 2.35 (s, 6H), 7.14 (d, J = 7.6 Hz, 2H), 7.23 (dd, J = 8.4 Hz, 7.6 Hz, 2H), 7.30-7.38 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.2, 89.2, 123.1, 128.2, 128.6, 129.1, 132.2, 138.0 ppm; HRMS (ESI) calculated for C16H14Na ([M+Na]+): 229.0988, found 229.0987. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The resulting crude product was purified with a preparative GPC column attached to a recycling HPLC to obtain 1,2-di-m-tolylethine (43.1 mg, 0.209 mmol) with a yield of 42%. The identity of 1,2-di-m-tolylethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ = 2.35 (s, 6H), 7.14 (d, J = 7.6 Hz, 2H), 7.23 (dd, J = 8.4 Hz, 7.6 Hz, 2H), 7.30-7.38 (m, 4H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ = 21.2, 89.2, 123.1, 128.2, 128.6, 129.1, 132.2, 138.0 ppm; HRMS (ESI) calculated for C 16 H 14 Na ([ M+Na] + ): 229.0988, found 229.0987.
（実施例５）o－メチルフェニル誘導体　表１
Figure JPOXMLDOC01-appb-C000016
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。ｏ－トリルボロン酸（３３８．７ｍｇ、２．４９ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５８．０ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８２．４ｍｇ、０．４９７ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 5) o-methylphenyl derivative Table 1
Figure JPOXMLDOC01-appb-C000016
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding o-tolylboronic acid (338.7 mg, 2.49 mmol) and Pd(PPh 3 ) 4 (58.0 mg, 0.05 mmol), THF (1.0 mL) was added and stirring was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (82.4 mg, 0.497 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ジ－ｏ－トリルエチン（３０．０ｍｇ、０．１４５ｍｍｏｌ）を収率２９％で得た。１，２－ジ－ｏ－トリルエチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 2.53 (s, 6H), 7.13-7.28 (m, 6H), 7.51 (d, J= 7.2 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 20.9, 92.3, 123.3, 125.6, 128.2, 129.5, 131.8, 139.9 ppm; HRMS (ESI) calculated for C16H14Na ([M+Na]+): 229.0988, found 229.0984. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The obtained crude product was purified by a preparative GPC column attached to a recycling HPLC to obtain 1,2-di-o-tolylethine (30.0 mg, 0.145 mmol) with a yield of 29%. The identity of 1,2-di-o-tolylethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ= 2.53 (s, 6H), 7.13-7.28 (m, 6H), 7.51 (d, J= 7.2 Hz, 2H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ = 20.9, 92.3, 123.3, 125.6, 128.2, 129.5, 131.8, 139.9 ppm; HRMS (ESI) calculated for C 16 H 14 Na ([M+Na] + ): 229.0988, found 229.0984.
（実施例６）ｐ－エチルフェニル誘導体　表１
Figure JPOXMLDOC01-appb-C000017
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。（ｐ－エチルフェニル）ボロン酸（３７５．２ｍｇ、２．５０ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．７ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８２．１ｍｇ、０．４９５ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 6) p-ethylphenyl derivative Table 1
Figure JPOXMLDOC01-appb-C000017
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding (p-ethylphenyl)boronic acid (375.2 mg, 2.50 mmol) and Pd(PPh 3 ) 4 (57.7 mg, 0.05 mmol), THF (1.0 mL) was added and stirring was started. . A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (82.1 mg, 0.495 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ビス（ｐ－エチルフェニル）エチン（６６．９ｍｇ、０．２８５ｍｍｏｌ）を収率５８％で得た。１，２－ビス（ｐ－エチルフェニル）エチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 1.24 (t, J = 8.0 Hz, 6H), 2.66 (q, J = 8.0 Hz, 4H), 7.17 (d, J = 7.6 Hz, 4H), 7.45 (d, J = 7.6 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 15.3, 28.8, 88.9, 120.6, 127.9, 131.5, 144.4 ppm; HRMS (ESI) calculated for C18H18Na ([M+Na]+): 257.1301, found 257.1296. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The resulting crude product was purified by a preparative GPC column attached to a recycling HPLC to obtain 1,2-bis(p-ethylphenyl)ethyne (66.9 mg, 0.285 mmol) with a yield of 58%. Ta. The identity of 1,2-bis(p-ethylphenyl)ethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ = 1.24 (t, J = 8.0 Hz, 6H), 2.66 (q, J = 8.0 Hz, 4H), 7.17 (d, J = 7.6 Hz, 4H), 7.45 (d, J = 7.6 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3 ): δ = 15.3, 28.8, 88.9, 120.6, 127.9, 131.5, 144.4 ppm; HRMS (ESI) calculated for C18H18 Na ([M+Na] + ): 257.1301, found 257.1296.
（実施例７）ｐ－（ｎ－プロピル）フェニル誘導体　表１
Figure JPOXMLDOC01-appb-C000018
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。（ｐ－（n－プロピル）フェニル）ボロン酸（４０９．８ｍｇ、２．５０ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．４ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８３．０ｍｇ、０．５００ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 7) p-(n-propyl) phenyl derivative Table 1
Figure JPOXMLDOC01-appb-C000018
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding (p-(n-propyl)phenyl)boronic acid (409.8 mg, 2.50 mmol) and Pd(PPh 3 ) 4 (57.4 mg, 0.05 mmol), THF (1.0 mL) was added. Agitation was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (83.0 mg, 0.500 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ビス（ｐ－（ｎ－プロピル）フェニル）エチン（６９．６ｍｇ、０．２６５ｍｍｏｌ）を収率５３％で得た。１，２－ビス（ｐ－（ｎ－プロピル）フェニル）エチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 0.93 (t, J = 7.6 Hz, 6H), 1.63 (sext, J = 7.6 Hz, 4H), 2.58 (t, J = 7.6 Hz, 4H), 7.14 (d, J = 8.0 Hz, 4H), 7.43 (d, J = 8.0 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 13.7, 24.4, 37.9, 88.9, 120.6, 128.5, 131.4, 142.9 ppm; HRMS (ESI) calculated for C20H22Na ([M+Na]+): 285.1614, found 285.1606. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The resulting crude product was purified by a preparative GPC column attached to a recycling HPLC to yield 1,2-bis(p-(n-propyl)phenyl)ethyne (69.6 mg, 0.265 mmol). obtained at 53%. The identity of 1,2-bis(p-(n-propyl)phenyl)ethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ = 0.93 (t, J = 7.6 Hz, 6H), 1.63 (sext, J = 7.6 Hz, 4H), 2.58 (t, J = 7.6 Hz, 4H), 7.14 (d, J = 8.0 Hz, 4H), 7.43 (d, J = 8.0 Hz, 4H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ = 13.7, 24.4, 37.9, 88.9, 120.6, 128.5, 131.4 , 142.9 ppm; HRMS (ESI) calculated for C20H22Na ([M+Na] + ): 285.1614 , found 285.1606.
（実施例８）ｐ－（ｎ－ブチル）フェニル誘導体　表１
Figure JPOXMLDOC01-appb-C000019
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。（ｐ－（ｎ－ブチル）フェニル）ボロン酸（４４４．１ｍｇ、２．４９ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．０ｍｇ、０．０４９ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８２．９ｍｇ、０．５０ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 8) p-(n-butyl) phenyl derivative Table 1
Figure JPOXMLDOC01-appb-C000019
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding (p-(n-butyl)phenyl)boronic acid (444.1 mg, 2.49 mmol) and Pd(PPh 3 ) 4 (57.0 mg, 0.049 mmol), THF (1.0 mL) was added. Agitation was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (82.9 mg, 0.50 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ビス（ｐ－（ｎ－ブチル）フェニル）エチン（９９．６ｍｇ、０．３４３ｍｍｏｌ）を収率６９％で得た。１，２－ビス（ｐ－（ｎ－ブチル）フェニル）エチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 0.92-1.00 (m, 6H), 1.32-1.45 (m, 4H), 1.57-1.70 (m, 4H), 2.64 (t, J = 7.2 Hz, 4H), 7.17 (d, J = 8.0 Hz, 4H), 7.47 (d, J = 8.0 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 13.9, 22.3, 33.4, 35.6, 88.9, 120.6, 128.4, 131.4, 143.1 ppm; HRMS (ESI) calculated for C22H26Na ([M+Na]+): 313.1927, found 313.1924. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The resulting crude product was purified by a preparative GPC column attached to a recycling HPLC to give 1,2-bis(p-(n-butyl)phenyl)ethyne (99.6mg, 0.343mmol) as a yield. 69% obtained. The identity of 1,2-bis(p-(n-butyl)phenyl)ethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ = 0.92-1.00 (m, 6H), 1.32-1.45 (m, 4H), 1.57-1.70 (m, 4H), 2.64 (t, J = 7.2 Hz, 4H ), 7.17 (d, J = 8.0 Hz, 4H), 7.47 (d, J = 8.0 Hz, 4H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ = 13.9, 22.3, 33.4, 35.6, 88.9, 120.6, 128.4, 131.4, 143.1 ppm; HRMS ( ESI ) calculated for C22H26Na ([M+Na] + ): 313.1927, found 313.1924.
（実施例９）ｐ－（t－ブチル）フェニル誘導体　表１
Figure JPOXMLDOC01-appb-C000020
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。（ｐ－（t－ブチル）フェニル）ボロン酸（４４４．５ｍｇ、２．５０ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．８ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８３．３ｍｇ、０．５０２ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 9) p-(t-butyl) phenyl derivative Table 1
Figure JPOXMLDOC01-appb-C000020
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding (p-(t-butyl)phenyl)boronic acid (444.5 mg, 2.50 mmol) and Pd(PPh 3 ) 4 (57.8 mg, 0.05 mmol), THF (1.0 mL) was added. Agitation was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (83.3 mg, 0.502 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ビス（ｐ－（t－ブチル）フェニル）エチン（８９．１ｍｇ、０．３０７ｍｍｏｌ）を収率６１％で得た。１，２－ビス（ｐ－（t－ブチル）フェニル）エチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 1.32 (s, 18H), 7.36 (d, J = 8.4 Hz, 4H), 7.46 (d, J = 8.4 Hz, 4H) ppm;13C NMR (100 MHz, CDCl3): δ = 31.2, 34.8, 88.8, 120.4, 125.3, 131.3, 151.3 ppm; HRMS (ESI) calculated for C22H26Na ([M+Na]+): 313.1927, found 313.1924. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The obtained crude product was purified by a preparative GPC column attached to a recycling HPLC, yielding 1,2-bis(p-(t-butyl)phenyl)ethyne (89.1 mg, 0.307 mmol). obtained at 61%. The identity of 1,2-bis(p-(t-butyl)phenyl)ethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ = 1.32 (s, 18H), 7.36 (d, J = 8.4 Hz, 4H), 7.46 (d, J = 8.4 Hz, 4H) ppm; 13 C NMR (100 MHz, CDCl3 ): δ = 31.2, 34.8, 88.8, 120.4, 125.3, 131.3, 151.3 ppm; HRMS ( ESI ) calculated for C22H26Na ([M+Na] + ): 313.1927, found 313.1924.
（実施例１０）ｐ－メトキシフェニル誘導体　表１
Figure JPOXMLDOC01-appb-C000021
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。（ｐ－メトキシフェニル）ボロン酸（３７８．７ｍｇ、２．４９ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．２ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８３．５ｍｇ、０．５０４ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 10) p-methoxyphenyl derivative Table 1
Figure JPOXMLDOC01-appb-C000021
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding (p-methoxyphenyl)boronic acid (378.7 mg, 2.49 mmol) and Pd(PPh 3 ) 4 (57.2 mg, 0.05 mmol), THF (1.0 mL) was added and stirring was started. . A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (83.5 mg, 0.504 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ビス（ｐ－メトキシフェニル）エチン（２８．２ｍｇ、０．１１８ｍｍｏｌ）を収率２３％で得た。１，２－ビス（ｐ－メトキシフェニル）エチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 3.81 (s, 6H), 6.83-6.89 (m, 4H), 7.40-7.48 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 55.2, 87.9, 113.9, 115.7, 132.8, 159.3 ppm; HRMS (ESI) calculated for C16H14O2Na ([M+Na]+): 261.0886, found261.0887. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The obtained crude product was purified by a preparative GPC column attached to a recycling HPLC to obtain 1,2-bis(p-methoxyphenyl)ethyne (28.2 mg, 0.118 mmol) with a yield of 23%. Ta. The identity of 1,2-bis(p-methoxyphenyl)ethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ= 3.81 (s, 6H), 6.83-6.89 (m, 4H), 7.40-7.48 (m, 4H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ = 55.2, 87.9, 113.9, 115.7 , 132.8 , 159.3 ppm; HRMS (ESI) calculated for C16H14O2Na ([M+Na] + ): 261.0886, found261.0887.
（実施例１１）ｐ－フルオロフェニル誘導体　表１
Figure JPOXMLDOC01-appb-C000022
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。（ｐ－フルオロフェニル）ボロン酸（３４９．３ｍｇ、２．５０ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．４ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８２．７ｍｇ、０．４９９ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 11) p-fluorophenyl derivative Table 1
Figure JPOXMLDOC01-appb-C000022
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding (p-fluorophenyl)boronic acid (349.3 mg, 2.50 mmol) and Pd(PPh 3 ) 4 (57.4 mg, 0.05 mmol), THF (1.0 mL) was added and stirring was started. . A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (82.7 mg, 0.499 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ビス（ｐ－フルオロフェニル）エチン（５．８ｍｇ、０．０２７ｍｍｏｌ）を収率５％で得た。１，２－ビス（ｐ－フルオロフェニル）エチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 7.00-7.09 (m, 4H), 7.45-7.56 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 87.9, 115.7 (d, J= 22.0 Hz), 119.2 (d, J = 3.8 Hz), 133.4 (d, J = 8.6 Hz), 162.5 (d, J = 248.8 Hz). HRMS (ESI) calculated for C14H9F2 ([M+H]+): 215.0667, found 215.0664. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The obtained crude product was purified by a preparative GPC column attached to a recycling HPLC to obtain 1,2-bis(p-fluorophenyl)ethyne (5.8 mg, 0.027 mmol) with a yield of 5%. Ta. The identity of 1,2-bis(p-fluorophenyl)ethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ= 7.00-7.09 (m, 4H), 7.45-7.56 (m, 4H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ= 87.9, 115.7 (d , J = 22.0 Hz), 119.2 (d, J = 3.8 Hz), 133.4 (d, J = 8.6 Hz), 162.5 ( d , J = 248.8 Hz) . [M+H] + ): 215.0667, found 215.0664.
（実施例１２）ｐ－（トリフルオロメチル）フェニル誘導体　表１
Figure JPOXMLDOC01-appb-C000023
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。（ｐ－トリフルオロメチルフェニル）ボロン酸（４７３．８ｍｇ、２．４９ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．３ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８２．２ｍｇ、０．４９６ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 12) p-(trifluoromethyl)phenyl derivative Table 1
Figure JPOXMLDOC01-appb-C000023
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. After adding (p-trifluoromethylphenyl)boronic acid (473.8 mg, 2.49 mmol) and Pd(PPh 3 ) 4 (57.3 mg, 0.05 mmol), THF (1.0 mL) was added and stirred. started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (82.2 mg, 0.496 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ビス（ｐ－トリフルオロメチルフェニル）エチン（４６．０ｍｇ、０．１４６ｍｍｏｌ）を収率２９％で得た。１，２－ビス（ｐ－トリフルオロメチルフェニル）エチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 7.59-7.68 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3): δ = 90.1, 123.8 (q, J = 270.8 Hz), 125.4 (q, J = 3.8 Hz), 126.4, 130.5 (q, J = 33.4 Hz), 132.0 ppm; HRMS (ESI) calculated for C16H8F6Na ([M+Na]+): 337.0422, found 337.0421. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The obtained crude product was purified by a preparative GPC column attached to a recycling HPLC, and 1,2-bis(p-trifluoromethylphenyl)ethyne (46.0 mg, 0.146 mmol) was obtained with a yield of 29%. I got it in The identity of 1,2-bis(p-trifluoromethylphenyl)ethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ= 7.59-7.68 (m, 8H) ppm; 13 C NMR (100 MHz, CDCl 3 ): δ = 90.1, 123.8 (q, J = 270.8 Hz), 125.4 ( q, J = 3.8 Hz), 126.4, 130.5 (q, J = 33.4 Hz), 132.0 ppm; HRMS (ESI) calculated for C 16 H 8 F 6 Na ([M+Na] + ): 337.0422, found 337.0421.
（実施例１３）２－ナフチル誘導体　表１
Figure JPOXMLDOC01-appb-C000024
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした２－ナフチルボロン酸（４２９．７ｍｇ、２．５０ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．８ｍｇ、０．０５ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、テトラクロロエチレン（８３．０ｍｇ、０．５０１ｍｍｏｌ）を加えた後、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 13) 2-naphthyl derivative Table 1
Figure JPOXMLDOC01-appb-C000024
 After evacuating a glass test tube reactor, 2-naphthylboronic acid (429.7 mg, 2.50 mmol) and Pd(PPh 3 ) 4 (57.8 mg, 0.05 mmol) were placed under a nitrogen atmosphere. After the addition, THF (1.0 mL) was added and stirring was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, tetrachlorethylene (83.0 mg, 0.501 mmol) was added, and then stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、１，２－ジ（ナフチレン－２－イル）エチン（３８．９ｍｇ、０．１４０ｍｍｏｌ）を収率２８％で得た。１，２－ジ（ナフチレン－２－イル）エチンの同定は、次のスペクトルから判断した。
1H NMR (100 MHz, CDCl3): δ= 7.44-7.57 (m, 4H); 7.62 (d, J = 8.8 Hz, 2H), 7.76-7.94 (m, 6H), 8.10 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 90.2, 120.6, 126.6, 126.7, 127.8 (overlapping), 128.0, 128.4, 131.5, 132.9, 133.1 ppm; HRMS (ESI) calculated for C22H14Na ([M+Na]+): 301.0988, found 301.0955. After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The resulting crude product was purified by a preparative GPC column attached to a recycling HPLC to give 1,2-di(naphthylene-2-yl)ethyne (38.9 mg, 0.140 mmol) with a yield of 28%. Obtained. The identity of 1,2-di(naphthylene-2-yl)ethyne was determined from the following spectra.
1 H NMR (100 MHz, CDCl 3 ): δ= 7.44-7.57 (m, 4H); 7.62 (d, J = 8.8 Hz, 2H), 7.76-7.94 (m, 6H), 8.10 (s, 2H) ppm 13 C NMR (100 MHz, CDCl 3 ): δ = 90.2, 120.6, 126.6, 126.7, 127.8 (overlapping), 128.0, 128.4, 131.5, 132.9, 133.1 ppm; HRMS (ESI) calculated for C 22 H 14 Na ( [M+Na] + ): 301.0988, found 301.0955.
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
（実施例１４）テトラブロモエチレンの合成
　非特許文献３の手順を参考に合成を行った。シュレンク管にペンタブロモエタン（１．６９ｇ、３．９８ｍｍｏｌ）を加え、２０Ｍ　ＮａＯＨ水溶液（１０ｍＬ）を室温で加えた。その後、溶液を５時間、室温にて撹拌した。水（２ｍＬ）を加え、混合物からＥｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層を塩化カルシウムで乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、テトラブロモエチレン（１．１１ｇ、３．２３ｍｍｏｌ）を収率８１％で得た。またスペクトル測定により純度は高かった。テトラブロモエチレンの同定は、次のスペクトルから判断した。
13C NMR (100 MHz, CDCl3): δ= 92.3 ppm; HRMS (ESI) calculated for C2HBr4 ([M+ H]+): 340.6806, found 340.6794. (Example 14) Synthesis of tetrabromoethylene Synthesis was performed with reference to the procedure of Non-Patent Document 3. Pentabromoethane (1.69 g, 3.98 mmol) was added to the Schlenk tube and 20 M NaOH aqueous solution (10 mL) was added at room temperature. The solution was then stirred for 5 hours at room temperature. Water (2 mL) was added and organics were extracted from the mixture with Et 2 O (20 mL×3). The combined organic layers were dried with calcium chloride. Filtration through a cotton plug, concentration, and evacuation were performed to obtain tetrabromoethylene (1.11 g, 3.23 mmol) with a yield of 81%. Also, the purity was high by spectral measurement. The identity of tetrabromoethylene was determined from the following spectra.
13 C NMR (100 MHz, CDCl 3 ): δ= 92.3 ppm; HRMS (ESI) calculated for C 2 HBr 4 ([M+ H] + ): 340.6806, found 340.6794.
（実施例１５）テトラブロモエチレンを原料に用いたジフェニルアセチレン合成の反応
Figure JPOXMLDOC01-appb-C000026
 　ガラス製の試験管型反応器を真空引きの後、窒素雰囲気下にした。フェニルボロン酸（３０４．６ｍｇ、２．５０ｍｍｏｌ）とＰｄ（ＰＰｈ３）４（５７．５ｍｇ、０．０５ｍｍｏｌ）を加え、次にテトラブロモエチレン（１７２．０ｍｇ、０．５０１ｍｍｏｌ）を加えた後、ＴＨＦ（１．０ｍＬ）を加え撹拌を開始した。これに５Ｍ　ＫＯＨ水溶液（０．５ｍＬ）を加え、アルミブロック式スターラーにて６０℃で撹拌を１８時間続けた。その後、反応液に水（１０ｍＬ）を加え反応を停止した後、Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、真空引きを行うことで、粗生成物をナスフラスコに得た。 (Example 15) Diphenylacetylene synthesis reaction using tetrabromoethylene as raw material
Figure JPOXMLDOC01-appb-C000026
 A glass test tube reactor was evacuated and then placed under a nitrogen atmosphere. Phenylboronic acid (304.6 mg, 2.50 mmol) and Pd( PPh3 ) 4 (57.5 mg, 0.05 mmol) were added followed by tetrabromoethylene (172.0 mg, 0.501 mmol) followed by THF (1.0 mL) was added and stirring was started. A 5 M KOH aqueous solution (0.5 mL) was added thereto, and stirring was continued at 60° C. for 18 hours with an aluminum block stirrer. After that, water (10 mL) was added to the reaction solution to stop the reaction, and organic matter was extracted with Et 2 O (20 mL×3 times). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. A crude product was obtained in an eggplant flask by performing filtration through a cotton plug, concentration, and evacuation.
　粗生成物の入っているナスフラスコに対して窒素置換を行った後、低水分ＴＨＦ（５．０ｍＬ）を加え、溶解させ、ナスフラスコを－７８℃の恒温槽に付けて撹拌をした。このナスフラスコに、ｎ－ＢｕＬｉ（１．５８Ｍヘキサン溶液、１．０ｍＬ、１．６ｍｍｏｌ）を滴下して０．５時間、同じ温度で撹拌を続けた。その後、撹拌を続けながら－７８℃から室温に０．５時間かけてゆっくりと昇温を行った。水（１０ｍＬ）を加え、反応を停止した。Ｅｔ２Ｏ（２０ｍＬ×３回）で有機物を抽出した。合体させた有機層は、飽和食塩水（２０ｍＬ×１回）で洗浄を行い、その後、無水硫酸ナトリウムで有機層を乾燥させた。綿栓ろ過と濃縮を行い、さらにシリカゲルを用いたショートカラム（溶媒：ヘキサン／酢酸エチル＝１０：１）を行い、濃縮と真空引きを行い、粗生成物を得た。得られた粗生成物はリサイクル型ＨＰＬＣに装着した分取ＧＰＣカラムにより精製を行い、ジフェニルアセチレン（４５．８ｍｇ、０．２５７ｍｍｏｌ）を収率５１％で得た。ジフェニルアセチレンの同定は、実施例１のスペクトルとの比較で行った。 After the eggplant flask containing the crude product was purged with nitrogen, low-moisture THF (5.0 mL) was added and dissolved, and the eggplant flask was placed in a -78°C constant temperature bath and stirred. n-BuLi (1.58 M hexane solution, 1.0 mL, 1.6 mmol) was added dropwise to this eggplant flask, and stirring was continued at the same temperature for 0.5 hours. Thereafter, the temperature was slowly raised from −78° C. to room temperature over 0.5 hours while stirring was continued. Water (10 mL) was added to quench the reaction. Organics were extracted with Et 2 O (20 mL×3). The combined organic layers were washed with saturated brine (20 mL×1 time), and then dried over anhydrous sodium sulfate. Filtration through a cotton plug and concentration were performed, followed by short column chromatography using silica gel (solvent: hexane/ethyl acetate=10:1), and concentration and evacuation were performed to obtain a crude product. The resulting crude product was purified with a preparative GPC column attached to a recycling HPLC to obtain diphenylacetylene (45.8 mg, 0.257 mmol) with a yield of 51%. Identification of diphenylacetylene was performed by comparison with the spectrum of Example 1.

Claims (7)

  1. 　下記式（１）：
    Figure JPOXMLDOC01-appb-C000001
     （式中、Ｒ１からＲ５は、同一でも異なっていてもよく、水素、ハロゲン元素、水酸基、アミノ基又は１価の有機基であり、Ｒ１からＲ５の２つ以上が組み合わさって縮合環を形成していてもよい。）
    で表されるジアリールアセチレン誘導体の製造方法であって、
    （ａ）下記式（２）：
    Figure JPOXMLDOC01-appb-C000002
     （式中、Ｘはハロゲン元素を表す）
    で表されるテトラハロゲン化エチレンと、下記式（３）：
    Figure JPOXMLDOC01-appb-C000003
     （式中、Ｒ１からＲ５は前記のとおりである）
    で表されるアリールボロン酸誘導体とを、触媒及び塩基の存在下で反応させて、下記式（４）：
    Figure JPOXMLDOC01-appb-C000004
     （式中、Ｒ１からＲ５、及びＸは前記の通りである）
    で表されるジアリールジハロゲン化エチレンを得る工程、そして
    　前記式（４）で表されるジアリールジハロゲン化エチレンに有機アルカリ金属を作用させて、前記式（１）で表されるジアリールアセチレン誘導体を得る工程を含む、方法。     Formula (1) below:
    Figure JPOXMLDOC01-appb-C000001
     (Wherein, R1 to R5 may be the same or different and are hydrogen, a halogen element, a hydroxyl group, an amino group or a monovalent organic group, and two or more of R1 to R5 are combined to form a condensed ring. may be.)
    A method for producing a diarylacetylene derivative represented by
    (a) the following formula (2):
    Figure JPOXMLDOC01-appb-C000002
     (Wherein, X represents a halogen element)
    and a tetrahalogenated ethylene represented by the following formula (3):
    Figure JPOXMLDOC01-appb-C000003
     (Wherein, R1 to R5 are as described above)
    is reacted with an arylboronic acid derivative represented by the following formula (4) in the presence of a catalyst and a base:
    Figure JPOXMLDOC01-appb-C000004
     (wherein R1 to R5 and X are as defined above)
    and a step of reacting the diaryldihalogenated ethylene represented by the formula (4) with an organic alkali metal to obtain the diarylacetylene derivative represented by the formula (1). A method, including
  2. 　前記１価の有機基が、アルコキシ基、アルキルアミノ基、アルキルエステル基、及びアシルアミノ基からなる群から選ばれる、請求項１に記載の方法。 The method according to claim 1, wherein the monovalent organic group is selected from the group consisting of an alkoxy group, an alkylamino group, an alkylester group, and an acylamino group.
  3. 　前記縮合環が、ナフタレン環又はアントラセン環である、請求項１に記載の方法。 The method according to claim 1, wherein the condensed ring is a naphthalene ring or an anthracene ring.
  4. 　前記触媒及び塩基が、テトラキス（トリフェニルホスフィン）パラジウム及びＫＯＨの組み合わせ、並びに、テトラキス（トリフェニルホスフィン）パラジウム及びＫ３ＰＯ４の組み合わせからなる群から選ばれる、請求項１～３のいずれかに記載の方法。 4. Any of claims 1-3, wherein the catalyst and base are selected from the group consisting of a combination of tetrakis(triphenylphosphine)palladium and KOH, and a combination of tetrakis(triphenylphosphine) palladium and K3PO4 . described method.
  5. 　前記有機アルカリ金属が、アルキルリチウムである、請求項１～３のいずれかに記載の方法。 The method according to any one of claims 1 to 3, wherein the organic alkali metal is alkyllithium.
  6. 　前記触媒及び塩基が、テトラキス（トリフェニルホスフィン）パラジウム及びＫＯＨの組み合わせ、並びに、テトラキス（トリフェニルホスフィン）パラジウム及びＫ３ＰＯ４の組み合わせからなる群から選ばれ、前記有機アルカリ金属が、アルキルリチウムである、請求項１～３のいずれかに記載の方法。 wherein said catalyst and base are selected from the group consisting of a combination of tetrakis(triphenylphosphine)palladium and KOH , and a combination of tetrakis(triphenylphosphine)palladium and K3PO4 , and said organic alkali metal is alkyllithium; The method according to any one of claims 1 to 3, wherein the method is
  7. 　下記式（１）：
    Figure JPOXMLDOC01-appb-C000005
     （式中、Ｒ１からＲ５は、同一でも異なっていてもよく、水素、ハロゲン元素、水酸基、アミノ基又は１価の有機基であり、Ｒ１からＲ５の２つ以上が組み合わさって縮合環を形成していてもよい。）
    で表されるジアリールアセチレン誘導体。
          Formula (1) below:
    Figure JPOXMLDOC01-appb-C000005
     (Wherein, R1 to R5 may be the same or different and are hydrogen, a halogen element, a hydroxyl group, an amino group or a monovalent organic group, and two or more of R1 to R5 are combined to form a condensed ring. may be.)
    A diarylacetylene derivative represented by
PCT/JP2023/005415 2022-02-17 2023-02-16 Method for producing diarylacetylene derivative WO2023157909A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5194829A (en) * 1975-02-19 1976-08-19
JPS615031A (en) * 1984-06-19 1986-01-10 Dainippon Ink & Chem Inc Novel trans hydrocarbon compound
JPH03169827A (en) * 1989-11-01 1991-07-23 Bayer Ag Preparation of symmetric diaryl acetylene

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5194829A (en) * 1975-02-19 1976-08-19
JPS615031A (en) * 1984-06-19 1986-01-10 Dainippon Ink & Chem Inc Novel trans hydrocarbon compound
JPH03169827A (en) * 1989-11-01 1991-07-23 Bayer Ag Preparation of symmetric diaryl acetylene

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EDDARIR SAID; KAJJOUT MOHAMMED; ROLANDO CHRISTIAN: "Building block synthesis of predominantly (E) symmetrical and unsymmetrical 1,2-difluorostilbenes from 1,2-dibromo-1,2-difluoroethene", TETRAHEDRON, ELSEVIER SIENCE PUBLISHERS, AMSTERDAM, NL, vol. 69, no. 52, 1 January 1900 (1900-01-01), AMSTERDAM, NL , pages 11191 - 11196, XP028793504, ISSN: 0040-4020, DOI: 10.1016/j.tet.2013.10.067 *
RANU BRINDABAN C, SANKAR K. GUCHHAIT AND ARUNKANTI SARKAR : " Stereoselective debromination of aryl-substituted vic-dibromide with indium metal.", CHEMICAL COMMUNICATIONS, no. 19, 1 January 1998 (1998-01-01), pages 2113 - 2114, XP093086852, DOI: 10.1039/A806530F *

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