JP4839678B2 - Method for producing dihalogenated biaryl derivative - Google Patents

Description

  The present invention relates to a method for producing a dihalogenated biaryl derivative useful as an electronic material or an intermediate for medical and agricultural chemicals.

  Although there are few reports on the production methods of dihalogenated biaryl derivatives, the following are known. For example, the product obtained by treating o-dibromobenzene with 0.5 equivalent of n-butyllithium is recrystallized with ethanol to obtain 2,2′-dibromobiphenyl in 74% yield ( Non-patent document 1). Similarly, the product obtained by treating 2,3-dibromonaphthalene with 0.5 equivalent of n-butyllithium was subjected to column chromatography with a solvent of hexane and benzene 4 to 1 in a yield of 60%. , 3′-dibromo-2,2′-binaphthyl has been obtained (see Non-Patent Document 2 or 3). Recently, a product obtained by treating 2,3-dibromonaphthalene with 0.55 equivalents of n-butyllithium was recrystallized with a mixed solvent of benzene and ethanol to yield 3, 79% yield. A method for obtaining 3′-dibromo-2,2′-binaphthyl has been reported (see Non-Patent Document 3). However, the above-described method using a lithiating agent is suitable for producing a bilaterally symmetric compound. However, when a bilaterally asymmetric compound is to be obtained, a mixture of a plurality of products is obtained and the selectivity and yield are reduced. The rate is greatly reduced. Also in the purification, the column chromatography method is inefficient when a large amount of solvent is used and the used solvent needs to be concentrated again, and purification is performed in large amounts. . Furthermore, the yield tends to decrease due to loss due to adsorption into the column. On the other hand, in the case of recrystallization, since the selection of the solvent affects the yield and purity, the selection of the solvent is important. Non-Patent Document 3 has obtained the target product with a good yield of 79%, but benzene used as a recrystallization solvent is designated as a specific chemical substance and is harmful to the human body. There is a problem in safety and safety.

“Journal of Organic Chemistry” (USA), 1957, pp. 447-449. Tetrahedron Letters (USA), 1998, pages 5393-5396 "Journal of Chemical Society Parkin Transaction I" (UK), 2001, pp. 159-165 "Bretin Chemical Society of Japan" (Japan), 78, 2005, 142-146

  Accordingly, in view of the above-described problems of the prior art, an object of the present invention is to provide a novel production method capable of producing a wide range of dihalogenated biaryl derivatives with high purity. Such dihalogenated biaryl derivatives are useful as intermediates in electronic materials and medicines and agrochemicals.

  As a result of intensive studies to solve the above problems, the present inventors have made a cross-coupling reaction between a 2-haloaryl metal reagent and an aryl dihalide, and the resulting product is converted into an aliphatic hydrocarbon solvent and a halogen-based solvent. By recrystallizing with a mixed solvent, the inventors have found a novel production method that makes it possible to produce a wide range of dihalogenated biaryl derivatives, which were difficult to produce by conventional methods, with high purity, and completed the present invention. .

  The present invention is described in detail below.

The dihalogenated biaryl derivative represented by the following general formula (1) of the present invention is prepared by reacting an aryl dihalide with zinc chloride or trimethoxyborane after performing a halogen / metal exchange reaction with a Grignard reagent. The 2-haloaryl metal reagent represented by (2) and the aryl dihalide represented by the following general formula (3) are selected from the group consisting of tetrahydrofuran, diethyl ether, dioxane, toluene, xylene, hexane, cyclohexane, ethanol and water. In at least one kind of solvent, tetrakis (triphenylphosphine) palladium is used as a catalyst to carry out a cross-coupling reaction at 10 to 120 ° C.

（ここで、ｍ，ｎは０又は１であり、Ｘ^１，Ｘ^２は各々独立してヨウ素原子、臭素原子又は塩素原子を表し、置換基Ｒ^１〜Ｒ^１２は水素原子、フッ素原子、炭素数１〜２０のアルキル基若しくはハロゲン化アルキル基、又は炭素数４〜２０のアリール基を示す。）

(Here, m and n are 0 or 1, X ¹ and X ² each independently represent an iodine atom, a bromine atom or a chlorine atom, and the substituents R ^{1 to} R ¹² are a hydrogen atom, a fluorine atom, and a carbon atom. An alkyl group having 1 to 20 carbon atoms or a halogenated alkyl group, or an aryl group having 4 to 20 carbon atoms.)

（ここで、Ｘ^１はヨウ素原子、臭素原子又は塩素原子を表し、ＭはＢ（ＯＨ） _２ 又はＺｎＣｌを示す。その他の記号は一般式（１）で示される記号と同意義を示す。）

(Here, X ¹ represents an iodine atom, a bromine atom or a chlorine atom, and M represents B (OH) ₂ or ZnCl . Other symbols have the same meanings as those represented by the general formula (1).)

（ここで、Ｘ^２，Ｘ^３は各々独立してヨウ素原子、臭素原子又は塩素原子を表し、その他の記号は一般式（１）で示される記号と同意義を示す。）
本発明の一般式（１）の置換基について、さらに述べる。

(Here, X ² and X ³ each independently represent an iodine atom, a bromine atom or a chlorine atom, and the other symbols have the same meaning as the symbol represented by the general formula (1).)
The substituent of the general formula (1) of the present invention will be further described.

R ^{1 to} R ^{12 in} the general formula (1) represent a hydrogen atom, a fluorine atom, an alkyl group having 1 to 20 carbon atoms or a halogenated alkyl group, or an aryl group having 4 to 20 carbon atoms, and having 1 to 20 carbon atoms. Although it does not specifically limit as a specific example of an alkyl group, For example, a methyl group, an ethyl group, a propyl group, n-butyl group, an isobutyl group, a dodecyl group etc. can be mentioned, As a specific example of a halogenated alkyl group, Although it does not specifically limit, a trifluoromethyl group, a perfluorohexyl group, etc. can be mentioned. As the specific examples of the aryl group having 4 to 20 carbon atoms of the substituents ^R 1 ^{to R 12} of the general formula (1) are not particularly limited, for example, a phenyl group, p- tolyl group, p- fluorophenyl group, pentafluorophenyl Group, p- (trifluoromethyl) phenyl group, 2-pyridinyl group, 2-bi (pyridinyl) group, 2-thienyl group, 2-bi (thienyl) group and the like.

  In the general formula (1), m and n are 0 or 1, preferably 1.

X ¹ and X ^{2 in} the general formula (1) are preferably iodine or bromine.

  The dihalogenated biaryl derivative represented by the general formula (1) of the present invention is not particularly limited, and examples thereof include the following compounds and compounds obtained by replacing the bromine atom of these compounds with other halogen atoms (chlorine atom, iodine atom). be able to.

一般式（２）及び（３）の置換基について、さらに述べる。

The substituents of the general formulas (2) and (3) will be further described.

Substituent X ¹ in the general formula (2) is preferably bromine or iodine. The substituent M is a halide, hydroxide, alkoxide, or alkylated substance of Mg, B, Zn, Sn, or Si. For example, MgCl, MgBr, B (OH) ₂ , ZnCl, ZnBr, ZnI, Sn (Bu— n) ₃ or Si (Bu-n) ₃ may be mentioned, and B (OH) ₂ or ZnCl is preferable.

The 2-haloaryl metal reagent represented by the general formula (2) is not particularly limited. For example, the following compounds and B (OH) ₂ of these compounds are changed to ZnCl, ZnBr, MgCl, MgBr, Sn (Bu-n) _3. Or the compound substituted by Si (Bu-n) ₃ is mentioned.

なお、一般式（２）で示される２−ハロアリール金属試薬は、例えば、その原料であるアリールジハロゲン化物をイソプロピルマグネシウムブロマイド等のグリニャール試薬あるいはｎ−ブチルリチウム等の有機リチウム試薬によりハロゲン／金属交換反応を行った後、塩化亜鉛、トリメトキシボラン等と反応させることで好適に調製することができる。

The 2-haloaryl metal reagent represented by the general formula (2) is, for example, a halogen / metal exchange reaction of an aryl dihalide as a raw material with a Grignard reagent such as isopropylmagnesium bromide or an organic lithium reagent such as n-butyllithium. Then, it can be suitably prepared by reacting with zinc chloride, trimethoxyborane or the like.

The substituents X ² and X ³ in the general formula (3) are preferably bromine or iodine.

  The aryl dihalide represented by the general formula (3) is not particularly limited. For example, 1,2-dibromobenzene, 1,2-diiodobenzene, 1-bromo-2-chlorobenzene, 1-bromo-2-iodobenzene, 2,3-dibromonaphthalene, 2,3-diiodonaphthalene, 2-chloro-3-bromonaphthalene, 2-bromo-3-iodonaphthalene, 2,3-dibromoanthracene, 2,3-diiodoanthracene, 2- Chloro-3-bromoanthracene, 2-bromo-3-iodoanthracene, 1,2-dibromo-4,5-difluorobenzene, 1,2-diiodo-4,5-difluorobenzene, 1,2-dibromo-4, 5-di (trifluoromethyl) benzene, 1,2-diiodo-4,5-di (trifluoromethyl) benzene, 1,2-dibro -4,5-dimethylbenzene, 1,2-diiodo-4,5-dimethylbenzene, 1,2-dichloro-4,5-dimethoxybenzene, 1,2-dibromo-4,5-dimethoxybenzene, 1,2 -Diiodo-4,5-dimethoxybenzene, 1,2-dibromo-4,5-di (n-octyl) benzene, 1,2-diiodo-4,5-di (n-octyl) benzene, 1,2- Dibromo-4-perfluorohexylbenzene, 1,2-diiodo-4-perfluorohexylbenzene, 1-chloro-2-bromo-4-perfluorohexylbenzene, 1-bromo-2-iodo-4-perfluorohexyl Benzene, 2,3-dibromo-1,4,5,6,7,8-hexamethylnaphthalene, 2,3-diiodo-1,4,5,6,7,8-hexamethylnaphtha 10,11-dibromo-9,12-dimethyl-1,2,3,4,5,6,7,8-octahydrotriphenylene, 10,11-diiodo-9,12-dimethyl-1,2, Examples include 3,4,5,6,7,8-octahydrotriphenylene.

  The catalyst used for the cross-coupling reaction of the 2-haloaryl metal reagent represented by the general formula (2) and the aryl dihalide represented by the general formula (3) is not particularly limited as long as it is a palladium and / or nickel catalyst. Specific examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium / triphenylphosphine mixture, dichlorobis (triphenylphosphine) palladium, bis (tri-tert-butylphosphine) palladium, diacetatobis ( Triphenylphosphine) palladium, dichloro (1,2-bis (diphenylphosphino) ethane) palladium, palladium acetate / triphenylphosphine mixture, palladium acetate / 2- (dicyclohexylphosphino)- , 1'-biphenyl mixtures, etc .; specific examples of nickel catalysts include dichlorobis (triphenylphosphine) nickel, dichloro (1,2-bis (diphenylphosphino) ethane) nickel, bis (1,5- And cyclooctadiene) nickel / triphenylphosphine mixture. Among these, a preferable catalyst is a zero-valent palladium compound, and a particularly preferable catalyst is tetrakis (triphenylphosphine) palladium.

  The amount of the catalyst used in the cross-coupling reaction is in the range of 0.5 to 20 mol% with respect to the aryl dihalide of the general formula (3). The amount of the 2-haloaryl metal reagent of the general formula (2) used is 0.6 to 1.5 equivalents, preferably 0.8 to 1.4 equivalents, more preferably the aryl dihalide of the general formula (3). It can be used in the range of 0.9 to 1.2 equivalents.

  The cross coupling reaction is preferably carried out in a solvent. Specific examples include tetrahydrofuran (hereinafter abbreviated as THF), diethyl ether, dioxane, toluene, xylene, hexane, cyclohexane, ethanol, water, and the like, and these solvents include one kind or a mixture of two or more kinds. It may be used. For example, it can also be used in a 2 to 3 component system such as toluene / water or toluene / ethanol / water.

  The temperature of the cross coupling reaction is 10 to 120 ° C., preferably 30 to 100 ° C., and the reaction time can be suitably carried out in the range of 1 to 48 hours.

  The dihalogenated biaryl derivative represented by the general formula (1) thus obtained is purified. The main impurity is an aryl monohalide obtained by dehalogenation, and this aryl monohalide has very high solubility in a halogen-based solvent and is recrystallized using a mixed solvent composed of an aliphatic hydrocarbon and a halogen-based solvent. Thus, a high-purity dihalogenated biaryl derivative of 98% by weight or more can be separated with good yield.

  The aliphatic hydrocarbon solvent used for the purification is not particularly limited, but n-hexane and n-heptane are preferably used. Moreover, although it does not specifically limit as a halogen-type solvent, A dichloromethane and chloroform are used suitably.

  The mixing ratio of these solvents varies depending on the kind of the dihalogenated biaryl derivative, but is 0.001 to 1000, preferably 0.01 to 10 with respect to the aliphatic hydrocarbon solvent 1. The above purification method is useful because it is relatively easy to operate and can be highly purified with high yield.

  The method for purifying a dihalogenated biaryl derivative of the present invention can also be applied to a dihalogenated biaryl derivative obtained by reacting a known aryl dihalide with n-butyllithium.

  In the method of the present invention, a dihalogen represented by the general formula (1) is prepared by cross-coupling the 2-haloaryl metal reagent represented by the general formula (2) and the aryl dihalide represented by the general formula (3). Biaryl halide derivatives can be produced, and a wide variety of dihalogenated biaryl derivatives, which were difficult to produce by conventional methods, can be produced.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited only to these Examples.

For identification of the product, ¹ H NMR spectrum and mass spectrum were used. The ¹ H NMR spectrum used JEOL GSX-270WB (270 MHz) manufactured by JEOL, and the mass spectrum (MS) used JEOL JMS-700 manufactured by JEOL. The sample was directly introduced and the electron impact (EI) method was used. (70 electron volts).

  For confirmation of the progress of the reaction, etc., gas chromatography (GC) and gas chromatography-mass spectrum (GCMS) analysis were used.

Gas chromatography analyzer Shimadzu GC14B
Column J & W Scientific, DB-1, 30m
Gas chromatography-mass spectrum analyzer Perkin Elmer Auto System XL (MS part; Turbomass Gold)
Column J & W Scientific, DB-1, 30m
A commercially available dehydrated solvent was used as the solvent for the reaction.

Reference example 1
Synthesis of 2-bromo-3-iodonaphthalene as a raw material was carried out using the method described in Synthetic Communications, Vol. 33, No. 15, 2751-2, 756, 2003.

Example 1
Under a nitrogen atmosphere, 2-bromo-3-iodonaphthalene (1.03 g, 3.1 mmol) and THF (6 mL) were added to a 300 mL Schlenk reaction vessel. This was cooled to −60 ° C., and isobutylmagnesium bromide (0.65M, 4.2 ml, 2.7 mmol) was added dropwise by syringe. After stirring at −60 ° C. for 75 minutes, zinc chloride (1.0 M, 2.7 ml, 2.7 mmol) was added dropwise. The temperature was naturally raised while stirring to −40 ° C., then the cooling bath was removed and the temperature was returned to 20 ° C. (room temperature). The solvent was distilled off under reduced pressure from the resulting solution to obtain a white powder. Tetrakistriphenylphosphine palladium (0) (136 mg, 4 mol%), 2-bromo-3-iodonaphthalene (0.97 g, 2.9 mmol) and THF 8 ml were added to the obtained white powder. The resulting solution was heated to 65 ° C. and stirred at that temperature for 5 hours. After cooling to room temperature, the reaction was quenched with 4 ml of 3N hydrochloric acid solution. The solution was concentrated, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The purity of the product at this point was 73% by weight, and the yield was 77%. After removing anhydrous sodium sulfate, dichloromethane was concentrated and removed, and the resulting residue was dissolved in a mixed solvent consisting of 20 ml of n-heptane and 5 ml of chloroform at 60 ° C. As a result of cooling to 20 ° C. (room temperature) and recrystallization, and filtering the precipitated solid, 1.26 g of a white solid was recovered. The purity of the white solid was 98.5% by weight, and the yield was 60%.

¹ H NMR spectrum (CDCl ₃ , 27 ° C.) of this solid product was measured and confirmed to be dibromobinaphthyl.

^{The 1} H NMR spectrum is shown in FIG. The spectrum was measured using JEOL GSX-270WB (270 MHz) manufactured by JEOL Ltd.
MS m / z: 412 (M ⁺ , 26%), 332 (M ⁺ -Br, 5), 252 (M ⁺ -2Br, 100), 126 ((M ⁺ -2Br) / 2, 54).

¹ H NMR spectrum (CDCl ₃ , 27 ° C.) of dibromobinaphthyl synthesized in Example 1

Claims (2)

In producing the dihalogenated biaryl derivative represented by the following general formula (1), the aryl dihalide was subjected to a halogen / metal exchange reaction with a Grignard reagent and then reacted with zinc chloride or trimethoxyborane. A 2-haloaryl metal reagent represented by the formula (2) and an aryl dihalide represented by the following general formula (3) are selected from the group consisting of tetrahydrofuran, diethyl ether, dioxane, toluene, xylene, hexane, cyclohexane, ethanol and water. A method for producing a dihalogenated biaryl derivative, wherein a tetracoupling (triphenylphosphine) palladium is used as a catalyst in a selected at least one solvent and a cross-coupling reaction is performed at 10 to 120 ° C.

(Here, m and n are 0 or 1, X ¹ and X ² each independently represent an iodine atom, a bromine atom or a chlorine atom, and the substituents R ^{1 to} R ¹² are a hydrogen atom, a fluorine atom, and a carbon atom. An alkyl group having 1 to 20 carbon atoms or a halogenated alkyl group, or an aryl group having 4 to 20 carbon atoms.)

(Here, X ¹ represents an iodine atom, a bromine atom or a chlorine atom, and M represents B (OH) ₂ or ZnCl . Other symbols have the same meanings as those represented by the general formula (1).)

(Here, X ² and X ³ each independently represent an iodine atom, a bromine atom or a chlorine atom, and the other symbols have the same meaning as the symbol represented by the general formula (1).) The purified dihalogenated biaryl derivative is recrystallized with a mixed solvent of a halogenated solvent composed of dichloromethane or chloroform and an aliphatic hydrocarbon solvent composed of n-hexane or n-heptane. 2. A process for producing a dihalogenated biaryl derivative according to 1.

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