JP4350281B2 - Process for producing phenylboronic acids and triphenylboroxines - Google Patents

Description

【０００８】
（式中、R¹は２位、３位、４位、5位または６位の置換基であり、水素原子、アルキル基、アルケニル基、アルコキシ基、ハロゲン原子を示す。ｎは１または２であり、n=2の場合、各R¹は同一でもあるいは異なってもよい。R²は、アルキル基、フェニル基を示す。Xは、塩素、臭素原子を示す。）
また、本発明は、下記式１で示されるフェニルグリニャール試薬と、非エーテル系芳香族溶剤に溶解された下記式２で示されるホウ酸エステルとを、−１０〜＋１５℃で反応させることにより、下記式３で示されるフェニルボロン酸類を生成させ、次いでこのフェニルボロン酸類を脱水することにより下記式４で示されるトリフェニルボロキシン類を得ることを特徴としている。
【０００９】
【化４】

【００１０】
（式中、R¹は２位、３位、４位、5位または６位の置換基であり、水素原子、アルキル基、アルケニル基、アルコキシ基、ハロゲン原子を示す。ｎは１または２であり、n=2の場合、各R¹は同一でもあるいは異なってもよい。R²は、アルキル基、フェニル基を示す。Xは、塩素、臭素原子を示す。）
また、本発明による製造方法において、前記非エーテル系芳香族溶剤が、トルエンまたはベンゼン、あるいはこれらの混合物であることが好ましい。
【００１１】
【発明の具体的説明】
本発明のフェニルボロン酸類およびトリフェニルボロキシン類の製造方法では、下記式１で示されるフェニルグリニャール試薬と、非エーテル系芳香族溶剤に溶解された下記式２で示されるホウ酸エステル（ボレート化合物）とを、−１０〜＋１５℃で反応させることにより下記式３で示されるフェニルボロン酸類を生成させるとともに、さらにこのフェニルボロン酸類を脱水することにより下記式４で示されるトリフェニルボロキシン類を得ている。
【００１２】
【化５】

【００１３】
（式中、R¹は２位、３位、４位、5位または６位の置換基であり、水素原子、アルキル基、アルケニル基、アルコキシ基、ハロゲン原子を示す。ｎは１または２であり、n=2の場合、各R¹は同一でもあるいは異なってもよい。R²は、アルキル基、フェニル基を示す。Xは、塩素、臭素原子を示す。）
なお、本発明においては、上記（３）と（４）をともに製造する場合に限られず、（１）と（２）から（３）のみを製造する態様、および（１）と（２）から（３）を製造してさらにこれを脱水して（４）のみを得る態様も包含される。
【００１４】
前記非エーテル系芳香族溶剤とは、エーテル結合を含まない芳香族溶剤を言い、ベンゼン又はトルエンのいずれか１種、またはベンゼンとトルエンの２種の混合溶剤が好ましく、特にトルエンが望ましい。
このように本発明においては、フェニルボロン酸類、さらにトリフェニルボロキシン類の合成において、溶解または希釈用の溶剤として非エーテル系溶剤のトルエンあるいはベンゼンなどを使用することにより、常温に近い−１０〜＋１５℃で反応させているにもかかわらず、予想外の高収率で上記目的化合物を得ている。式３で示されるフェニルボロン酸類のベンゼン環に結合する置換基の数および種類は，フェニルグリニャール試薬（１）のもととなるハロゲン化合物（５）においてその置換基の数および種類を選択することとなる。以下、本発明で用いられるフェニルグリニャール試薬（１）およびホウ酸エステル（２）、反応条件などについて、さらに具体的に説明する。
フェニルグリニャール試薬（１）
一般式１で示されるフェニルグリニャール試薬において、R¹は２位、３位、４位、5位または６位の置換基である。ｎは１または２であり、ｎ＝２の場合、各R¹は同一でもあるいは異なってもよい。R¹がアルキル基である場合は、炭素数が１〜１６、好ましくは１〜１０であることが望ましく、具体的にはメチル基、エチル基、ｎ−プロピル基、ｎ−ブチル基などが挙げられる。R¹がアルケニル基である場合には、炭素数が１〜１６、好ましくは１〜１０であることが望ましく、たとえば、エテニル基、プロペニル基、ブテニル基などが挙げられる。R¹がアルコキシ基である場合には、総炭素数が１〜１６、好ましくは１〜１０であることが望ましく、具体的にはメトキシ基、エトキシ基、ｎ−プロポキシ基、ｎ−ブトキシ基、ｔ−ブトキシ基などが挙げられる。R¹がハロゲン原子である場合には、具体的には、塩素、フッ素、臭素などが挙げられる。このようなフェニルグリニャール試薬(1)として、具体的には、フェニルマグネシウムブロミド、フェニルマグネシウムクロリド、４−メトキシフェニルマグネシウムクロリド、2，6−ジメチルフェニルマグネシウムブロミドなどを例示できる。
【００１５】
一般式１で表されるフェニルグリニャール試薬は、通常のグリニャール試薬と同様の調製法で得られるが、たとえば、活性化した金属マグネシウムを無水テトラヒドロフラン（THF）中で撹拌しつつ、前記一般式５で示されるハロゲン化合物を２０℃ないし溶剤の還流温度で滴下し、さらに１〜８時間撹拌することにより得られる。一般式５で示されるハロゲン化合物のハロゲンとしては、臭素が特に好ましいが、塩素でもよい。また、この時に使用される溶剤は、芳香族系溶剤との混合物であっても何ら差し支えない。
ホウ酸エステル（２）
一般式２で示されるホウ酸エステル、B(O R²)₃において、R²がアルキル基の場合には、炭素数が１〜１６、好ましくは１〜１０であることが望ましく、具体的にはメチル基、エチル基、ｎ−プロピル基、ｎ−ブチル基、ｎ−ペンチル基、ｎ−ヘキシル基などが挙げられる。このホウ酸エステル（２）は、たとえば、アルコールR²OHまたはナトリウムアルコキシドR²ONaとホウ酸または無水ホウ酸との反応により容易に合成できる。このようなホウ酸エステル(2)として、具体的には、トリメチルボレート、トリエチルボレート、トリブチルボレート、トリフェニルボレートなどが例示できる。
フェニルグリニャール試薬 (1) とホウ酸エステル (2) との反応
一般式１で表されるフェニルグリニャール試薬と、一般式２で表されるホウ酸エステルとの反応に際して、フェニルグリニャール試薬１モルに対して、ホウ酸エステルが0.1〜５モル、好ましくは0.8〜1.5モルの量を用いる。フェニルグリニャール試薬(1)とホウ酸エステル(2)とを交互に反応器中の冷却した溶剤に滴下するか、あるいは冷却したホウ酸エステル溶液にフェニルグリニャール試薬を滴下してもよい。
【００１６】
反応は溶剤中で、−10〜15℃、好ましくは、常圧下−10〜0℃の温度で、30分から30時間、好ましくは３時間から10時間撹拌することが望ましい。反応温度を上記範囲より低下させるとフェニルボロン酸類(3)またはトリフェニルボロキシン類(4)の反応収率は上がり、逆に上記範囲を超えて上昇させると反応の進行が早まるが、反面、副成物の生成が増加して収率低下が著しくなることから、反応温度の上限は１５℃以下にとどめるのが好ましい。
【００１７】
このような反応の際に、フェニルグリニャール試薬(1)と、ベンゼン、トルエンなどの非エーテル系芳香族溶剤により溶解または希釈したホウ酸エステル(2)とを反応させているため、反応収率は著しく上昇する。上記のような特定の溶剤の使用により予想外の高収率でフェニルボロン酸類(3)およびトリフェニルボロキシン類(4)を得られる点が本発明の最大の技術的特徴であり、本発明のように−10〜＋15℃で反応を行う場合に、エーテル系溶剤を含む他の溶剤を使用するとかかる高い収率を確保することはできない。すなわち、上記の溶解または希釈をたとえばエーテル、テトラヒドロフラン（THF）などのエーテル系溶剤で行うと、Organic Syntheses，Coll. Vol.IV, p68, John Wiley & Sons (1963)に記載されているように、反応温度が０〜15℃では、収率は49〜76％となってしまい、これより高収率で得ようとすれば、−60℃という極低温を終始維持して反応を行わなければならない。
【００１８】
本発明ではホウ酸エステル(2)を溶解または希釈する溶剤として、非エーテル系芳香族溶剤を使用するが、具体的な溶剤としては、トルエン、ベンゼン、キシレン、エチルベンゼンなどが例示さる。本発明では好ましくはトルエン、ベンゼンが用いられ、さらに好ましくはトルエンが用いられる。これらの溶剤を１種または、２種以上組合せて使用してもよい。これらの溶剤を使用すると、上記したように反応収率が著しく向上することに加えて、たとえばトルエン（引火点；4.4℃、沸点；110.6℃）を用いる場合には、低温引火性のエーテル（引火点；−４５℃、沸点；３５℃）よりもはるかに取り扱いやすく、しかもより安価に入手できる。トルエンの使用は溶剤として再利用の点でも問題がないため、特に大量の溶剤を使用するフェニルボロン酸類の工業的規模の生産において、決定的な利点となる。
【００１９】
反応収量に影響を与える他の要因として、撹拌効率があり、適切な撹拌機の選択により系全体の効率よい撹拌を実現することが望ましい。
上記のようにグリニャール試薬(1)とホウ酸エステル(2)とを反応させると、まず、（R¹）_nArB(OR²)₂（Ar:フェニル基）で示されるエステルが生成する。これを酸性条件下で、たとえば希硫酸などの希鉱酸により加水分解することにより容易にフェニルボロン酸類(3)が得られる。このフェニルボロン酸類を脱水すればトリフェニルボロキシン類(4)に変わる。たとえば、フェニルボロン酸類の反応液を濃縮したり、あるいは必要に応じて加熱脱水して無水物にすることで、あるいは共沸脱水を行うことで容易にトリフェニルボロキシン類となる。
【００２０】
このように、ホウ酸エステルをトルエンなどの非エーテル系芳香族溶剤で希釈することにより、従来技術よりはるかに常温に近い温度でも選択性よくフェニルボロン酸類(3)そしてトリフェニルボロキシン類(4)を高収率で合成することができる。
【００２１】
【発明の効果】
本発明の製造方法によれば、上記のように反応の高選択性と併せて、極低温下で反応を行わないために特殊な低温反応設備を必要とせず、また反応速度も上昇するので、従来技術の方法と比べて効率およびコスト面から格段の向上が可能である。
【００２２】
また、本発明の製造方法によれば、安価なトルエンなど非エーテル系芳香族溶剤を使用しており、低温引火性のエーテルを用いる場合と比較するとより安全性および取り扱いやすさに優れている。特に大量の溶剤を使用する工業的規模でフェニルボロン酸類およびトリフェニルボロキシン類の生産を行う場合には、エーテルから非エーテル系溶剤のトルエンなどへの変更を行うことは決定的に有利に作用する。
【００２３】
さらに、本発明の製造方法によれば、有用なフェニルボロン酸類およびトリフェニルボロキシン類の工業的生産の採算性を画期的に改善する。
【００２４】
【実施例】
以下、本発明によるフェニルボロン酸類およびトリフェニルボロキシンの製造方法について実施例によりさらに具体的に説明するが、本発明はこれら実施例に何ら限定されるものではない。
【００２５】
【実施例１】
フェニルボロン酸の合成
窒素置換した４つ口フラスコにマグネシウム７．３ｇを入れ、ＴＨＦ／トルエン（１／１）の混合溶剤１２５ｍｌで希釈したブロモベンゼン３９．３ｇを５０〜６０℃で４時間かけて滴下し、更に同温度で１時間熟成してフェニルマグネシウムブロミドを調製した。
【００２６】
窒素置換した別の４つ口フラスコにトリメチルボレート２６．０ｇとトルエン５０ｍｌを入れて混合し、予め０〜５℃に冷却しておいた。そこへ、先に調製したフェニルマグネシウムブロミドを０〜５℃で２時間かけて滴下し、更に同温度で１時間熟成した。熟成後、１０％硫酸水溶液１２８ｇを２０℃以下で滴下して注水分解を行なった。注水分解後１時間攪拌した。これを水層と有機層とに分液し、水層をトルエン５０ｍｌで抽出し、先に分液しておいた有機層に合わせた。この有機層を水２５ｇで２回水洗した。
【００２７】
得られた有機層に水２００ｍｌを加え減圧下に溶剤を半分程度留去し、更にヘプタン２００ｍｌを加えて氷水冷却下に攪拌し、結晶を十分に析出させた。これをろ過し、結晶をヘプタン１５０ｍｌで洗浄し、３０℃で乾燥させてフェニルボロン酸２１．９ｇを得た。
上記ろ液の溶剤を減圧下に半分程度留去し、ヘプタン５０ｍｌを加えて氷水冷却下攪拌し、結晶を十分に析出させた。これをろ過し、結晶をヘプタン５０ｍｌで洗浄し、３０℃で乾燥させてフェニルボロン酸３．９ｇを得た。合計２５．８ｇ
収率８４．６％
融点２１７．０〜２２０．０℃
【００２８】
【実施例２】
４−メチルフェニルボロン酸の合成
実施例１において、ブロモベンゼンのかわりに４−ブロモトルエンを用いた以外は実施例１と同様の操作を行い、４−メチルフェニルボロン酸を得た。
収率８３．９％
融点２４８〜２５０℃
【００２９】
【実施例３】
４−メトキシフェニルボロン酸の合成
実施例１においてブロモベンゼンのかわりに４−メトキシブロモベンゼンを用いた以外は実施例１と同様の操作を行い、４−メトキシフェニルボロン酸を得た。
収率８２．８％
融点２０４〜２０６℃
【００３０】
【実施例４】
４−クロロフェニルボロン酸の合成
実施例１においてブロモベンゼンのかわりに４−クロロブロモベンゼンを用いた以外は実施例１と同様の操作を行い４−クロロフェニルボロン酸を得た。
収率８２．１％
融点２８４〜２８９℃
【００３１】
【実施例５】
トリフェニルボロキシンの合成
窒素置換した４つ口フラスコにマグネシウム７．３ｇを入れ、ＴＨＦ／トルエン（１／１）の混合溶剤１２５ｍｌで希釈したブロモベンゼン３９．３ｇを５０〜６０℃で４時間かけて滴下し、更に同温度で１時間熟成してフェニルマグネシウムブロミドを調製した。
【００３２】
窒素置換した別の４つ口フラスコにトリメチルボレート２６．０ｇとトルエン５０ｍｌ入れて混合し、予め０〜５℃に冷却しておいた。そこへ、先に調製したフェニルマグネシウムブロミドを０〜５℃で２時間かけて滴下し、更に同温度で１時間熟成した。熟成後、１０％硫酸水溶液１２８ｇを２０℃以下の温度にて滴下して注水分解を行なった。注水分解後１時間攪拌した。これを水層と有機層とに分液し、水層をトルエン５０ｍｌで抽出し、先に分液しておいた有機層に合わせた。この有機層を水２５ｇで２回水洗した。
【００３３】
得られた有機層の溶剤を減圧下に留去し、粗トリフェニルボロキシン４９．８ｇを得た。そこへトルエン１５０ｍｌを加え５０℃の湯浴で結晶を溶解させ、更にヘプタン１５０ｍｌを加えて氷水冷却下に攪拌し、結晶を十分に析出させた。これをろ過し、結晶をヘプタン１５０ｍｌで洗浄し、８０℃で乾燥させてトリフェニルボロキシン１８．８ｇを得た。
【００３４】
上記ろ液の溶媒を減圧下に留去し、粗トリフェニルボロキシンを得た。そこへトルエン５０ｍｌを加え、加熱して結晶を溶解させた後、ヘプタン５０ｍｌを加えて氷水冷却下攪拌し、結晶を十分に析出させた。これをろ過し、結晶をヘプタン５０ｍｌで洗浄し８０℃で乾燥させてトリフェニルボロキシン３．０ｇを得た。合計２１．８ｇ
収率８３．９％
融点２１４．５〜２１６．０℃
【００３５】
【実施例６〜８】
実施例１において、表１に示すように反応温度を変えて反応させた以外は実施例１と同様の操作により、フェニルボロン酸を合成してその収率を求めた。
【００３６】
【実施例９】
２−メチルフェニルボロン酸の合成
実施例１において、ブロモベンゼンのかわりに２−ブロモトルエンを用いた以外は実施例1と同様の操作を行い、２−メチルフェニルボロン酸を得た。
収率 82.2%
融点 162〜164℃
【００３７】
【実施例１０】
３−メチルフェニルボロン酸の合成
実施例１において、ブロモベンゼンのかわりに３−ブロモトルエンを用いた以外は実施例1と同様の操作を行い、３−メチルフェニルボロン酸を得た。
収率 83.1%
融点 160〜162℃
【００３８】
【実施例１１】
２−メトキシフェニルボロン酸の合成
実施例１において、ブロモベンゼンのかわりに２−メトキシブロモベンゼンを用いた以外は実施例1と同様の操作を行い、２−メトキシフェニルボロン酸を得た。
収率 82.5%
融点 105〜110℃
【００３９】
【実施例１２】
3 −メトキシフェニルボロン酸の合成
実施例１において、ブロモベンゼンのかわりに３−メトキシブロモベンゼンを用いた以外は実施例1と同様の操作を行い、３−メトキシフェニルボロン酸を得た。
収率 83.4%
融点 160〜163℃
【００４０】
【比較例１】
フェニルボロン酸の合成
窒素置換した４つ口フラスコにマグネシウム７．３ｇを入れ、これにＴＨＦ１２５ｍｌで希釈したブロモベンゼン３７．３ｇを５０〜６０℃で４時間かけて滴下し、更に同温度で１時間熟成してフェニルマグネシウムブロミドを調製した。
【００４１】
窒素置換した別の４つ口フラスコにトリメチルボレート２６．０ｇとＴＨＦを５０ｍｌ秤取って入れ混合して、予め０〜５℃に冷却しておいた。そこへ、先に調製したフェニルマグネシウムブロミドを０〜５℃で２時間かけて滴下し、更に同温度で１時間熟成した。熟成後、１０％硫酸水溶液１２８ｇを２０℃以下で滴下して注水分解を行なった。注水分解後１時間攪拌した。これにトルエン１５０ｍｌを入れ攪拌後分液し、この有機層を水５０ｇで２回水洗した。
【００４２】
得られた有機層に水２００ｍｌを加え減圧下に溶媒を半分程度留去し、更にヘプタン２００ｍｌを加えて氷水冷却下に攪拌し、結晶を十分に析出させた。これをろ過し、結晶をヘプタン１００ｍｌで洗浄し、３０℃で乾燥させてフェニルボロン酸１３．４ｇを得た。
上記ろ液の溶媒を減圧下に半分程度留去し、ヘプタン５０ｍｌを加えて氷水冷却下攪拌し、結晶を十分に析出させた。これをろ過し、結晶をヘプタン５０ｍｌで洗浄し、３０℃で乾燥させてフェニルボロン酸１．５ｇを得た。合計１４．９ｇ
収率４８．９％
【００４３】
【比較例２】
フェニルボロン酸の合成
窒素置換した４つ口フラスコにマグネシウム７．３ｇを秤取って入れ、これにエーテル１２５ｍｌで希釈したブロモベンゼン３９．３ｇを３０〜４０℃で４時間かけて滴下し、更に同温度で１時間熟成してフェニルマグネシウムブロミドを調製した。
【００４４】
窒素置換した別の４つ口フラスコにトリメチルボレート２６．０ｇとエーテル５０ｍｌを秤取って入れ混合して、予め０〜５℃に冷却しておいた。そこへ、先に調製したフェニルマグネシウムブロミドを０〜５℃で２時間かけて滴下し、更に同温度で１時間熟成した。熟成後、１０％硫酸水溶液１２８ｇを２０℃以下で滴下して注水分解を行なった。注水分解後１時間攪拌した。これを水層と有機層に分液し、水層をエーテル５０ｍｌで抽出し、先に分液しておいた有機層に合わせた。この有機層を水２５ｇで２回水洗した。
【００４５】
得られた有機層に水２００ｍｌ加え減圧下に溶媒を半分程度留去し、更にヘプタン２００ｍｌを加えて氷水冷却下に攪拌し、結晶を十分に析出させた。これをろ過し、結晶をヘプタン１００ｍｌで洗浄し、３０℃で乾燥させてフェニルボロン酸１４．６ｇを得た。
上記ろ液の溶媒を減圧下に半分程度留去し、ヘプタン５０ｍｌを加えて氷水冷却下に攪拌し、結晶を十分に析出させた。これをろ過し、結晶をヘプタン５０ｍｌで洗浄し、３０℃で乾燥させてフェニルボロン酸１．６ｇを得た。合計１６．２ｇ
収率５３．１％
【００４６】
【比較例３】
４−メチルフェニルボロン酸の合成
比較例１において、ブロモベンゼンのかわりに４−ブロモトルエンを用いた以外は比較例１と同様の操作を行い、４−メチルフェニルボロン酸を得た。
収率４７．３％
実施例１〜４、６〜８および比較例１〜３の結果を表１に示す。なお、表１には、併せて文献、Organic Syntheses，Coll. Vol.IV, p68, John Wiley & Sons (1963)における記載例および国際公開公報特許WO9964428号の記載例も参考のために示した。
【００４７】
表１からわかるように本発明の製造方法に基づくと、ホウ酸エステルをトルエンなどの非エーテル系芳香族溶剤で溶解または希釈することにより、−１０〜＋１５℃の温度でフェニルボロン酸を７８％以上の収率で効率よく製造することができることがわかる。従来の方法では、これに匹敵する収率を得るためには、上記温度範囲よりも低い温度を必要とする。
【００４８】
【表１】

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing phenylboronic acids and triphenylboroxines. More specifically, the present invention relates to a method for producing a large amount of phenylboronic acids and triphenylboroxines useful as synthetic raw materials such as biphenyl compounds at low cost.
[0002]
TECHNICAL BACKGROUND OF THE INVENTION
Phenylboronic acids and triphenylboroxines are important compounds, for example, as starting materials for synthesizing various biphenyl compounds. As a method for synthesizing these compounds, a method described in Organic Syntheses, Coll. Vol. IV, p68, John Wiley & Sons (1963) is known. In the method described in this document, phenylboronic acid is obtained by reacting an alkyl borate with a phenyl Grignard reagent. However, this reaction has poor reaction selectivity and is easily influenced by temperature. That is, when the temperature is high, 2 or 3 equivalents of the phenyl Grignard reagent react with 1 equivalent of alkyl borate, resulting in the formation of diphenylborinic acid and triphenylborane. From this, in order to obtain phenylboronic acids with high selectivity, the reaction must be carried out in an ether solvent at a temperature of −60 ° C. or lower. However, enlarging the scale of the synthesis and carrying out it industrially at such a cryogenic temperature involves significant difficulties because it requires special equipment to maintain the cryogenic temperature during the reaction. Therefore, when producing phenylboronic acid and triphenylboroxine on an industrial scale, their profitability was not satisfactory.
[0003]
On the other hand, WO99 / 64428 discloses that phenyl Grignard reagent and alkyl borate are reacted at a ratio of 1: 1.5 in a tetrahydrofuran (THF) solvent which is an ether solvent at −10 to 0 ° C. Was obtained in a yield of 50-70%. However, this method has a problem that the production cost is increased due to excessive use of alkyl borate relative to the phenyl Grignard reagent, and there is still room for improvement in terms of yield.
[0004]
As a result of intensive studies to solve the above problems, the present inventors have surprisingly found that when a phenyl Grignard reagent is reacted with a boric acid ester dissolved in a non-ether aromatic solvent, −10 Even when the reaction was carried out at a temperature of ˜ + 15 ° C., the reaction proceeded with good selectivity, and it was found that phenylboronic acid and triphenylboroxine were obtained in extremely high yields, and the present invention was completed. In addition, special low temperature reaction equipment is not required for the reaction, and phenylboronic acids and triphenylboroxines can be easily produced at low cost industrially.
[0005]
OBJECT OF THE INVENTION
An object of the present invention is to provide a method for easily producing phenylboronic acids and triphenylboroxines at a high yield and at a low cost.
[0006]
Summary of the Invention
In the present invention, a phenyl Grignard reagent represented by the following formula 1 is reacted with a borate ester represented by the following formula 2 dissolved in a non-ether aromatic solvent at −10 to + 15 ° C. It is characterized in that phenylboronic acids represented by 3 are obtained.
[0007]
[Chemical 3]

[0008]
(In the formula, R ¹ is a substituent at the 2-position, 3-position, 4-position, 5-position or 6-position, and represents a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group or a halogen atom. N is 1 or 2. Yes, when n = 2, each R ¹ may be the same or different, R ² represents an alkyl group or a phenyl group, and X represents a chlorine or bromine atom.)
Further, the present invention comprises reacting a phenyl Grignard reagent represented by the following formula 1 with a boric acid ester represented by the following formula 2 dissolved in a non-ether aromatic solvent at −10 to + 15 ° C. It is characterized in that triphenylboroxins represented by the following formula 4 are obtained by producing phenylboronic acids represented by the following formula 3 and then dehydrating the phenylboronic acids.
[0009]
[Formula 4]

[0010]
(In the formula, R ¹ is a substituent at the 2-position, 3-position, 4-position, 5-position or 6-position, and represents a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group or a halogen atom. N is 1 or 2. Yes, when n = 2, each R ¹ may be the same or different, R ² represents an alkyl group or a phenyl group, and X represents a chlorine or bromine atom.)
In the production method according to the present invention, the non-ether aromatic solvent is preferably toluene, benzene, or a mixture thereof.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
In the method for producing phenylboronic acids and triphenylboroxines of the present invention, a phenyl Grignard reagent represented by the following formula 1 and a borate ester (borate compound) represented by the following formula 2 dissolved in a non-ether aromatic solvent ) At −10 to + 15 ° C. to produce phenylboronic acids represented by the following formula 3, and further dehydrating the phenylboronic acids to obtain triphenylboroxines represented by the following formula 4 It has gained.
[0012]
[Chemical formula 5]

[0013]
(In the formula, R ¹ is a substituent at the 2-position, 3-position, 4-position, 5-position or 6-position, and represents a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group or a halogen atom. N is 1 or 2. Yes, when n = 2, each R ¹ may be the same or different, R ² represents an alkyl group or a phenyl group, and X represents a chlorine or bromine atom.)
In addition, in this invention, it is not restricted to the case where both said (3) and (4) are manufactured, The aspect which manufactures only (3) from (1) and (2), and (1) and (2) An embodiment in which (3) is produced and further dehydrated to obtain only (4) is also included.
[0014]
The non-ether aromatic solvent refers to an aromatic solvent that does not contain an ether bond, and is preferably any one of benzene or toluene or a mixed solvent of two kinds of benzene and toluene, and particularly preferably toluene.
Thus, in the present invention, in the synthesis of phenylboronic acids, and further triphenylboroxines, by using a non-ether solvent such as toluene or benzene as a solvent for dissolution or dilution, the temperature is close to −10 to −10. Despite the reaction at + 15 ° C., the above-mentioned target compound was obtained in an unexpectedly high yield. The number and type of substituents bonded to the benzene ring of the phenylboronic acid represented by Formula 3 should be selected in the halogen compound (5) that is the basis of the phenyl Grignard reagent (1). It becomes. Hereinafter, the phenyl Grignard reagent (1) and borate ester (2) used in the present invention, reaction conditions, and the like will be described more specifically.
Phenyl Grignard reagent (1)
In the phenyl Grignard reagent represented by the general formula 1, R ¹ is a substituent at the 2-position, 3-position, 4-position, 5-position or 6-position. n is 1 or 2, and when n = 2, each R ¹ may be the same or different. When R ¹ is an alkyl group, the number of carbon atoms is preferably 1 to 16, and preferably 1 to 10, and specific examples include a methyl group, an ethyl group, an n-propyl group, and an n-butyl group. It is done. When R ¹ is an alkenyl group, it is desirable that the carbon number is 1 to 16, preferably 1 to 10, and examples thereof include an ethenyl group, a propenyl group, and a butenyl group. When R ¹ is an alkoxy group, the total number of carbon atoms is desirably 1 to 16, preferably 1 to 10, and specifically includes a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, Examples thereof include a t-butoxy group. When R ¹ is a halogen atom, specific examples include chlorine, fluorine, bromine and the like. Specific examples of the phenyl Grignard reagent (1) include phenyl magnesium bromide, phenyl magnesium chloride, 4-methoxyphenyl magnesium chloride, 2,6-dimethylphenyl magnesium bromide and the like.
[0015]
The phenyl Grignard reagent represented by the general formula 1 can be obtained by the same preparation method as the ordinary Grignard reagent. For example, while the activated metal magnesium is stirred in anhydrous tetrahydrofuran (THF), the general formula 5 The halogen compound shown can be added dropwise at 20 ° C. to the reflux temperature of the solvent and further stirred for 1 to 8 hours. The halogen of the halogen compound represented by the general formula 5 is particularly preferably bromine, but may be chlorine. Further, the solvent used at this time may be a mixture with an aromatic solvent.
Boric acid ester (2)
In the boric acid ester B (OR ² ) _{3 represented} by the general formula 2, when R ² is an alkyl group, it is desirable that the carbon number is 1 to 16, preferably 1 to 10, and specifically, Examples thereof include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, and an n-hexyl group. This boric acid ester (2) can be easily synthesized, for example, by reaction of alcohol R ² OH or sodium alkoxide R ² ONa with boric acid or boric anhydride. Specific examples of such boric acid ester (2) include trimethyl borate, triethyl borate, tributyl borate, triphenyl borate and the like.
Reaction of phenyl Grignard reagent (1) with borate ester (2) In the reaction of phenyl Grignard reagent represented by general formula 1 with borate ester represented by general formula 2, phenyl Grignard reagent An amount of 0.1 to 5 mol, preferably 0.8 to 1.5 mol, of boric acid ester is used per 1 mol. The phenyl Grignard reagent (1) and the boric acid ester (2) may be alternately dropped into the cooled solvent in the reactor, or the phenyl Grignard reagent may be dropped into the cooled boric acid ester solution.
[0016]
The reaction is desirably carried out in a solvent at −10 to 15 ° C., preferably at a temperature of −10 to 0 ° C. under normal pressure for 30 minutes to 30 hours, preferably 3 hours to 10 hours. When the reaction temperature is lowered from the above range, the reaction yield of the phenylboronic acid (3) or triphenylboroxine (4) increases, and conversely, when the reaction temperature is increased beyond the above range, the reaction progresses faster, Since the yield of by-products increases and the yield decreases remarkably, the upper limit of the reaction temperature is preferably limited to 15 ° C. or less.
[0017]
In such a reaction, since the phenyl Grignard reagent (1) is reacted with the boric acid ester (2) dissolved or diluted with a non-ether aromatic solvent such as benzene or toluene, the reaction yield is It rises remarkably. The most technical feature of the present invention is that phenylboronic acids (3) and triphenylboroxines (4) can be obtained in unexpectedly high yields by using the specific solvent as described above. When the reaction is performed at −10 to + 15 ° C. as described above, such a high yield cannot be ensured if other solvents including an ether solvent are used. That is, when the above dissolution or dilution is performed with an ether solvent such as ether or tetrahydrofuran (THF), as described in Organic Syntheses, Coll. Vol. IV, p68, John Wiley & Sons (1963), When the reaction temperature is 0 to 15 ° C., the yield is 49 to 76%, and if it is desired to obtain a higher yield than this, the reaction must be carried out while maintaining a very low temperature of −60 ° C. throughout. .
[0018]
In the present invention, a non-ether aromatic solvent is used as a solvent for dissolving or diluting the borate ester (2). Specific examples of the solvent include toluene, benzene, xylene, and ethylbenzene. In the present invention, toluene and benzene are preferably used, and toluene is more preferably used. These solvents may be used alone or in combination of two or more. When these solvents are used, the reaction yield is remarkably improved as described above. For example, when toluene (flash point: 4.4 ° C., boiling point: 110.6 ° C.) is used, a low-temperature flammable ether (flammable ether) is used. Point; −45 ° C., boiling point; 35 ° C.), which is much easier to handle and can be obtained at a lower cost. The use of toluene is not a problem in terms of reuse as a solvent, and is therefore a decisive advantage particularly in industrial scale production of phenylboronic acids using a large amount of solvent.
[0019]
Another factor affecting the reaction yield is the stirring efficiency, and it is desirable to achieve efficient stirring of the entire system by selecting an appropriate stirrer.
When the Grignard reagent (1) and the borate ester (2) are reacted as described above, first, an ester represented by (R ¹ ) _n ArB (OR ² ) ₂ (Ar: phenyl group) is generated. This is easily hydrolyzed with a dilute mineral acid such as dilute sulfuric acid to give the phenylboronic acid (3). If this phenylboronic acid is dehydrated, it is converted to triphenylboroxines (4). For example, triphenylboroxines can be easily obtained by concentrating the reaction solution of phenylboronic acids, or by dehydrating by heating to an anhydride as necessary, or by performing azeotropic dehydration.
[0020]
Thus, by diluting boric acid esters with non-ether aromatic solvents such as toluene, phenylboronic acids (3) and triphenylboroxines (4 ) Can be synthesized in high yield.
[0021]
【The invention's effect】
According to the production method of the present invention, in combination with the high selectivity of the reaction as described above, a special low-temperature reaction facility is not required because the reaction is not performed at an extremely low temperature, and the reaction rate is also increased. Compared with the prior art method, the efficiency and cost can be significantly improved.
[0022]
Further, according to the production method of the present invention, an inexpensive non-ether aromatic solvent such as toluene is used, which is superior in safety and ease of handling as compared with the case of using low-temperature flammable ether. In particular, when producing phenylboronic acids and triphenylboroxines on an industrial scale using a large amount of solvent, changing from ether to a non-ether solvent such as toluene is a decisive advantage. To do.
[0023]
Furthermore, according to the production method of the present invention, the profitability of industrial production of useful phenylboronic acids and triphenylboroxines is remarkably improved.
[0024]
【Example】
Hereinafter, the examples of the method for producing phenylboronic acids and triphenylboroxine according to the present invention will be described more specifically by way of examples. However, the present invention is not limited to these examples.
[0025]
[Example 1]
Synthesis of phenylboronic acid 7.3 g of magnesium was placed in a nitrogen-substituted four-necked flask, and 39.3 g of bromobenzene diluted with 125 ml of a THF / toluene (1/1) mixed solvent at 50 to 60C. The solution was added dropwise over 4 hours and further aged at the same temperature for 1 hour to prepare phenylmagnesium bromide.
[0026]
In another four-necked flask purged with nitrogen, 26.0 g of trimethylborate and 50 ml of toluene were added and mixed, and cooled to 0 to 5 ° C. in advance. Thereto, the previously prepared phenylmagnesium bromide was added dropwise at 0 to 5 ° C. over 2 hours, and further aged at the same temperature for 1 hour. After aging, 128 g of a 10% sulfuric acid aqueous solution was dropped at 20 ° C. or less to perform water injection decomposition. It stirred for 1 hour after water injection decomposition. This was separated into an aqueous layer and an organic layer, and the aqueous layer was extracted with 50 ml of toluene and combined with the previously separated organic layer. This organic layer was washed twice with 25 g of water.
[0027]
To the obtained organic layer, 200 ml of water was added and about half of the solvent was distilled off under reduced pressure. Further, 200 ml of heptane was added, and the mixture was stirred while cooling with ice water to sufficiently precipitate crystals. This was filtered, and the crystals were washed with 150 ml of heptane and dried at 30 ° C. to obtain 21.9 g of phenylboronic acid.
About half of the solvent in the filtrate was distilled off under reduced pressure, 50 ml of heptane was added, and the mixture was stirred while cooling with ice water to sufficiently precipitate crystals. This was filtered, and the crystals were washed with 50 ml of heptane and dried at 30 ° C. to obtain 3.9 g of phenylboronic acid. 25.8g in total
Yield 84.6%
Melting point 217.0-220.0 ° C.
[0028]
[Example 2]
Synthesis of 4-methylphenylboronic acid Example 1 was repeated except that 4-bromotoluene was used in place of bromobenzene to obtain 4-methylphenylboronic acid. .
Yield 83.9%
Melting point: 248-250 ° C
[0029]
[Example 3]
Synthesis of 4-methoxyphenylboronic acid The same operation as in Example 1 was carried out except that 4-methoxybromobenzene was used instead of bromobenzene in Example 1, to obtain 4-methoxyphenylboronic acid. .
Yield 82.8%
Melting point 204-206 ° C
[0030]
[Example 4]
Synthesis of 4-chlorophenylboronic acid The same operation as in Example 1 was performed except that 4-chlorobromobenzene was used instead of bromobenzene in Example 1, to obtain 4-chlorophenylboronic acid.
Yield 82.1%
Melting point 284-289 ° C
[0031]
[Example 5]
Synthesis of triphenylboroxine 7.3 g of magnesium was placed in a nitrogen-substituted four-necked flask, and 39.3 g of bromobenzene diluted with 125 ml of a THF / toluene (1/1) mixed solvent was added at 50 to 60C. Was added dropwise over 4 hours, and further aged at the same temperature for 1 hour to prepare phenylmagnesium bromide.
[0032]
In another four-necked flask purged with nitrogen, 26.0 g of trimethylborate and 50 ml of toluene were placed and mixed, and cooled to 0 to 5 ° C. in advance. Thereto, the previously prepared phenylmagnesium bromide was added dropwise at 0 to 5 ° C. over 2 hours, and further aged at the same temperature for 1 hour. After aging, 128 g of a 10% aqueous sulfuric acid solution was dropped at a temperature of 20 ° C. or less to perform water injection decomposition. It stirred for 1 hour after water injection decomposition. This was separated into an aqueous layer and an organic layer, and the aqueous layer was extracted with 50 ml of toluene and combined with the previously separated organic layer. This organic layer was washed twice with 25 g of water.
[0033]
The solvent of the obtained organic layer was distilled off under reduced pressure to obtain 49.8 g of crude triphenylboroxine. Thereto was added 150 ml of toluene, the crystals were dissolved in a 50 ° C. hot water bath, 150 ml of heptane was further added, and the mixture was stirred while cooling with ice water to sufficiently precipitate the crystals. This was filtered, and the crystals were washed with 150 ml of heptane and dried at 80 ° C. to obtain 18.8 g of triphenylboroxine.
[0034]
The solvent of the filtrate was distilled off under reduced pressure to obtain crude triphenylboroxine. 50 ml of toluene was added thereto and heated to dissolve the crystals, and then 50 ml of heptane was added and stirred under cooling with ice water to sufficiently precipitate the crystals. This was filtered, and the crystals were washed with 50 ml of heptane and dried at 80 ° C. to obtain 3.0 g of triphenylboroxine. Total 21.8g
Yield 83.9%
Mp 214.5-216.0 ° C
[0035]
Examples 6 to 8
In Example 1, phenylboronic acid was synthesized and the yield was determined by the same operation as in Example 1 except that the reaction was performed at a different reaction temperature as shown in Table 1.
[0036]
[Example 9]
Synthesis of 2-methylphenylboronic acid Example 1 was repeated except that 2-bromotoluene was used instead of bromobenzene to obtain 2-methylphenylboronic acid. .
Yield 82.2%
Melting point 162-164 ° C
[0037]
[Example 10]
Synthesis of 3-methylphenylboronic acid Example 1 was repeated except that 3-bromotoluene was used in place of bromobenzene to obtain 3-methylphenylboronic acid. .
Yield 83.1%
Melting point 160-162 ° C
[0038]
Example 11
Synthesis of 2-methoxyphenylboronic acid The same operation as in Example 1 was performed except that 2-methoxybromobenzene was used instead of bromobenzene in Example 1, to obtain 2-methoxyphenylboronic acid. It was.
Yield 82.5%
Melting point 105-110 ° C
[0039]
Example 12
3 - obtained in Synthesis <br/> Example 1 methoxyphenylboronic acid, following the procedure of Example 1 except for using 3-methoxy-bromobenzene instead of bromobenzene, 3-methoxyphenylboronic acid It was.
Yield 83.4%
Melting point 160-163 ° C
[0040]
[Comparative Example 1]
Synthesis of phenylboronic acid 7.3 g of magnesium was placed in a nitrogen-substituted four-necked flask, and 37.3 g of bromobenzene diluted with 125 ml of THF was added dropwise at 50-60 ° C. over 4 hours. After aging at temperature for 1 hour, phenylmagnesium bromide was prepared.
[0041]
In another four-necked flask purged with nitrogen, 26.0 g of trimethylborate and 50 ml of THF were weighed and mixed, and cooled in advance to 0 to 5 ° C. Thereto, the previously prepared phenylmagnesium bromide was added dropwise at 0 to 5 ° C. over 2 hours, and further aged at the same temperature for 1 hour. After aging, 128 g of a 10% sulfuric acid aqueous solution was dropped at 20 ° C. or less to perform water injection decomposition. It stirred for 1 hour after water injection decomposition. To this was added 150 ml of toluene, and the mixture was separated after stirring, and the organic layer was washed twice with 50 g of water.
[0042]
To the obtained organic layer, 200 ml of water was added and about half of the solvent was distilled off under reduced pressure. Further, 200 ml of heptane was added, and the mixture was stirred while cooling with ice water to sufficiently precipitate crystals. This was filtered, and the crystals were washed with 100 ml of heptane and dried at 30 ° C. to obtain 13.4 g of phenylboronic acid.
About half of the solvent in the filtrate was distilled off under reduced pressure, 50 ml of heptane was added, and the mixture was stirred while cooling with ice water to sufficiently precipitate crystals. This was filtered, and the crystals were washed with 50 ml of heptane and dried at 30 ° C. to obtain 1.5 g of phenylboronic acid. 14.9g in total
Yield 48.9%
[0043]
[Comparative Example 2]
Synthesis of phenylboronic acid 7.3 g of magnesium was weighed into a nitrogen-substituted four-necked flask, and 39.3 g of bromobenzene diluted with 125 ml of ether was added dropwise at 30 to 40 ° C. over 4 hours. The mixture was further aged at the same temperature for 1 hour to prepare phenylmagnesium bromide.
[0044]
In another four-necked flask purged with nitrogen, 26.0 g of trimethylborate and 50 ml of ether were weighed and mixed, and cooled in advance to 0 to 5 ° C. Thereto, the previously prepared phenylmagnesium bromide was added dropwise at 0 to 5 ° C. over 2 hours, and further aged at the same temperature for 1 hour. After aging, 128 g of a 10% sulfuric acid aqueous solution was dropped at 20 ° C. or less to perform water injection decomposition. It stirred for 1 hour after water injection decomposition. This was separated into an aqueous layer and an organic layer, and the aqueous layer was extracted with 50 ml of ether and combined with the previously separated organic layer. This organic layer was washed twice with 25 g of water.
[0045]
To the obtained organic layer, 200 ml of water was added and about half of the solvent was distilled off under reduced pressure. Further, 200 ml of heptane was added and stirred while cooling with ice water to sufficiently precipitate crystals. This was filtered, and the crystals were washed with 100 ml of heptane and dried at 30 ° C. to obtain 14.6 g of phenylboronic acid.
About half of the solvent in the filtrate was distilled off under reduced pressure, 50 ml of heptane was added, and the mixture was stirred while cooling with ice water to sufficiently precipitate crystals. This was filtered, and the crystals were washed with 50 ml of heptane and dried at 30 ° C. to obtain 1.6 g of phenylboronic acid. Total 16.2g
Yield 53.1%
[0046]
[Comparative Example 3]
Synthesis of 4-methylphenylboronic acid In Comparative Example 1, the same operation as in Comparative Example 1 was performed except that 4-bromotoluene was used instead of bromobenzene to obtain 4-methylphenylboronic acid. .
Yield 47.3%
Table 1 shows the results of Examples 1-4, 6-8, and Comparative Examples 1-3. Table 1 also shows a description example in the literature, Organic Syntheses, Coll. Vol. IV, p68, John Wiley & Sons (1963) and a description example in International Publication No. WO9964428 for reference.
[0047]
As can be seen from Table 1, according to the production method of the present invention, 78% phenylboronic acid was dissolved at a temperature of −10 to + 15 ° C. by dissolving or diluting the boric acid ester with a non-ether aromatic solvent such as toluene. It turns out that it can manufacture efficiently with the above yield. The conventional method requires a temperature lower than the above temperature range in order to obtain a yield comparable to this.
[0048]
[Table 1]

Claims (3)

A phenyl Grignard reagent represented by the following formula 1 is reacted with a boric acid ester represented by the following formula 2 dissolved in a non-ether aromatic solvent at −10 to + 15 ° C. The manufacturing method of phenyl boronic acid shown by these.

(In the formula, R ¹ is a substituent at the 2-position, 3-position, 4-position, 5-position or 6-position and represents a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group or a halogen atom. N is 1 or 2. Yes, when n = 2, each R ¹ may be the same or different, R ² represents an alkyl group or a phenyl group, and X represents a chlorine or bromine atom.) A phenyl Grignard reagent represented by the following formula 1 is reacted with a boric acid ester represented by the following formula 2 dissolved in a non-ether aromatic solvent at −10 to + 15 ° C. to give a phenyl represented by the following formula 3 A method for producing a triphenylboroxine represented by the following formula 4, characterized in that a boronic acid is produced and then the phenylboronic acid is dehydrated.

(In the formula, R ¹ is a substituent at the 2-position, 3-position, 4-position, 5-position or 6-position, and represents a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group or a halogen atom. N is 1 or 2. Yes, when n = 2, each R ¹ may be the same or different, R ² represents an alkyl group or a phenyl group, and X represents a chlorine or bromine atom.) The production method according to claim 1, wherein the non-ether aromatic solvent is toluene, benzene, or a mixture thereof.