WO2019159596A1 - 脱離基を有する有機化合物と有機ケイ素化合物とのカップリング体の製造方法 - Google Patents

脱離基を有する有機化合物と有機ケイ素化合物とのカップリング体の製造方法 Download PDF

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WO2019159596A1
WO2019159596A1 PCT/JP2019/001343 JP2019001343W WO2019159596A1 WO 2019159596 A1 WO2019159596 A1 WO 2019159596A1 JP 2019001343 W JP2019001343 W JP 2019001343W WO 2019159596 A1 WO2019159596 A1 WO 2019159596A1
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泰広 魚住
剛 浜坂
駿 市位
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大学共同利用機関法人自然科学研究機構
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Definitions

  • the present invention relates to a method for producing a coupling product of an organic compound having a leaving group and an organosilicon compound.
  • the coupling reaction between an organic compound having a leaving group and an organosilicon compound is generally referred to as the Hiyama reaction (see Non-Patent Document 1).
  • the Hiyama reaction is known as a useful reaction that can obtain a coupling body (biaryl compound etc.) useful in the synthesis of pharmaceuticals, liquid crystal materials, etc., using an organosilicon compound that is stable and non-toxic. .
  • a palladium catalyst is usually used for the Hiyama reaction, an amount of 1 to 10 mol% of the catalyst is required with respect to the substrate used for the reaction, and the removal requires a great cost. Further, palladium is a rare metal, and a reduction in the amount of use thereof is required.
  • an object of the present invention is to provide a production method capable of obtaining a coupling body for the Hiyama reaction with a good yield even when the amount of the palladium catalyst used is reduced.
  • the present inventors In the presence of an alcohol solvent, an inorganic base and a palladium catalyst each containing two adjacent carbon atoms having a hydroxyl group, the present inventors have represented a compound represented by the following general formula (1) and the following general formula (2). Even when the amount of the palladium catalyst to be used is reduced by the method for producing a coupling body, the coupling body represented by the following general formula (3) is obtained by reacting with the compound represented by formula (3). It was found that a coupling body was obtained with a good yield.
  • Ar 1 -X (1) [In the formula (1), Ar 1 represents an optionally substituted aryl group or an optionally substituted heteroaryl group, and X represents a bromine atom, an iodine atom, a methanesulfonyloxy group and a trifluoromethanesulfonyloxy group. Indicates the selected leaving group. ] Ar 2 —Si (OR) 3 (2) [In the formula (2), Ar 2 represents an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted vinyl group, and R represents an alkyl group having 1 to 5 carbon atoms. Indicates. A plurality of R may be the same or different. ] Ar 1 -Ar 2 (3) [In the formula (3), Ar 1 and Ar 2 are as defined above. ]
  • the alcohol solvent and the compound represented by the general formula (2) react in the presence of the inorganic base to form an intermediate represented by the following formula ( ⁇ ).
  • the amount of the palladium catalyst used is reduced because the reaction with the compound represented by the general formula (1) proceeds smoothly because this intermediate is more active than the intermediate in the conventional Hiyama reaction. Even so, the present inventors presume that a coupling body of the Hiyama reaction can be obtained with a good yield.
  • the intermediate represented by the formula ( ⁇ ) is an example when propylene glycol is used as the alcohol solvent, and M + represents a metal ion derived from an inorganic base.
  • the present invention it is possible to provide a production method capable of obtaining a coupling body for the Hiyama reaction with a good yield even when the amount of the palladium catalyst used is reduced.
  • a compound represented by the general formula (1) an organic compound having a leaving group
  • a general formula (2) in the presence of an alcohol solvent, an inorganic base, and a palladium catalyst.
  • a compound represented by the general formula (3) is obtained by reacting the compound (organosilicon compound) represented.
  • the alcohol solvent includes a site in which two adjacent carbon atoms each have a hydroxyl group.
  • the alcohol solvent may have 3 or more hydroxyl groups as long as the two adjacent carbon atoms each contain a hydroxyl group, but the number of hydroxyl groups is preferably 2 or 3. 2 is more preferable.
  • Examples of the alcohol solvent include ethylene glycol, propylene glycol, 1,2-butanediol, 2,3-butanediol, glycerol and the like.
  • the number of carbon atoms in the alcohol solvent is not particularly limited, but can be, for example, 2 to 6, preferably 2 to 4.
  • the solvent in the said manufacturing method may contain the other solvent in the range which does not inhibit the effect by this invention.
  • the amount of the alcohol solvent to be used is not particularly limited, but for example, an amount in which the concentration of the compound represented by the general formula (1) is 0.01 to 2 mol / L can be used.
  • inorganic bases include alkali metal or alkaline earth metal hydroxides, fluorides, phosphates, carbonates, and bicarbonates. Of these, alkali metal fluorides, carbonates or phosphates are preferred, potassium or cesium fluorides, carbonates or phosphates are more preferred, potassium fluoride, cesium fluoride, potassium carbonate or phosphoric acid. More preferred is potassium.
  • the amount of the inorganic base may be 1 equivalent or more with respect to the compound represented by the general formula (1).
  • 1.5 to 5 equivalents of an inorganic base can be used.
  • the palladium catalyst various known catalysts can be used, but a divalent palladium catalyst is preferable.
  • a divalent palladium catalyst those used in the examples such as the pincer complex can be suitably used.
  • the catalyst amount of the palladium catalyst in the above production method is not particularly limited, but from the viewpoint of reducing the amount of the palladium catalyst, it is preferably 1 to 5000 mol ppm in terms of palladium element, and more preferably 3 to 3000 mol ppm.
  • the catalyst amount is a ratio based on the compound represented by the general formula (1).
  • the compound represented by the general formula (2) can also be synthesized by the method described in, for example, A Hosomi et al. J.Org.Chem. 1999, 55, 2415.
  • aryl group in the “aryl group optionally having a substituent” include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, and a pyrenyl group.
  • the number of carbon atoms in the aryl group can be, for example, 1-20.
  • heteroaryl group in the “heteroaryl group optionally having substituent (s)” include a quinolyl group, a pyridyl group, a pyrimidinyl group, a furyl group, a thienyl group, an imidazolyl group, and an indolyl group.
  • the number of carbon atoms in the heteroaryl group can be, for example, 1-20.
  • aryl group optionally having substituent “heteroaryl group optionally having substituent” and “vinyl group optionally having substituent”,
  • alkyl group, alkenyl group, aryl group, arylalkyl group, alkoxy group, alkenyloxy group, aryloxy group, arylalkyloxy group, heterocycloalkyl group, perfluoroalkyl group, formyl group, fluorine atom, amino group, A cyano group, a nitro group, etc. are mentioned.
  • These groups can have, for example, 1 to 20 carbon atoms.
  • the number of substituents may be singular or plural.
  • the substituents may be bonded to each other to form a condensed ring together with the aryl group or heteroaryl group.
  • the “leaving group” is selected from a bromine atom, an iodine atom, a methanesulfonyloxy group, and a trifluoromethanesulfonyloxy group, and is preferably a bromine atom or an iodine atom.
  • optionally substituted vinyl group examples include a vinyl group, an isopropenyl group, a 1-butenyl group, a 4-octen-4-yl group, a styryl group, and a naphthylvinyl group. .
  • Examples of the “alkyl group having 1 to 5 carbon atoms” in R include a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group.
  • the amount of the compound represented by the general formula (2) with respect to the compound represented by the general formula (1) is not particularly limited, and an equimolar amount may be used, or one of them may be used in excess.
  • the production method of the present invention is usually carried out in an inert gas atmosphere such as nitrogen.
  • the reaction temperature in the production method of the present invention is not particularly limited, and can be, for example, 50 to 150 ° C.
  • Example 2 (Examples 4 to 6 and Comparative Examples 10 and 11) The reaction was performed in the same manner as in Example 2 except that the base used was changed as shown in Table 2 (see the following reaction formula (B)). The results are shown in Table 2.
  • Example 7 to 10 and Comparative Example 12 The reaction was performed in the same manner as in Example 2 except that the amount of catalyst and the reaction temperature were changed as shown in Table 3 (see the following reaction formula (C)). The results are shown in Table 3.
  • Example 11 to 18 The reaction was performed in the same manner as in Example 10 except that the palladium (Pd) catalyst was changed as shown below (see the following reaction formula (D)). The results are shown below. Specifically, the Pd catalyst used for each example is shown below together with the reaction rate (conv.) (%) And the yield (yield) (%) of the coupling body (4a).
  • Example 10 G. Hamasaka, F. Sakurai, Y. Uozumi, Chem. Commun. 2015, 51, 3886.
  • Example 11 F. Ragaini, M. Gasperini, S. Cenini, L. Arnera, A. Caselli, P. Macchi, N. Casati, Chem. Eur. J. 2009, 15, 8064.
  • Example 12 Newkome, G. R .; Pantaleo, D. C .; Puckett, W. E .; Ziefle, P. L .; Deutsch, W. A. J. Inorg. Nucl. Chem. 1981, 43, 1529.
  • Example 13 K. Takenaka, M. Minakawa, Y. Uozumi. J. Am. Chem. Soc. 2005, 127, 12273.
  • Example 19 to 38 The reaction was performed in the same manner as in Example 10 except that the substrate (1) to be used was changed (see the following reaction formula (E)). The results are shown below. Specifically, the structure of the obtained coupling body (4 ′) is shown below together with the yield (%) for each example. In the structure, the left side of the dotted line is a group derived from the substrate (1), and the right side is a group derived from the substrate (2a) (hereinafter the same).
  • Example 39 to 47 The reaction was performed in the same manner as in Example 10 except that the substrate (2 ′) to be used was changed (see the following reaction formula (F)). The results are shown below. Specifically, the structure of the obtained coupling body (4 ′′) is shown below together with the yield (%) for each example.
  • Palladium catalyst (3) (0.23 mg, 1.0 ⁇ 10 ⁇ 3 mmol) was dissolved in dichloromethylene (1 mL). This solution (0.18 mL, 5 mol ppm Pd) was added to the reaction solution, and the mixture was heated and stirred at 100 ° C. for 12 hours. After the heating was completed, water (36 mL) was added and stirred at room temperature for 10 minutes. The resulting reaction mixture was washed on celite with water and tert-butyl methyl ether. Tetrahydrofuran was used to elute the remaining product on the solid. The volatile organic substance was distilled off under reduced pressure to obtain adapalene (6.9 g, 93% isolated yield).
  • Example 49 to 56 The reaction was performed in the same manner as in Example 10 except that the substrate (1) and the substrate (2) to be used were changed and the amount of the catalyst was 100 mol ppm (see the following reaction formula (H)). The results are shown below. Specifically, the structure of the obtained coupling body (4) is shown below with the yield (%) for every Example.
  • Example 57 The reaction was performed in the same manner as in Example 10 except that the substrate to be used was changed from 4-bromotoluene (1a) to 4-iodotoluene (1c) (see the following reaction formula (I)). As a result, the desired coupling product (4a) was obtained with a yield of 87%.
  • Example 57 The reaction was performed in the same manner as in Example 10 except that the substrate to be used was changed to the substrate (1d) and the substrate (2c) (see the following reaction formula (J)). As a result, the desired dextromethorphan derivative was obtained with a yield of 90%. Dextromethorphan is a type of antitussive expectorant.
  • Example 58 The reaction was performed in the same manner as in Example 10 except that the substrate to be used was changed to the substrate (1e) and the substrate (2d) (see the following reaction formula (k)). As a result, the target liquid crystal compound was obtained with a yield of 88%.

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Abstract

隣接した２つの炭素原子がそれぞれ水酸基を有する部位を含むアルコール溶媒、無機塩基及びパラジウム触媒の存在下、下記一般式（１）で表される化合物と下記一般式（２）で表される化合物とを反応させて、下記一般式（３）で表されるカップリング体を得る、カップリング体の製造方法。 Ａｒ１－Ｘ　…（１） Ａｒ２－Ｓｉ（ＯＲ）３　…（２） Ａｒ１－Ａｒ２　…（３） ［式中、Ａｒ１は置換されていてもよいアリール基等を示し、Ｘは臭素原子等の脱離基を示し、Ａｒ２は置換されていてもよいアリール基等を示し、Ｒは炭素数１～５のアルキル基を示す。］

Description

脱離基を有する有機化合物と有機ケイ素化合物とのカップリング体の製造方法
　本発明は、脱離基を有する有機化合物と有機ケイ素化合物とのカップリング体の製造方法に関する。
　脱離基を有する有機化合物と有機ケイ素化合物とのカップリング反応は、一般に檜山反応と総称されている（非特許文献１参照）。檜山反応は、安定であり且つ毒性のない有機ケイ素化合物を用いて、医薬品や液晶材料等の合成において有用なカップリング体（ビアリール化合物等）を得ることができる、有用な反応として知られている。
Y. Nakano and T. Hiyama, Chemical Society Reviews, 2011, 40, 4893.
　ところで、檜山反応には通常パラジウム触媒が用いられるが、反応に用いる基質に対して１～１０ｍｏｌ％の量の触媒が必要となり、その除去に多大なコストが必要である。また、パラジウムは希少な金属であり、その使用量の低減が求められる。
　そこで本発明は、使用するパラジウム触媒の量を減らした場合であっても、良好な収率で檜山反応のカップリング体を得ることが可能な製造方法を提供することを目的とする。
　本発明者らは、隣接した２つの炭素原子がそれぞれ水酸基を有する部位を含むアルコール溶媒、無機塩基及びパラジウム触媒の存在下、下記一般式（１）で表される化合物と下記一般式（２）で表される化合物とを反応させて下記一般式（３）で表されるカップリング体を得る、カップリング体の製造方法により、使用するパラジウム触媒の量を減らした場合であっても、良好な収率でカップリング体が得られることを見出した。
Ａｒ１－Ｘ　…（１）
［式（１）中、Ａｒ１は置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を示し、Ｘは臭素原子、ヨウ素原子、メタンスルホニルオキシ基及びトリフルオロメタンスルホニルオキシ基から選ばれる脱離基を示す。］
Ａｒ２－Ｓｉ（ＯＲ）３　…（２）
［式（２）中、Ａｒ２は置換されていてもよいアリール基、置換されていてもよいヘテロアリール基又は置換されていてもよいビニル基を示し、Ｒは炭素数１～５のアルキル基を示す。なお、複数存在するＲは、それぞれ同一でも異なっていてもよい。］
Ａｒ１－Ａｒ２　…（３）
［式（３）中、Ａｒ１及びＡｒ２は上記と同義である。］
　本発明の製造方法によりこのような効果が奏される理由は必ずしも明らかでないが、本発明者等は以下のようなスキームにより、反応性が向上しているものと推察している。
　まず、上記アルコール溶媒と一般式（２）で表される化合物とが、上記無機塩基の存在下で反応することにより、下記式（α）で表される中間体を形成する。この中間体が、従来の檜山反応における中間体よりも活性が高いために、一般式（１）で表される化合物との反応が円滑に進行するため、使用するパラジウム触媒の量を減らした場合であっても、良好な収率で檜山反応のカップリング体を得ることができると本発明者等は推察している。なお、式（α）で表される中間体は、上記アルコール溶媒として、プロピレングリコールを用いた場合の例であり、Ｍ＋は無機塩基由来の金属イオンを示す。
Figure JPOXMLDOC01-appb-C000001
　本発明によれば、使用するパラジウム触媒の量を減らした場合であっても、良好な収率で檜山反応のカップリング体を得ることが可能な製造方法を提供することができる。
　以下、本発明の好適な実施形態について詳細に説明する。ただし、本発明は以下の実施形態に限定されるものではない。
　本発明のカップリング体の製造方法においては、アルコール溶媒、無機塩基及びパラジウム触媒の存在下、一般式（１）で表される化合物（脱離基を有する有機化合物）と一般式（２）で表される化合物（有機ケイ素化合物）とを反応させて、一般式（３）で表されるカップリング体を得る。
　上記アルコール溶媒は、隣接した２つの炭素原子がそれぞれ水酸基を有する部位を含む。上記アルコール溶媒は、隣接した２つの炭素原子がそれぞれ水酸基を有する部位を含むものであれば、３以上の水酸基を有するものであってもよいが、水酸基の数が２又は３であると好ましく、２であるとより好ましい。上記アルコール溶媒としては、例えば、エチレングリコール、プロピレングリコール、１，２－ブタンジオール、２，３－ブタンジオール、グリセロール等が挙げられる。上記アルコール溶媒における炭素原子数は特に限定されないが、例えば２～６、好ましくは２～４とすることができる。
　アルコール溶媒として、隣接した２つの炭素原子がそれぞれ水酸基を有する部位を含むものを用いた場合には、上記式（α）で表される中間体が形成され、反応性が飛躍的に向上するものと考えられる。なお、上記製造方法における溶媒は、本発明による効果を阻害しない範囲で、他の溶媒を含んでいてもよい。
　アルコール溶媒の使用量は特に限定されないが、例えば、一般式（１）で表される化合物の濃度が、０．０１～２ｍｏｌ／Ｌとなる量を使用することができる。
　無機塩基としては、例えば、アルカリ金属又はアルカリ土類金属の水酸化物、フッ化物、リン酸塩、炭酸塩、炭酸水素塩が挙げられる。これらの中で、アルカリ金属のフッ化物、炭酸塩又はリン酸塩が好ましく、カリウム又はセシウムのフッ化物、炭酸塩又はリン酸塩がより好ましく、フッ化カリウム、フッ化セシウム、炭酸カリウム又はリン酸カリウムが更に好ましい。
　無機塩基の量は、一般式（１）で表される化合物に対して１等量以上であればよいが、例えば１．５～５当量の無機塩基を用いることができる。
　パラジウム触媒としては、従来公知のものを種々用いることができるが、２価のパラジウム触媒であることが好ましい。２価のパラジウム触媒としては、ピンサー錯体等の実施例で用いられているものを好適に用いることができる。
　上記製造方法におけるパラジウム触媒の触媒量は特に限定されないが、パラジウム触媒の量を減らす観点から、パラジウム元素換算で１～５０００ｍｏｌ　ｐｐｍであると好ましく、３～３０００ｍｏｌ　ｐｐｍであるとより好ましい。ここで、触媒量は、一般式（１）で表される化合物を基準とした割合である。
　一般式（１）で表される化合物及び一般式（２）で表される化合物としては、従来公知の化合物を用いることができ、市販の化合物を用いてもよい。また、一般式（２）で表される化合物は、例えば、A Hosomi et al. J.Org.Chem. 1999, 55, 2415に記載の方法で合成することもできる。
　上記「置換基を有していてもよいアリール基」における「アリール基」としては、例えばフェニル基、ナフチル基、アントリル基、フェナントリル基、ピレニル基が挙げられる。アリール基における炭素数は、例えば１～２０とすることができる。
　上記「置換基を有していてもよいヘテロアリール基」における「ヘテロアリール基」としては、例えばキノリル基、ピリジル基、ピリミジニル基、フリル基、チエニル基、イミダゾリル基、インドリル基が挙げられる。ヘテロアリール基における炭素数は、例えば１～２０とすることができる。
　上記「置換基を有していてもよいアリール基」、「置換基を有していてもよいヘテロアリール基」及び「置換基を有していてもよいビニル基」における「置換基」としては、例えばアルキル基、アルケニル基、アリール基、アリールアルキル基、アルコキシ基、アルケニルオキシ基、アリールオキシ基、アリールアルキルオキシ基、ヘテロシクロアルキル基、パーフルオロアルキル基、ホルミル基、フッ素原子、アミノ基、シアノ基、ニトロ基等が挙げられる。これらの基の炭素数は例えば１～２０とすることができる。なお、置換基の数は単数であっても複数であってもよい。また、アリール基又はヘテロアリール基が複数の置換基を有する場合には、置換基同士が互いに結合して、アリール基又はヘテロアリール基とともに縮合環を形成していてもよい。
　上記「脱離基」は、臭素原子、ヨウ素原子、メタンスルホニルオキシ基及びトリフルオロメタンスルホニルオキシ基から選ばれるものであり、臭素原子又はヨウ素原子であると好ましい。
　上記「置換基を有していてもよいビニル基」の具体例としては、ビニル基、イソプロペニル基、１－ブテニル基、４－オクテン－４－イル基、スチリル基、ナフチルビニル基が挙げられる。
　Ｒにおける「炭素数１～５のアルキル基」としては、メチル基、エチル基、プロピル基、ブチル基、ペンチル基が挙げられる。
　一般式（１）で表される化合物に対する一般式（２）で表される化合物の量は特に限定されず等モル量を用いても、どちらか一方を過剰に用いてもよい。
　本発明の製造方法は、通常窒素等の不活性ガス雰囲気下で行われる。また、本発明の製造方法における反応温度は、特に限定されず、例えば５０～１５０℃とすることができる。
　以下、実施例に基づいて本発明を更に具体的に説明するが、本発明は実施例に何ら限定されるものではない。
（実施例１～３及び比較例１～９）
　下記反応式（Ａ）に従って、種々溶媒を変更した他は、同様の条件で、パラジウム錯体（３）及びフッ化カリウム（ＫＦ）の存在下、４－ブロモトルエン（１ａ）とトリメトキシフェニルシラン（２ａ）とのカップリング反応を行い、目的のカップリング体（４ａ）を得た。具体的な操作を以下に示す。
　テフロン（登録商標）被覆した攪拌子が入っている試験管へ、４－ブロモトルエン（１ａ）（０．５０ｍｍｏｌ）、フェニルトリメトキシシラン（２ａ）（０．６０ｍｍｏｌ）、パラジウム錯体（３）（０．１ｍｏｌ％，５．０×１０－４ｍｍｏｌ）、フッ化カリウム（１．５ｍｍｏｌ）を加えた。その後、表１に記載の溶媒（１ｍＬ）を加え、８０℃で４時間反応後、水を加えた。得られた混合物をtert－ブチルメチルエーテルで抽出し、得られた有機相に内部標準としてメシチレン(０．２５ｍｍｏｌ)を加え、ガスクロマトグラフィーを用いて反応基質の転化率及びカップリング生成物の収率を求めた。その結果を表１に示す。
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-T000003
　これらの結果から明らかであるように、「隣接した２つの炭素原子がそれぞれ水酸基を有する部位を含むアルコール溶媒」を用いた場合には、良好な収率で目的のカップリング体（４ａ）が得られたものの、その他の溶媒を用いた場合には目的のカップリング体（４ａ）がほとんど得られなかった。
（実施例４～６及び比較例１０、１１）
　用いる塩基を表２に示すように変更した他は、実施例２と同様にして、反応を行った（下記反応式（Ｂ）参照）。その結果を表２に示す。
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-T000005
　これらの結果から明らかであるように、無機塩基を用いた場合には、良好な収率で目的のカップリング体（４ａ）が得られたものの、有機塩基を用いた場合や塩基を用いなかった場合には目的のカップリング体が得られなかった。
（実施例７～１０及び比較例１２）
　触媒量及び反応温度を表３に示すように変更した他は、実施例２と同様にして、反応を行った（下記反応式（Ｃ）参照）。その結果を表３に示す。
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-T000007
　これらの結果から明らかであるように、触媒量を５ｍｏｌ　ｐｐｍまで減らした場合であっても、良好な収率で目的のカップリング体（４ａ）が得られたものの、触媒を用いなかった場合には目的のカップリング体が得られなかった。
（実施例１１～１８）
　パラジウム（Ｐｄ）触媒を以下に示すように変更した他は、実施例１０と同様にして、反応を行った（下記反応式（Ｄ）参照）。その結果を以下に示す。具体的には、実施例毎に、用いたＰｄ触媒を、反応率（ｃｏｎｖ．）（％）及びカップリング体（４ａ）の収率（ｙｉｅｌｄ）（％）とともに以下に示す。
Figure JPOXMLDOC01-appb-C000008
　なお、実施例１０～１３のパラジウム触媒としては、以下に示す文献に記載の方法で調製したものを用い、その他のパラジウム触媒としては市販品を用いた。
実施例１０：G. Hamasaka, F. Sakurai, Y. Uozumi, Chem. Commun. 2015, 51, 3886.
実施例１１：F. Ragaini, M. Gasperini, S. Cenini, L. Arnera, A. Caselli, P.Macchi, N. Casati, Chem. Eur. J. 2009, 15, 8064.
実施例１２：Newkome, G. R.; Pantaleo, D. C.; Puckett, W. E.; Ziefle, P. L.;Deutsch, W. A. J. Inorg. Nucl. Chem. 1981, 43, 1529.
実施例１３：K. Takenaka, M. Minakawa, Y. Uozumi. J. Am. Chem. Soc. 2005, 127,12273.
（実施例１９～３８）
　用いる基質（１）を変更した他は、実施例１０と同様にして、反応を行った（下記反応式（Ｅ）参照）。その結果を以下に示す。具体的には、実施例毎に、得られたカップリング体（４’）の構造を、その収率（％）とともに以下に示す。なお、構造中、点線よりも左側が基質（１）由来の基であり、右側が基質（２ａ）由来の基である（以下、同様）。
Figure JPOXMLDOC01-appb-C000009
（実施例３９～４７）
　用いる基質（２’）をそれぞれ変更した他は、実施例１０と同様にして、反応を行った（下記反応式（Ｆ）参照）。その結果を以下に示す。具体的には、実施例毎に、得られたカップリング体（４”）の構造を、その収率（％）とともに以下に示す。
Figure JPOXMLDOC01-appb-C000010
（実施例４８）
　ニキビ治療薬の有効成分であるアダパレンの合成を実施した（下記反応式（Ｇ）参照）。具体的な実験操作を以下に示す。
　テフロン（登録商標）被覆した攪拌子が入っている大型試験管へ、フッ化カリウム（ＫＦ）（３．１ｇ，５４．０ｍｍｏｌ）と６－ブロモ－２－ナフタレンカルボン酸（１ｂ）（４．５ｇ，１８．０ｍｍｏｌ）を入れ、プロピレングリコール（３６ｍＬ）を加えた。トリエトキシシラン誘導体（２ｂ）（８．７ｇ，２１．６ｍｍｏｌ）を反応容器へと加えた。
　パラジウム触媒（３）（０．２３ｍｇ，１．０×１０－３ｍｍｏｌ）をジクロロメチレン（１ｍＬ）へと溶解させた。この溶液（０．１８ｍＬ，５ｍｏｌ　ｐｐｍＰｄ）を反応溶液へと加え、１００℃で１２時間加熱攪拌した。加熱終了後、水（３６ｍＬ）を加え、室温下１０分間攪拌した。得られた反応混合物をセライト上で、水、ｔｅｒｔ－ブチルメチルエーテルを用い、洗浄した。テトラヒドロフランを用い、固体上に残った生成物を溶出させた。減圧下、揮発性有機物を留去することで、アダパレンを６．９ｇ、９３％単離収率で得た。
Figure JPOXMLDOC01-appb-C000011
（実施例４９～５６）
　用いる基質（１）及び基質（２）をそれぞれ変更し、且つ触媒量を１００ｍｏｌ　ｐｐｍとした他は、実施例１０と同様にして、反応を行った（下記反応式（Ｈ）参照）。その結果を以下に示す。具体的には、実施例毎に、得られたカップリング体（４）の構造を、その収率（％）とともに以下に示す。
Figure JPOXMLDOC01-appb-C000012
（実施例５７）
　用いる基質を４－ブロモトルエン（１ａ）から４－ヨードトルエン（１ｃ）に変更した他は、実施例１０と同様にして、反応を行った（下記反応式（Ｉ）参照）。その結果、収率８７％で目的のカップリング体（４ａ）が得られた。
Figure JPOXMLDOC01-appb-C000013
（実施例５７）
　用いる基質を基質（１ｄ）及び基質（２ｃ）に変更した他は、実施例１０と同様にして、反応を行った（下記反応式（Ｊ）参照）。その結果、収率９０％で目的のデキストロメトルファン誘導体が得られた。なお、デキストロメトルファンは、鎮咳去痰薬の一種である。
Figure JPOXMLDOC01-appb-C000014
（実施例５８）
　用いる基質を基質（１ｅ）及び基質（２ｄ）に変更した他は、実施例１０と同様にして、反応を行った（下記反応式（ｋ）参照）。その結果、収率８８％で目的の液晶化合物が得られた。
Figure JPOXMLDOC01-appb-C000015

Claims (1)

  1. 　隣接した２つの炭素原子がそれぞれ水酸基を有する部位を含むアルコール溶媒、無機塩基及びパラジウム触媒の存在下、下記一般式（１）で表される化合物と下記一般式（２）で表される化合物とを反応させて、下記一般式（３）で表されるカップリング体を得る、カップリング体の製造方法。
    Ａｒ１－Ｘ　…（１）
    ［式（１）中、Ａｒ１は置換されていてもよいアリール基又は置換されていてもよいヘテロアリール基を示し、Ｘは臭素原子、ヨウ素原子、メタンスルホニルオキシ基及びトリフルオロメタンスルホニルオキシ基から選ばれる脱離基を示す。］
    Ａｒ２－Ｓｉ（ＯＲ）３　…（２）
    ［式（２）中、Ａｒ２は置換されていてもよいアリール基、置換されていてもよいヘテロアリール基又は置換されていてもよいビニル基を示し、Ｒは炭素数１～５のアルキル基を示す。］
    Ａｒ１－Ａｒ２　…（３）
    ［式（３）中、Ａｒ１及びＡｒ２は上記と同義である。］
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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BLASZCZYK, IZABELA ET AL.: "Orthometallated palladium trimers in C-C coupling reactions", JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 710, 2012, pages 44 - 52, XP028417338 *
BLASZCZYK, IZABELA ET AL.: "Suzuki-Miyaura and Hiyama reactions catalyzed by orthopalladated triarylphosphite complexes", TETRAHEDRON, vol. 66, 2010, pages 9502 - 9507, XP027471728 *
HAMASAKA, GO ET AL.: "A palladium NNC-pincer complex: an efficient catalyst for allylic arylation at parts per billion levels", CHEMCOMMUN., vol. 51, 2015, pages 3886 - 3888, XP055636011 *
OMOTE, MASAAKI ET AL.: "Simple synthesis of beta -trifluoromethylstyrenes using (E)-trimethyl-(3,3,3-trifluoroprop-1-enyl)silane", ORGANIC LETTERS, vol. 14, no. 9, 2012, pages 2286 - 2289 *

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