JP2002249483A - Method of producing aryl substituted heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of producing an aryl substituted pyridine compound or an aryl substituted quinoline compound in high yield. SOLUTION: This method comprises reacting a halogen substituted heterocyclic compound with an arylborane compound in the coexistence of (c) a solvent- insoluble palladium catalyst with at least one selected from the group consisting of (a) a base and (b) a triarylphosphine and an alkali (alkaline earth) metal halide (excluding a fluoride), in a solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an aryl-substituted heterocyclic compound.

[0002]

2. Description of the Related Art As a method for producing an aryl-substituted pyridine compound and an aryl-substituted quinoline compound, a method is known in which a halogen-substituted pyridine compound or a halogen-substituted quinoline compound is reacted with an arylborane compound in the presence of a palladium complex. This reaction is, for example, Ch
em. Rev., 95, 1995, 2457-2483, Tetrahedron. 54, 19
98, 263-303.

[0003] In the above prior art, the palladium complex is usually Pd (PPh ₃ ) ₄ , Pd (OCOCH ₃ ) ₂ -P
Palladium catalysts Ph ₃ like. Here, Ph means a phenyl group.

[0004] However, the above-mentioned palladium catalyst is an expensive catalyst which is difficult to obtain. Moreover, since the palladium catalyst has a property of dissolving in the reaction solvent, the reaction is performed in a homogeneous system, and as a result, the catalyst cannot be recovered after the reaction is completed. Further, when the palladium catalyst comes into contact with oxygen, the catalytic activity is reduced or deactivated, so it is necessary to remove trace amounts of oxygen in the reaction system. Therefore, the above prior art method is actually a method that is difficult to implement industrially.

On the other hand, a method of producing a phenyl-substituted benzene compound by reacting a halogen-substituted benzene compound with a phenylboronic acid compound using palladium carbon as a catalyst is disclosed in Tetrahedron Letters, 35, 3277-3280 (1).
994). Since the palladium carbon used in this method is a solvent-insoluble palladium catalyst, the reaction is performed in a heterogeneous system, and as a result, there is an advantage that the catalyst can be easily recovered after the reaction is completed.

Therefore, the present inventor has applied the method disclosed in the above-mentioned literature to react a halogen-substituted pyridine compound or a halogen-substituted quinoline compound with an arylborane compound, thereby obtaining an aryl-substituted pyridine compound or an aryl-substituted quinoline compound. An attempt was made to produce the compound. That is, reacting a halogen-substituted pyridine compound or a halogen-substituted quinoline compound with an arylborane compound in a solvent in the presence of a base and a solvent-insoluble palladium catalyst to produce an aryl-substituted pyridine compound or an aryl-substituted quinoline compound. Tried.

[0007] However, as apparent from Comparative Example 1 described later, it was found that the intended aryl-substituted pyridine compound or aryl-substituted quinoline compound could be obtained only in a low yield.

Further, JP-A-2000-336045 discloses a ligand selected from the group consisting of (1) a metal palladium catalyst, (2) a phosphine, a diketone and a tertiary amine.
A method for producing a biaryl compound by performing a coupling reaction between an aromatic boronic acid compound and an aryl halide in the presence of (3) a base and (4) a phase transfer catalyst in a solvent is described.

However, the desired biaryl compound cannot be obtained in high yield even by the method described in the above publication. That is, the present inventor applies the method described in the above publication to react a halogen-substituted pyridine compound or a halogen-substituted quinoline compound with an arylborane compound to produce an aryl-substituted pyridine compound or an aryl-substituted quinoline compound. Tried. However, as apparent from Comparative Example 2 described later, it was found that, although the yield of the intended aryl-substituted pyridine compound or aryl-substituted quinoline compound was improved to some extent, the yield was still low.

[0010]

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrially advantageous production method capable of producing a target aryl-substituted pyridine compound or aryl-substituted quinoline compound in a high yield.

[0011]

Means for Solving the Problems The inventor of the present invention has conducted various studies to further solve the above-mentioned problems, and found that the above-mentioned Japanese Patent Application Laid-Open
In the publication No. 0-336045, among the components (1) to (4) used coexisting in the reaction system, the phase transfer catalyst as the component (4) is not present in the reaction system (1 When only three components of the metal palladium catalyst of the component, the triphenylphosphine of the component (2) and the base of the component (3) are present in the reaction system, the target aryl-substituted pyridine compound or aryl-substituted quinoline compound It has been found that the yield of is significantly improved.

The present inventor has further determined that even when an alkali (earth) metal halide (excluding fluoride) is used in place of the triphenylphosphine as the component (2), the desired aryl-substituted pyridine may be used. It has been found that the yield of the compound or the aryl-substituted quinoline compound is significantly improved.

The present invention has been completed based on such findings.

That is, the present invention provides a compound represented by the general formula (1):

[0015]

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[In the formula, X represents a halogen atom. R ¹ and R ² are the same or different and each represent a hydrogen atom, an alkyl group,
It represents an alkoxy group, a nitro group, a cyano group or a fluoroalkyl group. Alternatively, R ¹ and R ² may be bonded together with two adjacent carbon atoms on the pyridine ring to form a 6-membered aromatic ring. A halogen-substituted heterocyclic compound represented by the formula (I), at least one selected from the group consisting of (a) a base, (b) a triarylphosphine and an alkali (earth) metal halide (excluding fluoride) In the presence of one kind and (c) a solvent-insoluble palladium catalyst, a compound represented by the general formula (2):

[0017]

Embedded image

[In the formula, Z represents a carbon atom or a nitrogen atom. When Z represents a carbon atom, R ³ represents a hydrogen atom, an alkyl group, an alkoxy group or an acyl group, R ⁴ and R ⁵ represent a hydroxyl group, and n represents 1 or 2. When Z represents a nitrogen atom,
R ³ is a hydrogen atom, R ⁴ and R ⁵ are alkyl groups, and n is 1
Is shown. With the arylborane compound represented by the general formula (3):

[0019]

Embedded image

Wherein Z, R ¹ , R ² , R ³ and n are as defined above. And a process for producing an aryl-substituted heterocyclic compound represented by the formula:

According to the present invention, there is provided an industrially advantageous method for producing an aryl-substituted pyridine compound or an aryl-substituted quinoline compound.

That is, since the palladium catalyst used in the method of the present invention is a solvent-insoluble palladium catalyst, the reaction is carried out in a heterogeneous system, and as a result, the catalyst can be easily recovered after completion of the reaction. There is an advantage. Moreover, such a palladium catalyst is an easily available and inexpensive catalyst. In addition, the palladium catalyst used in the method of the present invention does not have a risk of its catalytic activity being reduced or deactivated even when it comes into contact with oxygen, and does not require an operation for removing a trace amount of oxygen in the reaction system.

Further, according to the method of the present invention, the desired aryl-substituted pyridine compound or aryl-substituted quinoline compound can be produced in high yield.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION In the halogen-substituted heterocyclic compound (1) used in the present invention, the above-mentioned general formula (1)
The groups represented by X, R ¹ and R ² therein are specifically as follows.

The halogen atom represented by X is specifically a chlorine atom, a bromine atom or an iodine atom.

The alkyl group represented by R ¹ and R ² includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, and an n-propyl group. Isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like. The alkyl group has 1 to 1 carbon atoms.
4 straight-chain or branched-chain alkyl groups are preferred, and methyl and ethyl groups are particularly preferred.

The alkoxy group represented by R ¹ and R ² includes, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, methoxy group, ethoxy group, n
-A propoxy group, an isopropoxy group, an n-butoxy group,
Examples thereof include a tert-butoxy group, an n-pentyloxy group, and an n-hexyloxy group. As the alkoxy group, a linear or branched alkoxy group having 1 to 4 carbon atoms is preferable.

Examples of the fluoroalkyl group represented by R ¹ and R ² include a methyl group and an ethyl group substituted with 1 to 5 fluorine atoms, and specific examples include a monofluoromethyl group and a difluoromethyl group. , Trifluoromethyl group, 1-fluoroethyl group, 1,2-difluoroethyl group, 1,1,2-trifluoroethyl group, 1,1,1,
Examples thereof include a 2-tetrafluoroethyl group, a 1,1,2,2-tetrafluoroethyl group, and a 1,1,1,2,2-pentafluoroethyl group.

The 6-membered aromatic ring group formed by combining R ¹ and R ² with two adjacent carbon atoms on the pyridine ring is specifically a phenyl group.

Specific examples of the halogen-substituted heterocyclic compound (1) include 2-chloropyridine, 2-bromopyridine, 3-bromopyridine, 4-bromopyridine, 2-chloro-6-methylpyridine, and 2-chloropyridine. -6-methoxypyridine, 2-chloro-3-nitropyridine, 2-bromo-3-nitropyridine, 2-chloro-5-nitropyridine, 2-bromo-5-nitropyridine, 3-bromo-
6-nitropyridine, 2-chloro-3-cyanopyridine, 2-chloro-5-cyanopyridine, 2-chloro-5
-Trifluoromethylpyridine, 3-bromoquinoline,
Examples thereof include 2-chloroquinoline and 4-bromoisoquinoline, but are not limited thereto.

The arylborane compounds used in the present invention (2), each group represented by R ³ in the general formula (2) it is specifically as each follows.

The alkyl group represented by R ³ is, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, ter
Examples thereof include a t-butyl group, an n-pentyl group, and an n-hexyl group. As the alkyl group, a linear or branched alkyl group having 1 to 4 carbon atoms is preferable, and a methyl group and an ethyl group are particularly preferable.

The alkoxy group represented by R ³ is, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, an n-propoxy group and an isopropoxy group. Group, n-butoxy group, ter
Examples thereof include a t-butoxy group, an n-pentyloxy group, and an n-hexyloxy group. As the alkoxy group, a linear or branched alkoxy group having 1 to 4 carbon atoms is preferable.

[0034] The acyl group represented by R ^3, alkylcarbonyl groups and arylcarbonyl groups are included. Examples of the alkylcarbonyl group include a linear or branched alkylcarbonyl group having 2 to 7 carbon atoms, specifically, an acetyl group, a 2-ethylcarbonyl group, a 3-propylcarbonyl group, and a 4-butylcarbonyl group. Group, 5-pentylcarbonyl group, 6-hexylcarbonyl group and the like. The arylcarbonyl group includes, for example, a phenylcarbonyl group, a naphthylcarbonyl group and the like, and about 1 to 2 substituents such as an alkyl group and an alkoxy group may be substituted on these phenyl rings.

Specific examples of the arylborane compound (2) include phenylboronic acid, 4-methylphenylboronic acid, 4-methoxyphenylboronic acid, 4-acetylphenylboronic acid, phenylenediboronic acid, diethyl (3-
Pyridyl) borane and the like, but are not limited thereto.

In the present invention, the starting compound, the halogen-substituted heterocyclic compound (1) and the arylborane compound (2) are both known compounds that are easily available.

In the present invention, the usage ratio of the halogen-substituted heterocyclic compound (1) and the arylborane compound (2) is not limited, but from the viewpoint of economy and the like,
The arylborane compound (2) is used in an amount of usually about 1 to 4 mol, preferably about 1 to 2 mol, per 1 mol of the halogen-substituted heterocyclic compound (1).

The reaction of the present invention is performed in a solvent. Examples of the solvent include water, ethers, amides, nitriles, ketones, alcohols, aromatic hydrocarbons and the like, and these can be used alone or as a mixture of two or more.

As the ethers, specifically, dimethoxyethane, tetrahydrofuran, 1,4-dioxane,
Diethyl ether and the like, amides, specifically, dimethylformamide, dimethylacetamide and the like, nitriles, specifically, acetonitrile, propionitrile and the like, ketones, specifically acetone, Methyl ethyl ketone and the like, as alcohols,
Specifically, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, tert-butyl alcohol, and the like, and specific examples of aromatic hydrocarbons include benzene, toluene, xylene, and the like. it can.

Preferred solvents are water and a mixed solvent of water and an organic solvent, and more preferred are water and a mixed solvent of water and an organic solvent miscible with water. Examples of the organic solvent miscible with water include ethers, amides, nitriles, ketones, and alcohols.

The amount of the solvent used is usually about 5 to 60 parts by weight, preferably about 10 to 40 parts by weight, based on 1 part by weight of the halogen-substituted heterocyclic compound (1).

When a mixed solvent of water and an organic solvent is used,
With respect to 1 part by weight of the halogen-substituted heterocyclic compound (1),
Water is usually about 0.1 to 30 parts by weight, preferably 0.5 to 30 parts by weight.
About 20 parts by weight, usually about 5 to 40 parts by weight of an organic solvent,
Preferably, about 10 to 30 parts by weight is used.

As the base to be present in the reaction system of the present invention, known inorganic bases can be widely used. Examples of the inorganic base include alkali metal carbonates, alkali metal hydroxides, alkali metal phosphates, alkali metal fluorides, basic salts of alkaline earth metals, and the like. These may be used alone or in combination of two or more. These can be mixed and used.

Specific examples of the alkali metal carbonate include sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate. Specific examples of the alkali metal hydroxide include sodium hydroxide, potassium hydroxide, and hydroxide. Lithium, cesium hydroxide, etc., as alkali metal phosphates, specifically sodium phosphate, potassium phosphate, lithium phosphate, cesium phosphate, etc .; Examples thereof include sodium fluoride, potassium fluoride, lithium fluoride, and cesium fluoride.

Examples of the alkaline earth metal basic salts include alkaline earth metal carbonates and alkaline earth metal hydroxides. Specific examples of the alkaline earth metal carbonate include magnesium carbonate and calcium carbonate, and specific examples of the alkaline earth metal hydroxide include magnesium hydroxide and calcium hydroxide.

Such a base is usually used in an amount of about 1 to 10 mol, preferably about 2 to 5 mol, per 1 mol of the halogen-substituted heterocyclic compound (1).

As the palladium catalyst to be present in the reaction system of the present invention, known palladium catalysts can be widely used as long as they are insoluble in a solvent.

The carrier on which metal palladium is supported includes, for example, silica, alumina, diatomaceous earth, activated clay, activated carbon, barium sulfate, calcium carbonate and the like. Among these carriers, alumina and activated carbon are preferred.

The palladium / carbon is obtained by supporting metallic palladium on activated carbon, and conventionally known palladium / carbon can be used. Palladium / carbon containing 1 to 10% by weight of palladium metal is preferred.

The palladium / alumina is obtained by supporting metal palladium on alumina, and conventionally known ones can be used. Palladium / alumina containing 1 to 10% by weight of palladium metal is preferred.

In the palladium catalyst, the metal palladium contained in the catalyst is usually about 0.1 to 100 mmol, preferably 1 to 1 mol per mol of the halogen-substituted heterocyclic compound (1).
It is preferable to use it so as to be about 50 mmol.

In the present invention, together with the base and the palladium catalyst, at least one kind (component (b)) selected from the group consisting of triarylphosphines and alkali (earth) metal halides (excluding fluorides) is used. Coexist in the reaction system, and do not allow the phase transfer catalyst to be present in the reaction system.
This is the most important feature of the present invention.

As the triarylphosphine, known ones can be widely used. Examples of the triarylphosphine include, for example, triphenylphosphine, trinaphthylphosphine, diphenylnaphthylphosphine, phenyldinaphthylphosphine and the like. Further, those in which about 1 to 3 substituents such as an alkyl group and an alkoxy group are substituted on the phenyl group or the naphthyl group are also included in the triarylphosphine of the present invention.

Known alkali (earth) metal halides can be widely used. The alkali (earth) metal halide means an alkali metal halide and an alkaline earth metal halide, and is preferably an alkali metal halide.

Examples of the alkali metal halide include alkali metal bromide, chloride and iodide, and preferably alkali metal bromide and chloride. Specific examples of the alkali metal bromide include sodium bromide, potassium bromide, lithium bromide and cesium bromide, and specific examples of the alkali metal chloride include sodium chloride,
Potassium chloride, lithium chloride, cesium chloride and the like can be exemplified, and specific examples of the alkali metal iodide include sodium iodide, potassium iodide, lithium iodide, cesium iodide and the like.

As the alkaline earth metal halide,
Examples thereof include bromide, chloride and iodide of alkaline earth metals. As the alkaline earth metal bromide, specifically, magnesium bromide and calcium bromide, etc., as the alkaline earth metal chloride, specifically, magnesium chloride, calcium chloride, etc., as the alkaline earth metal iodide Is specifically exemplified by magnesium iodide, calcium iodide and the like.

The above-mentioned triarylphosphines and alkali (earth) metal halides may be used alone or in combination of two or more.

The component (b) is usually used in an amount of about 0.01 to 10 mol, preferably about 0.01 to 3 mol, per 1 mol of the halogen-substituted heterocyclic compound (1).

In carrying out the method of the present invention, for example, a halogen-substituted heterocyclic compound (1), an arylborane compound (2), a base, a palladium catalyst, (b)
The components and the solvent are charged in predetermined amounts, and usually 50 to 15 with stirring.
Under heating at about 0 ° C, preferably about 75 to 100 ° C,
The reaction is usually performed for about 1 to 20 hours, preferably for about 2 to 10 hours.

From the reaction mixture after completion of the reaction of the present invention,
Known isolation and purification means, such as filtration, extraction, concentration, distillation,
The desired aryl-substituted heterocyclic compound of the general formula (3) can be isolated and purified by appropriately combining operations such as recrystallization and column chromatography.

[0061]

According to the present invention, there is provided an industrially advantageous method for producing an aryl-substituted pyridine compound or an aryl-substituted quinoline compound.

That is, since the palladium catalyst used in the method of the present invention is a solvent-insoluble palladium catalyst, the reaction is carried out in a heterogeneous system, and as a result, the catalyst can be easily recovered after completion of the reaction. There is an advantage. Moreover, such a palladium catalyst is an easily available and inexpensive catalyst. In addition, the palladium catalyst used in the method of the present invention does not have a risk of its catalytic activity being reduced or deactivated even when it comes into contact with oxygen, and does not require an operation for removing a trace amount of oxygen in the reaction system.

Further, according to the method of the present invention, the desired aryl-substituted pyridine compound or aryl-substituted quinoline compound can be produced in high yield.

[0064]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the following examples. In the following examples, "%" means "% by weight".

Example 1 Preparation of 3-phenylpyridine 420 mg (2.66 mmol) of 3-bromopyridine,
405 mg (2.66 mmol) of 80% phenylboronic acid and 122 mg (0.47 mg) of triphenylphosphine.
Mmol) was dissolved in 10 ml of 1,2-dimethoxyethane. To the solution was added 5.0 ml of a 2.0 mol / l sodium carbonate aqueous solution, and further 5% Pd / C (water content: 54%).
%) 545 mg (0.12 mmol) and
For 3 hours. After the reaction, the catalyst was filtered, washed four times with 20 ml of ethyl acetate, and the organic layer of the filtrate was washed with 30 ml of a 10% aqueous potassium hydroxide solution. Further, the organic layer was washed twice with 20 ml of saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 5: 1) to obtain 371 mg (yield 90.0%) of 3-phenylpyridine as a colorless oil. .

Example 2 Preparation of 3-phenylpyridine 122 mg of triphenylphosphine in Example 1
(0.47 mmol) instead of sodium bromide 411m
g (3.99 mmol), and the mixture was treated in the same manner as in Example 1 except that the mixture was heated and stirred at 80 ° C. for 9 hours.
0%).

Comparative Example 1 Preparation of 3-phenylpyridine 420 mg (2.66 mmol) of 3-bromopyridine and 506 mg (3.33 mmol) of 80% phenylboronic acid were dissolved in 10 ml of 1,2-dimethoxyethane. To the solution was added 5.0 ml of a 2.0 mol / l aqueous sodium carbonate solution, and further 5% Pd / C (water content 54%)
45 mg (0.12 mmol) was added, and the mixture was heated with stirring at 80 ° C. for 7 hours. After the reaction, the catalyst was filtered and ethyl acetate 20
After washing four times with 30 ml, the organic layer of the filtrate was washed with 30 ml of a 10% aqueous potassium hydroxide solution. Further, the organic layer was washed twice with 20 ml of saturated saline and dried over anhydrous sodium sulfate.
It was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to give 3-phenylpyridine 16 as a colorless oil.
9 mg (41.0% yield) was obtained.

Comparative Example 2 Preparation of 3-phenylpyridine In Example 1, 182 mg (0.80 mmol) of benzyltrimethylammonium chloride was further used, and
The same treatment as in Example 1 was carried out except that the mixture was heated and stirred at 0 ° C. for 4 hours, to give 3-phenylpyridine 277 as a colorless oil.
mg (67.2% yield).

Example 3 Preparation of 2-phenylpyridine In Example 1, 420 mg of 3-bromopyridine (2.
66 mg) instead of 420 mg of 2-bromopyridine
(2.66 mmol), except that 350 mg (yield: 85.0%) of 2-phenylpyridine as a colorless oil was obtained in the same manner as in Example 1.

Example 4 Preparation of 3-nitro-2-phenylpyridine In Example 1, 420 mg of 3-bromopyridine (2.
66 mmol), and treated in the same manner as in Example 1 except that 422 mg (2.66 mmol) of 2-chloro-3-nitropyridine was used and stirred at 80 ° C. for 5 hours to give a yellow oil. 498 mg (yield 93.5%) of certain 3-nitro-2-phenylpyridine was obtained.

Example 5 Preparation of 2-nitro-5-phenylpyridine In Example 1, 420 mg of 3-bromopyridine (2.
66 mmol) was replaced with 3-bromo-6-nitropyridine (540 mg, 2.66 mmol) and heated and stirred at 80 ° C. for 6 hours in the same manner as in Example 1 to give a pale yellow oil. 429 mg (80.6% yield) of 2-nitro-5-phenylpyridine was obtained.

Example 6 Preparation of 3-cyano-2-phenylpyridine In Example 1, 420 mg of 3-bromopyridine (2.
The reaction was carried out in the same manner as in Example 1 except that 369 mg (2.66 mmol) of 2-chloro-3-cyanopyridine was used instead of (66 mmol) and the mixture was heated and stirred at 80 ° C. for 7 hours. Next, in the post-reaction treatment of Example 1, a colorless solid was obtained in the same manner as in Example 1, except that the eluent used for purification by silica gel column chromatography was changed to n-hexane: ethyl acetate = 3: 1. 477 mg of 3-cyano-2-phenylpyridine (99.5 yield)
%).

Example 7 Preparation of 2-phenyl-5-trifluoromethylpyridine In Example 1, 420 mg of 3-bromopyridine (2.
482 mg (2.66 mmol) of 2-chloro-5-trifluoropyridine was used instead of
The reaction was carried out in the same manner as in Example 1, except that the mixture was heated and stirred at 7 ° C for 7 hours. Next, in the post-reaction treatment of Example 1, a colorless oil was obtained in the same manner as in Example 1 except that the eluent used for purification by silica gel column chromatography was changed to n-hexane: ethyl acetate = 15: 1. Some 2
-Phenyl-5-trifluoromethylpyridine 504 mg
(85.0% yield).

Example 8 Production of 3-phenylquinoline In Example 1, 420 mg of 3-bromopyridine (2.
553 mg of 3-bromoquinoline instead of 66 mmol)
The reaction was carried out in the same manner as in Example 1 except that (2.66 mmol) was used. Next, in the post-reaction treatment of Example 1, the same procedure as in Example 1 was carried out except that the eluent used for purification by silica gel column chromatography was changed to n-hexane: ethyl acetate = 9: 1, to obtain a colorless oil. 444 mg of a certain 3-phenylquinoline (yield 81.5
%).

Example 9 Preparation of 3-naphthylquinoline In Example 1, 420 mg of 3-bromopyridine (2.
435 mg of 2-chloroquinoline instead of 66 mmol)
(2.66 mmol), using 458 mg (2.66 mmol) of 2-naphthylboron instead of 405 mg (2.66 mmol) of 80% phenylboronic acid,
The reaction was carried out in the same manner as in Example 1 except that the mixture was heated and stirred at 0 ° C. for 5 hours. Next, in the post-reaction treatment of Example 1,
The same procedure as in Example 1 was carried out except that the eluent in the purification by silica gel column chromatography was changed to n-hexane: benzene = 1: 2, to obtain a colorless solid 2-
573 mg of (2-naphthyl) quinoline (yield 84.5)
%).

Example 10 Preparation of 2,3'-dipyridyl 420 mg (2.66 mmol) of 2-bromopyridine,
Diethyl (3-pyridyl) borane 300 mg (2 mmol) and triphenylphosphine 122 mg (0.47
Mmol) was dissolved in 10 ml of tetrahydrofuran. To the solution was added 336 mg (6.5 mmol) of potassium hydroxide, and 5% Pd / C (water content 54%) 545 was added.
mg (0.12 mmol) was added and the mixture was heated and stirred at 80 ° C. for 3 hours. After the reaction, the catalyst was filtered and ethyl acetate 20 ml
And washed 4 times. Further, the organic layer was washed with 20 ml of a saturated saline solution.
It was washed twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) to give 2,3′-dipyridyl 300 as a colorless oil.
mg was obtained quantitatively.

Continued on the front page F-term (reference) 4C055 AA01 BA01 BA02 BA08 BA51 CA01 CA02 CA08 CA13 CA51 CA59 CB14 DA01 EA01 FA01 FA03 FA32 FA34 FA37 4H039 CA41 CA42 CA51 CA70 CA72 CD20

Claims (6)

[Claims] 1. General formula (1): [Wherein, X represents a halogen atom. R ¹ and R ² are the same or different and are each a hydrogen atom, an alkyl group, an alkoxy group,
It represents a nitro group, a cyano group or a fluoroalkyl group. Alternatively, R ¹ and R ² may be joined together with two adjacent carbon atoms on the pyridine ring to form a 6-membered aromatic ring. A halogen-substituted heterocyclic compound represented by the formula:
In a solvent, at least one selected from the group consisting of (a) a base, (b) a triarylphosphine and an alkali (earth) metal halide (excluding fluoride), and (c) a solvent-insoluble palladium catalyst. The following is a general formula (2): [In the formula, Z represents a carbon atom or a nitrogen atom. When Z represents a carbon atom, R ³ represents a hydrogen atom, an alkyl group, an alkoxy group or an acyl group, R ⁴ and R ⁵ represent a hydroxyl group, and n represents 1 or 2. When Z represents a nitrogen atom, R ³ represents a hydrogen atom, R ⁴ and R ⁵ represent an alkyl group, and n represents 1. With an arylborane compound represented by the general formula (3): Wherein Z, R ¹ , R ² , R ³ and n are the same as above. A method for producing an aryl-substituted heterocyclic compound, characterized by obtaining the aryl-substituted heterocyclic compound represented by the formula: 2. The base is at least one inorganic selected from the group consisting of alkali metal carbonates, alkali metal hydroxides, alkali metal phosphates, alkali metal fluorides and basic salts of alkaline earth metals. 2. The method according to claim 1, which is a base. 3. The method according to claim 1, wherein the palladium catalyst is at least one selected from the group consisting of palladium carbon and palladium alumina. 4. An alkali (earth) metal halide,
The method according to claim 1, wherein the method is at least one selected from the group consisting of an alkali metal bromide and an alkali metal chloride. 5. The method according to claim 1, wherein the solvent is at least one selected from the group consisting of water, ethers, amides, nitriles, ketones, alcohols and aromatic hydrocarbons. 6. The method according to claim 1, wherein the reaction is carried out under heating at about 50 to 150 ° C.