JPS63295520A - Production of unsymmetrical biphenyl derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a raw material for drugs and agricultural chemicals industrially, readily and in high yield, by subjecting a readily obtainable halogenated phenylmagnesium and a halogenated phenyl to cross coupling in the presence of nickel chloride. CONSTITUTION:A halogenated phenylmagnesium shown by formula I (R<1>-R<5> are H, halogen, alkyl, allyl or aryl; X is halogen with the proviso that R<1>-R<5> are not H at the same time) and a halogenated phenyl shown by formula II (R<6>-R<10> are H, halogen, alkyl or aryl with the proviso that R<6>-R<10> are not H at the same time) are subjected to cross coupling in the presence of nickel chloride to give a compound (e.g. 3-chloro-2-methylphenylmagnesium chloride) shown by formula III (R<1>-R<10> are not H at the same time and a compound symmetric between the left and right halves). The reaction is preferably carried out in an aprotic solvent such as tetrahydrofuran.

Description

[Detailed description of the invention] (Industrial application field) The present invention is based on the general formula (1) (In the formula, R', R", R", R', R', R".

R', R'', R' and R'' each represent a hydrogen atom, a halogen atom, an alkyl group, an allyl group or an aryl group, provided that they are not all hydrogen atoms at the same time and are symmetrical on the left and right. The same definition applies hereinafter, except for the following.

), and more specifically relates to a method for producing an asymmetric biphenyl derivative represented by the general formula (where R", R
``, R'', R'Oyohi R' has the same meaning as above or represents a halogen atom) and a halogenated phenylmagnesium represented by the general formula Cm) (in the formula % R'', R', R ", R', R" and or the same meaning as above) (hereinafter referred to as halogenated phenyl (m)) is cross-coupled in the presence of nickel chloride. The present invention relates to a method for producing an asymmetric biphenyl derivative consisting of.

(Prior art) Conventional methods for producing biphenyl derivatives include the Gomberg-Bachmann reaction in which a diazonium salt derived from an aromatic amine is reacted with an alkaline aromatic hydrocarbon, and the biphenyl derivative is derived from an aromatic diazonium salt using copper powder as a catalyst. Gatter ■ ann reaction,! Ull Ann reaction, which generates substituted biphenyl by heating substituted halobenzene together with copper powder to over 100℃, and Vurtz-Fit, which uses lithium as a catalyst to generate two molecules of condensed hydrocarbon.
tig reaction (Barichte, e38.2211 (
1905), Comprehensive Org.
anoIIatallic Chemistry, 7.
45 (1982)), arylation reaction by decomposition of N-nitrosoacetanilide, biphenylation reaction by photoreaction (European Publication Patent No. 49.977 (1982)),
Reactions using palladium as a catalyst (Journal
of Orgnometallic Chemistry
y.

℃ Post, 281 (1977)) is disclosed. Also,
For a review, see Tetrahedron, 3327 (19
80) describes these reactions.

(Problems to be Solved by the Invention) Among these reactions, there are only a limited number of compounds that can be cross-coupled in reactions using aromatic diazonium salts, and the yields are also low.

The υl1mann reaction and the Vurtz-Fittig reaction also have similar drawbacks. In addition, biphenylation by decomposition of N-nitrosoacetanilide and photoreaction has many restrictions on the compounds that can be used, and yields are low.

Reactions using palladium as a catalyst also have many restrictions on compounds and require the use of expensive palladium.

As mentioned above, the conventional production methods are limited in the number of compounds that can be used, have low yields, and have disadvantages as industrial production methods, such as the use of expensive catalysts or the use of phosphines as ligands. There are many problems, so it is difficult to say that it is a practical method.

(Means for Solving the Problems) The present inventors have investigated an easy industrial method for producing asymmetric biphenyl derivatives by eliminating such drawbacks, and have found that:
A halogenated phenylmagnesium represented by general formula (II) (wherein R', R'', R'', R', R'' and or the same meaning as above) and general formula (III) (formula In the presence of nickel chloride, by cross-coupling with a halogenated phenyl [■] represented by R', R', R'', R't R'' and or the same meaning as above) in the presence of nickel chloride. General formula (I) (wherein R1, R", R", R', R', R@.

The present invention has been completed by discovering that an asymmetric biphenyl derivative represented by R', R@, R'', and R'' have the same meanings as described above can be obtained.

(The following is a blank space) The halogenated phenylmagnesium which is the starting material of the present invention has the general formula (IV) (wherein R'', R'', R'', R', R and or the same meaning as above). It can be easily obtained by reacting the represented halogenated phenyl (hereinafter referred to as halogenated phenyl (mV)) with magnesium by a conventional means for producing a Grignard reagent.

The reaction between halogenated phenylmagnesium and halogenated phenyl (II) of the present invention can be carried out easily in the presence of nickel chloride in an aprotic solvent.
The molar ratio of m) is 1:0.5 to 2.0, preferably 1:0
．． The reaction solvent for which 9 to 1.2 is suitable is not particularly limited as long as it is an aprotic solvent, but tetrahydrofuran is usually preferred. The amount of solvent used is 2 to 100 times the weight of the phenylmagnesium halide.
Preferably, 3 to 20 times the weight is suitable. Further, the amount of nickel chloride used as a catalyst may be generally 0.1 to 20 mol%, preferably 0.1 to 5%, based on the phenylmagnesium halide, but is not limited thereto.

The reaction temperature of this reaction is 6 to 100°C, preferably room temperature to 8°C.
A temperature of 0°C is desirable; too high a temperature is undesirable because the catalyst will be deactivated. 1. Reactions are usually completed within a few minutes to several hours, but the temperature may vary depending on changes in reaction conditions such as the reaction temperature and the amount of catalyst used. The desired biphenyl derivative is obtained by washing with water, then concentrating to remove the reaction solvent, followed by distillation and, if necessary, recrystallization.

(Effects) According to the production method of the present invention, asymmetric biphenyl derivatives, which are compounds useful as raw materials for pharmaceuticals and agricultural chemicals, can be produced industrially easily and in high yields.

(Examples and Experimental Examples) The present invention will be explained below with reference to Examples and Experimental Examples.

Experimental example 1 Magnesium 2 activated in 50g of tetrahydrofuran
4.3 g (1.0 mol) of 2,6-dichlorotoluene mixed with 161 g of tetrahydrofuran was added.
1 g (1.0 mol) was added dropwise and reacted at 60 to 70°C to synthesize 3-chloro-2-methylphenylmagnesium chloride. Grignard yield by iodine titration method is 9
It is 4%.

Example 1 133 g of bromobenzene in 50 g of tetrahydrofuran (
1.85 mol) and 1.0 g (0.01 mol) of anhydrous nickel chloride
157 g of 3-chloro-2-methylphenylmagnesium chloride obtained in Experimental Example 1 was added to a suspension containing 1 mole of
(0.85 mol) in tetrahydrofuran solution 396
g was added dropwise over a period of 4 hours while maintaining the reaction temperature at 50 to 60°C. After completion of the dropwise addition, the reaction was completed by aging at a reaction temperature of 55°C for 30 minutes.

After washing by adding 140 g of a dilute aqueous sulfuric acid solution, the mixture is left to stand and separated, and tetrahydrofuran is distilled off. The residue was further distilled under reduced pressure to obtain 155 g (0.76 mol) of 3-chloro-2-methylbiphenyl as a colorless liquid.

Yield: 89% (based on 3-chloro-2-methylphenylmagnesium chloride).

Boiling point 106-b Nuclear magnetic resonance absorption (CDC et al.) (δpp) 2.6 (S,
-CD5) 7.3-7.8 (broad*ring proton) infrared absorption spectrum (direct) (am-") 3050
(Aromatic C-H) 1560.1450.
142G, (ring C=H) 1050, 1000 (
C-H) Experimental Example 2 19.4 g of magnesium (
0.80 mol) and 102 g of 4-chlorotoluene (0.8 mol)
0 mol) 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 of bromobenzene in 40 g of tetrahydrofuran (
0.74 mol) and 0.8 g (0.00 mol) of anhydrous nickel chloride
4-methylphenylmagnesium chloride L L 2F obtained in Experimental Example 2, (0,
A tetrahydrofuran solution containing 74 mol) was added dropwise over 1 hour under reflux, and the reaction was completed by aging. By recrystallizing the fraction with cyclohexane, 94 g (0.56 mol) of 4-methylbiphenyl was obtained as white crystals. Yield: 76% (based on 4-methylphenylmagnesium chloride).

Melting point: 44°C Boiling point: 266-268°C Nuclear magnetic resonance absorption (CDCQ) (δppm) 2.3 (3
1,S, -C1,) 6.9-7.6 (IJH, broad, ring proton) Infrared absorption spectrum (diroct) (cm-1) 29
QO ~ 3100, 1600, 1500, 1000, 82
0,760 Experimental Example 3 Magnesium 2.4g (0
, 1 mol) and 13.4 g of 3-chlorotoluene (0,11 mol)
mol) 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 in 4 g of tetrahydrofuran (
0,074 mol) and anhydrous nickel chloride 0.08 g (0,074 mol)
0008 mol) obtained in Experimental Example 3.
-Methylphenylmagnesium chloride 11.2° (0
, 074 mol) was added dropwise under reflux, aged to complete the reaction, followed by the same post-treatment as in Example 1, and then distilled to produce 3-methylbiphenyl as a colorless liquid. 9.8 g (0,058 mol) was obtained. Yield: $78% (vs. 3-methylphenylmagnesium chloride).

Boiling point 270-272℃ Nuclear magnetic resonance absorption (CDC et al.) (δppm) 2.4 (3
H, S, -CD5) 7.0-7.6 (9H, broad, ring proton) Infrared absorption spectrum (diloct) (am-1) 290
0~3100,1600,1450,790,750,
690 Experimental Example 4 Magnesium 0.48g (
0.02 mol) and 2.5 g of 2-chlorotoluene (0.0 mol)
2 mol) in the same manner as in Experimental Example 1 to synthesize 2-methylphenylmagnesium chloride.

The Grignard yield by iodometric titration is 98%.

Example 4 2.96 g of bromobenzene in 2 g of tetrahydrofuran (
0,019 mol) and anhydrous nickel chloride 0.05 g (0,
0005 mol) obtained in Experimental Example 4.
-Methylphenylmagnesium chloride 2.9g (0,
A tetrahydrofuran solution containing 019 mol) of , Og (0,018 mol)
I got it. Yield 95% (based on 2-methylphenylmagnesium chloride).

Boiling point 254-256℃

Claims (1)

[Claims] 1. General formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, R^1, R^2, R^3, R^4 and R^5
each represents a hydrogen atom, a halogen atom, an alkyl group, an allyl group, or an aryl group, and X represents a halogen atom. However, R^1, R^2, R^3, R^4 and R^5 are never hydrogen atoms at the same time. ) and the general formula [III] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [III] (In the formula, R^6, R^7, R^8, R^9 and R^ 1
^0 represents a hydrogen atom, a halogen atom, an alkyl group, an allyl group, or an aryl group, and X represents a halogen atom. However, R^6, R^7, R^8, R^9 and R^1^0 are never hydrogen atoms at the same time. ) A general formula [I] characterized by cross-coupling a phenyl halide represented by , R^2, R^3, R^4, R^5, R
^6, R^7, R^8, R^9 and R^1^0 have the same meanings as above. However, not all atoms are hydrogen atoms at the same time, except for those that are symmetrical. ) A method for producing an asymmetric biphenyl derivative represented by