JP3541223B2 - Heck reaction using Pd / C catalyst in ionic liquid - Google Patents

Description

[式中、Ｒ’は、アルキル基、アリール基、アシル基、アルコキシ基、アリールオキシ基、シアノ基、アルコキシカルボニル基、アリールオキシカルボニル基、アシルオキシ基、カルボキシ基、カルバモイル基 、ハロゲン原子、イミド基、アルキルチオ基、アリールチオ基、スルホ基、スルフィノ基、ホスフィノ基、ホスフィニル基、ホスホノ基又はシリル基を表す]
を有するオレフィンとを反応させることにより、一般式III：
【化７】

[式中、Ａｒ及びＲ’は、上述の定義と同様である]
を有する化合物を製造する方法である。
【００１８】
本発明の別の形態は、イオン性液体中において、Ｐｄ／Ｃ触媒存在下に、一般式IV：
【化８】

[式中、
Ｒは、水素原子、アルキル基、アシル基、アルコキシ基、アシルオキシ基、アリール基、アリールオキシ基、ハロゲン原子、ヒドロキシ基、ニトロ基、シアノ基、イミド基、アルコキシカルボニル基、アリールオキシカルボニル基、カルボキシル基、ホルミル基、アミノ基、カルバモイル基、メルカプト基、アルキルチオ基、アリールチオ基、スルホ基、スルフィノ基、ホスフィノ基、ホスフィニル基又はホスホノ基を表し、
Ｘは、トルフルオロメタンスルホニルオキシ基、又はハロゲン原子を表す]
を有する化合物と、一般式II：
【化９】

[式中、Ｒ’は上述の定義と同様である]
を有するオレフィンとを反応させることにより、一般式Ｖ：
【化１０】

[式中、Ｒ及びＲ’は上述の定義と同様である]
を有する化合物を製造する方法である。
【００１９】
イオン性液体は、室温前後で融解できる、塩類、塩類の混合物、あるいは、塩類を生成する成分の混合物の液体であり、この用語は、例えば１００℃程度までの比較的に高い温度で融解する塩類にも適用され得うる。一般的なイオン性液体は、室温で蒸気圧がゼロであることと、高い溶解力と広い液体範囲（例えば、３００℃のオーダー）を有するという特徴がある。既知のイオン性液体には、ハロゲンアニオン、ヘキサフルオロホスフェートアニオン若しくはテトラフルオロボレートアニオンを有するアンモニウム塩、ホスホニウム塩、Ｎ，Ｎ’−ジアルキルイミダゾリウム塩又はＮ−アルキルピリジニウム塩等の化合物が挙げられる。例えば、テトラブチルアンモニウムブロミド、ヘキサデシルトリブチルホスホニウムブロミド、１−ブチル−３−メチルイミダゾリウムヘキサフルオロフォスフェート、Ｎ−ヘキシルピリジニウムテトラフルオロボレート、１−エチル−３−メチルイミダゾリウムクロリド又はＮ−ブチルピリジニウムクロリドである。本発明で使用するのに好ましいイオン性液体は、下記構造式を有する１−ブチル−３−メチルイミダゾリウムヘキサフルオロリン酸塩である。
【００２０】
【化１１】

【００２１】
本発明で使用するＰｄ／Ｃ触媒は、例えば１０質量％のＰｄ／Ｃ（川研ファインケミカル社製）である。Ｐｄ／Ｃ触媒は、安価でかつ安定で取扱いやすく、再使用可能であり、本発明において非常に有用である。
【００２２】
Ｐｄ／Ｃ触媒の添加量は、ハロゲン化アリール又はアリールトリフルオロメタンスルホネートに対して、０．０５ｍｏｌ％〜１０ｍｏｌ％、好ましくは０．１ｍｏｌ％〜８ｍｏｌ％、さらに好ましくは１ｍｏｌ％〜５ｍｏｌ％である。
【００２３】
Ａｒは、置換又は無置換の芳香族化合物を表し、単環式であっても、多環式であってもよい。また、不飽和炭素環式化合物であっても、複素環式化合物であってもよい。
【００２４】
Ｘは、トリフルオロメタンスルホニルオキシ基、又はハロゲン原子を表す。ハロゲン原子としては、好ましくは臭素又はヨウ素であり、さらに好ましくはヨウ素である。
【００２５】
Ｒ’は、アルキル基（炭素原子数１〜２０）、アリール基（炭素原子数６〜２０）、アシル基（炭素原子数２〜２０）、アルコキシ基（炭素原子数１〜２０）、アリールオキシ基（炭素原子数６〜２０）、シアノ基、アルコキシカルボニル基（炭素原子数２〜２０）、アリールオキシカルボニル基（炭素原子数７〜２０）、アシルオキシ基（炭素原子数２〜２０）、カルボキシ基、カルバモイル基 、ハロゲン原子、イミド基、アルキルチオ基（炭素原子数１〜２０）、アリールチオ基（炭素原子数６〜２０）、スルホ基、スルフィノ基、ホスフィノ基、ホスフィニル基、ホスホノ基又はシリル基を表す。特に、Ｒ’は、アリール基、シアノ基、アシル基、アルコキシカルボニル基が好ましく、そのような例として、具体的にフェニル基、シアノ基、アセチル基、プロピオニル基、エトキシカルボニル基が挙げられる。
【００２６】
Ｒは、水素原子、アルキル基（炭素原子数１〜２０）、アシル基（炭素原子数２〜２０）、アルコキシ基（炭素原子数１〜２０）、アシルオキシ基（炭素原子数２〜２０）、アリール基（炭素原子数６〜２０）、アリールオキシ基（炭素原子数６〜２０）、ハロゲン原子、ヒドロキシ基、ニトロ基、シアノ基、イミド基、アルコキシカルボニル基（炭素原子数２〜２０）、アリールオキシカルボニル基（炭素原子数７〜２０）、カルボキシル基、ホルミル基、アミノ基、カルバモイル基、メルカプト基、アルキルチオ基（炭素原子数１〜２０）、アリールチオ基（炭素原子数６〜２０）、スルホ基、スルフィノ基、ホスフィノ基、ホスフィニル基又はホスホノ基を表す。特に、Ｒは、水素原子、アルキル基、アルコキシ基、アシル基、ハロゲン原子、ニトロ基が好ましく、そのような例として、具体的に水素原子、メチル基、メトキシ基、アセチル基、臭素原子、塩素原子、ニトロ基が挙げられる。
【００２７】
Ｒは、ベンゼン環のどの位置に置換されても構わないが、好ましくは３位又は４位に、さらに好ましくは４位に置換される。またＲは、ベンゼン環に複数置換されても構わない。好ましくは一置換である。
【００２８】
上記に列挙したＲ及びＲ’は、さらに置換されてもよい。
【００２９】
本発明に従った芳香族化合物とオレフィンの反応は、温度２０〜２００℃、好ましくは６０〜１６０℃、さらに好ましくは８０〜１４０℃で行われる。
【００３０】
本発明の反応時間は、３０分〜４８時間、好ましくは１時間〜３６時間、さらに好ましくは６時間〜２４時間が好ましい。
【００３１】
反応中に生成してくる水素ハロゲン化物又はトリフルオロメタンスルホン酸は、反応の工程中に除去されるのが好ましい。この方法としては、塩基の添加によって中和するのが有利である。適当な塩基としては、第一級、第二級又は第三級アミン（例えば、トリエチルアミン）、およびカルボン酸のアルカリ金属またはアルカリ土類金属塩（例えば、ナトリウム、カリウム、及びマグネシウムの炭酸塩、炭酸水素塩または酢酸塩）が挙げられる。本発明において好ましい塩基は、トリエチルアミンである。
【００３２】
反応終了後、得られた反応生成物は、反応溶媒であるイオン性液体相に例えばヘキサン、ジエチルエーテルのような有機溶媒相を接触させ（この際、両者は相互作用溶解しない）、デカンテーションすることで溶媒相（ヘキサン相、ジエチルエーテル相）に反応生成物のみを抽出、分離することが可能である。
【００３３】
本発明に従った反応系において、遠心分離や濾過といった機械的な操作で容易にＰｄ／Ｃと溶媒を分離することが可能である。
【００３４】
反応終了後、濾過により分離回収したＰｄ／Ｃ触媒を繰り返し用いた場合も、活性の低下は見られなかった。従って、使用したＰｄ／Ｃ触媒を再使用することが可能である。
【００３５】
反応終了後、反応生成物抽出、イオン性液体から触媒の濾過による分離後、ＩＣＰ分光測定装置を用いてそのイオン性液体中のＰｄ濃度を分析した。また、基質を添加しないで、溶媒と触媒のみを同様の反応条件にさらしたものについても、同様の処理を行い、そのイオン性液体中のＰｄ濃度を分析した。その結果、イオン性液体にパラジウムが溶出していないことを確認した。従って、本発明に従った反応は、固液界面で進行する不均一反応であることがわかった。さらに、イオン性液体中にパラジウムが溶出しないことにより、イオン性液体の再生も容易である。
【００３６】
また、本発明に従った方法は、イオン性液体を用いることで、Ｐｄの金属表面上への塩類の堆積による活性低下現象が回避できることが明らかとなった。従ってイオン性液体を溶媒とすれば、担持金属触媒が使用可能となる。上述したようにＰｄ／Ｃ触媒は安価（有機パラジウム化合物の約１／１０程度の価格）で、しかも取扱いが容易であり、本発明によって触媒の再利用が可能であることが明らかなったので、ここで経済的なＨｅｃｋ反応の構築が可能となった。
【００３７】
本発明は、従来の有機パラジウム触媒を用いた場合とは異なり、Ｐｄ／Ｃ触媒を用いていることから溶媒と触媒の分離が容易であり、かつ触媒の再利用が可能で、また反応生成物の分離も容易で、有機化合物に汚染された水廃液が出ないなどの数多くの利点を有する。また、イオン性液体を用いていることから、担持金属化合物を利用することが可能となり、環境負荷も小さい。
【００３８】
従って、ここで初めて工業的・経済的に有利なＨｅｃｋ反応のプロセスを構築することができた。
【００３９】
本発明に従った製造方法は、医薬品等の各種物質の製造において、その製造過程中の一つの工程がＨｅｃｋ反応を使用している場合に、そこで本発明の反応と置き換えることが可能である。
【００４０】
本発明の方法は、医薬品、酵素機能抑制剤、農薬、香料、化粧用基剤（紫外線カット用化合物）、機能性ポリマー合成用原料（モノマー）のような物質を合成する際に、有用に使用され得る。医薬品としては、例として、タキソール（抗癌剤）、ネゾロシノール誘導体（鎮痒剤、防カビ剤、防腐剤）、スペローピペリジン誘導体（炎症、帯状疱疹後神経痛用治療薬）が挙げられる。化粧用基剤(紫外線カット剤）としては、桂皮酸エステル、機能性ポリマー合成用原料（モノマー）としては、例えば、アゼピン、ナフチリジン（含窒素芳香族化合物）が挙げられる。
【００４１】
以下の例を用いて、本発明の方法をさらに説明するが、本発明はこれら特定の例により限定されるものではない。
【００４２】
【実施例】
実施例１〜１５：
試験管中にて、１−ブチル−３−メチルイミダゾリウムヘキサフルオロリン酸塩１ｍｌ中に、ヨウ化ベンゼン２０４ｍｇ（１ｍｍｏｌ）及びアクリル酸エチル１０３μｌ（１．５ｍｍｏｌ）を添加し、窒素雰囲気下で攪拌した。そこに１０質量％Ｐｄ／Ｃ（３ｍｏｌ％）、トリエチルアミン２１０μｌ（１．５ｍｍｏｌ）を添加し、温度１００℃に加熱した。１２時間後、反応液を室温にまで冷却し、反応を停止させた。次に、反応液にヘキサン５ｍｌを接触させ、抽出、デカンテーションした。この抽出、デカンテーション操作を５回繰り返した。ヘキサンと目的物の分離は中圧液体クロマトグラフィ（シリカゲルカラム、溶媒；酢酸エチル：ｎ−ヘキサン＝１：４）で行い、目的物１５０ｍｇ（８５％）を得た。大量合成の場合は、蒸留等のそれ自体公知の方法により分離精製を行うことができる。得られた結果を下記表１に示す。
その他、ヨウ化アリール基質を種々変更させた結果も表１に示した。
【００４３】
【表１】

【００４４】
実施例１、実施例２、実施例６（ホスフィン添加）の結果から、本発明はホスフィン配位子が不要であることがわかった。
【００４５】
また、実施例４、実施例７〜１１の結果から、触媒を繰り返し（６回）用いた場合でも活性の低下は見られないことがわかる。
【００４６】
実施例１２（メチル基で置換）、実施例１３（メトキシ基で置換）、実施例１４（アセチル基で置換）、実施例１５（臭素基で置換）から分かるように、ベンゼン環が電子吸引性基や電子供与性で置換されていても反応は同様に進行する。
【００４７】
実施例１６〜１９：
ヨウ化ベンゼンの替わりに臭化ベンゼンを用い、温度１４０℃で反応させる以外は、実施例１〜１５と同様に反応、後処理、精製の操作を行った。得られた結果を下記表２に示す。その他、臭化アリール基質を変更させた結果も表２に示した。
【００４８】
【表２】

【００４９】
実施例２０〜２７
試験管中にて、１−ブチル−３−メチルイミダゾリウムヘキサフルオロリン酸塩１ｍＬ中に、ヨウ化ベンゼン２０４ｍｇ（１ｍｍｏｌ）及びアクリロニトリル１９８μｌ（３ｍｍｏｌ）を添加し、窒素雰囲気下にて攪拌した。そこに１０質量％Ｐｄ／Ｃ（３ｍｏｌ％）、トリエチルアミン２１０μｌ（１．５ｍｍｏｌ）を添加し、温度１００℃に加熱した。１２時間後、反応液を室温まで冷却し、反応を停止させた。次に、反応液にジエチルエーテル（５ｍｌ）を接触させ、抽出、デカンテーションした。この抽出、デカンテーション操作を７回繰り返した。ジエチルエーテルと目的物の分離は中圧液体クロマトグラフィ（シリカゲルカラム、溶媒；酢酸エチル：ｎ−ヘキサン＝１：２）で行い、目的物９７ｍｇ（７５％）を得た。大量合成の場合は、蒸留等のそれ自体公知の方法により分離精製を行うことができる。得られた結果を下記表３に示す。
その他、オレフィン基質として、スチレン、ビニルケトンを用いた場合についても、表３に結果を示した。
【００５０】
【表３】

【００５１】
その結果、本発明は、多様なオレフィンについて適用可能であることがわかった。
【００５２】
【発明の効果】
上記から明らかなように、本発明の方法は、下記のような特有の効果を奏する。
・生成物の分離に溶媒抽出方法が使える。
・イオン性液体が水に不溶であるため、生成物の分離が精製操作において有機物を微量溶解した水廃液がでない。
・毒性を有するホスフィン配位子が不要である。
・イオン性液体は非揮発性であり、水中に可溶に溶解しない。従って、環境への散逸（汚染）がない。
・副生成物であるハロゲン化物（塩）又はトリフルオロメタンスルホン酸塩は溶媒に可溶であるため、触媒表面上への析出がなく、触媒の寿命が長くなる。
・溶媒（イオン性液体）と触媒の分離が容易である。
・触媒と溶媒を単独に再利用することが可能である。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing an aromatic olefin by a Heck reaction using a reusable Pd / C catalyst in an ionic liquid having a small environmental load.
[0002]
[Prior art]
The reaction of forming a new CC bond by the reaction of an aryl halide or aryl trifluoromethanesulfonate with an olefin using a palladium catalyst is called the Heck reaction, and many researchers in the field of synthetic organic chemistry are still today. Basic and applied research is being conducted. Examples of similar reactions for forming a CC bond using a palladium catalyst include a Stille reaction and a Suzuki reaction. Each reaction has advantages and disadvantages, and the most suitable reaction is selected from the structure of the target product and restrictions on reaction conditions. Reactions for forming CC bonds are useful in the production of pharmaceuticals and the like, and industrialization of these reactions is desired.
[0003]
In the Stille reaction, a vinyltin compound is reacted, and a Pd-catalyzed reaction is performed after a substrate is once derived into a vinyltin compound. Organotin compounds have been shown to be toxic, and cannot be used in pharmaceutical production in practice.
[0004]
In the Suzuki reaction, an organic boron compound is reacted, and a Pd-catalyzed reaction is performed after a substrate is once derived into an organic boron compound. Since the use of organoboron compounds will also be prohibited in the future, it is becoming difficult to use the Suzuki reaction in pharmaceutical production.
[0005]
Therefore, the Heck reaction is useful as a reaction using a palladium catalyst, and is particularly applicable to a wide range. In the future, only the Heck reaction will survive in the production of pharmaceuticals and the like.
[0006]
In order to industrialize this Heck reaction, it is necessary to increase the economics of the process. In a reaction using an organic palladium compound as a catalyst in a general organic solvent, as the reaction proceeds, palladium precipitates as a metal, and becomes a state called palladium black, and the catalytic activity is lost. Therefore, the expensive organic palladium catalyst cannot be reused. Further, since a toxic phosphine ligand must be used to enhance the catalytic activity, there is a problem of environmental load. Furthermore, organic palladium has a drawback that it requires attention in handling due to its stability (chemical stability against air and moisture). Such a drawback has been a major problem when the Heck reaction is used industrially.
[0007]
Then, in order to solve the above-mentioned problems when the organic palladium catalyst is used, research on the Heck reaction using an ionic liquid instead of the organic solvent has already been performed. The use of ionic liquids is environmentally friendly because the use of organic solvents can be avoided, and ionic solvents have features not found in organic solvents, supercritical CO ₂ , and water, and are attracting attention as easy-to-use solvents .
[0008]
As the Heck reaction using an ionic liquid as a solvent, first, a Heck reaction using hexadecyltributylphosphonium bromide and tetraoctylammonium bromide as an ionic liquid, and using an aryl halide and butyl acrylate (DE Kaufmann) , M. Nouroozian, H. Henze SYNLETT, 1091-1092, 1996). In the Heck reaction, two kinds of organic palladium compounds and palladium chloride are used as catalysts, and triethylamine is added as a base. The product obtained by this reaction is extracted with dichloromethane by a liquid separation operation. Therefore, it is necessary to treat the waste water generated by washing after separation. This reaction indicated that no phosphine ligand was required. This article states that the reaction proceeded even after repeating the reaction several times, but does not show data such as the reaction rate. In this reaction system, it is difficult to separate the palladium compound from the ionic liquid, and the ionic liquid cannot be recovered.
[0009]
Second, a Heck reaction of an aryl halide or benzoic anhydride with an alkene (ethyl acrylate) using five kinds of ionic liquids can be mentioned (AJ Carmichael et al., Org. Lett., 1 (7), 997). ~ 1000, 1999). In this paper, the comparison of ionic liquids, the effects of additives, and the effects of bases were investigated. As a result, as ionic liquids, 1-butyl-3-methylimidazolium hexafluorophosphate ({bmin}) was used. {PF6}) gives the best results. If no phosphine ligand is added, the conversion will be low and the reaction temperature must be raised in order to obtain a high conversion. Further, the study on the reuse of the catalyst and the solvent has been carried out, and it is described that the activity is not reduced even after 6 repetitions (however, detailed data is not shown). In this reaction system, separation of the solvent and the catalyst is also difficult because the catalyst has solubility in the ionic liquid.
[0010]
Third, a Heck reaction using both an organic palladium complex synthesized independently and a commercially available organic palladium compound using eight kinds of ionic liquids as a catalyst (WA Herrmann, VPW Bohn, J. Orgametallic Chem.) ., 572, 141-145, 1999). Here, the optimum combination of the base, the additive, and the ionic liquid to be used is examined. The data show that the catalyst maintains high activity even when the solvent in which the catalyst is dissolved is used repeatedly eight times. This reaction system is a homogeneous system, and it is also difficult to separate the catalyst and the solvent.
[0011]
Fourth, a Heck reaction using Pd (OAc) ₂ as a catalyst using two types of ionic liquids is mentioned (L. Xu, W. Chen, J. Xiao Organometallics, 19, 1123-1127, 2000). Year). Here, it was proved that a carbene complex was formed by the reaction between Pd (OAc) ₂ and the ionic liquid (this functions as a catalyst). We are not considering catalyst reuse. This reaction system is also a homogeneous system, and it is difficult to separate the catalyst and the solvent.
[0012]
The above example showed that by using an ionic liquid as a solvent, an organic palladium metal catalyst + solvent could be reused. Thus, when an organic palladium compound is used as a catalyst using an ionic catalyst as a solvent, it is easy to separate the product from the mixed system of the solvent and the catalyst (easier than when an organic solvent is used, and a wastewater And the need for separation of salts is not required) .Also, there is the advantage that the solvent / catalyst mixture can be reused, but the solvent and catalyst are uniformly dissolved, and separation and purification of both are difficult. It is difficult to regenerate the catalyst alone.
[0013]
Therefore, in the Heck reaction in the ionic liquid, separation of the ionic liquid and the catalyst poses a problem. In the above examples, there is no example using a catalyst in which palladium is supported on a solid surface in an ionic liquid. Although research examples have been reported using supported metal catalysts such as Pd / C and Pd / Al ₂ O ₃ in organic solvents, it has been shown that the catalytic activity is generally lower than that of organic palladium compounds. Have been. In addition, when a supported metal catalyst is used, salts, which are by-products of the reaction, precipitate on the surface of the active site of the catalyst depending on the reaction system, the catalyst activity is rapidly reduced, and the catalyst is not reused.
[0014]
[Problems to be solved by the invention]
Therefore, in order to apply the Heck reaction in an ionic liquid to an actual industrial process, in the Heck reaction in an ionic liquid with a small environmental load, it is an issue to establish a reaction type in which the catalyst can be easily reused. ing.
[0015]
[Means for Solving the Problems]
The present invention uses an ionic liquid, which is expected as a new solvent in place of an organic solvent, as a solvent, and replaces the organic palladium compound generally used in the Heck reaction with a catalyst, and is easy and inexpensive to handle Pd / The above problem was solved by developing a Heck reaction using C.
[0016]
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, attention has been paid to Pd / C, which is inexpensive and easy to handle stably. That is, Pd / C, which is a supported metal catalyst in the form of solid fine particles in an ionic liquid, was able to show the catalytic activity against the Heck reaction for the first time in the world.
[0017]
One embodiment of the present invention is directed to a compound of the general formula I in the presence of a Pd / C catalyst in an ionic liquid:
Ar-H (I)
[Where,
Ar represents a substituted or unsubstituted aromatic compound,
X represents a trifluoromethanesulfonyloxy group or a halogen atom]
And a compound having the general formula II:
Embedded image

[Wherein R ′ is an alkyl group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, a cyano group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyloxy group, a carboxy group, a carbamoyl group , A halogen atom, an imide group, an alkylthio group, an arylthio group, a sulfo group, a sulfino group, a phosphino group, a phosphinyl group, a phosphono group or a silyl group]
With an olefin having the general formula III:
Embedded image

[Wherein, Ar and R ′ are the same as defined above]
Is a method for producing a compound having:
[0018]
Another embodiment of the present invention provides a method for preparing a compound of the general formula IV in the presence of a Pd / C catalyst in an ionic liquid:
Embedded image

[Where,
R represents a hydrogen atom, an alkyl group, an acyl group, an alkoxy group, an acyloxy group, an aryl group, an aryloxy group, a halogen atom, a hydroxy group, a nitro group, a cyano group, an imide group, an alkoxycarbonyl group, an aryloxycarbonyl group, a carboxyl group Group, formyl group, amino group, carbamoyl group, mercapto group, alkylthio group, arylthio group, sulfo group, sulfino group, phosphino group, phosphinyl group or phosphono group,
X represents a trifluoromethanesulfonyloxy group or a halogen atom]
And a compound having the general formula II:
Embedded image

[Wherein, R ′ is the same as defined above]
By reacting with an olefin having the general formula V:
Embedded image

[Wherein, R and R ′ are the same as defined above]
Is a method for producing a compound having:
[0019]
An ionic liquid is a liquid of a salt, a mixture of salts, or a mixture of components that form a salt, which can be melted at around room temperature. This term refers to a salt that melts at a relatively high temperature, for example, up to about 100 ° C. Can also be applied. General ionic liquids are characterized by having zero vapor pressure at room temperature, high dissolving power, and a wide liquid range (for example, on the order of 300 ° C.). Known ionic liquids include compounds such as ammonium salts having a halogen anion, hexafluorophosphate anion or tetrafluoroborate anion, phosphonium salts, N, N'-dialkylimidazolium salts or N-alkylpyridinium salts. For example, tetrabutylammonium bromide, hexadecyltributylphosphonium bromide, 1-butyl-3-methylimidazolium hexafluorophosphate, N-hexylpyridinium tetrafluoroborate, 1-ethyl-3-methylimidazolium chloride or N-butylpyridinium It is chloride. A preferred ionic liquid for use in the present invention is 1-butyl-3-methylimidazolium hexafluorophosphate having the following structural formula.
[0020]
Embedded image

[0021]
The Pd / C catalyst used in the present invention is, for example, 10% by mass of Pd / C (manufactured by Kawaken Fine Chemical Co., Ltd.). Pd / C catalysts are inexpensive, stable, easy to handle, and reusable, and are very useful in the present invention.
[0022]
The addition amount of the Pd / C catalyst is 0.05 mol% to 10 mol%, preferably 0.1 mol% to 8 mol%, more preferably 1 mol% to 5 mol%, based on the aryl halide or aryltrifluoromethanesulfonate.
[0023]
Ar represents a substituted or unsubstituted aromatic compound, and may be monocyclic or polycyclic. Further, it may be an unsaturated carbocyclic compound or a heterocyclic compound.
[0024]
X represents a trifluoromethanesulfonyloxy group or a halogen atom. The halogen atom is preferably bromine or iodine, and more preferably iodine.
[0025]
R 'represents an alkyl group (1 to 20 carbon atoms), an aryl group (6 to 20 carbon atoms), an acyl group (2 to 20 carbon atoms), an alkoxy group (1 to 20 carbon atoms), an aryloxy Group (C6-20), cyano group, alkoxycarbonyl group (C2-20), aryloxycarbonyl group (C7-20), acyloxy group (C2-20), carboxy Group, carbamoyl group , A halogen atom, an imide group, an alkylthio group (1 to 20 carbon atoms), an arylthio group (6 to 20 carbon atoms), a sulfo group, a sulfino group, a phosphino group, a phosphinyl group, a phosphono group or a silyl group. In particular, R ′ is preferably an aryl group, a cyano group, an acyl group, or an alkoxycarbonyl group, and specific examples thereof include a phenyl group, a cyano group, an acetyl group, a propionyl group, and an ethoxycarbonyl group.
[0026]
R represents a hydrogen atom, an alkyl group (1 to 20 carbon atoms), an acyl group (2 to 20 carbon atoms), an alkoxy group (1 to 20 carbon atoms), an acyloxy group (2 to 20 carbon atoms), An aryl group (6 to 20 carbon atoms), an aryloxy group (6 to 20 carbon atoms), a halogen atom, a hydroxy group, a nitro group, a cyano group, an imide group, an alkoxycarbonyl group (2 to 20 carbon atoms), Aryloxycarbonyl group (C7-20), carboxyl group, formyl group, amino group, carbamoyl group, mercapto group, alkylthio group (C1-20), arylthio group (C6-20), Represents a sulfo group, a sulfino group, a phosphino group, a phosphinyl group or a phosphono group. In particular, R is preferably a hydrogen atom, an alkyl group, an alkoxy group, an acyl group, a halogen atom, or a nitro group. Examples of such a group include a hydrogen atom, a methyl group, a methoxy group, an acetyl group, a bromine atom, and a chlorine atom. Atom and nitro group.
[0027]
R may be substituted at any position of the benzene ring, but is preferably substituted at the 3- or 4-position, more preferably at the 4-position. R may be substituted with a plurality of benzene rings. Preferably it is monosubstituted.
[0028]
R and R 'listed above may be further substituted.
[0029]
The reaction of the aromatic compound with the olefin according to the present invention is carried out at a temperature of from 20 to 200C, preferably from 60 to 160C, more preferably from 80 to 140C.
[0030]
The reaction time of the present invention is preferably 30 minutes to 48 hours, preferably 1 hour to 36 hours, more preferably 6 hours to 24 hours.
[0031]
The hydrogen halide or trifluoromethanesulfonic acid formed during the reaction is preferably removed during the reaction. As this method, it is advantageous to neutralize by adding a base. Suitable bases include primary, secondary or tertiary amines (eg, triethylamine), and alkali or alkaline earth metal salts of carboxylic acids (eg, sodium, potassium, and magnesium carbonates, carbonates Hydrogen salts or acetates). A preferred base in the present invention is triethylamine.
[0032]
After completion of the reaction, the obtained reaction product is decanted by bringing an organic solvent phase such as hexane or diethyl ether into contact with an ionic liquid phase as a reaction solvent (in this case, the two do not interact and dissolve). This makes it possible to extract and separate only the reaction product into the solvent phase (hexane phase, diethyl ether phase).
[0033]
In the reaction system according to the present invention, Pd / C and the solvent can be easily separated by a mechanical operation such as centrifugation or filtration.
[0034]
When the Pd / C catalyst separated and recovered by filtration after the reaction was used repeatedly, no decrease in the activity was observed. Therefore, it is possible to reuse the used Pd / C catalyst.
[0035]
After the completion of the reaction, the reaction product was extracted and the catalyst was separated from the ionic liquid by filtration, and the Pd concentration in the ionic liquid was analyzed using an ICP spectrometer. In addition, the same treatment was carried out for a sample in which only the solvent and the catalyst were exposed to the same reaction conditions without adding the substrate, and the Pd concentration in the ionic liquid was analyzed. As a result, it was confirmed that palladium was not eluted in the ionic liquid. Therefore, it was found that the reaction according to the present invention is a heterogeneous reaction that proceeds at the solid-liquid interface. Furthermore, since palladium does not elute in the ionic liquid, regeneration of the ionic liquid is also easy.
[0036]
In addition, it has been clarified that the method according to the present invention can avoid the phenomenon of activity reduction due to the deposition of salts on the metal surface of Pd by using an ionic liquid. Therefore, if the ionic liquid is used as the solvent, the supported metal catalyst can be used. As described above, the Pd / C catalyst is inexpensive (about 1/10 the price of an organic palladium compound), and is easy to handle, and it has been clarified that the catalyst can be reused by the present invention. This has made it possible to construct an economical Heck reaction.
[0037]
According to the present invention, unlike the case where a conventional organic palladium catalyst is used, the use of a Pd / C catalyst facilitates separation of the solvent and the catalyst, enables the catalyst to be reused, and has a reaction product. Has many advantages such as easy separation of water and no waste water contaminated with organic compounds. Further, since the ionic liquid is used, the supported metal compound can be used, and the environmental load is small.
[0038]
Therefore, the process of the Heck reaction, which is industrially and economically advantageous, could be constructed for the first time.
[0039]
The production method according to the present invention can be replaced with the reaction of the present invention when one step in the production process uses the Heck reaction in the production of various substances such as pharmaceuticals.
[0040]
INDUSTRIAL APPLICABILITY The method of the present invention is usefully used when synthesizing substances such as pharmaceuticals, enzyme function inhibitors, pesticides, fragrances, cosmetic bases (ultraviolet ray cut compounds), and raw materials (monomers) for synthesizing functional polymers. Can be done. Examples of the drug include taxol (an anticancer agent), a nezolocinol derivative (an antipruritic agent, an antifungal agent, an antiseptic), and a speropiperidine derivative (a therapeutic agent for inflammation and postherpetic neuralgia). Examples of the cosmetic base (ultraviolet ray cut agent) include cinnamic acid esters, and examples of the functional polymer synthesis raw materials (monomers) include azepine and naphthyridine (nitrogen-containing aromatic compounds).
[0041]
The following examples further illustrate the method of the present invention, but are not intended to limit the invention.
[0042]
【Example】
Examples 1 to 15:
In a test tube, 204 mg (1 mmol) of benzene iodide and 103 μl (1.5 mmol) of ethyl acrylate were added to 1 ml of 1-butyl-3-methylimidazolium hexafluorophosphate and stirred under a nitrogen atmosphere. did. Thereto were added 10% by mass Pd / C (3 mol%) and 210 μl (1.5 mmol) of triethylamine, and the mixture was heated to a temperature of 100 ° C. After 12 hours, the reaction was cooled to room temperature and the reaction was stopped. Next, 5 ml of hexane was brought into contact with the reaction solution, followed by extraction and decantation. This extraction and decantation operation was repeated five times. Separation of hexane and the desired product was carried out by medium pressure liquid chromatography (silica gel column, solvent; ethyl acetate: n-hexane = 1: 4) to obtain 150 mg (85%) of the desired product. In the case of mass synthesis, separation and purification can be performed by a method known per se such as distillation. The results obtained are shown in Table 1 below.
In addition, Table 1 also shows the results of various changes in the aryl iodide substrate.
[0043]
[Table 1]

[0044]
From the results of Examples 1, 2, and 6 (addition of phosphine), it was found that the present invention does not require a phosphine ligand.
[0045]
Further, from the results of Example 4 and Examples 7 to 11, it can be seen that even when the catalyst was used repeatedly (six times), no decrease in the activity was observed.
[0046]
As can be seen from Example 12 (substituted with a methyl group), Example 13 (substituted with a methoxy group), Example 14 (substituted with an acetyl group), and Example 15 (substituted with a bromine group), the benzene ring has an electron-withdrawing property. The reaction proceeds in the same manner even when substituted by a group or electron donating.
[0047]
Examples 16 to 19:
The operations of reaction, post-treatment and purification were performed in the same manner as in Examples 1 to 15, except that the reaction was carried out at a temperature of 140 ° C. using bromide benzene instead of iodide benzene. The results obtained are shown in Table 2 below. In addition, Table 2 also shows the results obtained by changing the aryl bromide substrate.
[0048]
[Table 2]

[0049]
Examples 20 to 27
In a test tube, 204 mg (1 mmol) of benzene iodide and 198 μl (3 mmol) of acrylonitrile were added to 1 mL of 1-butyl-3-methylimidazolium hexafluorophosphate and stirred under a nitrogen atmosphere. Thereto were added 10% by mass Pd / C (3 mol%) and 210 μl (1.5 mmol) of triethylamine, and the mixture was heated to a temperature of 100 ° C. After 12 hours, the reaction was cooled to room temperature to stop the reaction. Next, diethyl ether (5 ml) was brought into contact with the reaction solution, followed by extraction and decantation. This extraction and decantation operation was repeated seven times. Separation of diethyl ether and the desired product was carried out by medium pressure liquid chromatography (silica gel column, solvent; ethyl acetate: n-hexane = 1: 2) to obtain 97 mg (75%) of the desired product. In the case of mass synthesis, separation and purification can be performed by a method known per se such as distillation. The results obtained are shown in Table 3 below.
Table 3 also shows the results when styrene and vinyl ketone were used as olefin substrates.
[0050]
[Table 3]

[0051]
As a result, it was found that the present invention is applicable to various olefins.
[0052]
【The invention's effect】
As apparent from the above, the method of the present invention has the following specific effects.
-Solvent extraction can be used to separate products.
・ Since the ionic liquid is insoluble in water, there is no waste water in which a small amount of organic matter is dissolved in the purification operation to separate the product.
No need for toxic phosphine ligands.
-Ionic liquids are non-volatile and do not dissolve soluble in water. Therefore, there is no dissipation (contamination) to the environment.
The halide (salt) or trifluoromethanesulfonate as a by-product is soluble in the solvent, so that it does not deposit on the catalyst surface, and the catalyst life is extended.
・ Easy separation of solvent (ionic liquid) and catalyst.
-It is possible to reuse the catalyst and the solvent independently.

Claims (2)

In an ionic liquid, in the presence of a Pd / C catalyst, a compound of the general formula I:
Ar-X (I)
[Where,
Ar represents a substituted or unsubstituted aromatic compound,
X represents a trifluoromethanesulfonyloxy group or a halogen atom]
And a compound having the general formula II:

[Wherein R ′ is an alkyl group, an aryl group, an acyl group, an alkoxy group, an aryloxy group, a cyano group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyloxy group, a carboxy group, a carbamoyl group , A halogen atom, an imide group, an alkylthio group, an arylthio group, a sulfo group, a sulfino group, a phosphino group, a phosphinyl group, a phosphono group or a silyl group]
With an olefin having the general formula III:

[Wherein, Ar and R ′ are the same as defined above]
A method for producing a compound having the formula: In an ionic liquid, in the presence of a Pd / C catalyst, a compound of the general formula IV:

[Where,
R represents a hydrogen atom, an alkyl group, an acyl group, an alkoxy group, an acyloxy group, an aryl group, an aryloxy group, a halogen atom, a hydroxy group, a nitro group, a cyano group, an imide group, an alkoxycarbonyl group, an aryloxycarbonyl group, a carboxyl group Group, formyl group, amino group, carbamoyl group, mercapto group, alkylthio group, arylthio group, sulfo group, sulfino group, phosphino group, phosphinyl group or phosphono group,
X represents a trifluoromethanesulfonyloxy group or a halogen atom]
And a compound having the general formula II:

[Wherein, R ′ is the same as defined in claim 1]
By reacting with an olefin having the general formula V:

[Wherein, R and R ′ are the same as defined above]
A method for producing a compound having the formula: