JP4552405B2 - Method for producing biaryl compounds - Google Patents

Description

  The present invention relates to a method for coupling halogenated aryl compounds with aryl metal compounds in the presence of a transition metal-polydentate phosphite complex catalyst.

Conventionally, when a halogenated aryl compound and an aryl metal compound are subjected to a coupling reaction using a homogeneous metal catalyst, in the presence of a transition metal-phosphine complex catalyst or a transition metal-monodentate phosphite complex catalyst, A method of coupling reaction with an aryl boronic acid compound is known (see Non-Patent Documents 1 and 2).
However, the coupling reaction using the aforementioned transition metal-phosphine complex catalyst or transition metal-monodentate phosphite complex is usually 3 to 3 times with respect to the aryl halide compound in order to obtain a satisfactory yield of a cross-coupled product. There is a problem that a relatively large amount of a complex catalyst of 5 mol% or more is required, and a homo-coupled product in which halogenated aryl compounds are simultaneously coupled to each other is considerably produced as a by-product. In addition, there has been a demand for a coupling reaction that can be applied to an industrial application without requiring a complicated purification operation for removing a homo-coupled product that is physically and chemically similar in properties to the target product.
Miyaura and 1 other, “Chemical Reviews”, Volume 95 (1995), p. 2457 Beller M.M. , And one other, “Chemistry-A European Journal”, Volume 6 (2000), p. 1830

  As described above, the coupling reaction between an aryl halide compound and an aryl metal compound is not yet in an industrially satisfactory state. An object of this invention is to provide the industrially applicable method which can suppress the by-product of a homo coupling body and can obtain the target coupling body with high purity and a high yield.

  As a result of intensive studies in view of such circumstances, the present inventors have found that when a transition metal-multidentate phosphite complex catalyst is used as a catalyst, the intended coupling product can be obtained with high purity and high yield. As a result, the present invention has been completed.

That is, the gist of the present invention is a method for producing biaryl compounds by coupling halogenated aryl compounds and aryl metal compounds in the presence of a transition metal-polydentate phosphite complex catalyst ,
The metal atom constituting the aryl metal compound is a boron atom,
The transition metal-multidentate phosphite complex catalyst comprises a transition metal compound and the following general formula (4):

{In formula (4), R ^Three And R ^Four Each independently represents an aryl group having 6 to 15 carbon atoms which may have a substituent, wherein R ^Three And R ^Four May be bonded to each other to form a ring. R ^Five Is the following general formula (6)

Wherein ^(6), R 6 ~R ¹³ each independently represent a hydrogen atom, a methyl group, an isopropyl group, t- butyl group or a methoxy group. Zm represents a bond. ] The biphenylene group represented by this is shown. n represents 2. }
A biaryl compound formed of a bidentate phosphite ligand represented by the formula (I), wherein the metal atom constituting the transition metal compound is a nickel atom or a palladium atom: Method.

  According to the present invention, when a halogenated aryl compound and an aryl metal compound are coupled to produce a biaryl compound, compared with a catalyst system using phosphine or monophosphite as a ligand, By suppressing the by-product of the ring body, the desired coupling body can be obtained with high purity and high yield.

Embodiments of the present invention will be described below.
In the production method of the present invention, biaryl compounds are obtained by coupling halogenated aryl compounds and aryl metal compounds in the presence of a transition metal-polydentate phosphite complex catalyst.

(Halogenated aryl compounds)
The halogenated aryl compounds used in the present invention are not particularly limited as long as they are dissolved in a solvent in the reaction system or are themselves liquid, but usually a phenyl group having one or more halogen atoms as a substituent, Examples include compounds having 3 or less aromatic rings, preferably 2 or less, such as aryl groups such as naphthyl groups or heteroaryl groups such as pyridyl groups and thienyl groups.

The aryl group and heteroaryl group further have a structure (for example, sulfide, phosphine, etc.) capable of coordinating with a transition metal and reducing activity by having a substituent that does not poison the catalyst, that is, a lone pair. May be substituted with no substituent.
As the halogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like is used, and among them, a chlorine atom or a bromine atom is preferable. The number of halogen atoms contained in one molecule of the halogenated aryl compound is usually 3 or less.

Examples of the halogenated aryl compounds include those having a molecular weight of 100 or more and 1000 or less, preferably 600 or less, more preferably 400 or less.
Among these, what is represented by the following general formula (1) is preferable because it is relatively easy to obtain reaction raw materials.

[In formula (1), A ¹ represents a carbon atom or a heteroatom. X represents a leaving group, and R ¹ represents a hydroxyl group, a cyano group, a nitro group, an optionally substituted amino group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, or a substituted group. An aryloxy group, an acyl group, an acyloxy group, a group represented by —CO ₂ R (wherein R represents an optionally substituted hydrocarbon group), and a group represented by —CONR′R ″. Group (wherein R ′ and R ″ each independently represents a hydrogen atom or an optionally substituted hydrocarbon group), a group represented by —SOR (wherein R is substituted) An optionally substituted hydrocarbon group), a group represented by —SO ₂ R (where R represents an optionally substituted hydrocarbon group), or a group represented by —SiR ₃ (here. in R represents a.) indicating the optionally substituted hydrocarbon group, m ¹ is shown an integer of 0 to 5 . Here, when m ¹ is 2 or more, a plurality of R ¹ may be the same group or different groups. ]
A ¹ is a carbon atom or a hetero atom, preferably a carbon atom or a nitrogen atom.

  Examples of the leaving group for X include halogen atoms such as chlorine atom, bromine atom and iodine atom; alkoxy group such as methoxy group; alkylsulfonyloxy group such as methanesulfonyloxy group; arylsulfonyl such as p-toluenesulfonyloxy group Although it will not specifically limit if it is a leaving group normally used by coupling reaction, such as an oxy group, Among these, Preferably it is a halogen atom, a C1-C6 alkylsulfonyloxy group, or a C10 or less arylsulfonyloxy. Group, particularly preferably a chlorine atom or a bromine atom.

R ¹ represents a hydroxyl group, a cyano group, a nitro group, an optionally substituted amino group, an optionally substituted hydrocarbon group, an acyl group, an acyloxy group, or a group represented by —CO ₂ R (wherein R represents an optionally substituted hydrocarbon group.), A group represented by —CONR′R ″ (wherein R ′ and R ″ are each independently a hydrogen atom or a substituted group). also represents an hydrocarbon group), -. group (wherein R represented by SOR denotes the optionally substituted hydrocarbon group), -. group represented by SO ₂ R (where R is A hydrocarbon group which may be substituted) or a group represented by —SiR ₃ (wherein R represents a hydrocarbon group which may be substituted).

  Examples of the amino group which may be substituted include alkyl groups such as amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, methylethylamino group, phenylamino group, phenylmethylamino group, and diphenylamino group. And an amino group optionally substituted by 1 or 2 with an aryl group or an aryl group. Among them, a disubstituted amino group having no active hydrogen such as a dimethylamino group, a diethylamino group, or a methylethylamino group is preferable. .

  Examples of the hydrocarbon group that may be substituted include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, and a cyclohexyl group. Linear, branched or cyclic alkyl groups such as vinyl; 1-propenyl, 2-propenyl, isopropenyl, butenyl, 2-butenyl, butanedienyl, cyclohexenyl, etc. An alkynyl group such as an ethynyl group and a propynyl group; and an aryl group such as a phenyl group and a naphthyl group.

The substituent of the hydrocarbon group is not particularly limited as long as it does not adversely affect the coupling reaction. Specifically, the hydroxyl group, cyano group, nitro group, amino group, alkoxy group, aryloxy group, acyl group, an acyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group; a carbamoyl group, a group represented by -SOR, a group (here represented by the group or -SiR ₃ represented by -SO ₂ R R is a hydrocarbon group Are shown).

  The carbon number of the hydrocarbon group which may be substituted is usually 30 or less, preferably 20 or less. Particularly, the carbon number of the alkyl group, alkenyl group or alkynyl group is preferably 8 or less, more preferably. Is 6 or less, and the number of carbon atoms of the aryl group is preferably 22 or less, more preferably 14 or less.

  The alkoxy group which may be substituted is substituted with a halogen atom such as a methoxy group, an ethoxy group, a propyloxy group, a trifluoromethoxy group, a benzyloxy group or a methoxymethoxy group, an alkoxy group and an aryl group. An alkoxy group having 10 or less carbon atoms, preferably 6 or less carbon atoms may be used.

  The aryloxy group which may be substituted is an aryloxy group which may be substituted with an alkyl group such as a phenoxy group, a tolyloxy group, a xylyloxy group or a naphthyloxy group, preferably an aryloxy group having 10 or less carbon atoms. Is mentioned.

  Examples of the acyl group include an alkylcarbonyl group having 12 or less carbon atoms such as an acetyl group, a propionyl group, and a benzoyl group trifluoromethylcarbonyl group, or an arylcarbonyl group. Among these, carbons such as an acetyl group and a propionyl group are preferable. The number is 6 or less.

  Examples of the acyloxy group include an alkylcarbonyloxy group having 12 or less carbon atoms such as an acetyloxy group, a propionyloxy group, a benzoyloxy group, and a trifluoromethylcarbonyloxy group, and an arylcarbonyloxy group. Those having 6 or less carbon atoms, such as an oxy group and a propionyloxy group.

Groups represented by -CO ₂ R, a group represented by -SOR, as the R group represented by group and -SiR ₃ represented by -SO ₂ R, the same hydrocarbon group as described above Among them, an alkyl group having 6 or less carbon atoms, a benzyl group, or a phenyl group is preferable.

Here, as the group represented by —SiR ₃ , there are three Rs such as a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a dimethylphenylsilyl group, and a triphenylsilyl group, respectively. It may be the same or different.

  Examples of the group represented by NR′R ″ of the group represented by —CONR′R ″ include the same as the above-described optionally substituted amino group.

Of the above R ¹ , a nitro group, an alkoxy group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms is preferable.
m ¹ is an integer of 0 to 5, preferably 0 or 1, and the substitution position is preferably p-position with respect to the halogen atom.

(Aryl metal compounds)
The aryl metal compounds used in the present invention are not particularly limited as long as they are dissolved in a solvent in the reaction system or are themselves liquid, but usually an aryl group such as phenyl group or naphthyl group, pyridyl group, thienyl group, etc. And a metal compound having an aryl group or heteroaryl group having 3 or less aromatic rings, such as a heteroaryl group.

The aryl group and heteroaryl group may have a substituent that does not poison the catalyst.
The molecular weight of the aryl metal compounds is usually 1000 or less, preferably 600 or less, more preferably 400 or less.
What is represented by the following general formula (2) is preferable because the reaction raw materials are relatively easily obtained.

(In formula (2), A ² represents a carbon atom or a hetero atom. R ² represents a hydroxyl group, a cyano group, a nitro group, an optionally substituted amino group, an optionally substituted hydrocarbon group, or a substituted group. An optionally substituted alkoxy group, an optionally substituted aryloxy group, an acyl group, an acyloxy group, or a group represented by —CO ₂ R (wherein R represents an optionally substituted hydrocarbon group). ), A group represented by —CONR′R ″ (wherein R ′ and R ″ each independently represents a hydrogen atom or an optionally substituted hydrocarbon group), represented by —SOR. Group (wherein R represents an optionally substituted hydrocarbon group), a group represented by —SO ₂ R (wherein R represents an optionally substituted hydrocarbon group) or group (wherein R represented by -SiR ₃ shows the optionally substituted hydrocarbon group. Are shown, m ² represents an integer of 0 to 5. Here, when m ² is 2 or more, R ² existing in plural, it may be different even for the same group group M represents a metal atom, Y represents an anionic group bonded to the metal atom, and n represents an integer of 0 to 3.)
A ² is a carbon atom or a hetero atom, preferably a carbon atom or a nitrogen atom.

Examples of R ² include the same groups as R ¹ in the above general formula (1). Among these, a halogen atom or an alkyl group having 1 to 4 carbon atoms is preferable.
M ² is an integer of 0 to 5, preferably 0 or 1, and the substitution position is preferably p-position relative to the MY _n group.
Examples of the metal atom of M include a typical metal atom such as a boron atom, an aluminum atom, a silicon atom, a germanium atom, and a tin atom, and a boron atom or an aluminum atom is preferable.

The anionic group of Y is not particularly limited as long as it is an atom or atomic group that can be a 1-3 valent anion bonded to a metal, preferably a hydroxyl group, an alkoxy group, or a halogen atom, more preferably A methoxy group, an ethoxy group, or a hydroxyl group, particularly preferably a hydroxyl group.
n is an integer of 0 to 5, preferably 2 or 3.

(Transition metal-multidentate phosphite complex catalyst)
In the production method of the present invention, a transition metal-multidentate phosphite complex catalyst is used as a catalyst.
Although there is no restriction | limiting in particular as this transition metal compound, Preferably it is an element of the periodic table 8-10 group, More preferably, they are nickel, palladium, platinum, rhodium, or ruthenium, Most preferably, they are palladium or nickel. .

Substituents or ligands that these transition metals have by bonding or coordination include halogen atoms; inorganic acid residues; organic acid residues; phosphine compounds; phosphite compounds; alkene compounds; nitrile compounds; Or a combination thereof.
In the following, preferred specific examples of the transition metal compound are exemplified by the case where the metal atom is palladium or nickel, but the same compound can be used for metal atoms other than palladium and nickel.

When the metal species is palladium, specific palladium compounds include, for example, Pd (0), PdCl ₂ , PdBr ₂ , PdCl ₂ (COD), PdCl ₂ (PPh ₃ ) ₂ , Pd (PPh ₃ ) ₄ , Pd (Dba) ₂ , Pd ₂ (dba) ₃ , Pd ₂ (dba) ₃ .CHCl ₃ , K ₂ PdCl ₄ , K ₂ PdCl ₆ , PdCl ₂ (PhCN) ₂ , PdCl ₂ (CH ₃ CN) ₂ , Pd ( NO ₃ ) ₂ , PdSO ₄ , Pd (OAc) ₂ , Pd (CF ₃ COO) ₂ , Pd (acac) _2, etc., among which Pd (OAc) ₂ , Pd (acac) palladium compound having a carboxylic acid residue or a 1,3-diketonate group ₂ and the like are preferable (here, COD: cyclooctadiene, dba: dibenzylidene acetone, acac: acetyl acetonate Representing the over door). In addition to the above monomers, multimers such as allyl palladium chloride dimers can also be used.

Specific nickel compounds include, for example, Ni (O), NiCl ₂ , NiBr ₂ , NiCl ₂ (COD), Ni (COD) ₂ , NiCl ₂ (PPh ₃ ) ₂ , Ni (PPh ₃ ) ₄ , Ni (Acac) ₂ can be mentioned, and among these, nickel alkene compounds such as Ni (COD) ₂ are particularly preferable (here, COD: cyclooctadiene, acac: acetylacetonate).

  Although the multidentate phosphite ligand used for this invention is not specifically limited as long as it can coordinate to the said transition metal compound, The multidentate phosphite compound represented by following General formula (4) is preferable.

In Formula (4), R ³ and R ⁴ each independently represent a hydrocarbon group that may have a substituent, and R ⁵ represents an n-valent organic group. Here, R ³ and R ⁴ may form a bond or a condensed ring with each other within and / or between the molecules. Further, R ³ or R ⁴ bonded to different phosphorus atoms via an oxygen element, or substituents thereof may further form a bond or a condensed ring.

The hydrocarbon group represented by R ³ or R ⁴ in the general formula (4) is a linear or branched alkyl group having 1 to 30 carbon atoms, preferably 20 or less, more preferably 10 or less, and cycloalkyl. Group, a linear or branched alkenyl group, an aryl group having 6 to 30 carbon atoms, preferably 20 or less, more preferably 15 or less.
Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, and an octyl group. Examples of the cycloalkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the alkenyl group include a vinyl group, Examples include an aryl group, 2-cyclohexenyl group, and the aryl group includes a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 9-phenanthranyl group, a 1-anthranyl group, a 2-anthranyl group, and a 9-anthranyl group. Is mentioned.

When R ³ and R ⁴ form a bond or a condensed ring to form a divalent group, the divalent group has 1 to 30 carbon atoms, preferably 20 or less, more preferably 10 carbon atoms. The following linear or branched alkylene groups, cycloalkylene groups, linear or branched alkenylene groups, and arylene groups having 6 to 30 carbon atoms, preferably 20 or less, and more preferably 15 or less. Examples of the alkylene group include a methylene group, an ethylene group, a propylene group, a butylene group, and an octylene group. Examples of the cycloalkylene group include a cyclopropylene group, a cyclopentylene group, and a cyclohexylene group. Examples of the alkenylene group include Examples include a vinylene group, an arylene group, and a 2-cyclohexenylene group. Examples of the arylene group include a 1,2-phenylene group, a 1,3-phenylene group, a 1,4-phenylene group, a 1,2-naphthylene group, Examples include 1,3-naphthylene group, 1,4-naphthylene group, 1,5-naphthylene group, 1,8-naphthylene group, and 2,6-naphthylene group.

Examples of the substituent for R ³ and R ⁴ include hydroxyl group, cyano group, nitro group, amino group, alkoxy group, aryloxy group, acyl group, acyloxy group, alkoxycarbonyl group, aryloxycarbonyl group; carbamoyl group, and —SOR. And a group represented by —SO ₂ R or a group represented by —SiR ₃ (wherein R represents a hydrocarbon group).
Among the polydentate phosphite compounds represented by the general formula (4), compounds in which R ³ and R ⁴ are aromatic hydrocarbon groups are preferable.

Specific examples when R ³ and R ⁴ are aromatic hydrocarbon groups include, as unsubstituted aromatic groups, phenyl group, 1-naphthyl group, 2-naphthyl group, 9-phenanthranyl group, 1-anthranyl group, Examples include 2-anthranyl group and 9-anthranyl group, and monosubstituted aromatic groups include 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, and 3-ethylphenyl group. 4-ethylphenyl group, 2-propylphenyl group, 3-propylphenyl group, 4-propylphenyl group, 2-isopropylphenyl group, 3-isopropylphenyl group, 4-isopropylphenyl group, 2-normalbutylphenyl group, 3-normal butylphenyl group, 4-normal butylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-t-butylphenyl group, 3-t-butylphenyl group, 4-t-butylphenyl group, 2-t-amylphenyl group, 3-t-amylphenyl group, 4-t- Amylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 4-ethoxyphenyl group, 2-ethoxycarbonylphenyl group, 3-ethoxy Rubonylphenyl group, 4-octylphenyl group, 4-nonylphenyl group, 4-ethoxycarbonylphenyl group, 4-chlorophenyl group, 4-nitrophenyl group, 4-cyanophenyl group, 4-dimethylaminophenyl group, 2-methyl A -1-naphthyl group is mentioned.

  Examples of the disubstituted aromatic group include 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 2,4-di-t- Butylphenyl group, 2-methoxy-4-methylphenyl group, 2-methyl-4-methoxyphenyl group, 2-methoxy-4-t-butylphenyl group, 2-t-butyl-4-methoxyphenyl group, 3, 6-di-t-butyl-2-naphthyl group, and trisubstituted aromatic groups include 2,4,6-trimethylphenyl group, 2,4-di-t-butyl-5-methylphenyl group, 2,4-di-t-butyl-6-methylphenyl group, 2,4-di-t-butyl-6-phenylphenyl group, 2,4-di-t-butyl-6-nitrophenyl group, 2, 6-di-t-butyl-4-methoxyphenyl , 2,6-di -t- butyl-4-methoxycarbonylphenyl group and a 3,6,8-tri -t- butyl-2-naphthyl group.

Among this RaKaoru aromatic hydrocarbon group, a phenyl group, 1-naphthyl, 2-naphthyl, 9 phenanthranyl group, 1-anthranyl group, 2-anthranyl group, 9-anthranyl group, 2-methylphenyl group 3-methylphenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-octylphenyl group, 4-nonylphenyl group, 4-ethoxycarbonylphenyl group, 4-chlorophenyl group, 4-nitrophenyl group, 4-cyano Phenyl group, 2,5-dimethylphenyl group, 2,4-di-t-butylphenyl group, 2-methoxy-4-t-butylphenyl group, 2-t-butyl-4-methoxyphenyl group, 3,6 -Di-t-butyl-2-naphthyl group, 2,4-di-t-butyl-6-methylphenyl group, 3,6-di-t-butyl-2-naphthyl group are preferred More preferably, 1-naphthyl group, 2-naphthyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-octylphenyl group, 4-nonylphenyl Group, 2,5-dimethylphenyl group, 2,4-di-t-butylphenyl group, 2-t-butyl-4-methoxyphenyl group, 3,6-di-t-butyl-2-naphthyl group, 2 , 4-di-t-butyl-6-methylphenyl group and 3,6-di-t-butyl-2-naphthyl group, and 1-naphthyl group and 2-naphthyl group are particularly preferable.

R ⁵ in the above formula (4) is an n-valent organic group. In the present invention, the polydentate phosphite ligand is preferably a bidentate ligand (that is, n = 2), and more preferably a divalent group represented by the following general formula (5). preferable.

In the formula, Ar ¹ and Ar ² each represent a substituted or unsubstituted divalent aromatic hydrocarbon group, and the substituents on Ar ¹ and Ar ² may be bonded to each other. Z ¹ and Z ³ represent a substituted or unsubstituted divalent aliphatic or alicyclic hydrocarbon group, and Z ² represents a substituted or unsubstituted divalent aliphatic or alicyclic carbonization. Represents a hydrogen group or an oxygen atom. m ³ , m ⁴ , m ⁵ , m ⁶ and m ⁷ represent 0 or a positive integer, and at least one of them is a positive integer.

In the general formula (5), examples of the hydrocarbon group represented by Z ¹ , Z ² and Z ³ include an alkylene group having 1 to 30 carbon atoms and a cycloalkylene group, and an aromatic represented by Ar ¹ and Ar ^2. Examples of the group hydrocarbon group include a substituted or unsubstituted divalent arylene group having 6 to 30 carbon atoms, among which a phenylene group or a naphthylene group is preferable, for example, a 1,2-phenylene group or a 1,3-phenylene group. 1,4-phenylene group, 1,2-naphthylene group, 1,3-naphthylene group, 1,4-naphthylene group, 1,5-naphthylene group, 1,8-naphthylene group, 2,6-naphthylene group Can be mentioned.

M ³ , m ⁴ , m ⁵ , m ⁶ and m ⁷ are preferably 0 or 1.
The substituent of ^{Ar 1, Ar 2, Z 1} , Z 2 and Z ^3, a hydroxyl group, a cyano group, a nitro group, an amino group, an alkoxy group, an aryloxy group, an acyl group, an acyloxy group, an alkoxycarbonyl group, an aryloxy A carbonyl group; a carbamoyl group, a group represented by —SOR, a group represented by —SO ₂ R, or a group represented by —SiR ₃ (wherein R represents a hydrocarbon group). The substituents may be the same or different.

As the divalent group —Z ¹ m ³ —Ar ¹ m ⁴ —Z ² m ⁵ —Ar ² m ⁶ —Z ³ m ⁷ —, specifically, a methylene group comprising only an aliphatic hydrocarbon group , Ethylene group, 1,3-propylene group, 1,4-butylene group, 1,5-pentylene group and the like. As constituted only by an aromatic hydrocarbon group, 1,2-phenylene group, 1,3-phenylene group, 1,4-phenylene group, 1,2-naphthylene group, 2,3-naphthylene group, 2, 2'-biphenylene group, 4,5-anthranylene group, 4,5-phenanthranylene group, 3,3'-dimethyl-2,2'-biphenylene group, 2,2 '-(1,1')- Binaphthylene group, 1,1 ′-(2,2 ′)-binaphthylene group, 3,3′-dimethyl-2,2 ′-(1,1′-binaphthylene group) and the like, and aliphatic hydrocarbon group Consisting of aromatic hydrocarbon groups, 1,2-dimethylenebenzene, 1,3-dimethylenebenzene, 1,4-dimethylenebenzene, 1,2-dimethylenenaphthalene, 2,3-dimethylene Naphthalene, 2,2′-dimethylenebiphenyl, 3,3 ′, , 5'-tetra-t-butyl-2,2'-dimethylenebiphenyl, 3,3'-di-t-butyl-5,5'-dimethoxy-2,2'-dimethylenebiphenyl, 2,2 ' -Dimethylene- (1,1'-binaphthalene), 2,2'-dimethylene-3,
3 ', 6,6'-tetra-t-butyl- (1,1'-binaphthalene), 4,5-dimethylene-phenanthrene, 2-methylenephenyl group, 2-t-butyl-6-methylenephenyl group, etc. Illustrated.

  Among those represented by the general formula (5), as a particularly preferable compound that can more effectively suppress by-product formation of the homo-coupled body and improve the yield of the intended cross-coupled body as compared with the conventional method. And a 2,2′-biphenylene group represented by the following general formula (6).

Wherein ^(6), R 6 ~R ¹³ may each be the same or different, these are the same as the substituents of the ^{Ar 1, Ar 2, Z 1} , Z 2 and Z ^3. Zm has the same meaning as Z ² m ⁵ .
Among those represented by the general formula (6), particularly when R ⁶ or R ^{13 is a} bulky substituent, specifically, a branched alkyl group having 3 or more carbon atoms, the selectivity of the target cross-coupled product For example, 3-isopropyl-1,2-phenylene group, 3-t-butyl-1,2-phenylene group, 3,5-di-isopropyl-1,2-phenylene group, 3,5-di -T-butyl-1,2-phenylene group, 3-t-butyl- [e] -benzo-1,2-phenylene group, among which 3-t-butyl-1,2-phenylene group is particularly preferable. A 3,5-di-t-butyl-1,2-phenylene group is preferred.

Specific examples of the bidentate phosphite ligand used in the present invention in which R ⁵ in the general formula (4) is represented by the general formula (6) are shown below.

  The transition metal-polydentate phosphite complex catalyst of the present invention may be obtained by bringing the transition metal compound and the polydentate phosphite into contact with each other in a compatible solvent. The transition metal compound and polydentate phosphite may be contacted in advance in a solvent to prepare the complex catalyst, and then contacted with the raw material substrate. However, the raw material substrate, transition metal and multidentate phosphite are charged into the reaction system. It is preferable to mix in the system because it is simple.

When the contact treatment is performed in advance, the same solvent as the organic solvent used in the reaction described later can be used. The lower limit is usually 0.0001 mmol / ml or more, preferably 0.001 mmol / ml or more, and the upper limit is usually 1 mmol / ml or less, preferably 0.1 mmol / ml or less as the transition metal concentration. It is.
The temperature during the contact treatment is usually 10 ° C. or more and 70 ° C. or less, but it is convenient and preferable to carry out at room temperature.

The amount of the transition metal compound used is not particularly limited, but from the viewpoint of catalytic activity and economy, the lower limit is usually 0.001 mol or more with respect to the halogenated aryl compound as the reaction raw material, preferably The upper limit is usually 10 mol or less, preferably 5 mol or less, more preferably 3 mol or less.
The amount of the polydentate phosphite ligand used is usually 0.5 mol times or more, preferably 1 mol times or more, usually 10 mol times or less, preferably 6 mol times the phosphorus atom relative to 1 mol of the transition metal compound. Used in the following range. The multidentate phosphite ligand may be used alone, or a mixture of two or more phosphite ligands may be used as necessary.

(Coupling reaction)
The use ratio of the halogenated aryl compounds and aryl metal compounds used in the production method of the present invention is not limited, but from the viewpoint of economy and reactivity, the aryl metal compounds are converted to halogenated aryl compounds. On the other hand, it is usually 1 mol or more, usually 10 mol times or less, preferably 5 mol times or less, more preferably 2 mol times or less, and most preferably 1.5 mol times or less.

In the production method of the present invention, the reaction can be carried out without using a solvent if the reaction substrate is liquid in the reaction system, but usually a solvent is used. The solvent is not particularly limited as long as it dissolves the reaction substrate and the catalyst, and water or any organic solvent can be used, but it is preferable to use an organic solvent.
The type of organic solvent is not particularly limited as long as it does not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene and styrene; aliphatic hydrocarbons such as pentane and hexane; diethyl ether, tetrahydrofuran, Ethers such as 1,4-dioxane; alcohols such as methanol, ethanol, propanol, ethylene glycol and propylene glycol; amides such as dimethylformamide and dimethylacetamide; pyrrolidones such as N-methyl-2-pyrrolidone; acetone, Examples thereof include ketones and sulfoxides such as ethyl methyl ketone and dimethyl sulfoxide; nitriles such as acetonitrile. Here, these solvents may be used alone or in combination of two or more.

Among them, a preferable solvent is an aromatic hydrocarbon solvent or an alcohol solvent, particularly preferably toluene as the aromatic hydrocarbon organic solvent, and methanol or ethanol as the alcohol organic solvent.
The amount of the solvent to be used is not particularly limited, but is usually 1 times or more, preferably 5 times or more, usually 100 times or less, preferably 60 times or less with respect to the halogenated aryl compound. Industrially preferable from the viewpoint of economy.

The reaction of the present invention is usually performed in the presence of a base.
As the base, known inorganic bases and organic bases can be widely used, but inorganic bases are preferably used.
Examples of inorganic bases include alkali metal carbonates, alkali metal hydroxides, alkali metal phosphates, alkali metal fluorides, alkaline earth metal basic salts, and the like, and examples of organic bases include trimethylamine, triethylamine, and triethylamine. Examples include various amines such as isopropylamine and pyridine. These may be used individually by 1 type, and may mix and use multiple types.

  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 water. Examples of the alkali metal phosphate include sodium phosphate, potassium phosphate, lithium phosphate, and cesium phosphate, and examples of the alkali metal fluoride include lithium oxide and cesium hydroxide. Specifically, sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride and the like can be mentioned.

Examples of the alkaline earth metal basic salt include an alkaline earth metal carbonate, an alkaline earth metal hydroxide, and the like. 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.
Among inorganic bases, phosphates such as sodium phosphate, potassium phosphate, lithium phosphate and cesium phosphate are particularly preferable.

Such a base is usually used in such a range that the lower limit is usually 1 mol times or more, preferably 2 mol times or more, and the upper limit is usually 10 mol times or less, preferably 5 mol times or less with respect to the halogenated aryl compounds. Is good.
In carrying out the method of the present invention, when a predetermined amount of aryl halide compounds, aryl metal compounds, base, transition metal compound, polydentate phosphite ligand and solvent are introduced into the reactor and mixed, Good. The method and order of introduction into the reactor are not particularly limited, but usually the transition metal compound, the polydentate phosphite ligand, the solvent, the aryl boron compound, the base, and the halogen-substituted aromatic compound are introduced in this order.
Thereafter, under stirring, usually 0 ℃ or higher, preferably 25 ° C. or higher, usually 200 ° C. or less, preferably at 0.99 ° C. or less, the reaction within 24 hours or 1 minute.

  Thus, a biaryl compound which is the target compound in the production method of the present invention, preferably a biaryl compound represented by the following general formula (3) is produced.

(In the formula, A ¹ and A ² each independently represent a carbon atom or a hetero atom. R ¹ and R ² each independently represent a hydroxyl group, a cyano group, a nitro group, or an optionally substituted amino group. , An optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an acyl group, an acyloxy group, a group represented by —CO ₂ R (where R is Represents an optionally substituted hydrocarbon group.), A group represented by —CONR′R ″ (wherein R ′ and R ″ each independently represents a hydrogen atom or an optionally substituted group). A hydrocarbon group), a group represented by —SOR (where R represents an optionally substituted hydrocarbon group), a group represented by —SO ₂ R (where R is a substituted group). Or a group represented by —SiR ₃ (here, R Represents an optionally substituted hydrocarbon group), and m ¹ and m ² each independently represents an integer of 0 to 5, where m ¹ and m ² are 2 or more. And a plurality of R ¹ or R ² may be the same group or different groups.)
In the formula (3), A ¹ , A ² , R ¹ , R ² , m ¹ , and m ² are synonymous with those in the formulas (1) and (2).

The production method of the present invention is suitable for obtaining an asymmetric biaryl compound because of high selectivity of cross-coupling between halogenated aryl compounds and aryl metal compounds.
The biaryl compound thus obtained can be isolated and purified by appropriately combining known isolation and purification means such as filtration, extraction, concentration, distillation, recrystallization, column chromatography and the like.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples, unless the summary is exceeded.

[Example 1] Synthesis of 4-methylbiphenyl Under a nitrogen atmosphere, 3.0 mg (0.01 mmol) of Pd (acac) ₂ in a Schlenk tube with a capacity of 30 ml, a multidentate phosphite coordination represented by the above formula (13) After 0.01 mol of children and 3.0 ml of toluene were charged and stirred at room temperature for 30 minutes, 0.204 g (1.5 mmol) of p-tolylboronic acid, 0.424 g (2.0 mmol) of potassium phosphate, And 0.157 g (1.0 mmol) of bromobenzene were added and reacted at 110 ° C. for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, the catalyst was removed by suction filtration using celite, and the mixture was washed 3 times with 5 ml of ethyl acetate. When this filtrate was concentrated and analyzed by gas chromatography, the conversion of bromobenzene was 100%. The organic layer of the filtrate was washed with 30 ml of 10% aqueous potassium hydroxide, and the organic layer was further washed twice with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1), and 0.165 g (yield 98% (analysis by gas chromatography) of colorless plate crystals 4-methylbiphenyl. 99.9%)).
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 2.40 (3H, s), 7.23-7.62 (9H, m)

Example 2 Synthesis of 4-methoxy- 4′- methylbiphenyl The same as Example 1 except that 0.202 g (1.0 mmol) of 4-methoxybromobenzene was used instead of bromobenzene in Example 1. The operation of was repeated. 0.178 g (yield 97%) of 4-methoxy- 4′- methylbiphenyl as colorless plate crystals was obtained.
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 3.84 (3H, s), 6.96-7.58 (9H, m)

Example 3 4-Nitro-4 '- instead of bromobenzene in Example 1, methyl biphenyl, but using 4-nitro-bromobenzene 0.202 g (1.0 mmol), as in Example 1 The operation of was repeated. 0.183 g (yield 86%) of 4-nitro-4′-methylbiphenyl as yellow plate crystals was obtained.
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 2.41 (3H, s), 7.41 (4H, dd), 8.00 (4H, dd)

[Example 4] Synthesis of 4-nitrobiphenyl Instead of p-tolylboronic acid and bromobenzene in Example 1, 0.183 g (1.5 mmol) of phenylboronic acid, 0.202 g (1.0 mmol) of 4-nitrobromobenzene The same operation as in Example 1 was repeated except that 0.191 g (yield 96%) of 4-nitrobiphenyl was obtained as yellowish brown plate crystals.
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 7.40-8.34 (9H, m)

Example 5 Synthesis of 3-fluorobiphenyl The same procedure as in Example 1 except that 0.210 g (1.5 mmol) of 3-fluorophenylboronic acid was used instead of p-tolylboronic acid in Example 1. Was repeated. 0.109 g (yield 63%) of 3-fluorobiphenyl as yellow crystals was obtained.
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 7.00-7.62 (9H, m)

Example 6 3-fluoro-4 '- instead of p- tolylboronic acid and bromobenzene in Example 1, the methoxy-biphenyl, 3-fluorophenyl boronic acid 0.210 g (1.5 mmol), 4-methoxy-bromo The same operation as in Example 1 was repeated except that 0.187 g (1.0 mmol) of benzene was used. 0.171 g (yield 85%) of 3-fluoro-4′-methoxybiphenyl as yellow crystals was obtained.
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 3.83 (3H, s), 6.95-7.53 (8H, m)

Example 7 Production of 2-methyl-5- (3-fluorophenyl) pyridine 8.3 mg (0.03 mmol) of bis (1,5-cyclooctadiene) nickel complex in a 30 mL volumetric flask under nitrogen atmosphere Then, 62.6 mg (0.06 mmol) of the polydentate phosphite ligand represented by the above formula (13) and 8 mL of anhydrous toluene were charged, and the mixture was stirred at room temperature for 1 hour. 0.63 g (4.5 mmol) of phenylboronic acid, 0.52 g (3 mmol) of 2-methyl-5-bromopyridine and 1.27 g (6 mmol) of potassium phosphate were added and reacted at 80 ° C. for 6 hours. When this reaction solution was analyzed by liquid chromatography, the conversion of 2-methyl-5-bromopyridine was 100%. The salt by filtration was removed at room temperature, and the solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to give 0.54 g (yield) of 2-methyl-5- (3-fluorophenyl) pyridine as a colorless oil. 96%).
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 2.60 (3H, s), 7.06 (1H, d), 7.26 (2H, d), 7.00-7.45 (2H, m), 7.73 (1H, d), 8.70 (1H, d).

[Example 8] Production of 3- (3-fluorophenyl) pyridine Example 8 except that 0.48 g (3 mmol) of 3-bromopyridine was used instead of 2-methyl-5-bromopyridine in Example 7. The same operation as 7 was repeated. As a colorless oil, 0.48 g (yield 92%) of 3- (3-fluorophenyl) pyridine was obtained.
^{1 H-NMR (300MHz, CDCl} 3, δppm): 7.15 (1H, d), 7.23 (1H, d), 7.22-7.44 (3H, m), 7.82 (1H, d), 8.61 (1H, d), 8.81 (1H, d).

[Example 9] Production of 2-methyl-5- (3-chlorophenyl) pyridine Except for using 2.0 g (13 mmol) of 3-chlorophenylboronic acid instead of 3-fluorophenylboronic acid in Example 7, The same operation as in Example 7 was repeated. As a colorless oil, 1.67 g (yield 82%) of 2-methyl-5- (3-chlorophenyl) pyridine was obtained.

Example 10 Production of 3- (3-fluorophenyl) pyridine Example 1 except that 1.68 g (10 mmol) of 3-bromopyridine was used instead of 2-methyl-5-bromopyridine in Example 7. The same operation as 7 was repeated. As a colorless oil, 1.58 g (yield 91%) of 3- (3-fluorophenyl) pyridine was obtained.
¹ H-NMR (300 MHz, CDCl ₃ , δ ppm): 7.15 (1H, d), 7.23 (1H, d), 7.22-7.44 (3H, m), 7.82 (1H, d), 8.61 (1H, d), 8.81 (1H, d).

Example 11 Production of 3- (3-fluorophenyl) pyridine Example 1 except that 1.14 g (10 mmol) of 3-chloropyridine was used instead of 2-methyl-5-bromopyridine in Example 7. The same operation as 7 was repeated. As a colorless oil, 1.49 g (yield 86%) of 3- (3-fluorophenyl) pyridine was obtained.

[Comparative Example 1-4] Instead of the multidentate phosphite ligand 0.01mmol in Synthesis Example 1 1-methyl-4-phenyl-benzene using monodentate phosphites or phosphines, phosphine or monodentate shown in Table 1 The same operation as in Example 1 was repeated except that phosphite (0.02 mmol) was used.

  The results are shown in Table 1 below.

According to the production method of the present invention, the desired biaryl compound can be obtained with high purity and high yield by suppressing the by-product of the homo-coupled product.

Claims (4)

A method for producing biaryl compounds by coupling halogenated aryl compounds and aryl metal compounds in the presence of a transition metal-polydentate phosphite complex catalyst ,
The metal atom constituting the aryl metal compound is a boron atom,
The transition metal-multidentate phosphite complex catalyst comprises a transition metal compound and the following general formula (4):

{In Formula (4), R ³ and R ⁴ each independently represents an aryl group having 6 to 15 carbon atoms which may have a substituent, wherein R ³ and R ⁴ are They may be bonded to each other to form a ring. R ⁵ represents the following general formula (6)

Wherein ^(6), R 6 ~R ¹³ each independently represent a hydrogen atom, a methyl group, an isopropyl group, t- butyl group or a methoxy group. Zm represents a bond. ] The biphenylene group represented by this is shown. n represents 2. }
A biaryl compound formed of a bidentate phosphite ligand represented by the formula (I), wherein the metal atom constituting the transition metal compound is a nickel atom or a palladium atom: Method. Biaryl compounds are represented by the following general formula (3)

[In Formula (3), A < ¹ > and A < ² > represent a carbon atom or a hetero atom each independently. R ¹ and R ² are each independently a hydroxyl group, a cyano group, a nitro group, an optionally substituted amino group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, or a substituted group. An aryloxy group, an acyl group, an acyloxy group, a group represented by —CO ₂ R (wherein R represents an optionally substituted hydrocarbon group), and a group represented by —CONR′R ″. Group (wherein R ′ and R ″ each independently represents a hydrogen atom or an optionally substituted hydrocarbon group), a group represented by —SOR (wherein R is substituted) An optionally substituted hydrocarbon group), a group represented by —SO ₂ R (where R represents an optionally substituted hydrocarbon group), or a group represented by —SiR ₃ (here. And R represents an optionally substituted hydrocarbon group.), M ¹ and m ² represent Each independently represents an integer of 0 to 5. Here, when m ¹ and m ² are 2 or more, a plurality of R ¹ or R ² may be the same group or different groups. ]
The production method according to claim 1, wherein the compound is represented by the formula: The production method according to claim 2, wherein the group represented by (R ¹ ) m ¹ and the group represented by (R ² ) m ² in Formula (3) are not the same. Aryl metal compounds are represented by the following general formula (2)

[In Formula (2), A ² Represents a carbon atom or a hetero atom. R ² Is a hydroxyl group, a cyano group, a nitro group, an optionally substituted amino group, an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an acyl group , Acyloxy group, -CO ₂ A group represented by R (wherein R represents an optionally substituted hydrocarbon group), a group represented by —CONR′R ″ (where R ′ and R ″ are each independently A hydrogen atom or an optionally substituted hydrocarbon group), a group represented by —SOR (wherein R represents an optionally substituted hydrocarbon group), —SO. ₂ A group represented by R (wherein R represents an optionally substituted hydrocarbon group) or -SiR; _Three (Wherein R represents an optionally substituted hydrocarbon group), m ² Represents an integer of 0 to 5. Where m ² When R is 2 or more, there are a plurality of R ² May be the same or different groups. M represents a boron atom, and Y represents an anionic group bonded to M. n represents an integer of 2 or 3. ]
The production method according to claim 1, wherein the compound is represented by the formula: