JPH08231454A - Production of biphenyl compound - Google Patents
Production of biphenyl compoundInfo
- Publication number
- JPH08231454A JPH08231454A JP7256965A JP25696595A JPH08231454A JP H08231454 A JPH08231454 A JP H08231454A JP 7256965 A JP7256965 A JP 7256965A JP 25696595 A JP25696595 A JP 25696595A JP H08231454 A JPH08231454 A JP H08231454A
- Authority
- JP
- Japan
- Prior art keywords
- triphenylphosphine
- mol
- nickel
- general formula
- palladium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明はアミン化合物を反応
系に添加するビフェニル化合物の製造方法に関するもの
であり、より詳しくは、一般式1で示されるビフェニル
化合物の新規な製造方法である。TECHNICAL FIELD The present invention relates to a method for producing a biphenyl compound by adding an amine compound to a reaction system, and more particularly to a novel method for producing a biphenyl compound represented by the general formula 1.
【0002】[0002]
【従来の技術】本発明の目的物であるビフェニル化合物
は、高血圧症や心臓疾患などの心臓血管系の症候群の処
置および中枢神経系の疾患の処置等において有用である
アンギオテンシンII拮抗剤の重要中間体として使用する
ことができる。BACKGROUND OF THE INVENTION The biphenyl compound which is the object of the present invention is an important intermediate of angiotensin II antagonists which is useful in the treatment of cardiovascular syndromes such as hypertension and heart diseases and the treatment of central nervous system diseases. Can be used as a body.
【0003】従来の技術としては多くの文献、特許にお
いてビアリール誘導体の合成が試みられている。例えば
ジャーナルオブオーガニックケミストリィー(J. Org.
Chem.)1977年、42巻、1821頁ではハロゲン化アリール誘
導体としてフェニル亜鉛クロライドとp−ヨウ化アニソ
ールをNi(0)触媒存在下において反応させ、85%の
収率で非対称ビアリール体を得ている。As a conventional technique, synthesis of biaryl derivatives has been attempted in many documents and patents. For example, Journal of Organic Chemistry (J. Org.
Chem.) 1977, 42, 1821, phenylzinc chloride as a halogenated aryl derivative and p-iodinated anisole were reacted in the presence of a Ni (0) catalyst to obtain an asymmetric biaryl compound in a yield of 85%. There is.
【0004】その他多くの文献に関しても同様に原料の
ハロゲン化アリール誘導体のハロゲンは反応性の良い臭
素あるいはヨウ素であり、塩素での反応例は少ない。ま
た、特開平6-65153 号公報に記載された方法では、o−
ブロモベンゾニトリルとp−ブロモトルエンを原料と
し、59%の収率で目的物を得ている。しかし、原料のハ
ロゲン誘導体を塩素化物に変えた場合は未反応である。Similarly in many other documents, the halogen of the aryl halide derivative as the raw material is bromine or iodine having a high reactivity, and there are few reaction examples with chlorine. Further, in the method described in Japanese Patent Laid-Open No. 6-65153, o-
Using bromobenzonitrile and p-bromotoluene as raw materials, the target product is obtained with a yield of 59%. However, when the halogen derivative of the raw material is changed to a chlorinated product, no reaction occurs.
【0005】[0005]
【発明が解決しようとする課題】原料であるo−置換ハ
ロベンゼンのハロゲンが臭素やヨウ素の場合、比較的容
易にカップリング反応が進行するが、ハロゲンが塩素の
場合、反応は極めて低収率でしか進行しない。そこで本
発明では原料に価格の安い塩素誘導体を使用しても、高
収率で目的のクロスカップリング生成物を与える方法を
提供するものである。When the halogen of the raw material o-substituted halobenzene is bromine or iodine, the coupling reaction proceeds relatively easily, but when the halogen is chlorine, the reaction is extremely low in yield. Only progresses. Therefore, the present invention provides a method for providing a target cross-coupling product in high yield even when a low-priced chlorine derivative is used as a raw material.
【0006】[0006]
【課題を解決するための手段】本発明者らは、アミン化
合物を反応系へ添加することによって、o−置換ハロベ
ンゼンのハロゲンが反応性の低い塩素の場合であっても
臭素化物やヨウ素化物の場合と同様、目的のクロスカッ
プリング反応が短時間で飛躍的に進行することを発見し
た。Means for Solving the Problems By adding an amine compound to a reaction system, the inventors of the present invention have prepared a bromide or iodide compound even if the halogen of o-substituted halobenzene is chlorine having low reactivity. As in the case, it was discovered that the target cross-coupling reaction dramatically progressed in a short time.
【0007】即ち本発明は、エーテル系溶媒中、アミン
化合物の存在下、ハロゲン化亜鉛、一般式2で示される
p−トリルマグネシウムハライド、一般式3で示される
o−置換ハロベンゼンを用い、ニッケル(0)、ニッケ
ル(II)、パラジウム(0)あるいはパラジウム(II)
からなる群から選択された触媒存在下、一般式1で示さ
れるビフェニル化合物を高収率で製造する方法を提供す
るものである。 (式中、Aは炭素数3〜9のジアルコキシメチル基、炭
素数3〜5の飽和ジオキソ環基、あるいはシアノ基を表
し、X及びYは塩素あるいは臭素を表わす。)That is, the present invention uses a zinc halide, a p-tolylmagnesium halide represented by the general formula 2 and an o-substituted halobenzene represented by the general formula 3 in an ether solvent in the presence of an amine compound, and a nickel ( 0), nickel (II), palladium (0) or palladium (II)
The present invention provides a method for producing a biphenyl compound represented by the general formula 1 in high yield in the presence of a catalyst selected from the group consisting of: (In the formula, A represents a dialkoxymethyl group having 3 to 9 carbon atoms, a saturated dioxo ring group having 3 to 5 carbon atoms, or a cyano group, and X and Y represent chlorine or bromine.)
【0008】以下に本発明を詳細に説明する。本発明方
法の原料として使用する一般式2で示されるp−トリル
マグネシウムハライドは具体的にはp−トリルマグネシ
ウムクロライドあるいはp−トリルマグネシウムブロマ
イドである。The present invention will be described in detail below. The p-tolylmagnesium halide represented by the general formula 2 used as a raw material for the method of the present invention is specifically p-tolylmagnesium chloride or p-tolylmagnesium bromide.
【0009】また、もう一方の原料である一般式3のo
−置換ハロベンゼンは、置換基Yは塩素あるいは臭素で
あり、また置換基Aは炭素数3〜9のジアルコキシメチ
ル基、炭素数3〜5の飽和ジオキソ環基、あるいはシア
ノ基である。炭素数3〜9のジアルコキシメチル基の具
体例としてはジメトキシメチル基、ジエトキシメチル
基、ジブトキシメチル基等であり、炭素数3〜5の飽和
ジオキソ環基の具体例としては1−(2,5−ジオキソ
ラニル)基、1−(2,6−ジオキサニル)基等であ
る。なお、1−(2,5−ジオキソラニル)基、1−
(2,6−ジオキサニル)基の構造はそれぞれ以下のも
のである。 The other raw material, o of the general formula 3
In the -substituted halobenzene, the substituent Y is chlorine or bromine, and the substituent A is a dialkoxymethyl group having 3 to 9 carbon atoms, a saturated dioxo ring group having 3 to 5 carbon atoms, or a cyano group. Specific examples of the dialkoxymethyl group having 3 to 9 carbon atoms include dimethoxymethyl group, diethoxymethyl group and dibutoxymethyl group, and specific examples of the saturated dioxo ring group having 3 to 5 carbon atoms include 1- ( 2,5-dioxolanyl) group, 1- (2,6-dioxanyl) group and the like. In addition, 1- (2,5-dioxolanyl) group, 1-
The structures of the (2,6-dioxanyl) group are as follows.
【0010】一般式2で示される化合物は一般式3で示
されるo−置換ハロベンゼンに対してモル比で、 0.5〜
2.5、好ましくは 0.8〜 2.0を用いることができる。The compound represented by the general formula 2 has a molar ratio of 0.5 to the o-substituted halobenzene represented by the general formula 3.
2.5, preferably 0.8 to 2.0 can be used.
【0011】本発明方法において使用する触媒はニッケ
ル錯体化合物あるいはパラジウム錯体化合物を挙げるこ
とができる。具体的にいえば、ジクロロビス(トリフェ
ニルホスフィン)ニッケル(II)、ジブロモビス(トリ
フェニルホスフィン)ニッケル(II)、テトラキス(ト
リフェニルホスフィン)ニッケル(0)、ジクロロビス
(トリフェニルホスフィン)パラジウム(II)、ジブロ
モビス(トリフェニルホスフィン)パラジウム(II)、
テトラキス(トリフェニルホスフィン)パラジウム
(0)であり、好ましくはジクロロビス(トリフェニル
ホスフィン)ニッケル(II)である。また、該触媒の使
用量は式3で示されるo−置換ハロベンゼンに対してモ
ル比で、0.03〜0.20、好ましくは0.05〜0.15の範囲で使
用することができる。The catalyst used in the method of the present invention may be a nickel complex compound or a palladium complex compound. Specifically, dichlorobis (triphenylphosphine) nickel (II), dibromobis (triphenylphosphine) nickel (II), tetrakis (triphenylphosphine) nickel (0), dichlorobis (triphenylphosphine) palladium (II), Dibromobis (triphenylphosphine) palladium (II),
Tetrakis (triphenylphosphine) palladium (0), preferably dichlorobis (triphenylphosphine) nickel (II). The catalyst can be used in a molar ratio of 0.03 to 0.20, preferably 0.05 to 0.15 with respect to the o-substituted halobenzene represented by the formula 3.
【0012】さらに本発明方法においてアミンとして使
用するものは特に制限はないが、好ましくはN,N,
N′,N′−テトラメチルエチレンジアミン、N,N,
N′,N″,N″−ペンタメチルジエチレントリアミ
ン、N,N′−ジメチルピペラジン、1,4−ジアザビ
シクロ−[2,2,2]−オクタン等のポリアミン類、
N,N−ジメチルアニリン、トリエチルアミン、トリフ
ェニルアミン、トリ−n−オクチルアミン、トリイソオ
クチルアミン、トリス(2−エチルヘキシル)アミン等
の三級アミン類、ピリジン、ピコリン、ルチジン、o−
フェナントロリン、2,2′−ビピリジル等の芳香族性
アミン類であり、とくに好ましくはN,N,N′,N′
−テトラメチルエチレンジアミン、N,N,N′,
N″,N″−ペンタメチルジエチレントリアミンあるい
はN,N−ジメチルアニリンである。該アミン類の使用
量は原料であるo−置換ハロベンゼンに対してモル比で
0.3〜 3.0であり、好ましくは 0.9〜 2.5である。The amine used in the method of the present invention is not particularly limited, but preferably N, N,
N ', N'-tetramethylethylenediamine, N, N,
Polyamines such as N ′, N ″, N ″ -pentamethyldiethylenetriamine, N, N′-dimethylpiperazine, 1,4-diazabicyclo- [2,2,2] -octane,
Tertiary amines such as N, N-dimethylaniline, triethylamine, triphenylamine, tri-n-octylamine, triisooctylamine, tris (2-ethylhexyl) amine, pyridine, picoline, lutidine, o-
Aromatic amines such as phenanthroline and 2,2'-bipyridyl, particularly preferably N, N, N ', N'.
-Tetramethylethylenediamine, N, N, N ',
It is N ″, N ″ -pentamethyldiethylenetriamine or N, N-dimethylaniline. The amount of the amines used is molar ratio to the raw material o-substituted halobenzene.
It is 0.3 to 3.0, preferably 0.9 to 2.5.
【0013】本発明において使用するハロゲン化亜鉛は
具体的には塩化亜鉛あるいは臭化亜鉛であり、好ましく
は塩化亜鉛である。ハロゲン化亜鉛の使用量は上記アミ
ン化合物に対してモル比で 0.2〜 2.0であり、好ましく
は 0.5〜 1.8である。The zinc halide used in the present invention is specifically zinc chloride or zinc bromide, preferably zinc chloride. The zinc halide is used in a molar ratio of 0.2 to 2.0, preferably 0.5 to 1.8, based on the amine compound.
【0014】また、本発明方法において使用するエーテ
ル系溶媒としては具体的にはジエチルエーテル、ジプロ
ピルエーテル、ジイソプロピルエーテル、ジブチルエー
テル、ジイソアミルエーテル、1,2−ジメトキシエタ
ン、1,2−ジエトキシエタン、ジ−2−メトキシエチ
ルエーテル、テトラヒドロフラン、テトラヒドロピラ
ン、1,4−ジオキサンであり、好ましくはテトラヒド
ロフランである。また原料の一つであるp−トリルマグ
ネシウムハライドもこれらの溶媒の溶液として用いるこ
とが好ましく、濃度は5から50重量%である。Specific examples of the ether solvent used in the method of the present invention include diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, diisoamyl ether, 1,2-dimethoxyethane and 1,2-diethoxy. It is ethane, di-2-methoxyethyl ether, tetrahydrofuran, tetrahydropyran or 1,4-dioxane, preferably tetrahydrofuran. Further, p-tolylmagnesium halide, which is one of the raw materials, is also preferably used as a solution of these solvents, and the concentration thereof is 5 to 50% by weight.
【0015】本発明方法における反応温度範囲は−10〜
80℃の範囲であり、特に好ましくは30〜70℃である。The reaction temperature range in the method of the present invention is -10 to
The temperature is in the range of 80 ° C, particularly preferably 30 to 70 ° C.
【0016】以上の製造方法によって製造することがで
きるビフェニル化合物は具体的には4−メチル−2′−
[1−(2,5−ジオキソラニル)]ビフェニル、4−
メチル−2′−[1−(2,5−ジオキサニル)]ビフ
ェニル、4−メチル−2′−(ジメトキシメチル)ビフ
ェニル、4−メチル−2′−(ジエトキシメチル)ビフ
ェニル、4−メチル−2′−(ジプロポキシメチル)ビ
フェニル、4−メチル−2′−シアノビフェニル等を好
適なものとして挙げることができる。The biphenyl compound which can be produced by the above production method is specifically 4-methyl-2'-
[1- (2,5-dioxolanyl)] biphenyl, 4-
Methyl-2 '-[1- (2,5-dioxanyl)] biphenyl, 4-methyl-2'-(dimethoxymethyl) biphenyl, 4-methyl-2 '-(diethoxymethyl) biphenyl, 4-methyl-2 Preferred examples include ′-(dipropoxymethyl) biphenyl and 4-methyl-2′-cyanobiphenyl.
【0017】[0017]
【発明の効果】本発明方法はアミン化合物、ハロゲン化
亜鉛、及びニッケルあるいはパラジウム触媒の存在下、
一般式2で示されるp−トリマグネシウムハライドと一
般式3で示されるo−置換ハロベンゼンをクロスカップ
リングさせることにより一般式1で示されるビフェニル
化合物を製造するものである。通常、芳香族類のクロス
カップリング反応においては基質がクロロ化合物である
場合、収率が極めて低く、さらにホモカップリング生成
物が増加するため選択性も極めて低い。本発明方法にお
いてはアミン化合物を化学量論量用いることにより、基
質がクロロ化合物であっても高収率、高選択性を達成す
ることができた。このことはハロゲン化誘導体のなかで
も安価とされるクロロ化合物を使用して製造できるプロ
セスを提供するという点で工業的価値は甚大である。The method of the present invention is carried out in the presence of an amine compound, a zinc halide, and a nickel or palladium catalyst,
The biphenyl compound represented by the general formula 1 is produced by cross-coupling the p-trimagnesium halide represented by the general formula 2 and the o-substituted halobenzene represented by the general formula 3. Usually, in the cross-coupling reaction of aromatics, when the substrate is a chloro compound, the yield is extremely low, and the homocoupling product increases, so the selectivity is also extremely low. In the method of the present invention, by using a stoichiometric amount of the amine compound, it was possible to achieve high yield and high selectivity even if the substrate was a chloro compound. This is of great industrial value in that it provides a process that can be produced using a chloro compound, which is considered to be inexpensive among halogenated derivatives.
【0018】[0018]
【実施例】以下に実施例により本発明方法を具体的に説
明する。EXAMPLES The method of the present invention will be specifically described below with reference to examples.
【0019】(実施例1)300ml三口フラスコに窒素雰
囲気下、塩化亜鉛11.0g(0.08mol)、o−クロロ[1−
(2,5−ジオキソラニル)]ベンゼン 9.7g(0.05mo
l)およびジクロロビス(トリフェニルホスフィン)ニッ
ケル(II) 3.1g(0.005mol)を量り取り、50mlのテト
ラヒドロフランで溶解させた。溶解後、室温でN,N,
N′,N′−テトラメチルエチレンジアミン 9.8g(0.
07mol)を加えた。それから、50℃で30分間攪拌し、その
後、濃度20.6%のp−トリルマグネシウムクロライドの
テトラヒドロフラン溶液60g(0.083mol)を同温度で滴
下した。その後、50℃で2時間攪拌して、室温に戻した
後、2N−塩酸水溶液で加水分解した。有機層を分離し
た後、水層をヘキサンで抽出した。合わせた有機層を水
洗(2回)し、その有機層を無水硫酸マグネシウムで乾
燥した。その溶液を濃縮後、得られた茶色油状物をHP
LCにより測定した結果、4−メチル−2′−[1−
(2,5−ジオキソラニル)]ビフェニルが99%の収率
で得られた。このときのクロスカップリング選択率は90
%であった。Example 1 In a 300 ml three-necked flask, under nitrogen atmosphere, 11.0 g (0.08 mol) of zinc chloride and o-chloro [1-]
(2,5-Dioxolanyl)] benzene 9.7 g (0.05mo
l) and 3.1 g (0.005 mol) of dichlorobis (triphenylphosphine) nickel (II) were weighed and dissolved in 50 ml of tetrahydrofuran. After dissolution, N, N,
N ', N'-tetramethylethylenediamine 9.8 g (0.
07 mol) was added. Then, the mixture was stirred at 50 ° C. for 30 minutes, and then 60 g (0.083 mol) of a tetrahydrofuran solution of p-tolylmagnesium chloride having a concentration of 20.6% was added dropwise at the same temperature. Then, the mixture was stirred at 50 ° C for 2 hours, returned to room temperature, and then hydrolyzed with a 2N-hydrochloric acid aqueous solution. After separating the organic layer, the aqueous layer was extracted with hexane. The combined organic layers were washed with water (twice), and the organic layers were dried over anhydrous magnesium sulfate. After concentrating the solution, the resulting brown oily matter was added to HP.
As a result of measurement by LC, 4-methyl-2 '-[1-
(2,5-Dioxolanyl)] biphenyl was obtained with a yield of 99%. The cross-coupling selectivity at this time is 90.
%Met.
【0020】HPLC測定条件 定量法;ビフェニルを内部標準とした内部標準法 カラム;STR−ODSII 4.6mm*25cm 移動相;緩衝液(Na2 HPO4 inH2 O)/アセトニ
トリル、 検出器;UV(254nm)HPLC measurement conditions Quantitative method: Internal standard method using biphenyl as an internal standard Column: STR-ODSII 4.6 mm * 25 cm Mobile phase: Buffer (Na 2 HPO 4 inH 2 O) / acetonitrile, Detector: UV (254 nm )
【0021】(実施例2)100ml三口フラスコに窒素雰
囲気下、塩化亜鉛1.10g(0.008mol)、o−クロロ(ジ
メトキシメチル)ベンゼン0.98g(0.005mol)およびジ
クロロビス(トリフェニルホスフィン)ニッケル(II)
0.31g(0.5mmol)を量り取り、20mlのテトラヒドロフラ
ンで溶解させた。溶解後、室温でN,N,N′N′−テ
トラメチルエチレンジアミン0.98g(0.007mol)を加え
た。それから、50℃で30分間攪拌し、その後、濃度20.6
%のp−トリルマグネシウムクロライドのテトラヒドロ
フラン溶液 6.0g(0.008mol)を同温度で滴下した。そ
の後、50℃で2時間攪拌して、室温に戻した後、2N−
塩酸水溶液で加水分解した。有機層を分離した後、水層
をヘキサンで抽出した。合わせた有機層を水洗(2回)
し、その有機層を無水硫酸マグネシウムで乾燥した。そ
の溶液を濃縮後、得られた茶色油状物をHPLCにより
測定した結果、4−メチル−2′−(ジメトキシメチ
ル)ビフェニルが83%の収率で得られた。このときのク
ロスカップリング選択率は87%であった。Example 2 1.10 g (0.008 mol) of zinc chloride, 0.98 g (0.005 mol) of o-chloro (dimethoxymethyl) benzene and dichlorobis (triphenylphosphine) nickel (II) in a 100 ml three-necked flask under a nitrogen atmosphere.
0.31 g (0.5 mmol) was weighed out and dissolved in 20 ml of tetrahydrofuran. After the dissolution, 0.98 g (0.007 mol) of N, N, N'N'-tetramethylethylenediamine was added at room temperature. Then, the mixture was stirred at 50 ° C for 30 minutes, and then the concentration was adjusted to 20.6
6.0 g (0.008 mol) of a tetrahydrofuran solution of 10% p-tolylmagnesium chloride was added dropwise at the same temperature. Then, after stirring at 50 ° C for 2 hours and returning to room temperature, 2N-
It was hydrolyzed with an aqueous hydrochloric acid solution. After separating the organic layer, the aqueous layer was extracted with hexane. Wash the combined organic layers with water (twice)
The organic layer was dried over anhydrous magnesium sulfate. After the solution was concentrated, the obtained brown oily substance was measured by HPLC. As a result, 4-methyl-2 '-(dimethoxymethyl) biphenyl was obtained in a yield of 83%. The cross coupling selectivity at this time was 87%.
【0022】(実施例3)1000ml四口フラスコに窒素雰
囲気下、塩化亜鉛61.0g(0.44mol)、o−クロロベンゾ
ニトリル38.2g(0.28mol)およびジクロロビス(トリフ
ェニルホスフィン)ニッケル(II)18.4g(0.03mol)を
量り取り、 250mlのテトラヒドロフランで溶解させた。
溶解後、室温でN,N,N′N′−テトラメチルエチレ
ンジアミン52.2g(0.45mol)を加えた。このときの温度
は65℃まで上昇した。それから、50℃で30分間攪拌し、
その後、濃度20.6%のp−トリルマグネシウムクロライ
ドのテトラヒドロフラン溶液 325.6g(0.44mol)を同温
度で滴下した。その後、50℃で2時間攪拌して、室温に
戻した後、2N−塩酸水溶液 440mlで加水分解した。有
機層を分離した後、水層をヘキサン 300mlで抽出した。
合わせた有機層を水洗(200ml×2回)し、その有機層を
無水硫酸マグネシウムで乾燥した。その溶液を濃縮後、
得られた茶色油状物をHPLCにより測定した結果、4
−メチル−2′−シアノビフェニルが82.3%の収率で得
られた。このときのクロスカップリング選択率は91.2%
であった。さらにこの油状物をイソプロピルアルコール
とヘキサンより再結晶化の後、淡白色の4−メチル−
2′−シアノビフェニル38gを得た。これは71%の単離
収率に相当する。また、この際のHPLCによる純度測
定は99.1%であった。Example 3 In a 1000 ml four-necked flask, under nitrogen atmosphere, 61.0 g (0.44 mol) of zinc chloride, 38.2 g (0.28 mol) of o-chlorobenzonitrile and 18.4 g of dichlorobis (triphenylphosphine) nickel (II). (0.03 mol) was weighed out and dissolved in 250 ml of tetrahydrofuran.
After the dissolution, 52.2 g (0.45 mol) of N, N, N'N'-tetramethylethylenediamine was added at room temperature. The temperature at this time rose to 65 ° C. Then stir at 50 ° C for 30 minutes,
Thereafter, 325.6 g (0.44 mol) of a tetrahydrofuran solution of p-tolylmagnesium chloride having a concentration of 20.6% was added dropwise at the same temperature. Then, the mixture was stirred at 50 ° C. for 2 hours, returned to room temperature, and hydrolyzed with 440 ml of 2N-hydrochloric acid aqueous solution. After separating the organic layer, the aqueous layer was extracted with 300 ml of hexane.
The combined organic layers were washed with water (200 ml × 2 times), and the organic layers were dried over anhydrous magnesium sulfate. After concentrating the solution,
As a result of measuring the obtained brown oily substance by HPLC, 4
-Methyl-2'-cyanobiphenyl was obtained with a yield of 82.3%. The cross coupling selectivity at this time is 91.2%.
Met. Further, this oily substance was recrystallized from isopropyl alcohol and hexane, and then pale white 4-methyl-
38 g of 2'-cyanobiphenyl was obtained. This corresponds to an isolated yield of 71%. The purity measured by HPLC at this time was 99.1%.
【0023】(実施例4)100ml三口フラスコに窒素雰
囲気下、塩化亜鉛2.06g(0.015mol)、o−クロロベン
ゾニトリル1.30g(0.01mol)およびジクロロビス(トリ
フェニルホスフィン)ニッケル(II)0.62g(0.001mo
l)を量り取り、15mlのテトラヒドロフランで溶解させ
た。溶解後、室温でN,N,N′,N″,N″−ペンタ
メチルジエチレントリアミン2.66g(0.015mol)を加え
た。それから、50℃で30分間攪拌し、その後、濃度20.6
%のp−トリルマグネシウムクロライドのテトラヒドロ
フラン溶液11.0g(0.015mol)を同温度で滴下した。そ
の後、50℃で2時間攪拌して、室温に戻した後、2N−
塩酸水溶液30mlで加水分解した。有機層を分離した後、
水層をヘキサン15mlで抽出した。合わせた有機層を水洗
(20ml×2回)し、その有機層を無水硫酸マグネシウム
で乾燥した。その溶液を濃縮後、得られた茶色油状物を
HPLCにより測定した結果、4−メチル−2′−シア
ノビフェニルが81.0%の収率で得られた。このときのク
ロスカップリング選択率は88.7%であった。EXAMPLE 4 2.06 g (0.015 mol) of zinc chloride, 1.30 g (0.01 mol) of o-chlorobenzonitrile and 0.62 g of dichlorobis (triphenylphosphine) nickel (II) in a 100 ml three-necked flask under a nitrogen atmosphere. 0.001mo
l) was weighed out and dissolved in 15 ml of tetrahydrofuran. After dissolution, 2.66 g (0.015 mol) of N, N, N ', N ", N" -pentamethyldiethylenetriamine was added at room temperature. Then, the mixture was stirred at 50 ° C for 30 minutes, and then the concentration was adjusted to 20.6
11.0 g (0.015 mol) of a tetrahydrofuran solution of 100% p-tolylmagnesium chloride was added dropwise at the same temperature. Then, after stirring at 50 ° C for 2 hours and returning to room temperature, 2N-
It was hydrolyzed with 30 ml of an aqueous hydrochloric acid solution. After separating the organic layer,
The aqueous layer was extracted with 15 ml of hexane. The combined organic layer was washed with water (20 ml × 2 times), and the organic layer was dried over anhydrous magnesium sulfate. After the solution was concentrated, the obtained brown oily substance was measured by HPLC. As a result, 4-methyl-2'-cyanobiphenyl was obtained in a yield of 81.0%. The cross coupling selectivity at this time was 88.7%.
【0024】(実施例5)100ml三口フラスコに窒素雰
囲気下、塩化亜鉛3.02g(0.022mol)、o−クロロベン
ゾニトリル1.89g(0.014mol)およびジクロロビス(ト
リフェニルホスフィン)ニッケル(II)0.45g(0.001m
ol)を量り取り、15mlのテトラヒドロフランで溶解させ
た。溶解後、室温でトリエチルアミン2.38g(0.024mo
l)を加えた。それから、50℃で30分間攪拌し、その
後、濃度20.6%のp−トリルマグネシウムクロライドの
テトラヒドロフラン溶液16.1g(0.022mol)を同温度で
滴下した。その後、50℃で2時間攪拌して、室温に戻し
た後、2N−塩酸水溶液30mlで加水分解した。有機層を
分離した後、水層をヘキサン15mlで抽出した。合わせた
有機層を水洗(20ml×2回)し、その有機層を無水硫酸
マグネシウムで乾燥した。その溶液を濃縮後、得られた
茶色油状物をHPLCにより測定した結果、4−メチル
−2′−シアノビフェニルが66.4%の収率で得られた。
このときのクロスカップリング選択率は77.7%であっ
た。Example 5 In a 100 ml three-necked flask, under nitrogen atmosphere, 3.02 g (0.022 mol) of zinc chloride, 1.89 g (0.014 mol) of o-chlorobenzonitrile and 0.45 g of dichlorobis (triphenylphosphine) nickel (II) ( 0.001m
ol) was weighed and dissolved in 15 ml of tetrahydrofuran. After dissolution, at room temperature triethylamine 2.38g (0.024mo
l) was added. Then, the mixture was stirred at 50 ° C. for 30 minutes, and then 16.1 g (0.022 mol) of a tetrahydrofuran solution of p-tolylmagnesium chloride having a concentration of 20.6% was added dropwise at the same temperature. Then, the mixture was stirred at 50 ° C. for 2 hours, returned to room temperature, and hydrolyzed with 30 ml of 2N hydrochloric acid aqueous solution. After separating the organic layer, the aqueous layer was extracted with 15 ml of hexane. The combined organic layer was washed with water (20 ml × 2 times), and the organic layer was dried over anhydrous magnesium sulfate. After the solution was concentrated, the obtained brown oily substance was measured by HPLC. As a result, 4-methyl-2'-cyanobiphenyl was obtained in a yield of 66.4%.
The cross coupling selectivity at this time was 77.7%.
【0025】(実施例6)100ml三口フラスコに窒素雰
囲気下、塩化亜鉛2.36g(0.017mol)、o−クロロベン
ゾニトリル1.46g(0.011mol)およびジクロロビス(ト
リフェニルホスフィン)ニッケル(II)0.69g(0.001m
ol)を量り取り、15mlのテトラヒドロフランで溶解させ
た。溶解後、室温でN,N−ジメチルアニリン2.10g
(0.017mol)を加えた。それから、50℃で30分間攪拌
し、その後、濃度20.6%のp−トリルマグネシウムクロ
ライドのテトラヒドロフラン溶液12.4g(0.017mol)を
同温度で滴下した。その後、50℃で2時間攪拌して、室
温に戻した後、2N−塩酸水溶液30mlで加水分解した。
有機層を分離した後、水層をヘキサン15mlで抽出した。
合わせた有機層を水洗(20ml×2回)し、その有機層を
無水硫酸マグネシウムで乾燥した。その溶液を濃縮後、
得られた茶色油状物をHPLCにより測定した結果、4
−メチル−2′−シアノビフェニルが78.1%の収率で得
られた。このときのクロスカップリング選択率は84.9%
であった。Example 6 In a 100 ml three-necked flask under a nitrogen atmosphere, 2.36 g (0.017 mol) of zinc chloride, 1.46 g (0.011 mol) of o-chlorobenzonitrile and 0.69 g of dichlorobis (triphenylphosphine) nickel (II) (II). 0.001m
ol) was weighed and dissolved in 15 ml of tetrahydrofuran. 2.10 g of N, N-dimethylaniline at room temperature after dissolution
(0.017 mol) was added. Then, the mixture was stirred at 50 ° C. for 30 minutes, and then 12.4 g (0.017 mol) of a tetrahydrofuran solution of p-tolylmagnesium chloride having a concentration of 20.6% was added dropwise at the same temperature. Then, the mixture was stirred at 50 ° C. for 2 hours, returned to room temperature, and hydrolyzed with 30 ml of 2N hydrochloric acid aqueous solution.
After separating the organic layer, the aqueous layer was extracted with 15 ml of hexane.
The combined organic layer was washed with water (20 ml × 2 times), and the organic layer was dried over anhydrous magnesium sulfate. After concentrating the solution,
As a result of measuring the obtained brown oily substance by HPLC, 4
-Methyl-2'-cyanobiphenyl was obtained with a yield of 78.1%. Cross-coupling selectivity at this time is 84.9%
Met.
【0026】(実施例7)100ml三口フラスコに窒素雰
囲気下、塩化亜鉛2.62g(0.019mol)、o−クロロベン
ゾニトリル2.67g(0.01mol)およびジクロロビス(トリ
フェニルホスフィン)ニッケル(II)0.38g(0.001mo
l)を量り取り、10mlのテトラヒドロフランで溶解させ
た。溶解後、室温でピリジン1.62g(0.021mol)を加え
た。それから、50℃で30分間攪拌し、その後、濃度20.6
%のp−トリルマグネシウムクロライドのテトラヒドロ
フラン溶液14.3g(0.019mol)を同温度で滴下した。そ
の後、50℃で2時間攪拌して、室温に戻した後、2N−
塩酸水溶液30mlで加水分解した。有機層を分離した後、
水層をヘキサン15mlで抽出した。合わせた有機層を水洗
(20ml×2回)し、その有機層を無水硫酸マグネシウム
で乾燥した。その溶液を濃縮後、得られた茶色油状物を
HPLCにより測定した結果、4−メチル−2′−シア
ノビフェニルが67.5%の収率で得られた。このときのク
ロスカップリング選択率は82.0%であった。Example 7 In a 100 ml three-necked flask, under nitrogen atmosphere, 2.62 g (0.019 mol) of zinc chloride, 2.67 g (0.01 mol) of o-chlorobenzonitrile and 0.38 g of dichlorobis (triphenylphosphine) nickel (II) ( 0.001mo
l) was weighed out and dissolved in 10 ml of tetrahydrofuran. After the dissolution, 1.62 g (0.021 mol) of pyridine was added at room temperature. Then, the mixture was stirred at 50 ° C for 30 minutes, and then the concentration was adjusted to 20.6
% Of p-tolylmagnesium chloride in tetrahydrofuran solution 14.3 g (0.019 mol) was added dropwise at the same temperature. Then, after stirring at 50 ° C for 2 hours and returning to room temperature, 2N-
It was hydrolyzed with 30 ml of an aqueous hydrochloric acid solution. After separating the organic layer,
The aqueous layer was extracted with 15 ml of hexane. The combined organic layer was washed with water (20 ml × 2 times), and the organic layer was dried over anhydrous magnesium sulfate. After the solution was concentrated, the obtained brown oily substance was measured by HPLC. As a result, 4-methyl-2'-cyanobiphenyl was obtained in a yield of 67.5%. The cross coupling selectivity at this time was 82.0%.
【0027】(比較例1)100ml三口フラスコに窒素雰
囲気下、塩化亜鉛0.98g(0.007mol)、o−クロロ[1
−(2,5−ジオキソラニル)]ベンゼン1.29g(0.00
7mol)およびジクロロビス(トリフェニルホスフィン)
ニッケル(II)0.17g(0.3mmol)を量り取り、10mlのテ
トラヒドロフランで溶解させた。溶解後、50℃で30分間
攪拌し、その後、濃度20.6%のp−トリルマグネシウム
クロライドのテトラヒドロフラン溶液5.69g(0.008mo
l)を同温度で滴下した。その後、50℃で2時間攪拌し
て、室温に戻した後、2N−塩酸水溶液で加水分解し
た。有機層を分離した後、水層をヘキサンで抽出した。
合わせた有機層を水洗(2回)し、その有機層を無水硫
酸マグネシウムで乾燥した。その溶液を濃縮後、得られ
た茶色油状物をHPLCにより測定した結果、4−メチ
ル−2′−[1−(2,5−ジオキソラニル)]ビフェ
ニルが32.0%の収率で得られた。このときのクロスカッ
プリング選択率は70.0%であった。Comparative Example 1 0.98 g (0.007 mol) of zinc chloride and o-chloro [1] were placed in a 100 ml three-necked flask under a nitrogen atmosphere.
-(2,5-Dioxolanyl)] benzene 1.29 g (0.00
7mol) and dichlorobis (triphenylphosphine)
0.17 g (0.3 mmol) of nickel (II) was weighed out and dissolved in 10 ml of tetrahydrofuran. After dissolution, the mixture was stirred at 50 ° C. for 30 minutes, and then 5.69 g (0.008 mol) of a tetrahydrofuran solution of p-tolylmagnesium chloride having a concentration of 20.6%
l) was added dropwise at the same temperature. Then, the mixture was stirred at 50 ° C for 2 hours, returned to room temperature, and then hydrolyzed with a 2N-hydrochloric acid aqueous solution. After separating the organic layer, the aqueous layer was extracted with hexane.
The combined organic layers were washed with water (twice), and the organic layers were dried over anhydrous magnesium sulfate. After the solution was concentrated, the brown oil obtained was measured by HPLC. As a result, 4-methyl-2 ′-[1- (2,5-dioxolanyl)] biphenyl was obtained in a yield of 32.0%. The cross coupling selectivity at this time was 70.0%.
【0028】(比較例2)100ml三口フラスコに窒素雰
囲気下、塩化亜鉛0.98g(0.007mol)、o−クロロベン
ゾニトリル1.00g(0.007mol)およびジクロロビス(ト
リフェニルホスフィン)ニッケル(II)0.17g(0.3mmo
l)を量り取り、10mlのテトラヒドロフランで溶解させ
た。溶解後、50℃で30分間攪拌し、その後、濃度20.6%
のp−トリルマグネシウムクロライドのテトラヒドロフ
ラン溶液5.69g(0.008mol)を同温度で滴下した。その
後、50℃で2時間攪拌して、室温に戻した後、2N−塩
酸水溶液30mlで加水分解した。有機層を分離した後、水
層をヘキサン15mlで抽出した。合わせた有機層を水洗
(20ml×2回)し、その有機層を無水硫酸マグネシウム
で乾燥した。その溶液を濃縮後、得られた茶色油状物を
HPLCにより測定した結果、4−メチル−2′−シア
ノビフェニルが38.0%の収率で得られた。このときのク
ロスカップリング選択率は73.0%であった。(Comparative Example 2) 0.98 g (0.007 mol) of zinc chloride, 1.00 g (0.007 mol) of o-chlorobenzonitrile and 0.17 g of dichlorobis (triphenylphosphine) nickel (II) in a 100 ml three-necked flask under a nitrogen atmosphere. 0.3mmo
l) was weighed out and dissolved in 10 ml of tetrahydrofuran. After dissolution, stir at 50 ° C for 30 minutes, then concentration 20.6%
5.69 g (0.008 mol) of a tetrahydrofuran solution of p-tolylmagnesium chloride of was added dropwise at the same temperature. Then, the mixture was stirred at 50 ° C. for 2 hours, returned to room temperature, and hydrolyzed with 30 ml of 2N hydrochloric acid aqueous solution. After separating the organic layer, the aqueous layer was extracted with 15 ml of hexane. The combined organic layer was washed with water (20 ml × 2 times), and the organic layer was dried over anhydrous magnesium sulfate. After the solution was concentrated, the obtained brown oily substance was measured by HPLC. As a result, 4-methyl-2'-cyanobiphenyl was obtained in a yield of 38.0%. The cross coupling selectivity at this time was 73.0%.
フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 FI 技術表示箇所 C07D 317/14 C07D 317/14 319/06 319/06 // C07B 61/00 300 C07B 61/00 300 Continuation of front page (51) Int.Cl. 6 Identification number Office reference number FI Technical display location C07D 317/14 C07D 317/14 319/06 319/06 // C07B 61/00 300 C07B 61/00 300
Claims (6)
下、ハロゲン化亜鉛、一般式2で示されるp−トリルマ
グネシウムハライド、一般式3で示されるo−置換ハロ
ベンゼンを用い、ニッケル(0)、ニッケル(II)、パ
ラジウム(0)あるいはパラジウム(II)からなる群か
ら選択された触媒存在下、一般式1で示されるビフェニ
ル化合物を製造する方法。 (式中、Aは炭素数3〜9のジアルコキシメチル基、炭
素数3〜5の飽和ジオキソ環基、あるいはシアノ基を表
し、X及びYは塩素あるいは臭素を表わす。)1. In an ether solvent, in the presence of an amine compound, zinc halide, p-tolylmagnesium halide represented by the general formula 2 and o-substituted halobenzene represented by the general formula 3 are used, and nickel (0), A method for producing a biphenyl compound represented by the general formula 1 in the presence of a catalyst selected from the group consisting of nickel (II), palladium (0) and palladium (II). (In the formula, A represents a dialkoxymethyl group having 3 to 9 carbon atoms, a saturated dioxo ring group having 3 to 5 carbon atoms, or a cyano group, and X and Y represent chlorine or bromine.)
トラメチルエチレンジアミン、N,N,N′,N″,
N″−ペンタメチルジエチレントリアミン、N,N′−
ジメチルピペラジン、1,4−ジアザビシクロ−[2,
2,2]−オクタン等のポリアミン類、N,N−ジメチ
ルアニリン、トリエチルアミン、トリフェニルアミン、
トリ−n−オクチルアミン、トリイソオクチルアミン、
トリス(2−エチルヘキシル)アミン等の三級アミン
類、ピリジン、ピコリン、ルチジン、o−フェナントロ
リン、2,2′−ビピリジル等の芳香族性アミン類であ
る、請求項1記載の方法。2. The amine compound is N, N, N ′, N′-tetramethylethylenediamine, N, N, N ′, N ″,
N "-pentamethyldiethylenetriamine, N, N'-
Dimethylpiperazine, 1,4-diazabicyclo- [2,
2,2] -octane and other polyamines, N, N-dimethylaniline, triethylamine, triphenylamine,
Tri-n-octylamine, triisooctylamine,
The method according to claim 1, which is a tertiary amine such as tris (2-ethylhexyl) amine, or an aromatic amine such as pyridine, picoline, lutidine, o-phenanthroline, or 2,2′-bipyridyl.
合物 0.2〜 2.0モルを用いる請求項2記載の方法。3. The method according to claim 2, wherein 0.2 to 2.0 mol of the amine compound is used per mol of the zinc halide.
フィン)ニッケル(II)、ジブロモビス(トリフェニル
ホスフィン)ニッケル(II)、テトラキス(トリフェニ
ルホスフィン)ニッケル(0)、ジクロロビス(トリフ
ェニルホスフィン)パラジウム(II)、ジブロモビス
(トリフェニルホスフィン)パラジウム(II)、テトラ
キス(トリフェニルホスフィン)パラジウム(0)であ
り、一般式3で示されるo−置換ハロベンゼン1モル当
たり、触媒を0.03〜0.20モル用いる請求項1〜3までの
いずれか1項記載の方法。4. The catalyst is dichlorobis (triphenylphosphine) nickel (II), dibromobis (triphenylphosphine) nickel (II), tetrakis (triphenylphosphine) nickel (0), dichlorobis (triphenylphosphine) palladium (II). , Dibromobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and 0.03 to 0.20 mol of the catalyst is used per mol of the o-substituted halobenzene represented by the general formula 3. The method according to any one of 3 to 3.
ン1モル当たり、一般式2で示される化合物 0.5〜 2.5
モルを用いる、請求項1〜4までのいずれか1項記載の
方法。5. The compound represented by the general formula 2 in an amount of 0.5 to 2.5 per mol of the o-substituted halobenzene represented by the general formula 3.
The method according to any one of claims 1 to 4, wherein moles are used.
請求項1〜5のいずれか1項記載の方法。6. The reaction temperature is -10 to 80 ° C.,
The method according to any one of claims 1 to 5.
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Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
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