JP2006306758A - Method for producing biaryl compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for synthesizing a biaryl compound, making it possible that an unstable triarylborane compound is industrially used in a stable form by Suzuki-Miyaura reaction and economically useful. <P>SOLUTION: This method for producing the biaryl compound expressed by Ar<SP>1</SP>-Ar<SP>2</SP>(Ar<SP>1</SP>is phenyl or the like; and Ar<SP>2</SP>is phenyl or the like) comprises reacting any one of a triarylboron amine complex expressed by Ar<SP>1</SP><SB>3</SB>B-NR<SP>1</SP>R<SP>2</SP>R<SP>3</SP>(R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>are each H, an aklyl or the like) and an organic boron-alkali metal hydroxide adduct expressed by Ar<SP>1</SP><SB>3</SB>B-WOH (W is Na or the like) with an aromatic or unsaturated heterocyclic compound expressed by Ar<SP>2</SP>X (Ar<SP>2</SP>is phenyl or the like; and X is a halogen or the like) in the presence of a transition metal-based catalyst expressed by MY<SB>n</SB>L<SB>m</SB>and, if necessary, a phosphine ligand and in the coexistence of a base. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel process for producing biaryl compounds important as intermediates for medicines and agricultural chemicals.

  Several methods for producing a biaryl compound have been known so far, but as an efficient synthesis method thereof, an organoboron compound has recently been converted to a halogenated aryl compound or a sulfonic acid in the presence of a palladium catalyst and a base. A method utilizing the Suzuki-Miyaura reaction, which is characterized by carrying out a coupling reaction with the aryl esters of the above, has been attracting attention.

As an organic boron compound used for such a reaction, an arylboric acid derivative, a tetraarylborate derivative, a triarylborane derivative, and the like are known.
Among these boron compounds, tetraarylborate derivatives such as sodium tetraphenylborate are known to react with 2-trifluoromethanesulfonyloxynaphthalene in the presence of a palladium catalyst to produce 2-phenylnaphthalene. (Non-Patent Document 1). In this case, sodium tetraphenylborate has four phenyl groups in the molecule, but when only one phenyl group is consumed by the first coupling reaction, triphenylborane is produced, and then the produced triphenylborane is produced. It has been reported that the phenyl group of phenylborane sequentially reacts to finally generate four molecules of 2-phenylnaphthalene (Non-patent Document 1).

However, the triarylborane derivative is unstable in the air or the reason is not clear, but no synthesis example of a biaryl compound using this directly has been reported yet.
On the other hand, triarylborane derivatives are known to form stable complexes with amines. For example, it has been reported that triphenylborane reacts with various amines to produce a triphenylborane / methylamine complex, a triphenylborane / pyridine complex, a triphenylborane / octadecylamine complex, etc. 2, Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5). These triarylboraneamine complexes are known to have activity as antifouling agents for ship bottom paints or fishing nets, or as agricultural fungicides or insecticides. Is not known to produce.

  Furthermore, these triarylborane derivatives are also known to form stable adducts with alkali metal hydroxides such as sodium hydroxide and potassium hydroxide (Patent Documents 2 and 7).

It has also been reported that a triphenylborane-amine complex can be easily obtained by the reaction of triphenylborane sodium hydroxide adduct or triphenylborane potassium hydroxide adduct with various amines. (Patent Document 8)
However, it is not known that these triarylboron complex compounds react with aryl halides to form biaryl compounds.
Tetrahedron Letters, 1992, 33, 4815 Journal of the American Chemical Society, 83, 2663 U.S. Pat. No. 3,321,679 US Pat. No. 3,268,401 U.S. Pat. No. 3,475,496 Japanese Patent Laid-Open No. 10-330381 Japanese Patent Laid-Open No. 11-29283 Japanese Patent Publication No.62-277307 JP-A-62-32197 JP-A-8-311074

As described above, in the production of biaryl compounds using the Suzuki-Miyaura reaction, among the usable organic boron compounds, arylboric acid derivatives have been most commonly used in the past. Is disadvantageous. In addition, since the arylboric acid compound has one aryl group in the molecule, the production of a biaryl compound using the Suzuki-Miyaura reaction requires equimolar amounts with respect to the aryl compound as the reaction partner. It is disadvantageous in terms of efficient use.

  On the other hand, triarylborane derivatives and tetraarylborate derivatives have 3 or 4 aryl groups in the molecule, and all these aryl groups can participate in the reaction, so that boron should be used efficiently. Can do.

  Tetraaryl borates such as sodium tetraphenylborate are produced at a relatively low cost compared to aryl boric acid derivatives. However, triarylborane derivatives are produced as intermediates, and triarylborane derivatives as intermediates are produced. A wider range of derivatives can be used if they can be used directly in the Suzuki-Miyaura reaction. However, these triarylborane derivatives have a problem in stability in air such as being ignitable, and are difficult to use in industrial production.

  The present invention is intended to solve the problems associated with the prior art as described above, and is a biaryl compound that can produce a biaryl compound useful in the chemical industry in a safer, more efficient and less expensive manner. The object is to provide a novel manufacturing method.

  The inventors of the present invention have made extensive studies in order to achieve the above object. As a result, we found that by converting triarylborane derivatives into stable and easy-to-handle compounds in air, they can be handled more safely and easily, and biaryl compounds can be produced safely and efficiently at low cost. The present invention has been completed.

That is, the first method for producing a biaryl compound according to the present invention includes:
Any one of the organic boron amine complex compound represented by the following general formula (1-A) and the organic boron-alkali metal hydroxide adduct represented by the general formula (1-B);
An aromatic or unsaturated heterocyclic compound represented by the general formula (2),
In the presence of a transition metal catalyst and, if necessary, a phosphine ligand added, a base is allowed to coexist (more specifically, a transition metal, a transition metal compound or a transition metal complex of formula (6) alone Or in addition to various phosphine ligands and in the presence of a base, the reaction is carried out in the method for producing a biaryl compound represented by the following general formula (7).

Organic boron amine complex compound (1-A):
Ar ¹ ₃ B · NR ¹ R ² R ³ (1-A)
[In the formula (1-A), a plurality of Ar ¹ 's each independently represent a phenyl group, a naphthyl group or a pyridyl group, and these groups are each independently a lower alkyl group, a lower alkoxy group, a lower alkoxy group, It may be substituted with 1 to 5 substituents selected from a group-containing lower alkyl group, lower haloalkyl group, and halogen atom, and the lower alkyl group moiety and lower alkoxy group moiety in each of the above groups Each independently has 1 to 6 carbon atoms,
R ¹ , R ² and R ³ are each independently a hydrogen atom, a linear or branched alkyl group having 1 to 20 carbon atoms; a linear or branched alkenyl group having 2 to 20 carbon atoms; carbon A linear or branched alkynyl group having 2 to 20 carbon atoms; a cycloalkyl group having 3 to 20 carbon atoms; a phenyl group; an aralkyl group; or a heterocyclic group, or N, R ¹ , R ² and R ³ forms a ring and represents a saturated or unsaturated heterocycle,
The phenyl group and the aralkyl group are each independently substituted with 1 to 5 substituents selected from a lower alkyl group, a lower alkoxy group, a lower alkoxy group-containing lower alkyl group, a lower haloalkyl group, and a halogen atom. May also have been
The lower alkyl group moiety and the lower alkoxy group moiety in the substituent each independently have 1 to 6 carbon atoms,
The heterocyclic group is a saturated group or an unsaturated group and includes a nitrogen atom, an oxygen atom or a sulfur atom, and N, R ¹ , R ² and R ^{3 in} the formula (1-A) are bonded to each other. A ring structure may be formed. ]
Organoboron-alkali metal hydroxide adduct (1-B):
_{^{Ar 1 3 B · WOH ·········· (}} 1-B)
[In Formula (1-B), Ar ¹ represents the same meaning as described above, and W represents sodium, potassium, or lithium. ]
Aromatic or unsaturated heterocyclic compound (2):
Ar ² X (2)
[In the formula (2), Ar ² represents a phenyl group, a naphthyl group or a pyridyl group, and
These groups are each independently a lower alkyl group, lower alkoxy group, lower alkoxy group-containing lower alkyl group, lower haloalkyl group, halogen atom, lower alkoxycarbonyl group, carboxy group, formyl group, lower alkylcarbonyl group, lower alkylsulfonyl group. Group, a cyano group and a nitro group may be substituted with 1 to 5 substituents, and the lower alkyl group moiety and the lower alkoxy group moiety in each of the above groups are each independently carbon. It is number 1-6,
X is a halogen atom or a sulfonyloxy group represented by the general formula (3),
R ⁴ SO ₂ O- (3)
{In Formula (3), R ⁴ is a linear or branched alkyl group having 1 to 20 carbon atoms;
-20 linear or branched alkenyl group; linear or branched alkynyl group having 2 to 20 carbon atoms; cycloalkyl group having 3 to 20 carbon atoms; phenyl group; naphthyl group; aralkyl group; A methyl group; and any one of pentafluoroethyl groups;
The phenyl group, naphthyl group and aralkyl group are each independently 1 to 5 substituents selected from a lower alkyl group, a lower alkoxy group, a lower alkoxy group-containing lower alkyl group, a lower haloalkyl group, and a halogen atom. May be substituted with a group,
The lower alkyl group part and the lower alkoxy group part in the substituent each independently have 1 to 6 carbon atoms. }
Or the acyloxy group represented by General formula (4) is shown.
R ⁴ COO- (4)
(In formula (4), R ⁴ has the same meaning as described above.)]
Biaryl compound (7):
Ar ¹ -Ar ² (7)
[In the formula (7), Ar ¹ and Ar ² have the same meaning as described above. ].

A second method for producing a biaryl compound according to the present invention includes:
Boron amine complex compound represented by the general formula (1-A):
Ar ¹ ₃ B · NR ¹ R ² R ³ (1-A)
[In the formula (1-A), Ar ¹ , R ¹ , R ² and R ³ have the same meaning as described above. ]
When,
Aromatic or unsaturated heterocyclic compound represented by general formula (2):
Ar ² X (2)
[In the formula (2), Ar ² and X have the same meaning as described above. ]
And
In the presence of a transition metal catalyst represented by the general formula (6) consisting of a transition metal, a transition metal compound or a transition metal complex, and a phosphine ligand added if necessary, the reaction is carried out in the presence of a base. In the method for producing a biaryl compound represented by the general formula (7),
MY _n L _m (6)
[In the formula (6), M represents nickel, palladium or rhodium having a valence of 0 to 2, Y represents a halogen ion, nitrate ion or acetoxy ion, and n represents an integer of 0 to 2. , M represents 0 or an integer of 1 to 4.

In the formula (6), when m is an integer other than 0, 1 to a plurality of Ls are independently of each other R ⁵ R ⁶ R ⁷ P, R ⁸ R ⁹ P (CH ₂ ) qPR ^10. R ¹¹ , R ¹² COCH ₂ COR ¹³ , R ¹⁴ CN,
A linear or cyclic alkene having 4 to 20 carbon atoms and two or more double bonds, or R ¹⁵ COR ¹⁶ , wherein R ^{5 to} R ¹⁶ may be the same as or different from each other;
A linear or branched alkyl group having 1 to 20 carbon atoms; a linear or branched alkenyl group having 2 to 20 carbon atoms; a linear or branched alkynyl group having 2 to 20 carbon atoms; 3 to 20 cycloalkyl groups; a phenyl group; any group selected from a naphthyl group and an aralkyl group;
The phenyl group, naphthyl group and aralkyl group are each independently 1 to 5 substituents selected from a lower alkyl group, a lower alkoxy group, a lower alkoxy group-containing lower alkyl group, a lower haloalkyl group, and a halogen atom. May be substituted with a group,
The alkenyl group may be substituted with a phenyl group,
The lower alkyl group moiety and the lower alkoxy group moiety in the substituent each independently have 1 to 6 carbon atoms,
q represents an integer of 1 to 10. ]
Ar ¹ -Ar ² (7)
[In the formula (7), Ar ¹ and Ar ² have the same meaning as described above. ].

A third method for producing a biaryl compound according to the present invention includes:
Organoboron-alkali metal hydroxide adduct represented by the above general formula (1-B):
_{^{Ar 1 3 B · WOH ····· (}} 1-B)
[In the formula (1-B), Ar ¹ and W have the same meaning as described above. ]
When,
Aromatic or unsaturated heterocyclic compound represented by the general formula (2):
Ar ² X (2)
[In the formula (2), Ar ² and X have the same meaning as described above. ]
And
In the presence of a transition metal catalyst represented by the above general formula (6) consisting of a transition metal, a transition metal compound or a transition metal complex, and a phosphine ligand added if necessary, a reaction is carried out in the presence of a base. There exists in the manufacturing method of the biaryl compound represented by General formula (7) characterized by making it produce.
Ar ¹ -Ar ² (7)
[In the formula (7), Ar ¹ and Ar ² represent the same meaning as described above. ]
That is, the present invention provides any one of an organoboron amine complex compound (1-A) and an organoboron-alkali metal hydroxide adduct (1-B),
An aromatic or unsaturated heterocyclic compound (2), that is, an aryl compound (2) substituted by a halogen atom, a sulfonic acid group, or an acyloxy group,
It is characterized by using a transition metal catalyst (6) such as a transition metal or a transition metal complex alone, or adding various phosphine ligands if necessary, and performing a coupling reaction in the presence of a base. And a method for producing a biaryl compound (7).

  According to the present invention, by converting the triarylborane derivative into a stable and easy-to-handle compound in the air, it can be easily handled without special care such as handling in an oxygen-free state. A novel method for producing a biaryl compound is provided so that the above useful biaryl compound can be produced more safely, efficiently and inexpensively.

Hereinafter, the method for producing a biaryl compound according to the present invention will be specifically described.
[Method for producing biaryl compound]
In the method for producing a biaryl compound according to the present invention, as represented by the following formula (X), the organic boron amine complex compound represented by the general formula (1-A) and the general formula (1-B) Any of the organoboron-alkali metal hydroxide adducts to be produced;
An aromatic or unsaturated heterocyclic compound represented by the general formula (2),
In the presence of a transition metal catalyst and, if necessary, a phosphine ligand added, a base is allowed to coexist. A catalyst obtained by adding a transition metal, a transition metal compound, or a transition metal complex (these are collectively referred to as a transition metal-based catalyst) alone, or by adding various phosphine ligands to any one or more of them as necessary. In the presence of the system, a base is allowed to coexist if necessary} and the reaction is carried out in a normal solvent to produce a biaryl compound represented by the general formula (7).

[In formula (X), the definition of each symbol in (1-A), (1-B), (2), (7) is the same as above. ]
In the above reaction, the organic boron amine complex compound (1-A) (component (1-A)) or the organic boron-alkali is used per 1 mol of the aromatic or unsaturated heterocyclic compound (2) (component (2)). The metal hydroxide adduct (1-B) (component (1-B)) is theoretically an amount of 1/3 mol, and usually the component (1-A) or the component (1-B) is 0. Used in an amount of 25-0.7 mol, preferably 0.3-0.6 mol, usually carried out at a temperature in the range from −100 ° C. to the reflux temperature of the solvent under a pressure of 0-1000 KPa. However, considering points such as reaction efficiency, operability, and safety, it is often carried out at 0 to 150 ° C. under normal pressure.

Hereinafter, each component used in the above reaction will be described in detail.
<Organic boron amine complex compound (1-A)>
Ar ¹ ₃ B · NR ¹ R ² R ³ (1-A)
Ar ¹ :
In the organoboronamine complex compound (1-A), a plurality of Ar ^{1 s} independently represent a phenyl group, a naphthyl group, or a pyridyl group, and these groups are each independently a lower alkyl group, a lower alkoxy group. Group, lower alkoxy group-containing lower alkyl group, lower haloalkyl group, and optionally substituted with 1 to 5 substituents selected from halogen atoms, and the lower alkyl group moiety in each of the above groups, Each lower alkoxy group has 1 to 6 carbon atoms independently.

Here, the lower alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, normal propyl group, normal butyl group, normal pentyl group, normal hexyl. Group, 1-methylethyl group, 1-methylpropyl group, 2-methylpropyl group, 3-methylbutyl group, 4-methylpentyl group, 1,1-dimethylethyl group, 1,1-dimethylpropyl group, 2,2 -A dimethylpropyl group etc. are mentioned.

  The lower alkoxy group represents an alkoxy group having 1 to 6 carbon atoms and having a linear or branched alkyl group. For example, a methoxy group, an ethoxy group, a normal propoxy group, a normal butoxy group, a normal pentyloxy group, Normal hexyloxy group, 1-methylethoxy group, 1-methylpropoxy group, 2-methylpropoxy group, 2-methylbutoxy group, 3-methylbutoxy group, 1,1-dimethylethoxy group, 1,1-dimethylpropoxy group 2,2-dimethylpropoxy group and the like.

  The lower alkoxy group-containing lower alkyl group represents a lower alkyl group substituted with an alkoxy group having a linear or branched alkyl group, each having 1 to 6 carbon atoms in the alkyl group part and the alkoxy part. For example, methoxymethyl group, ethoxymethyl group, normal propoxymethyl group, 1-methoxyethyl group, 1-ethoxyethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 1-methoxypropyl group, 2-methoxypropyl Group, 3-methoxypropyl group, 4-methoxybutyl group, 4-methoxypentyl group, 4-methoxyhexyl group, 1-methoxy-1-methylethyl group, 2-methoxy-1-methylethyl group, 1,1- Dimethoxymethyl group, 1,1-diethoxymethyl group, 1,1-dimethoxyethyl group, 1,1-diethoxyethyl group And the like.

  Examples of lower haloalkyl groups include trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, heptafluoropropyl, trichloromethyl, 2,2,2-trichloroethyl, and the like. It is done.

Examples of the phenyl group, naphthyl group or pyridyl group which may be substituted as described above include, for example, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3 -Ethylphenyl group, 4-ethylphenyl group, 2-normalpropylphenyl group, 3-normalpropylphenyl group, 4-normalpropylphenyl group, 2-isopropylphenyl group, 3-isopropylphenyl group, 4-isopropylphenyl group, 2-tertiarybutylphenyl group, 3-tertiarybutylphenyl group, 4-tertiarybutylphenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 3, 4-dimethylphenyl group, 3,5-dimethylphenyl group, 4-ethylphenyl group 2-isopropylphenyl group, 3-isopropylphenyl group, 4-isopropylphenyl group, 2-tertiarybutylphenyl group, 3-tertiarybutylphenyl group, 4-tertiarybutylphenyl group, 2-chlorophenyl group, 3-chlorophenyl Group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, 2, 5-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 2,3,4,5,6-pentafluorophenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4 -Methoxyphenyl group, 2,3-dimethoxyphenyl group, 2,4-dimeth Siphenyl group, 2,5-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 3,4,5-trimethoxyphenyl group, 2-tertiary butoxyphenyl group, 3-tertiary Butoxyphenyl group, 4-tert-butoxyphenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 1-naphthyl group, 2-naphthyl group, 2-methyl- 1-naphthyl group, 3-methyl-1-naphthyl group, 4-methyl-1-naphthyl group, 5-methyl-1-naphthyl group, 6-methyl-1-naphthyl group, 7-methyl-1-naphthyl group, 8-methyl-1-naphthyl group, 3-methyl-2-naphthyl group, 4-methyl-2-naphthyl group, 5-methyl-2-naphthyl group, 6- Tyl-2-naphthyl group, 7-methyl-2-naphthyl group, 6-fluoro-1-naphthyl group, 7-fluoro-1-naphthyl group, 6-fluoro-2-naphthyl group, 7-fluoro-2-naphthyl group Group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-methyl-2-pyridyl group, 4-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2- Pyridyl group, 2-methyl-3-pyridyl group, 4-methyl-3-pyridyl group, 4-fluoro-2-pyridyl group, 2,5-dimethyl-4-pyridyl group, 3,5-dimethyl-2-pyridyl group Groups and the like.
R ¹ , R ² and R ³ :
R ¹ , R ² and R ³ are each independently a hydrogen atom, a linear or branched alkyl group having 1 to 20 carbon atoms; a linear or branched alkenyl group having 2 to 20 carbon atoms; carbon A linear or branched alkynyl group having 2 to 20 carbon atoms; a cycloalkyl group having 3 to 20 carbon atoms; a phenyl group; an aralkyl group; or a heterocyclic group;
The phenyl group and the aralkyl group are each independently substituted with 1 to 5 substituents selected from a lower alkyl group, a lower alkoxy group, a lower alkoxy group-containing lower alkyl group, a lower haloalkyl group, and a halogen atom. May also have been
The lower alkyl group moiety and the lower alkoxy group moiety in the substituent each independently have 1 to 6 carbon atoms,
The heterocyclic group is a saturated group or an unsaturated group and may contain a nitrogen atom, an oxygen atom or a sulfur atom, and N, R ¹ , R ² and R ^{3 in the} formula (1-A) May be bonded to each other to form a ring structure. {When N, R ¹ , R ² and R ³ are bonded to each other to form a ring structure, N, R ¹ , R ² , R ³ can be A ring structure is formed, and the ring structure includes any one of nitrogen atom (N), oxygen atom (O), sulfur atom (S) (only the same kind of atoms) or two or more kinds. The total number of atoms (including different atoms) may be 0 to 4 (where N is 1 or more). }
Here, the alkyl group represents a linear or branched alkyl group, and examples thereof include the same groups as described above, such as a methyl group, an ethyl group, and a normal propyl group.

  Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl 1-propenyl, 1,1-dimethyl-2 -A propenyl group, 3-pentenyl group, 4-pentenyl group, etc. are mentioned.

  Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl 1-propynyl, 1,1-dimethyl-2 -A propynyl group, 3-pentynyl group, 4-pentynyl group, etc. are mentioned.

  Examples of aralkyl groups include benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 1-methyl-1-phenylethyl group, etc. Is mentioned.

The cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a 2-methylcyclopentyl group, a 2-methylcyclohexyl group, or a 2,2-dimethylcyclopropyl group. 2,2-dimethylcyclopentyl group, 2,2-dimethylcyclohexyl group and the like.

  Examples of the heterocyclic group or heterocyclic compound include pyrrolidine, piperidine, morpholine, 2,2,6,6-tetramethylpiperidine, pyridine, quinoline, pyrazole, imidazole, 1,3-thiazole, indole, benzimidazole, 1,3-benzothiazole, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,4-dimethylpyridine, 2,6-dimethylpyridine 3,5-dimethylpyridine, 2-methoxypyridine, 3-methoxypyridine, 4-methoxypyridine, 2-chloropyridine, 4-isopropylpyridine, 1-methylpyrazole, 1,3-dimethylpyrazole, 3,5-dimethyl Pyrazole, 1,3,5-trimethylpyra Lumpur, 1-methylimidazole, 1-methylimidazole, 2,5-dimethyl imidazole.

Among such R ¹ , R ² and R ³ , a hydrogen atom, the above alkyl group, and a heterocyclic pyridyl group formed by jointly N and R ¹ , R ² and R ³ are preferred, R ¹ , When R ² and R ³ are each composed of H or an alkyl group, they may be the same as or different from each other. Specifically, for example, R ¹ , R ² , R ³ are all alkyl groups, for example, triethyl (amine), any two are alkyl groups, and one is H (one), etc. Is mentioned.

Of these various organic boron amine complex compounds (1-A) of Ar ¹ , R ¹ , R ² and R ³ , the phenyl group contained may be substituted with a lower alkyl group. Borane / pyridine complex, triphenylborane / mono, di, tri-lower alkylamine complex, etc. are preferable,
Specific examples of the triphenylborane / pyridine complex which may be alkyl-substituted include a triphenylborane / pyridine complex and a tris (4-methylphenyl) borane / pyridine complex.

Examples of the triphenylborane-mono, di, and tri-lower alkylamine complexes include triphenylborane / triethylamine complexes, triphenylborane / diethylamine complexes, and triphenylborane / isopropylamine complexes.
<Organic boron-alkali metal hydroxide adduct (1-B)>
_{^{Ar 1 3 B · WOH ·········· (}} 1-B)
[In Formula (1-B), Ar ¹ represents the same meaning as described above, and W represents sodium, potassium, or lithium. ]
That is, in the formula (1-B), a plurality of Ar ¹ each independently represent a phenyl group, a naphthyl group or a pyridyl group, and these groups are each independently a lower alkyl group, a lower alkoxy group, a lower group, It may be substituted with 1 to 5 substituents selected from an alkoxy group-containing lower alkyl group, a lower haloalkyl group, and a halogen atom, and a lower alkyl group moiety, a lower alkoxy group in each of the above groups Each part has 1 to 6 carbon atoms independently.

As such an organic boron-alkali metal hydroxide adduct (1-B), specifically, for example, triphenylborane sodium hydroxide adduct, triphenylborane potassium hydroxide adduct, triphenylborane hydroxide adduct Examples include lithium adducts.
<Aromatic or unsaturated heterocyclic compound (2)>
Ar ² X (2)
[In the formula (2), Ar ² represents a phenyl group, a naphthyl group or a pyridyl group, and
These groups are each independently a lower alkyl group, lower alkoxy group, lower alkoxy group-containing lower alkyl group, lower haloalkyl group, halogen atom, lower alkoxycarbonyl group, carboxy group, formyl group, lower alkylcarbonyl group, lower alkylsulfonyl group. Group, a cyano group and a nitro group may be substituted with 1 to 5 substituents, and the lower alkyl group moiety and the lower alkoxy group moiety in each of the above groups are each independently carbon. Formula 1-6.

X is a halogen atom or a sulfonyloxy group represented by the general formula (3),
R ⁴ SO ₂ O- (3)
{In Formula (3), R ⁴ is a linear or branched alkyl group having 1 to 20 carbon atoms;
-20 linear or branched alkenyl group; linear or branched alkynyl group having 2 to 20 carbon atoms; cycloalkyl group having 3 to 20 carbon atoms; phenyl group; naphthyl group; aralkyl group; A methyl group; and any one of pentafluoroethyl groups;
The phenyl group, naphthyl group and aralkyl group are each independently 1 to 5 substituents selected from a lower alkyl group, a lower alkoxy group, a lower alkoxy group-containing lower alkyl group, a lower haloalkyl group, and a halogen atom. May be substituted with a group,
The lower alkyl group part and the lower alkoxy group part in the substituent each independently have 1 to 6 carbon atoms. },
Or the acyloxy group represented by General formula (4) is shown.
R ⁴ COO- (4)
(In formula (4), R ⁴ has the same meaning as described above.)]
Specific examples of such aromatic compounds or unsaturated heterocyclic compounds (also referred to as compounds (2) and aryl compounds (2)) include, for example, 4-bromoanisole, 1-bromo- 4-methoxy benzene), 4-bromotoluene, 4-chloroiodobenzene, bromobenzene, 4-chloroacetophenone (metyl-4-chloro-phenyl ketone), 2-trifluoromethanesulfonyloxynaphthalene, etc. Group compounds;
And unsaturated heterocyclic compounds such as 3-bromopyridine.
<Biaryl compound (7)>
Ar ¹ -Ar ² (7)
[In the formula (7), Ar ¹ and Ar ² have the same meaning as described above. ].

As such a biaryl compound (7), specifically, 4-methoxybiphenyl, 4-
Methylbiphenyl, 4-acetylbiphenyl, 2-phenylnaphthalene, 4-chloro-4'-
Examples include methylbiphenyl, 3-phenylpyridine, 4-fluorobiphenyl, 4-phenylbenzoic acid, 4-formylbiphenyl, and the like.

When a heterocyclic compound such as 3-bromopyridine (see Example 13) is used as the aromatic or unsaturated heterocyclic compound (2), an aromatic-heterocyclic compound is produced as the compound (7). However, in the present invention, including such compounds, the biaryl compound (7) is generically called for convenience. Similarly, the aromatic compound and the unsaturated heterocyclic compound (2) may be collectively referred to as an aryl compound (2) for convenience.
<Solvent>
The above reaction is usually performed in a solvent.

As a solvent, water; or
Alcohol solvents such as methanol, ethanol, normal propyl alcohol, isopropyl alcohol, normal butyl alcohol, isobutyl alcohol, secondary butyl alcohol, tertiary butyl alcohol, normal pentyl alcohol, cyclopentyl alcohol, cyclohexyl alcohol, ethylene glycol, propylene glycol, glycerol;
Ether solvents such as diethyl ether, di-normal butyl ether, methyl tertiary butyl ether, 1,2-dimethoxyethane, 1,3-dimethoxypropane, tetrahydrofuran and 1,4-dioxane;
Aromatic hydrocarbon solvents such as benzene, toluene, xylene;
Hydrocarbon solvents such as normal hexane, normal heptane, isooctane, cyclopentane, cyclohexane;
Nitrile solvents such as acetonitrile and propionitrile;
N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethylimidazolidinone, N-methylpyrrolidone (1-methyl-2-pyrrolidone, N-methyl-2-
Amide solvents such as pyrrolidone);
Sulfoxide solvents such as dimethyl sulfoxide and sulfolane;
Or these mixed solvents can be used.

  In the present invention, water, methanol, ethanol, normal propanol, isopropanol, tetrahydrofuran, 1,4-dioxane and a mixed solvent thereof are preferably used. In addition, the solvent which can be used by this invention is not restricted to these.

Although the amount of these solvents to be added is not particularly limited, the solvent is usually used in an amount of about 0 (not included) to about 100 times mol per 1 mol of the organoboronamine complex compound (1-A). <Transition metal catalyst, phosphine ligand>
Transition metal catalysts:
The transition metal catalyst used in the present invention is represented by the following general formula (6).
MY _n L _m (6)
[In the formula (6), M represents nickel, palladium or rhodium having a valence of 0 to 2, Y represents a halogen ion, nitrate ion or acetoxy ion, and n represents an integer of 0 to 2. , M represents 0 or an integer of 1 to 4.

In the formula (6), when m is an integer other than 0, 1 to a plurality of Ls are independently of each other R ⁵ R ⁶ R ⁷ P, R ⁸ R ⁹ P (CH ₂ ) qPR ^10. R ¹¹ , R ¹² COCH ₂ COR ¹³ , R ¹⁴ CN,
A linear or cyclic alkene having 4 to 20 carbon atoms and two or more double bonds, or R ¹⁵ COR ¹⁶ , wherein R ^{5 to} R ¹⁶ may be the same as or different from each other;
A linear or branched alkyl group having 1 to 20 carbon atoms; a linear or branched alkenyl group having 2 to 20 carbon atoms; a linear or branched alkynyl group having 2 to 20 carbon atoms; 3 to 20 cycloalkyl groups; a phenyl group; any group selected from a naphthyl group and an aralkyl group;
The phenyl group, naphthyl group and aralkyl group are each independently 1 to 5 substituents selected from a lower alkyl group, a lower alkoxy group, a lower alkoxy group-containing lower alkyl group, a lower haloalkyl group, and a halogen atom. May be substituted with a group,
The alkenyl group may be substituted with a phenyl group,
The lower alkyl group part and the lower alkoxy group part in the substituent each independently have 1 to 6 carbon atoms, and q represents an integer of 1 to 10. ]
This transition metal catalyst (6) can be represented by the following formula (5-A) when m = 0 in formula (6).
MY _n (5-A)
[In the formula (5-A), M represents nickel, palladium or rhodium having a valence of 0 to 2, Y represents a halogen ion, nitrate ion or acetoxy ion, and n is an integer of 0 to 2. Indicates. ]
Among the transition metal-based catalysts (6) (or (5-A)) (corresponding to n = 0 and m = 0 in the formula (6)), the metal catalyst M is as described above. Palladium, nickel, rhodium, etc. are mainly used.

Further, as the transition metal catalyst (6), m = 0, in particular, palladium (II) chloride, palladium (II) acetate, palladium (II) nitrate, nickel chloride (N) represented by the formula (5-A) II), nickel acetate (II), nickel nitrate (II), rhodium chloride (III), and the like are mentioned. Palladium salts such as palladium chloride (II) and palladium (II) acetate are preferably used.

When the transition metal catalyst (6) is a metal complex catalyst, such transition metal complexes include tetrakis (triphenylphosphine) palladium (0), bis (acetylacetonato) palladium (II), dichlorobis (Acetonitrile) palladium (II), bisbenzonitriledichloropalladium (II), bis (benzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichloro [1,1'-bis (diphenylphosphine) Fino) ferrocene] palladium (II), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (tricyclohexylphosphine) palladium (II), bis (triphenylphosphine) palladium (II) diacetate, dichloro (1,5- Cyclooctadiene) palladium (II), dichloro [1,2 Bis (diphenylphosphino) ethane] palladium (II), dichloro [1,3-bis (diphenylphosphino) propane] palladium (II), dichloro [1,4-bis (diphenylphosphino) butane] palladium (II) Etc.

The catalyst is used in an aromatic or unsaturated heterocyclic compound represented by the general formula (2) as a substrate (wherein Ar ¹ , X, R ^{4 and the} like have the same meaning as described above). On the other hand, it is selected between 0.00001 and 50 mol%, preferably 0.0001 to 5 mol%.
Ligand:
Moreover, as a transition metal catalyst (6), especially as a ligand used by adding to a metal catalyst,
Triphenylphosphine, tritertiary butylphosphine, tricyclopentylphosphine, tricyclohexylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphine) Phosphine ligands such as fino) butane, 1,1′-bis (diphenylphosphino) ferrocene;
Diketones such as acetylacetone and dibenzylideneacetone;
Dienes such as butadiene and cyclooctadiene;
Is mentioned. These ligands may be used alone or in combination of two or more.

  In the present invention, among these ligands, phosphine ligands such as triphenylphosphine, tritertiary butylphosphine, tricyclopentylphosphine, and tricyclohexylphosphine are preferable.

Although the addition amount of these ligands can be used in the range of 0.1 to 10 times the molar amount of the metal catalyst to be used, it is preferably in the range of 1 to 6 times.
<Base>
In the present invention, a base is preferably used (combined) together with the transition metal catalyst (also simply referred to as “catalyst”).
Bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, monosodium phosphate, disodium phosphate, trisodium phosphate, monopotassium phosphate, Inorganic bases such as dipotassium phosphate, tripotassium phosphate, sodium hydrogen phosphate, disodium hydrogen phosphate, sodium fluoride, potassium fluoride, cesium fluoride, cesium carbonate;
Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium normal propoxide, sodium isopropoxide, sodium tertiary butoxide, potassium tertiary butoxide;
(Chain) amines such as ammonia, methylamine, ethylamine, aniline, dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, trimethylamine, triethylamine, trinormalbutylamine, N, N-dimethylaniline, N, N-diethylaniline;
Pyrrolidine, piperidine, N-methylpyrrolidine, N-methylpiperidine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,8-diazabicyclo [5,4,0] undec-7-ene, etc. Cyclic amines of
Heterocyclic amines such as pyridine, quinoline, 2-methylpyridine, 2,6-lutidine, 4-dimethylaminopyridine, collidine;
Etc. In the present invention, these bases can be used alone or in combination.

Among these bases, the above inorganic bases are preferable, and sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and tripotassium phosphate are particularly preferable.
The amount of the base used is usually not particularly limited, but in consideration of the reaction rate, yield, economy and the like, it is an amount of about 0.5 to 100 mol with respect to 1 mol of the aryl compound (2). Used. <Synthesis of raw material boron amine complex compound and raw material organic boron-alkali metal hydroxide adduct>
In the present invention, the organic boron amine complex compound (1-A) (boron amine complex compound) used for the synthesis reaction of the biaryl compound (7) and the organic boron-alkali metal hydroxide adduct (1- B), an organic boron-alkali metal hydroxide adduct (
1-B), for example, a triphenyl boron-sodium hydroxide adduct is disclosed in JP-B-62-32.
As described in Japanese Patent No. 197, etc., 1 mol of isopropyl orthoborate is reacted with 3 mol of phenyl sodium in a cyclohexane solvent to obtain triphenylborane sodium isopropoxide, followed by hydrolysis with water. Further, by removing the alcohol by azeotropic distillation, an aqueous triphenylboron-sodium hydroxide adduct solution can be easily produced.

Further, the boron amine complex compound (1-A) is a Berichte 57B.
Vol. 813 (1924) reports that various triphenylborane-amine complexes can be synthesized by reacting anhydrous triphenylborane ether solution with amines such as methylamine, ethylamine, normalpropylamine and pyridine. It may be prepared according to the description in this publication. Further, JP-A-8-311074 discloses various triphenylborane-amine complexes by reacting a triphenylborane sodium hydroxide adduct or triphenylborane potassium hydroxide adduct with various amines in an aqueous solution. It has been reported that it can be synthesized with good yield, and may be prepared according to the description in this publication. Therefore, any of these raw material compounds (1-A) and (1-B) can be easily synthesized by a method according to the above-mentioned known or known methods.

[Example]
EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example, this invention is not limited to the following Example. (The structure of each compound (7) produced was confirmed by ¹ H-NMR, IR, Mass, literature values, etc.)

[Example 1] Production of 4-methoxybiphenyl A 300 ml four-necked flask equipped with a stirrer, a thermometer and a refluxer and purged with nitrogen was charged with 12.8 g (0.04 mol) of triphenylboranepyridine complex, sodium hydrogen carbonate. 12.6 g (0.15 mol), dichlorobis (triphenylphosphine) palladium (II) 0.7 g (0.001 mol), water 100 g, tetrahydrofuran 43 g and 4-
18.7 g (0.1 mol) of bromoanisole was weighed and heated to reflux with stirring for 2 hours. The organic layer was analyzed by gas chromatography to confirm the disappearance of 4-bromoanisole and complete the reaction. After completion of the reaction, 100 ml of toluene was added for liquid separation, and the obtained organic layer was washed with 100 ml of water. After toluene in the organic layer was distilled off under reduced pressure, purification was performed by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 50: 1) to obtain 16.8 g of colorless crystals. Its melting point was 83-84 ° C., and the yield was 91.2% based on 4-bromoanisole. The nuclear magnetic resonance spectrum (NMR) was measured and confirmed to be 4-methoxybiphenyl.

¹ H-NMR spectrum (δ in CDCl ₃ ):
7.55-6.96 (m, 9H),
3.86 (s, 3H)

[Example 2] Production of 4-methoxybiphenyl A 200 ml four-necked flask equipped with a stirrer, a thermometer and a refluxer and purged with nitrogen was charged with 6.87 g (0.02 mol) of triphenylborane triethylamine complex, sodium hydrogen carbonate. 6.3 g (0.075 mol), dichlorobis (triphenylphosphine) palladium (II) 0.35 g (0.5 mmol), water 50 g, tetrahydrofuran 22 g and 4-bromoanisole 9.4 g (0.05 mol) were weighed, The mixture was heated under reflux for 2 hours with stirring. The organic layer was analyzed by gas chromatography to confirm the disappearance of 4-bromoanisole and complete the reaction. After completion of the reaction, 80 ml of toluene was added for liquid separation, and the resulting organic layer was washed with 80 ml of water. After toluene in the organic layer was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 50: 1) to obtain 7.92 g of the title compound as colorless crystals. Its melting point was 83-84 ° C., and the yield was 86.0% based on 4-bromoanisole. Recrystallization from a normal hexane-toluene mixed solvent showed a melting point of 83-84 ° C. The structure was confirmed by ¹ H-NMR in the same manner as in Example 1.

[Example 3] Production of 4-methoxybiphenyl A stirrer, a thermometer, and a reflux condenser were attached, and a nitrogen-substituted 100 ml four-necked flask was charged with 3.2 g (0.01 mol) of triphenylborane diethylamine complex, sodium hydrogen carbonate. Weigh out 3.2 g (0.038 mol), dichlorobis (triphenylphosphine) palladium (II) 0.18 g (0.25 mmol), water 25 g, tetrahydrofuran 11 g and 4-bromoanisole 4.7 g (0.025 mol), The mixture was heated under reflux for 2 hours with stirring. The organic layer was analyzed by gas chromatography to confirm the disappearance of 4-bromoanisole and complete the reaction. After completion of the reaction, 50 ml of toluene was added for liquid separation, and the obtained organic layer was washed with 50 ml of water. After toluene in the organic layer was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 50: 1) to obtain 3.87 g of the title compound as colorless crystals. Its melting point was 83-84 ° C., and the yield was 84.0% based on 4-bromoanisole. Recrystallization from a normal hexane-toluene mixed solvent showed a melting point of 83-84 ° C. The structure was confirmed by ¹ H-NMR in the same manner as in Example 1.

[Example 4] Production of 4-methoxybiphenyl A stirrer, a thermometer and a reflux condenser were attached, and a nitrogen-substituted 100 ml four-necked flask was charged with 3.0 g (0.01 mol) of triphenylborane isopropylamine complex, hydrogen carbonate. Weigh out 3.2 g (0.038 mol) of sodium, 0.18 g (0.25 mmol) of dichlorobis (triphenylphosphine) palladium (II), 25 g of water, 11 g of tetrahydrofuran and 4.7 g (0.025 mol) of 4-bromoanisole. The mixture was heated under reflux for 2 hours with stirring. The organic layer was analyzed by gas chromatography to confirm the disappearance of 4-bromoanisole and complete the reaction. After completion of the reaction, 50 ml of toluene was added for liquid separation, and the obtained organic layer was washed with 50 ml of water. After toluene in the organic layer was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 50: 1) to obtain 3.82 g of the title compound as colorless crystals. The structure was confirmed by ¹ H-NMR in the same manner as in Example 1. The yield was 83.0% based on 4-bromoanisole. Furthermore, recrystallization from a normal hexane-toluene mixed solvent showed a melting point of 83-84 ° C.

[Example 5] Production of 4-methylbiphenyl A 300-ml four-necked flask equipped with a stirrer, a thermometer and a refluxer and purged with nitrogen was charged with 4.3 g (0.014 mol) of triphenylboranepyridine complex, sodium carbonate 7 .95 g (0.075 mol), palladium chloride 0.133 g (0.75 mmol), water 25 ml, N, N-dimethylformamide 100 ml, 4-bromotoluene 4.28 g (0.025 mol) were weighed and stirred at room temperature. Went. While stirring was continued, heating was further performed at 110 ° C. for 3 hours. The reaction solution was analyzed by gas chromatography, and disappearance of 4-bromotoluene was confirmed to complete the reaction. After removing insolubles by filtration, 50 ml of toluene was added, the mother liquor was separated, and the resulting organic layer was washed with 50 ml of water. After toluene was distilled off under reduced pressure, purification was performed by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 100: 1) to obtain 3.41 g of 4-methylbiphenyl as a white solid. The yield was 81.2% based on 4-bromotoluene. Recrystallization from n-hexane showed a melting point of 44-47 ° C.

[Example 6] Production of 2,5-dimethylbiphenyl A stirrer, a thermometer and a reflux condenser were attached, and into a 100 ml four-necked flask purged with nitrogen, 4.3 g (0.014 mol) of triphenylboranepyridine complex, carbonic acid Sodium 7.95 g (0.075 mol), dichlorobistriphenylphosphine palladium (II) 0.18 g (0
. 25 mmol), water 25 ml, N, N-dimethylformamide 100 ml, 1,3-dimethyl-6
4.63 g (0.025 mol) of bromobenzene was weighed and stirred at room temperature. While stirring was continued, heating was further performed at 110 ° C. for 3 hours. The reaction solution was analyzed by gas chromatography, and disappearance of 1,3-dimethyl-6-bromobenzene was confirmed to complete the reaction. After removing insolubles by filtration, 50 ml of toluene was added, the mother liquor was separated, and the resulting organic layer was washed with 50 ml of water. After toluene was distilled off under reduced pressure, purification was performed by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 100: 1) to obtain 3.42 g of 2,5-dimethylbiphenyl as a rod-like substance. The yield was 75.2% based on 1,3-dimethyl-6-bromobenzene. The nuclear magnetic resonance spectrum (NMR) was measured and confirmed to be 2,5-dimethylbiphenyl.

¹ H-NMR spectrum (δ in CDCl ₃ ):
7.40-7.00 (m, 8H),
2.34 (s, 3H),
2.22 (s, 3H)

[Example 7] Production of 2-cyano-4'-methylbiphenyl A 100 ml four-necked flask equipped with a stirrer, a thermometer and a refluxer and purged with nitrogen was charged with 4.3 g of a triphenylborane pyridine complex. (0.014 mol), sodium carbonate 4.7 g (0.045 mol), palladium chloride 0.133 g (0.75 mmol), tricyclohexylphosphine 0.53 g (1.87 mmol), 1-methyl-2-pyrrolidone 30 ml and 2 -4.5 g (0.025 mol) of bromobenzonitrile was weighed and stirred at room temperature. While stirring was continued, heating was further performed at 120 ° C. for 8 hours. The reaction solution was analyzed by gas chromatography, and disappearance of 2-bromobenzonitrile was confirmed to complete the reaction. After removing insolubles by filtration, 50 ml of toluene was added, the mother liquor was separated, and the resulting organic layer was washed with 50 ml of water. After distilling off toluene under reduced pressure, purification was performed by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 100: 1) to obtain 3.72 g of 2-cyano-4′-methylbiphenyl as a white solid. It was. The yield was 77.0% based on 2-bromobenzonitrile. Recrystallization from normal hexane showed a melting point of 50-53 ° C.

[Example 8] Preparation of 4-acetylbiphenyl A stirrer, a thermometer and a reflux condenser were attached, and 0.82 g (2.6 mmol) of triphenylboranepyridine complex was added to a 100 ml four-necked flask thoroughly purged with nitrogen, 3-bis (diphenylphosphino) propane 0.26 g (0.64 mmol), potassium carbonate 1.8 g (13 mmol), palladium acetate 72 mg (0.32 mmol), water 2 ml, 1-methyl-2-pyrrolidone 40 ml, 4
-0.99 g (6.4 mmol) of chloroacetophenone was weighed out and stirred. While stirring, the mixture was heated at 80 ° C. for 5 hours. A small amount of the reaction solution was taken, diluted with toluene, and the organic layer was analyzed by gas chromatography to confirm that the reaction did not proceed and the reaction was terminated. After completion of the reaction, 20 ml of toluene was added for liquid separation, and the resulting organic layer was washed with 50 ml of water. After toluene in the organic layer was distilled off under reduced pressure, purification was performed by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 50: 1) to obtain 0.89 g of the title compound as a colorless solid. (Yield is 71% based on 4-chloroacetophenone).
The solid was recrystallized from n-hexane and showed a melting point of 114-116 ° C.

[Example 9] Production of 2-phenylnaphthalene A stirrer, a thermometer, and a reflux condenser were attached, and 2.79 g (0.009 mol) of triphenylboranepyridine complex, carbonic acid was added to a 300 ml four-necked flask thoroughly purged with nitrogen. 7.95 g (0.075 mol) of sodium, 0.133 g (0.75 mmol) of palladium chloride, 25 ml of water, 100 ml of N, N-dimethylformamide, 6.90 g (0.025 mol) of 2-trifluoromethanesulfonyloxynaphthalene are weighed out. Stirring was performed. Heating was performed at 120 ° C. for 3 hours while stirring was continued. A small amount of the reaction solution was taken, diluted with toluene, and the organic layer was analyzed by gas chromatography to confirm the disappearance of 2-trifluoromethanesulfonyloxynaphthalene and complete the reaction. After removing insolubles by filtration, 50 ml of toluene was added, the mother liquor was separated, and the resulting organic layer was washed with 50 ml of water. After toluene in the organic layer was distilled off under reduced pressure, purification was performed by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 50: 1) to obtain 4.34 g of 2-phenylnaphthalene as a colorless oil. (Yield: 85.0%, based on 2-trifluoromethanesulfonyloxynaphthalene).
The structure was confirmed by the following instrument data.
Mass spectrum: m / e 204 (bp), 101
IR (cm ⁻ ): 3070, 1603, 1578,

[Example 10] Production of 4-chloro-4'-methylbiphenyl A tris (4-methylphenyl) boranepyridine complex was placed in a 300 ml four-necked flask equipped with a stirrer, a thermometer and a refluxer, and sufficiently purged with nitrogen. 3.6 g (0.01 mol), sodium carbonate 7.9 g (0.075 mol), palladium acetate 0.168 g (0.75 mmol), water 60 ml, isopropyl alcohol 60 ml and 4-chloroiodobenzene 6.0 g (0.025 mol) ) Was weighed and stirred. While stirring was continued, heating was performed at 80 ° C. for 5 hours. A small amount of the reaction solution was taken, diluted with toluene, and the organic layer was analyzed by gas chromatography to confirm the disappearance of 4-chloroiodobenzene, and the reaction was completed. After concentrating the reaction solution under reduced pressure, 80 ml of toluene was added, insoluble materials were removed by filtration, the mother liquor was separated, and the resulting organic layer was washed with 50 ml of water. After toluene in the organic layer was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 50: 1) to give 4.05 g of 4-chloro-4′-methylbiphenyl as white. Obtained as a solid. The yield was 90.0% based on 4-chloroiodobenzene. The solid showed a melting point of 75-77 ° C. when recrystallized from a mixed solvent of n-hexane-toluene.

[Example 11] Production of biphenyl A 300 ml four-necked flask equipped with a stirrer, a thermometer and a refluxer and sufficiently purged with nitrogen was charged with 6.12 g (0.02 mol) of triphenylboranepyridine complex, tripotassium phosphate 31 0.8 g (0.15 mol), tris (dibenzylideneacetone) dipalladium (0) 0.69 g (0.75 mmol), dioxane 120 ml and bromobenzene 7.85 g (0.05 mol) were weighed and stirred. While stirring was continued, heating was performed at 80 ° C. for 5 hours. A small amount of the reaction solution was taken, diluted with toluene, and the organic layer was analyzed by gas chromatography to confirm the disappearance of bromobenzene and to complete the reaction. After concentrating the reaction solution under reduced pressure, 80 ml of toluene was added, insoluble materials were removed by filtration, the mother liquor was separated, and the resulting organic layer was washed with 50 ml of water. After toluene in the organic layer was distilled off under reduced pressure, purification was performed by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 50: 1) to obtain 6.72 g of biphenyl as a white solid. The yield was 87.1% based on bromobenzene. Recrystallization from a mixed solvent of n-hexane-toluene showed a melting point of 68-72 ° C.

[Example 12] Production of 4-methoxybiphenyl A 200 ml four-necked flask equipped with a stirrer, a thermometer and a refluxer and sufficiently purged with nitrogen was placed in an aqueous solution of triphenylborane sodium hydroxide adduct 80.6 g (0. 015 mol), sodium bicarbonate 6.30 g (0.075 mol), dichlorobis (triphenylphosphine) palladium 0.35 g (0.5 mmol), tetrahydrofuran 22 g, 4-bromoanisole 9.4 g (0.05 mol), Stirring was performed. While stirring was continued, heating under reflux was performed for 2 hours. The organic layer was analyzed by gas chromatography to confirm the disappearance of 4-bromoanisole, and the reaction was completed. After completion of the reaction, 80 ml of toluene was added for liquid separation, and the resulting organic layer was washed with 80 ml of water. After toluene in the organic layer was distilled off under reduced pressure, purification was performed by silica gel chromatography to obtain 8.82 g of 4-methoxybiphenyl as a white solid. The yield was 95.8% based on 4-bromoanisole. The white solid was recrystallized from a normal hexane-toluene mixed solvent to show a melting point of 83-84 ° C.

[Example 13] Production of 3-phenylpyridine A 200 ml 4-neck flask equipped with a stirrer, a thermometer, and a refluxer and sufficiently purged with nitrogen was placed in an aqueous solution of triphenylborane sodium hydroxide adduct 80.6 g (0. 015 mol), 6.30 g (0.075 mol) of sodium hydrogen carbonate, 0.35 g (0.5 mmol) of dichlorobis (triphenylphosphine) palladium, 22 g of tetrahydrofuran and 7.9 g (0.05 mol) of 3-bromopyridine, The mixture was heated under reflux for 2 hours with stirring. The organic layer was analyzed by gas chromatography to confirm the disappearance of 3-bromopyridine, and the reaction was completed. After completion of the reaction, 80 ml of toluene was added for liquid separation, and the resulting organic layer was washed with 80 ml of water. After toluene in the organic layer was distilled off under reduced pressure, purification was performed by silica gel chromatography to obtain 6.65 g of 3-phenylpyridine as a white solid. The yield was 85.8% based on 3-bromopyridine. The white solid was recrystallized from a normal hexane-toluene mixed solvent to show a melting point of 173 to 176 ° C.

[Example 14] Production of 4-fluorobiphenyl A 200 ml four-necked flask equipped with a stirrer, a thermometer and a refluxer and thoroughly purged with nitrogen was placed in an aqueous solution of triphenylborane sodium hydroxide adduct 80.6 g (0. 015 mol), sodium hydrogen carbonate 6.30 g (0.075 mol), palladium acetate 0.168 g (0.75 mmol), tetrahydrofuran 22 g, 4-fluorobromobenzene 8.8 g (0.05 mol) were weighed and stirred. . While stirring was continued, heating under reflux was performed for 2 hours. The organic layer was analyzed by gas chromatography to confirm the disappearance of 4-fluorobromobenzene, and the reaction was completed. After completion of the reaction, 80 ml of toluene was added for liquid separation, and the resulting organic layer was washed with 80 ml of water. Toluene in the organic layer was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 7.4 g of 4-fluorobiphenyl as a white solid. The yield was 85.7% based on 4-bromoanisole. Recrystallization of the white solid from normal hexane showed a melting point of 74-74.5 ° C.

[Reference Production Example 1]
Synthesis of triphenylborane triethylamine complex A 300 ml four-necked flask fully purged with nitrogen was equipped with a stirrer, a thermometer and a reflux condenser, and an aqueous solution of sodium triphenylborane hydroxide (containing triphenylborane sodium hydroxide adduct) 157 g (rate 7-9%) was weighed and stirred. While continuing stirring, 6.1 g (60 mmol) of triethylamine was added dropwise at room temperature over 1 hour, and the mixture was stirred as it was for 3 hours. The precipitated white crystals were suction filtered, washed with water and dried to obtain 16.1 g of triphenylborane triethylamine complex.

As a result of analyzing and identifying this by the method shown below, it was confirmed to be a triphenylborane triethylamine complex. Each analysis value and physical property value were as follows. (1) Melting point 108-112 ° C
(2) ¹ H-NMR spectrum (δ in CD ₃ OD),
7.40-7.36 (m, 6H),
7.07-7.01 (m, 6H),
6.94-6.87 (m, 3H),
2.95 (q, J = 6.43 Hz, 6H),
1.18 (t, J = 6.62 Hz, 9H).

  According to the present invention, in the production of biaryl compounds by the Suzuki-Miyaura reaction, it is possible to industrially use unstable raw material triarylborane compounds in a stable form, which is also useful from the economical aspect. A safe, efficient and inexpensive method for synthesizing such biaryl compounds can be provided.

In addition, the biaryl compound obtained by the present invention is useful as an asymmetric source in various asymmetric reactions, and liquid crystals such as drugs (eg, diflunisal having analgesic and anti-inflammatory effects), agricultural chemicals, ferroelectric liquid crystals ( (Example: 4-alkyl-4′-cyanobiphenyl) and the like can also be used as an intermediate for production.

Claims (3)

Any one of the organic boron amine complex compound represented by the following general formula (1-A) and the organic boron-alkali metal hydroxide adduct represented by the general formula (1-B);
An aromatic or unsaturated heterocyclic compound represented by the general formula (2),
The biaryl compound (7) represented by the following general formula (7) is characterized by reacting in the presence of a transition metal catalyst and a phosphine ligand added as necessary in the presence of a base. Production method:
Organic boron amine complex compound (1-A):
Ar ¹ ₃ B · NR ¹ R ² R ³ (1-A)
[In the formula (1-A), a plurality of Ar ¹ 's each independently represent a phenyl group, a naphthyl group or a pyridyl group, and these groups are each independently a lower alkyl group, a lower alkoxy group, a lower alkoxy group, It may be substituted with 1 to 5 substituents selected from a group-containing lower alkyl group, lower haloalkyl group, and halogen atom, and the lower alkyl group moiety and lower alkoxy group moiety in each of the above groups Each independently has 1 to 6 carbon atoms,
R ¹ , R ² and R ³ are each independently a hydrogen atom, a linear or branched alkyl group having 1 to 20 carbon atoms; a linear or branched alkenyl group having 2 to 20 carbon atoms; carbon A linear or branched alkynyl group having 2 to 20 carbon atoms; a cycloalkyl group having 3 to 20 carbon atoms; a phenyl group; an aralkyl group or a heterocyclic group, or N, R ¹ , R ² and R ³ Represents a saturated or unsaturated heterocycle forming a ring,
The phenyl group and the aralkyl group are each independently substituted with 1 to 5 substituents selected from a lower alkyl group, a lower alkoxy group, a lower alkoxy group-containing lower alkyl group, a lower haloalkyl group, and a halogen atom. May also have been
The lower alkyl group moiety and the lower alkoxy group moiety in the substituent each independently have 1 to 6 carbon atoms,
The heterocyclic group is a saturated group or an unsaturated group and includes a nitrogen atom, an oxygen atom or a sulfur atom, and N, R ¹ , R ² and R ^{3 in} the formula (1-A) are bonded to each other. A ring structure may be formed. ]
Organoboron-alkali metal hydroxide adduct (1-B):
_{^{Ar 1 3 B · WOH ·········· (}} 1-B)
[In Formula (1-B), Ar ¹ represents the same meaning as described above, and W represents sodium, potassium, or lithium. ]
Aromatic or unsaturated heterocyclic compound (2):
Ar ² X (2)
[In the formula (2), Ar ² represents a phenyl group, a naphthyl group or a pyridyl group, and
These groups are each independently a lower alkyl group, lower alkoxy group, lower alkoxy group-containing lower alkyl group, lower haloalkyl group, halogen atom, lower alkoxycarbonyl group, carboxy group, formyl group, lower alkylcarbonyl group, lower alkylsulfonyl group. Group, a cyano group and a nitro group may be substituted with 1 to 5 substituents, and the lower alkyl group moiety and the lower alkoxy group moiety in each of the above groups are each independently carbon. It is number 1-6,
X is a halogen atom or a sulfonyloxy group represented by the general formula (3),
R ⁴ SO ₂ O- (3)
{In Formula (3), R ⁴ is a linear or branched alkyl group having 1 to 20 carbon atoms;
-20 linear or branched alkenyl group; linear or branched alkynyl group having 2 to 20 carbon atoms; cycloalkyl group having 3 to 20 carbon atoms; phenyl group; naphthyl group; aralkyl group; A methyl group; and any one of pentafluoroethyl groups;
The phenyl group, naphthyl group and aralkyl group are each independently 1 to 5 substituents selected from a lower alkyl group, a lower alkoxy group, a lower alkoxy group-containing lower alkyl group, a lower haloalkyl group, and a halogen atom. May be substituted with a group,
The lower alkyl group part and the lower alkoxy group part in the substituent each independently have 1 to 6 carbon atoms. }
Or the acyloxy group represented by General formula (4) is shown.
R ⁴ COO- (4)
(In formula (4), R ⁴ has the same meaning as described above.)]
Biaryl compound (7):
Ar ¹ -Ar ² (7)
[In the formula (7), Ar ¹ and Ar ² have the same meaning as described above. ]. Boron amine complex compound represented by the general formula (1-A):
Ar ¹ ₃ B · NR ¹ R ² R ³ (1-A)
[In the formula (1-A), Ar ¹ , R ¹ , R ² and R ³ have the same meaning as described above. ]
When,
Aromatic or unsaturated heterocyclic compound represented by general formula (2):
Ar ² X (2)
[In the formula (2), Ar ² and X have the same meaning as described above. ]
And
In the presence of a transition metal catalyst represented by the general formula (6) consisting of a transition metal, a transition metal compound or a transition metal complex, and a phosphine ligand added if necessary, the reaction is carried out in the presence of a base. A method for producing a biaryl compound represented by the general formula (7):
MY _n L _m (6)
[In the formula (6), M represents nickel, palladium or rhodium having a valence of 0 to 2, Y represents a halogen ion, nitrate ion or acetoxy ion, and n represents an integer of 0 to 2. , M represents 0 or an integer of 1 to 4.
In the formula (6), when m is an integer other than 0, 1 to a plurality of Ls are independently of each other R ⁵ R ⁶ R ⁷ P, R ⁸ R ⁹ P (CH ₂ ) qPR ^10. R ¹¹ , R ¹² COCH ₂ COR ¹³ , R ¹⁴ CN,
A linear or cyclic alkene having 4 to 20 carbon atoms and two or more double bonds, or R ¹⁵ COR ¹⁶ , wherein R ^{5 to} R ¹⁶ may be the same as or different from each other;
A linear or branched alkyl group having 1 to 20 carbon atoms; a linear or branched alkenyl group having 2 to 20 carbon atoms; a linear or branched alkynyl group having 2 to 20 carbon atoms; 3 to 20 cycloalkyl groups; a phenyl group; any group selected from a naphthyl group and an aralkyl group;
The phenyl group, naphthyl group and aralkyl group are each independently 1 to 5 substituents selected from a lower alkyl group, a lower alkoxy group, a lower alkoxy group-containing lower alkyl group, a lower haloalkyl group, and a halogen atom. May be substituted with a group,
The alkenyl group may be substituted with a phenyl group,
The lower alkyl group moiety and the lower alkoxy group moiety in the substituent each independently have 1 to 6 carbon atoms,
q represents an integer of 1 to 10. ]
Ar ¹ -Ar ² (7)
[In the formula (7), Ar ¹ and Ar ² have the same meaning as described above. ]. Organoboron-alkali metal hydroxide adduct represented by the general formula (1-B):
_{^{Ar 1 3 B · WOH ····· (}} 1-B)
[In the formula (1-B), Ar ¹ and W have the same meaning as described above. ]
When,
Aromatic or unsaturated heterocyclic compound represented by general formula (2):
Ar ² X (2)
[In the formula (2), Ar ² and X have the same meaning as described above. ]
And
The reaction is carried out in the presence of a base in the presence of the transition metal catalyst according to claim 2 and a phosphine ligand added if necessary.
Ar ¹ -Ar ² (7)
[In the formula (7), Ar ¹ and Ar ² represent the same meaning as described above. ] The manufacturing method of the biaryl compound represented by this.