JPH0825922B2 - Process for producing asymmetric biphenyl derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention provides a compound of the general formula [I] (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each a hydrogen atom, a halogen atom, an alkyl group, an allyl group or an aryl group. However, not all of them are hydrogen atoms at the same time, and the same definition is applied to the following except for those having left-right symmetry.) The method for producing an asymmetric biphenyl derivative represented by Formula [II] (In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above, and X represents a halogen atom.), And a halogenated phenylmagnesium represented by the general formula [III] (In the formula, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and X have the same meanings as described above.) And a halogenated phenyl (hereinafter, referred to as halogenated phenyl [III]) , A method for producing an asymmetric biphenyl derivative, which comprises cross-coupling in the presence of nickel chloride.

(Prior Art) Conventionally, as a method for producing a biphenyl derivative, a Gomberg-Bachmann reaction in which a diazonium salt derived from an aromatic amine is reacted with an aromatic hydrocarbon in an alkaline manner, a Gattermann derived from an aromatic diazonium salt using copper powder as a catalyst
Reaction, Ullmann reaction to generate substituted biphenyl by heating substituted halobenzene with copper powder to 100 ℃ or more, Wurtz-Fittig reaction to generate two condensed hydrocarbons using lithium as a catalyst (Berichte., 38 , 2211 ( 1905), Co
mprehensive Organometallic Chemistry, 7 , 45 (198
2)), arylation reaction by decomposition of N-nitrosoacetanilide, biphenylation reaction by photoreaction (European Patent Publication 49,977 (1982)), reaction using palladium as a catalyst (Journal of Orgnometallic Chemistry, 12).
5, 281 (1977)) have been disclosed. As a review, these reactions are described in Tetrahedron, 3327 (1980).

(Problems to be Solved by the Invention) Of these reactions, among the reactions utilizing an aromatic diazonium salt, the compounds capable of cross-coupling are limited and the yield is low. Also, Ullmann reaction, W
The urtz-Fittig reaction has similar drawbacks. Decomposition of N-nitrosoacetanilide and biphenylation by photoreaction are also many restrictions on the compound that can be used, and the yield is also large.
In addition, the reaction using palladium as a catalyst has many restrictions on the compound, and it is necessary to use expensive palladium.

As described above, the conventional production methods have drawbacks as industrial production methods such as limited compounds that can be used, low yields, expensive catalysts, and phosphines as ligands. However, this is not a practical method.

(Means for Solving the Problems) The inventors of the present invention have investigated the industrially easy production method of an asymmetric biphenyl derivative except for the above drawbacks, and as a result, the general formula [II] (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X have the same meanings as described above), and a halogenated phenylmagnesium represented by the general formula [III] (In the formula, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and X have the same meanings as described above.) Cross-coupling with halogenated phenyl [III] represented by the following formula: The general formula [I] (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ have the same meanings as described above.) The inventors have found that a derivative can be obtained and completed the present invention.

Phenylmagnesium halide which is the starting material of the present invention has the general formula [IV] (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X have the same meanings as described above), and phenyl halide (hereinafter referred to as halogenated phenyl [IV]) and magnesium Is easily obtained by reacting with a usual means for producing a Grignard reagent.

The reaction between the phenylmagnesium halide [II] and the phenyl halide [III] of the present invention easily proceeds in the presence of nickel chloride in an aprotic solvent. The molar ratio of phenyl magnesium halide [II] and phenyl halide [III] used in the reaction is 1: 0.5 to 2.0, preferably 1: 0.9 to 1.2. The reaction solvent is not particularly limited as long as it is an aprotic solvent, but tetrahydrofuran is usually preferable. The amount of the solvent used is suitably 2 to 100 times by weight, preferably 3 to 20 times by weight that of the phenylmagnesium halide. The amount of nickel chloride used as a catalyst may be usually 0.1 to 20 mol% with respect to the phenylmagnesium halide, particularly 0.1 to 20 mol%.
5% is preferable, but not limited to this.

The reaction temperature of this reaction is 0 to 100 ° C., preferably room temperature to 80
C is desirable, and if the temperature is too high, the catalyst is deactivated, which is not preferable. The reaction is usually completed in several minutes to several hours, but it varies depending on the reaction conditions such as the reaction temperature and the amount of the catalyst used. After completion of the reaction, the reaction solvent is removed by washing with water and concentrating, followed by distillation and recombining if necessary to obtain the desired biphenyl derivative.

(Effect) By the production method of the present invention, an asymmetric biphenyl derivative, which is a compound useful as a raw material for pharmaceuticals and a raw material for agricultural chemicals, can be industrially easily obtained in high yield.

(Examples and Experimental Examples) Hereinafter, the present invention will be described with reference to Examples and Experimental Examples.

Experimental Example 1 Magnesium activated in 50 g of tetrahydrofuran 24.
3 g (1.0 mol) was added, and 161 g of tetrahydrofuran was added to this.
161 g (1.0 mol) of 2,6-dichlorotoluene mixed in was added dropwise and reacted at 60 to 70 ° C. to synthesize 3-chloro-2-methylphenylmagnesium chloride. The Grignard yield by iodometric titration is 94%.

Example 1 133 g (1.85) of bromobenzene in 50 g of tetrahydrofuran
Mol) and 1.0 g (0.011 mol) of anhydrous nickel chloride were added to a suspension of 396 g of a tetrahydrofuran solution containing 157 g (0.85 mol) of 3-chloro-2-methylphenylmagnesium chloride obtained in Experimental Example 1 at the reaction temperature. Was maintained at 50 to 60 ° C. for 4 hours and added dropwise. After completion of the dropping, the reaction was completed by aging at a reaction temperature of 55 ° C. for 30 minutes. Next, 140 g of a dilute sulfuric acid aqueous solution is added, and the mixture is washed, then left standing and separated, and the tetrahydrofuran is distilled off. The residue was further distilled under reduced pressure to give 3-chloro-2-methylbiphenyl as a colorless liquid.
5 g (0.76 mol) were obtained. Yield 89% (vs 3-chloro-2-
Methylphenyl magnesium chloride).

Boiling point 106 to 108 ° C. / 2 mmHg Nuclear magnetic resonance _{(CDCl 3) (δppm) 2.6} (S, -CH 3) 7.3~7.8 (broad, ring protons) Infrared absorption spectrum ^{(direct) (cm -1) 3050} (Aromatic C-H) 1560,1450,1420, (ring C = H) 1050,1000 (C-H) Experimental example 2 Magnesium 19.4 g (0.8
0 mol) and 4-chlorotoluene 102 g (0.80 mol),
Reaction was performed in the same manner as in Experimental Example 1 to synthesize 4-methylphenylmagnesium chloride. The Grignard yield by iodometric titration is 92%.

Example 2 116 g (0.74) of bromobenzene in 40 g of tetrahydrofuran
Mol) and 0.8 g (0.008 mol) of anhydrous nickel chloride were added to a tetrahydrofuran solution containing 112 g (0.74 mol) of 4-methylphenylmagnesium chloride obtained in Experimental Example 2 under reflux for 1 hour. After dripping, the mixture was aged to complete the reaction. Then, the same post-treatment as in Example 1 was performed, and the fraction obtained by distillation was reconstituted with cyclohexane to give 94 g of 4-methylbiphenyl as white crystals.
(0.56 mol) was obtained. Yield 76% (vs. 4-methylphenyl magnesium chloride).

Mp 44 ° C. boiling two hundred and sixty-six to two hundred and sixty-eight ° C. Nuclear magnetic resonance _{(CDCl 3) (δppm) 2.3} (3H, S, -CH 3) 6.9~7.6 (9H, broad, ring protons) Infrared absorption spectrum (direct) (cm ^{- 1} ) 2900 to 3100,1600,1500,1000,820,760 Experimental Example 3 In a tetrahydrofuran solvent, magnesium 2.4 g (0.1
Mol) and 3-chlorotoluene 13.4 g (0.11 mol),
Reaction was carried out in the same manner as in Experimental Example 1 to synthesize 3-methylphenylmagnesium chloride. The Grignard yield by iodometric titration is 91%.

Example 3 11.6 g of bromobenzene (0.074
Mol) and 0.08 g (0.0008 mol) of anhydrous nickel chloride were added to a suspension of a tetrahydrofuran solution containing 11.2 g (0.074 mol) of 3-methylphenylmagnesium chloride obtained in Experimental Example 3 under reflux, After aging to complete the reaction, the same post-treatment as in Example 1 was carried out, followed by distillation to give 3-methylbiphenyl as a colorless liquid (9.8 g).
(0.058 mol) was obtained. Yield 78% (vs 3-methylphenylmagnesium chloride).

Boiling point 270-272 ° C. Nuclear magnetic resonance _{(CDCl 3) (δppm) 2.4} (3H, S, -CH 3) 7.0~7.6 (9H, broad, ring protons) Infrared absorption spectrum (direct) (cm ^-1) 2900 ~ 3100,1600,1450,790,750,690 Experimental Example 4 0.48 g (0.0
2 mol) and 2-chlorotoluene 2.5 g (0.02 mol),
2-Methylphenyl magnesium chloride was synthesized by reacting in the same manner as in Experimental Example 1. The Grignard yield by the iodometric titration method is 98%.

Example 4 2.96 g (0.019 g) of bromobenzene in 2 g of tetrahydrofuran
Mol) and 0.05 g (0.0005 mol) of anhydrous nickel chloride were added to a suspension of tetrahydrofuran solution containing 2.9 g (0.019 mol) of 2-methylphenyl magnesium chloride obtained in Experimental Example 4 under reflux, After aging to complete the reaction, post-treatment was carried out in the same manner as in Example 1, and then distilled to give 3.0 g of 2-methylbiphenyl as a colorless liquid.
(0.018 mol) was obtained. Yield 95% (vs. 2-methylphenyl magnesium chloride).

Boiling point two hundred fifty-four to two hundred and fifty-six ° C. Nuclear magnetic resonance _{(CDCl 3) (δppm) 2.4} (3H, S, -CH 3) 6.9~7.7 (9H, broad, ring protons)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07C 17/263 25/18 25/24 // B01J 27/128 X C07B 61/00 300

Claims (1)

[Claims] 1. ^{(Wherein, R 1, R 2, R} 3, R 4 and R ⁵ are each a hydrogen atom, a halogen atom, an alkyl group, an allyl group or an aryl group, X represents a halogen atom. However, R ^1, R ² , R ³ , R ⁴
And R ⁵ are not hydrogen atoms at the same time. ) Phenylmagnesium halide represented by the general formula [III] (Wherein, R ^6, R ^7, R ^8, R ⁹ and R ¹⁰ are each a hydrogen atom, a halogen atom, an alkyl group, an allyl group or an aryl group, X represents a halogen atom. However, R ^6, R ⁷ , R ⁸ , R ⁹
And R ¹⁰ are not the same as R ¹ , R ² , R ³ , R ⁴ and R ⁵ at the same time. ) A halogenated phenyl represented by the formula (I) is cross-coupled in the presence of nickel chloride. (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ have the same meanings as described above, provided that all are hydrogen atoms at the same time. The production method of an asymmetric biphenyl derivative represented by the formula (1), which does not exist and which is symmetrical on the left and right.