WO2006085628A1 - Method for producing compound through coupling - Google Patents

Abstract

Disclosed is a method for producing a compound (D) through coupling by subjecting an organic compound (A) having a leaving group and an organic metal compound or metal hydride compound (B) to a coupling reaction. This method is characterized in that the organic compound (A) having a leaving group and the organic metal compound or metal hydride compound (B) are reacted with each other in the presence of a catalyst composition (C) containing a transition metal compound (C-1) and a ligand (C-2) which has a coordinating group and a protic group in such a manner that the coordinating group and the protic group are next to each other. This method is useful for efficiently producing a compound through coupling.

Description

 Specification

 Manufacturing method of coupling compounds

 The present invention relates to a method for producing a coupling compound that is useful when producing pharmaceuticals, agricultural chemicals, liquid crystal materials, and the like. Background art

 Coupling reactions of organic halides or sulfonates such as halogenated aryls and their analogs with transition metal catalysts such as nickel or palladium and organic metal compounds are the basis for materials science and pharmaceutical synthesis. Technology. In order to industrialize such a coupling reaction, it is desirable to use an aromatic chloride which is inexpensive and available in large quantities as a halogenated aryl. However, when a palladium catalyst is used, in addition to the problem that palladium itself is very expensive, special ligands (bulky tertiary phosphine, nitrogen-containing cyclic carbene, etc.) are required. There are problems such as. Furthermore, these ligands have drawbacks such as air instability and complicated synthesis.

On the other hand, nickel is more reactive than palladium and is much less expensive, so some practical applications such as coupling reactions between vinyl chloride and Aryl Grignard reagents using nickel-bidentate phosphine complexes, etc. (Japanese Patent Laid-Open No. 1-1060835, Japanese Patent Laid-Open No.2-1600739, T. Banno, Y. Hayakawa, M. Umeno, J. Organomet. Chem. 2002) , 653, 288-291), but generality is insufficient. In particular, the coupling reaction between a halogenated arylene and an aryl metal compound is inefficient, and for example, a few percent nickel catalyst is usually used for coupling between an aryl chloride and an aryl reel reagent (for example, nitrogen-containing). See VPW Bohm, T. WesKamp, CWK Gstottmayr, WA Herrmann, Angew. Chem., Int. Ed. 2000, 39, 1602 for using carbene ligands Using secondary phosphine sulfide as a ligand GY Li, WJ Marshall, Organometallics, 2002, 21, 590, Special Table 2 0 0 4 -5 0 1 8 7 7)) Materials / Methods for synthesizing biaryl compounds, important as pharmaceutical and agrochemical intermediates, from halogenated aryls such as chlorides with high efficiency and low catalytic amount (1, below) Is not established.

 Furthermore, in recent years, a force-coupling reaction between halogenated aryls and Grignard reagents using iron catalysts has been reported (A. FUrstner, A. Leitner, M. Mendez, H. Krause, Journal of the American Chemical Society, 2002). , 124, 13856, US Patent Application Publication No. 2 0 0 3/0 2 2 0 4 98), and biaryl synthesis has a problem of low efficiency. Disclosure of the invention

 In the above situation, development of a more efficient method for producing a coupling compound (coupling reaction product) of an organic compound having a leaving group and an organometallic compound is desired.

 As a result of intensive studies to solve the above problems, the present inventors have found that in a coupling reaction between an organic compound having a leaving group and an organometallic compound or a metal hydride compound, a transition metal compound, Reacting in the presence of a catalyst composition comprising a ligand having a coordinating group and a protic group, wherein the coordinating group and the ligand group are arranged so as to be adjacent to each other. As a result, the reaction efficiency was remarkably improved and the present invention was completed.

 That is, this invention provides the manufacturing method of the following coupling compounds.

[1] In a method for producing a coupling compound (D) by subjecting an organic compound (A) having a leaving group and an organometallic compound or a metal hydride compound (B) to a coupling reaction, A metal compound (C-1), a ligand having a coordinating group and a protic group, and the coordinating group and the protic group are arranged adjacent to each other (C- 2)) in the presence of the catalyst composition (C), and the organic compound (A) having the leaving group is reacted with the organometallic compound or the metal hydride compound (B). And how to.

 [2] Organic compounds having a leaving group (A) 1 Formula (1)

R ¹ + x) n (In the formula, R ¹ represents a hydrocarbon group, X represents a leaving group, and n represents an integer of 1 or more.)

An organometallic compound or a metal hydride compound (B), formula (2)

R ² —— m (2)

(Wherein R ² represents a hydrocarbon group or a hydrogen atom, and m represents a metal element.) A transition metal compound (C-1) force formula (3)

 M (3)

A transition metal compound represented by the following formula: Ligand (C—2) Force Formula (4) YZ ^R3 \ _Z (4)

(Wherein, Y represents a coordinating group, R ³ is optionally substituted Ci-e alkyl group, optionally substituted C ₆ - ₁₂ Ariru group, an optionally substituted Ci - 6 § alkyl - represents C 6 ₂ Ariru group, or an optionally substituted C ₆ _ ₁₂ Ariru group _C alkyl group, Z is representative of a protic group).

Coupling compound (D) force formula (5)

(Wherein RR ² and n have the same meaning as described above.)

The method according to [1] above, wherein the compound is represented by:

[3] In the formula (1), R ¹ is an alkyl group which may have a substituent, an aryl group which may have a substituent, or a heterocyclic group which may have a substituent. , An alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an acyl group which may have a substituent, and X is a halogen atom, a sulfonyloxy group The method according to [2] above, which is an alkylthio group, an arylthio group or a diazonium group.

[4] In the formula (2), R ² has a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. A heterocyclic group that may be substituted, an alkenyl group that may have a substituent, an alkynyl group that may have a substituent, or an acyl group that may have a substituent, in the above [2] The method described. [5] Transition metal compound represented by M (C 1), Periodic Table Group 8 element, Periodic Table Group 9 element, Periodic Table Group 10 element and Periodic Table Group 1 element The above [1] ~ which also contains a kind of element! : The method according to any one of 4].

[6] The method according to any one of [1] to [5] above, wherein the transition metal compound represented by M (C-1) contains at least one element selected from Group 10 elements of the periodic table.

[7] Transition metal compound represented by M (C-1) Force Nickel halide, Bis (cyclooctagen) Nickel, Nickel (II) Acetylacetonate, Nickel nitrate (11), Nickel sulfate (11) The method according to any one of [1:] to [6] above, which is nickel acetate (II) or nickel hydroxide (II).

[8] The above-mentioned [1:!, Characterized in that the coordinating group and the protic group are bonded via 2 to 4 atoms. -The method in any one of [7].

 [9] The method according to any one of [1] to [8] above, wherein the coordinating group is a group containing a trivalent phosphorus atom, nitrogen atom, sulfur atom or carbon atom.

 [10] The method according to any one of [1] to [9], wherein the protic group is a hydroxy group, an amino group, or a mercapto group.

 [11] Ligand (C-2) is 2-diphenylphosphinophenol, 2-diphenylphosphinobenzil alcohol, 1 (2-diphenylphosphinophenyl alcohol) ethanol, 2-diphenyl-norenophosph Inocyclohexanol, 1 (Selected from 2-Diphenenophosphosinocyclohexenole) Ethanol, 2-Diphenylphosphinoa diphosphorus, 2-Diphenylphosphinobenzylamine, 2-Diphenylphosphinocyclohexylamine The method described in [1] to [10] above.

[12] catalyst composition (c), nickel halide, bis (cyclocactogen) nickel, nickel (II) acetyl cetate, nickel nitrate (11), nickel sulfate (II), nickel acetate (II) and Transition metal compound selected from nickel hydroxide (II) (C-1), 2-diphenylphosphinobenzylaminereconole, 1 (2-diphenenorephosphinofenenore) ethanol, 2-diphee Nylphosphino hexanol and 1- (2-diphenylphosphino hexyl) containing ligands (C-2) and ligands (C-2) selected from ethanol Above [1 :! ~ The method according to [11]. [13] The catalyst composition (C) 1 described in any one of the above [1] to [: 12], which is a compound in which a transition metal compound (C-1) and a ligand (C-2) are complexed the method of.

[14] Compound having a leaving group (A) 1 The method according to any one of [1] to [13] above, which is a halogenated aryl or a halogenated alkenyl.

[15] Organometallic compound or metal hydride compound (B) Force Group 1 element of the periodic table, Group 2 element of the periodic table, Group 4 element of the periodic table, Group 1 element of the periodic table, Periodic table 1 2 The method according to any one of [1] to [14] above, which comprises a metal element selected from a group element, a Group 13 element of the periodic table, a Group 14 element of the periodic table, and a Group 15 element of the periodic table.

[16] Organometallic compound or metal hydride compound (B) Force Alkylmagnesium halide, A ^^ Chenolene magnesium halide, Anolequini Magnesium halide, Allylmagnesium halide, Dialkylmagnesium, Dianolecenylmagnesium, Dialkynylmagnesium The method according to the above [15], which is um or garyl magnesium. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail.

 The present invention relates to a method for producing a coupling compound by subjecting an organic compound (Α) having a leaving group and an organometallic compound or a metal hydride compound (Β) to a coupling reaction. A ligand having a coordinating group and a protonic group, and the coordinating group and the protonic group are arranged adjacent to each other (C-2) And an organic compound (触媒) having a leaving group is reacted with the organometallic compound or metal hydride compound (反 応) in the presence of a catalyst composition (C) containing Provide a method.

 Hereinafter, regarding the constituent elements of the present invention, specifically, a catalyst composition (C) containing a transition metal compound (C-1) and a ligand (C-2), an organic compound having a leaving group (基) The organometallic compound or the metal hydride compound (i) and the coupling reaction will be described in order.

 1. Catalyst composition (C)

In the present invention, since the catalyst composition, particularly the ligand, is characteristic, The composition (C) will be described. The “catalyst composition” of the present invention has a transition metal compound (C 11), a coordinating group and a protonic group, and the coordinating group and the protonic group are adjacent to each other. And a ligand (C 1 2) arranged in such a manner. The catalyst composition may be a mixture of a transition metal compound and the ligand, or may be a compound in which the transition metal compound and the ligand are complexed. In the present specification, “transition metal compound” is used in the meaning including a transition metal alone.

In this specification, “a ligand in which a coordinating group and a protic group are arranged adjacent to each other” means, for example, that the coordinating group Y is coordinated to the transition metal M ¹ and When the tonic group Z forms a bond with the metal m (see the following formula (6)), the metal compound M ¹ and m have an organic compound (A) having a leaving group, respectively, and the hydrocarbon group R ¹ is eliminated. The arrangement is such that the group X can interact substantially simultaneously. Specifically, “can interact substantially simultaneously” means that when M ¹ and m have a spatially appropriate positional relationship, the nucleophilic metal atom M ¹ and the electrophilic carbonization Hydrogen group R For example, orbital interaction between pi bonds of halogenated aryls and electrostatic interaction between electrically positive metal m and electrically negative leaving group X occur simultaneously, Preferably, the coordinating group and the protonic group are arranged via 2 to 6 atoms (more preferably 2, 3 or 4 atoms, particularly preferably 2 or 3 atoms).

In the following formula (6), the metal m is not necessarily a metal element derived from the organometallic compound or the metal hydride compound (B). For example, a metal carbonate, a metal alkoxide, It may be derived from a metal compound such as a metal amide, a metal halide, or a metal oxide.

 R

 6 1.1 Transition metal compounds (C-1)

Next, the transition metal compound (C-1) is explained. Transition metals included in the “transition metal compounds” include Group 8 elements of the periodic table such as iron, ruthenium and osmium, Group 9 elements of the periodic table such as cobalt, rhodium and iridium, and periods of nickel, palladium, platinum, etc. Examples include Group 10 elements in the table and Group 1 elements in the periodic table such as copper, silver, and gold, Group 10 elements in the periodic table are preferable, nickel and palladium are more preferable, and nickel is more preferable. Here, the “transition metal compound” means a compound containing at least one element selected from the transition metals. Examples of such transition metal compounds include transition metal salts, transition metal complex salts, transition metal hydroxides, transition metal complex compounds, transition metal oxides, and the like.

 Examples of the salt include a halide, a salt of a transition metal and an inorganic acid or an organic acid. Specifically, examples of the halide include chloride, bromide, and iodide. Examples of inorganic acid salts include hydrohalides such as nitrates, sulfates, phosphates, perhalogenates, hydrochloric acid and hydrobromic acid. Examples of organic acid salts include methanesulfonic acid, ethanesulphonic acid, benzenesulfonic acid, p-toluenesulphonic acid, trifluoromethanesulfonic acid and other sulfonates, phosphonates, formic acid, acetic acid, propionic acid, etc. Carboxylate salts of the above. Examples of complex salts include T-min complexes and acetylacetyl complex salts. The transition metal compound may be an anhydride or a hydrate. In addition, the transition metal compound may be fixed on a support such as activated carbon, silica, alumina, or titania.

A preferred example of the transition metal compound is a nickel compound, and an example of the nickel compound is a divalent or zero-valent nickel compound. Specific examples include nickel salts, divalent nickel complex salts, nickel hydroxides, divalent or zerovalent nickel π complex compounds, and nickel oxides. Examples of the nickel salt include nickel halide, or a salt of nickel and an inorganic acid or an organic acid. Specifically, nickel fluoride (1 1), nickel chloride (1 1), bromide Nickel halides such as nickel (11), nickel iodide (II), nickel nitrate (11), nickel sulfate (II), ammonium nickel sulfate (II), next Inorganic acid salts such as nickel phosphite (II), nickel acetate (1 1), nickel formate (II), nickel stearate (1 1), cyclohexane pentylate nickel (II), nickel quenate ( 1 1) and organic acid salts such as nickel naphthenate (II).

 Examples of complex salts of divalent nickel include amine complexes such as hexaamminenickel chloride (11), hexaamminenickel iodide (II), nickel (II) acetylacetonate, and nickel (II) hexane. Acetylaseton complex salts such as fluoroacetylacetonate are listed.

 Examples of the nickel hydroxide include nickel hydroxide (I I).

Examples of π complex compounds of divalent nickel include bis (7] ³ -aryl) nickel (II), bis (η -cyclopentaenyl) nickel (1 1), and nickel chloride dimer. It is done.

 Examples of the zero-valent nickel π complex compound include bis (1,5-cyclochlorogen) nickel (0), nickelocarboninole (0), and the like.

 An example of nickel oxide is nickel oxide.

Nickel compounds include halides, bis (cyclooctagen) nickel, nickel (II) acetyl cetate (N i (acac) ₂ ), nickel nitrate (1 1), nickel sulfate (1 1) Nickel acetate (1 1) and nickel hydroxide (II) are preferred, and further halides, bis (cyclocactogen) nickel, Nikkenole (II) acetylacetate (N i (acac) ₂ ). Is preferred.

 1. 2 Ligand (C— 2)

 Next, the ligand (C-2) will be described. The “ligand” of the present invention has a coordinating group and a protonic group, and is arranged so that the coordinating group and the protonic group are adjacent to each other. Such ligands include, for example, formula (4)

, Z \, (4)

(Wherein Y represents a coordinating group, R ³ is an optionally substituted alkyl group, Optionally substituted C e ₂ Ariru group, an optionally substituted C ^ ₆ alkyl Lou C _{6 1 2} Ariru group, or an optionally substituted C _{6 1 2} § Li Ichirumoto C ^ e Represents an alkyl group, and Z represents a protonic group. )

And a ligand (C-2) represented by

The ligand may have an asymmetric point in either the coordinating group Y, the group represented by R ³ , or the protonic group 、. Furthermore, the ligand may be supported on a polymer, such as a resin that does not dissolve in the reaction solvent.

 The “coordinating group” may be any group that can coordinate to the transition metal. Examples of the “coordinating group” include a group containing a phosphorus atom such as a group containing a trivalent phosphorus atom such as a phosphino group or a phosphite group, or a group containing a nitrogen atom such as an amino group, an imino group or a pyridyl group. And groups containing a sulfur atom such as a sulfido group, and groups containing a carbon atom such as carbene and its precursor, and a group containing a trivalent phosphorus atom is preferred, and a phosphino group is particularly preferred. The “coordinating group” may be substituted with a water-soluble group.

 Examples of the group containing a phosphorus atom include a phosphino group, a phenylphosphino group, a diphenylphosphino group, an arylenophosphino group such as a ditolylphosphino group, a methinorefenylphosphino group, and an isopropinolephenyl. Phosphino group, Butylpheninorephosphino. Group, Cyclohexylphenylphosphino group, (t-Putinole) Monoalkyl monoarylphosphino group such as phenylphosbuino group, Methylphosphino group, Dimethylphosphino group, Jetylphosphino group Alkyl phosphino groups such as diisopropylphosphino group, dibutylphosphino group, dicyclohexylphosphino group, di (t-butyl) phosphino group, di (2-furinole) phosphino group, phosphine oxide group, phosphite group, Phosphate group, h Hosufue one such preparative group and the like, preferably § reel phosphine Ino group, more Jifueniruhosu Fuino group.

The aryl group in the aryl phosphino group or monoalkyl monomonoaryl phosphino group includes, for example, a C e—i ₂ aryl group such as a phenyl group, a naphthyl group, a biphenyl group, a biphenyl-2-oleyl-2,2′-diyl group, etc. Group. Is an alkyl group in Monoaruki Lou mono § reel phosphine Ino group or an alkyl phosphine Ino group, for example, straight-chain or branched-chain C ^ e alkyl or C ₃ _ ₆ Shikuroa C- ₆ alkyl groups such as an alkyl group, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s_butyl group, a t-butyl group, a pentinole group, Examples thereof include a cyclopentinole group, a hexinole group, and a cyclohexenole group.

 Examples of the group containing a nitrogen atom include an amino group, a substituted amino group, an imino group, and a nitrogen-containing heterocyclic group. Specific examples of the substituted amino group include alkylamino groups such as a dimethylamino group, a jetylamino group, and a dibutylamino group. Specific examples of the nitrogen-containing heterocyclic group include 5-membered ring groups such as pyrrolyl group and imidazolyl group, 6-membered ring groups such as pyridyl group, pyrajuryl group and pyrimidinyl group, and condensed heterocyclic groups such as phenantholinyl group. Etc.

 Examples of the group containing a sulfur atom include a thiocarboxy group, a dithiocarboxyl group, a thiocyanato group, an isothiocyanato group, a thioformyl group, a thiocarbonyl group, a mercapto group, an alkylthio group, an arylthio group, a thioacetyl group, a thiocarbamoyl group, and a sulfamoyl group. Alkylsulfamoyl group, arylsulfamoyl group, alkylthio group, sulfonyl group, alkylsulfonyl group, arylsulfonyl group, sulfiel group, alkylsulfinyl group, arylsulfinyl group and the like.

The alkyl group in R ^3, for example, straight-chain or branched _alkyl group or a C ₃ _ ₆ cycloalkyl group and the like, preferably C ₃ _ ₆ cycloalkyl group, a cyclohexyl group is preferred further cyclohexylene.

Examples of the C _{6 — 12} aryl group for R ³ include a phenyl group, a naphthyl group, and a biphenyl group, and a phenyl group is preferable.

! ^ To Okeru ^^ Arukiru - The d_ ₆ alkyl group in Ariru group or C ₆ _ ₁₂ Ariru one Cn alkyl group, such as straight-chain or branched alkyl group or a C ₃ _ ₆ cycloalkyl group mentioned It is preferably a linear or branched C i ₆ alkyl group, preferably more linear or branched ci _ ₆ alkyl group, particularly a methyl group, is Echiru group. The C ₆ _ ₁₂ Ariru group in C ^ ₆ Al Kill _C ₆ _ ₁₂ Ariru group or C _{6 12} Ariru one C ₆ alkyl group in R ^3, Fuweniru group, a naphthyl group, is Bifue two Le group mentioned, A benzyl group is preferred. Examples of alkyl 1 C ₆ _ _{1 2} 7 reel group or C ₆ _ _{1 2} aryl 1 C ₆ alkyl group in R ³ include benzyl group, phenylethyl group, orthoxylyl group, and metaxylyl group. preferable.

R ³ is preferably a cyclic hydrocarbon group such as an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted cycloalkyl group. The aryl group in the optionally substituted aryl group includes a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, etc., and an aryl group of ₂ is preferable. Examples of the heterocyclic group which may be substituted include pyridyl group, quinazolinyl group, quinolyl group, pyrimidyl group, furyl group, chenyl group, pyrrolyl group, imidazolyl group, tetrazolyl group, phenanthoxylinyl group. Among them, a 5- to 12-membered heterocyclic group is preferable. Examples of the cycloalkyl group in the cycloalkyl group which may be substituted include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, and the like. cycloalkyl group having ₄ _ ₈ are preferred.

When R ³ is a cyclic hydrocarbon group, the coordinating group Y and the protic group Z are preferably bonded to adjacent atoms forming a ring.

As the substituent in R ³ , for example, as the “substituent”, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group , Alkyl groups such as isopropyl group, s-butyl group, t-butyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group, heptyl group, cycloheptyl group, octyl group, cyclooctyl group, trifluoromethyl group, etc. Alkenyl groups such as vinyl group, propenyl group, isopropenyl group, aryl group, butur group, pentur group, geranyl group, and guanesyl group; alkynyl groups such as ethur group, propier group, and butcher group; Groups, naphthyl groups, anthracenyl groups, phenanthryl groups and the like; Heterocyclic groups such as zircyl group, quinazolinyl group, quinolyl group, pyrimidinyl group, furyl group, chenyl group, piaryl group, imidazolyl group, tetrazolyl group, phenanthral linyl group; Hydroxyl group; Si group, ethoxy group, butoxy group, t-butoxy group, etc .; aryloxy group such as phenoxy group; menolecapto group; alkylthio group such as methylthio group; arylothio group such as phenylthio group; cyano group; nitro group Amino group; methylamino group, ethylamino group, cyclohexylamino group, dimethylamino group, dimethylamino group, dibutylamino group, substituted amino group such as acetylamino group; carbamate group such as t-butylcarbamate group, methylcarbamate group; benzenesulfone Sulfonamide groups such as amide and menthanesulfonamide groups; Imino groups; Imido groups such as phthalimide groups; Formyl groups; Carbonyl groups; Acyl groups such as acetyl groups, propionyl groups, and benzoyl groups; ; Mexica Po two group, an ethoxycarbonyl group, Anorekokishi force Ruponiru group such as butoxycarbonyl group; and § reel O alkoxycarbonyl group such as phenoxyethanol carbonyl group.

In addition, the substituent in R ³ may be a water-soluble group, and is preferably a water-soluble group.

The “protic group” means a group capable of producing a proton in a reaction mixture or reaction solvent, or a group in which a proton is eliminated from a group capable of producing a proton in the reaction mixture or reaction solvent. Protic groups include, for example, hydroxyl, amino, mercapto, -C0 ₂ H, 1 S0 ₃ H, 1 P0 ₃ H, -NHOH, — S0 ₂ NH ₂ , 1 0 ^_ , — NH— , 1 S ^_ ,-C0 ₂ —, — S0 ₃ 1, 1 P0 ₃ —, — NHO ^_ , 1 SO ₂ NH_, etc., preferably a hydroxyl group, an amino group, a mercapto group, and more preferably a hydroxyl group Is preferred.

When the protic group is a group in which the proton is eliminated from a group capable of generating a proton in the reaction mixture or in the reaction solvent, examples of the counter force thione include Na ⁺ , Li +, K +, (C ₄ H ₉ ) ₄ N + and the like.

 The “protic group” may be substituted with a water-soluble group.

The water-soluble group in the coordinating group Y, R ³ or the protic group よ く may be a free form or a salt. For example, a sulfonic acid group, a salt of a sulfonic acid group, a carboxy group, a salt of a carboxy group, a hydroxyl group Mercapto group, amino group, ammonio group, sulfonamido group, acylsulfamoyl group, sulfonylsulfamoyl group, active methine group, Or a substituent containing these groups, preferably a sulfonic acid group, a salt of a sulfonic acid group, a carboxy group, a salt of a carboxy group, and the like, and more preferably a salt of a sulfonic acid group or a salt of a carboxy group.

In the ligands used in the present invention, coordinating groups and pro tons groups are coordinating groups coordinated to the transition metal M ¹ transition metal compound, pro tons groups organometallic compound or metal arsenate It is preferable that when a bond is formed with the metal element m in the dry compound, the organic compound having a leaving group and the two metal elements can interact with each other substantially simultaneously. In order to achieve such an arrangement, the coordinating group and the protic group are preferably bonded via 2 to 6 atoms, and more preferably bonded via 2 to 4 atoms. It is particularly preferred that they are bonded via 2 or 3 atoms.

As a ligand in which a coordinating group and a protic group are bonded via two atoms, for example, the following formula

(In the formula, Y represents a coordinating group, and Z represents a protic group.)

The ligand represented by these is mention | raise | lifted.

Examples of the ligand in which the coordinating group Y and the protic group Z are bonded via 3 atoms include, for example, the following formula

 (In the formula, Y and Z have the same meaning as described above.)

The ligand represented by these is mention | raise | lifted.

For example, a coordination group in which a coordinating group Y and a protonic group Z are bonded via four atoms is represented by the following formula:

(In the formula, Y and Z have the same meaning as described above.)

The ligand represented by these is mention | raise | lifted.

As ligands, in particular:

 (In the formula, Y and Z have the same meaning as described above.)

The ligand represented by these is preferable.

 Specific examples of ligands include 2-diphenylphosphinophenol, 2-diphenylphosphinobenzinoreanolenoconole, 1- (2-diphenylphosphinophenyl) ethanol, 2- Diphenylphosphinocyclohexanol, 1 1 (2-Diphenenophosbuinocyclohexenole) Ethanol, 2-Dipheninophosphosinoaniline, 2-Dipheninophosphinopenzinoreamine, 2-Diphenyl / Lephosphinocyclohexamine, 2-Diphenylphosphinobenzyla Norecone, 1- (2-Diphenenolesphosphinofenore) Ethanol, 2-Diphenninolephosphinox mouth hexanol or 1- ( 2-diphenylphosphine hexyl) Ethanol is preferred, and 2-diphenylphosphite Novenyl dioleo cornore, 1- (2-diphenylenophosphinophenyl) ethanol is preferred. Of these, 1- (2-diphenylphosphinophenyl) ethanol is particularly preferable because it has particularly high activity. 1- (2-Diphenylphosphinophenyl) Using ethanol can further reduce the amount of catalyst used, organometallic compound or metal hydride compound, etc. Coupling reaction of polyhalogenated aryl can be performed with high efficiency.

 The amount of the ligand (C-2) used may be an amount that enhances the activity of the transition metal compound (C 1 1). Mol, preferably from 0.1 mol to 20 mol, more preferably from 0.2 mol to 5 mol, still more preferably from 0.5 mol to 2 mol, particularly preferably from 0.9 mol to 1.1 mol. It is moderate.

The transition metal or transition metal compound (C-1) and the ligand (C_2) are complexed A compound (complex) may be formed.

 1.3 Combinations of transition metal compounds and ligands

 The catalyst composition used in the present invention is preferably at least one selected from Group 8 elements of the periodic table, Group 9 elements of the periodic table, Group 10 elements of the periodic table and Group 11 elements of the periodic table A transition metal compound containing an element, a selected from a phosphorus atom, a nitrogen atom, a sulfur atom, and a carbon atom, and a coordinating group and a protic group containing any atom, and the coordinating group And a ligand arranged so that the protonic group is adjacent to each other.

 A more preferable catalyst composition is selected from a transition metal compound containing at least one element selected from Group 10 elements of the periodic table, a coordination group containing a phosphorus atom, a hydroxy group, an amino group, and a mercapto group. And a ligand having a protic group. A more preferable catalyst composition includes a transition metal compound containing nickel, and a ligand having a coordinating group containing a trivalent phosphorus atom and a protic group consisting of a hydroxyl group.

Particularly preferred catalyst compositions are nickel halide, nickel nitrate (II), nickel sulfate (1 1), ammonium nickel sulfate (1 1), nickel hypophosphite (1 1), nickel acetate (1 1 ), Nickel formate (1 1), dikenore diztearate (II), nickel nickel cyclohexane (II), nickel oleate taenoate (1 1), nickel naphthenate (1 1), nickel hexaammine chloride (1 1), Hexaammine nickel iodide (1 1), Nickel (II) Acetylacetate, Nickel (II) Hexafluoroacetylacetonate, Nickel (II) hydroxide, Bis ( eta ³ - § Rinore) nickel (II), bis (eta - Shikuropentaji Eniru) nickel (1 1), Arirunikkeru dimer chloride, bis (Shikurookutaji E down) nickel (0), nickel-carbonitrile A transition metal compound selected from ruthenium (0) and nickel oxide, 2-diphenylphosphinophenol, 2-diphenylphosphinobenzinorea ^ / cor ^^, 1- (2-diphenenorephosphinophenol Nole) Ethanol, 2-Diphenenorephosphinocyclohexanol, 1- (2-Dipheninolephosphinocyclohexenole) Ethanol, 2-Diphenenophosphosinoanilin, 2-Diphenenolephosphinobendylamine 2-Pi-diphenylphosphino And a ligand selected from chlorohexamine.

The most preferred catalyst compositions are nickel halide, bis (cycloactagen) nickel, nickel (II) acetyl cetate (N i (acac) ₂ ), nickel nitrate (II), nickel sulfate (11), acetic acid Transition metal compounds selected from nickel (II) and nickel hydroxide (II), 2-diphenylphosphinobenzyl alcohol, 1- (2-diphenylphosphinophenyl) ethanol, 2-diphenylphosphine Innocyclohexanol and 1- (2-diphenylphosphine hexyl) with a ligand selected from ethanol.

 These catalyst compositions may be a mixture of a transition metal compound and the ligand, or may be a compound in which the transition metal compound and the ligand are complexed. These catalyst compositions may further contain a co-catalyst such as a metal salt or a base, if necessary.

 2. Organic compounds having a leaving group (A)

 Since the present invention is characterized by using a specific catalyst composition as described above, the starting material is not particularly limited. Here, the “organic compound having a leaving group” is not particularly limited as long as a coupling reaction is possible.

(In the formula, R ¹ represents a hydrocarbon group, X represents a leaving group, and n represents an integer of 1 or more.)

The organic compound represented by these is mention | raise | lifted.

 Examples of the “hydrocarbon group” in the “organic compound having a leaving group” include an alkyl group which may have a substituent, an aryl group which may have a substituent, and a substituent. A heterocyclic group which may be substituted, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an acyl group which may have a substituent, and the like. . The “hydrocarbon group” may be a group in which all hydrogen atoms are replaced by other atoms, for example, a perhalogenoalkyl group.

The “alkyl group” may be linear, branched or cyclic, for example, C i — ₂ . A linear or branched alkyl group or a cyclic alkyl group, Specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group, heptyl Group, cycloheptyl group, octyl group, cyclooctyl group and the like.

The "Ariru group", for example, are exemplified Ariru group C 6 _8, specifically, phenyl group, naphthyl group, anthracenyl group, Fuenantoriru group Nadogaa up.

 Examples of the “heterocyclic group” include 5-membered to 18-membered heterocyclic groups. Specifically, for example, pyridyl group, quinazolinyl group, quinolyl group, pyrimidinyl group, furyl group, chenyl group, pyrrolyl, and the like. Group, imidazolyl group, tetrazolyl group, phenanthrolinyl group and the like.

As the "alkenyl group" may be linear or branched, for example, a straight-chain or branched alkenyl groups c ₂ _ _{2 0,} specifically, Bulle group, Purobe sulfonyl group , Isopropenyl group, allyl group, butenyl group, pentenyl group, gerael group, farnesyl group and the like.

The “alkynyl group” may be linear or branched, for example, C ₂ _ ₂ . Examples thereof include a straight chain or branched chain alkynyl group, and specific examples include an ethynyl group, a propiel group, and a ptynyl group.

 Examples of the “acyl group” include an acetyl group, a formyl group, a propionyl group, a butyryl group, an isoptyryl group, a bivaloyl group, a benzoyl group, a benzyloxycarbonyl group, and the like.

 Preferable “hydrocarbon group” is preferably aryl which may have a substituent, alkenyl which may have a substituent, or alkyl which may have a substituent. Preferred are aryl and optionally substituted alkenyl.

As the “substituent” of “hydrocarbon group”, for example, halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom; methyl group, ethyl group, propyl group, isopropyl group, butynole group, isobutyl group, s-Putinole group, t-Butyl group, Pentyl group, Cyclopentinole group, Hexinole group, Cyclohexinole group, Heptyl group, Cyclohe Alkyl groups such as butyl, octyl, cyclooctyl and trifluoromethyl groups; vinyl, propenyl, isopropenyl, allyl, butyr, pentenyl, geranyl and farnesyl Alkenyl groups; alkynyl groups such as ether, propylene, and butcher groups; aryl groups such as phenyl, naphthyl, anthracenyl, and phenanthryl groups; pyridyl, quinazolinyl, quinolyl, pyrimidinyl, furyl, and cheenyl Group, pyrrolyl group, imidazolyl group, tetrazolyl group, phenantyl linyl group, etc .; aralkyl group such as benzyl group, phenethyl group, etc .; hydroxyl group; methoxy group, ethoxy group, butoxy group, t — Alkoxy groups such as butoxy groups; phenoxy groups, etc. Alkyloxy group such as methylthio group; arylthio group such as phenylthio group; cyano group; nitro group; amino group; methylamino group, ethyl amino group, cyclohexylamino group, dimethylamino group, jetylamino group, Substituted amino groups such as dibutylamino and acetylamino groups; t-butylcarbamate and methylcarbamate and other strong rubamate groups; benzenesulfonamido and menthanesulfonamide and other sulfonamido groups; imino group and phthalimid Formyl group; carbonyl group; acetyl group such as acetyl group, propionyl group and benzoyl group; carboxy group; alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group and butoxycarbonyl group; Etc. § reel O alkoxycarbonyl group such as enoxy carbonyl group.

 The “leaving group” in the “organic compound having a leaving group” is not particularly limited as long as it can be removed by a coupling reaction, and examples thereof include a halogen atom, a sulfonoxy group, an alkylthio group, an arylthio group, Examples include diazonium groups. Here, examples of the “halogen atom” include a fluorine atom, a chlorine atom ^ ”, a bromine atom and an iodine atom, and a fluorine atom, a chlorine atom and a bromine atom are preferable. As the“ sulfonyloxy group ”, a substituent Examples thereof include an alkylsulfonoxy group which may have a group and an arylsulfonyloxy group which may have a substituent.

The “aryl group” in the “aryl group” includes, for example, an aryl group of C ₆ — ₁₈ , specifically, a phenyl group, a naphthyl group, an anthracenyl group, And phenanthryl group.

 The “alkyl group” in the “alkylthio group” may be linear, branched or cyclic, for example, Straight chain or branched alkyl group or cyclic alkyl group, specifically, methyl group, ethyl group, propyl group, isopropinole group, pentinole group, isobutyl group, s-butyl group, t Examples thereof include a monobutyl group, a pentynole group, a cyclopentyl group, a hexyl group, a cyclohexyl group, a heptyl group, a cycloheptyl group, an octyl group, and a cyclooctyl group.

 Examples of the “substituent” in the “optionally substituted alkylsulfonyloxy group” include halogen atoms such as fluorine, chlorine, bromine and iodine, a methyl group, an ethyl group, a propyl group, and an isopropyl group. , Butyl group, isobutyl group, s_butyl group, t-butyl group, pentyl group, hexyl group and other Ce alkyl groups, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group And alkoxy groups. Specific examples of the alkylsulfonyloxy group which may have a substituent include a methanesulfonyloxy group, an ethanesulfonyloxy group, a trifluoromethane sulphonyloxy (OT f) group, and a chloromethane. Examples thereof include a sulfoninoreoxy group, a trichloromethane sulphonyloxy group, and a nonafluorobutanesulfonyloxy group.

Examples of the “substituent” in the “arylaryloxy group optionally having substituent (s)” include halogen atoms such as fluorine, chlorine, bromine and iodine, methyl group, ethyl group, propyl group, isopropyl Groups, butyl groups, isobutyl groups, s_butyl groups, t-butyl groups, pentyl groups, hexyl groups and other Ci- ₆ alkyl groups, methoxy groups, ethoxy groups, propoxy groups, isopropoxy groups, butoxy groups, Examples include an alkoxy group such as an isobutoxy group, a nitro group, and a cyano group. Specific examples of the arylsulfonylsulfonyl group which may have a substituent include benzenesulfonyloxy group, p-toluenesulfonyloxy group, 1_naphthalenesulfonyloxy group, 2-naphthalene. Sulfoninoreoxy group, p-nitrobenzene sulfonyloxy group, m-nitrobenzene sulphonyloxy group, m-toluene sulphoninoreoxy group, o-tonoleene sulfonyloxy group, 4-chlorobenzene sulphoninoreoxy group, 3—Black benzene senorephonino reoxy group, 4—Methoxybenzase And n-sulfonyloxy group.

 The leaving group used in the present invention is preferably a halogen atom or a sulfonyloxy group, and more preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group.

 The number of leaving groups (n) in the “organic compound having a leaving group” is not particularly limited as long as it is a number that an organic compound can have. The number of leaving groups (n) varies depending on the structure of the organic compound. For example, 1 to 100, 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 1 0, 1 to 9-1 to 8, 1 to 7, 1-· ο, 1 to 5, 1 to 4, 丄 to 3, 1 to 2 or 1 may be used. For example, when the hydrocarbon group in the “organic compound having a leaving group” is a phenyl group, the number of leaving groups (η) is preferably 1 to 6, more preferably :! ~ 4.

 Examples of the organic compound having two or more leaving groups include polyhalogenated aryls such as polychlorinated aryls and polyfluorinated aryls, polyalkylated alkyls such as polyalkyl chlorides and polyfluorinated alkyls, and the like.

 The organic compound having a leaving group used in the present invention is preferably an organic halide or sulfonic acid ester, more preferably an organic halide, and still more preferably a halogenated aryl, an alkyl halide or Halogenated alkenyl, most preferably halogenated aryl or halogenated alkeninole.

3. Organometallic compounds or metal hydride compounds (Β)

 Next, the organometallic compound or the metal hydride compound (Β) will be described.

 The “organometallic compound or metal hydride compound” is not particularly limited as long as a coupling reaction is possible. For example, the compound (2)

R ² — m (2)

(Wherein R ² represents a hydrocarbon group or a hydrogen atom, and m represents a metal element.) An organometallic compound or a metal hydride compound represented by

When the hydrocarbon group is an aryl group, benzyl group, etc., it can take a delocalized form ( _π -aryl, etc.) when bonded to a metal element, but the hydrocarbon group and metal The bond with the element may be in such a delocalized form.

Examples of the “hydrocarbon group” in the “organometallic compound” include a substituent. An optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted alkenyl group, and a substituent. An alkynyl group which may be substituted, an acyl group which may have a substituent, and the like. The alkyl group in R ^2, as the Ariru group, a heterocyclic group, an alkenyl group, Al Kiniru group, Ashiru groups and substituents, those exemplified with respect to R ¹ may be mentioned, preference is also same as those described for R ¹ It is.

 Examples of metal elements in the “organic metal compound or metal hydride compound” include Group 1 elements of the periodic table such as lithium, sodium, and potassium, Group 2 elements of the periodic table such as magnesium and calcium, titanium, zirconium, and the like. Periodic Table Group 4 elements, copper, silver, gold, etc. Periodic Table Group 1 elements, zinc, force domum, mercury and other periodic table Group 1 elements, boron, aluminum, gallium, indium, thallium, etc. Periodic Table 1 Group 3 elements, Kay, Germanium, Tin, Lead, etc. Periodic Table 1 Group 4 elements and Bismuth etc. Periodic Table 1 Group 5 elements, Periodic Table Group 2 elements are preferred Furthermore, magnesium is preferable.

The “organometallic compound” preferably used in the present invention is an “organomagnesium compound”, particularly a Grignard reagent. Grignard reagents include, for example, alkyl magnesium halides (for example, C alkyl magnesium halides such as methylmagnesium chloride, ethylmagnesium bromide, butylmagnesium bromide, cyclohexylmagnesium bromide), alkenylmagnesium halides. (Eg, C _{2 — 20} alkenyl magnesium halides such as vinyl magnesium bromide, propenyl magnesium bromide), alkynyl magnesium halides (eg, C _{2 20} alkynyl magnesium halides such as acetylene magnesium bromide) ), Arylmagnesium halides (eg, phenylmagnesium bromide, naphthylmagnesium promide, trilphenylmagnesium bromide, trimethylphenyl) C ₆ _ ₁₈ allyl magnesium halide such as gnesium promide), aralkyl magnesium halide (eg, benzyl magnesium bromide, allyl C alkyl magnesium halide), and the like.

Examples of organomagnesium compounds include dialkyl magnesium (for example, Ci—2. Dialkylmagnesium), dialkenylmagnesium (eg C ₂ —

₂₀ dialkenyl magnesium), di-alkynyl magnesium (e.g., C ₂ _ ₂₀ di alkynyl magnesium), di § reel magnesium (e.g., C ₆ - ₁₈ di § reel magnesium) and the like may be mentioned, among others diphenyl magnesium, Jinafu Chill Diary magnesium such as magnesium is preferred.

 Examples of the metal hydride compound include lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride, sodium cyanoborohydride, diborane, borane-tetrahydrofuran complex, borane-dimethylsulfide. Complexes, 9-borabicyclo [3.3.1] nonane, magnesium hydride, tributyltin hydride, phenyldimethylsilane, trichlorosilane and the like.

 4. Coupling reaction

 Next, the coupling reaction will be described.

 The reaction formula of the coupling reaction of the present invention is shown below (Reaction Formula 1). In the following, the reaction formula will be described.

[Reaction Formula 1]

 M (C-1)

_Y Z \ _Z (C-2)

R ¹ + X) _n + R ² 1 ^m ► R ¹ -fR ² ) _n

(A) (B) (D)

(In the formula, RX, R ² , m, M., Y, R ³ , Z, and n have the same meaning as described above.)

In the force pulling reaction of the present invention, a solvent is usually used, preferably in an organic solvent. Examples of the solvent include, but are not limited to, aliphatic or aromatic hydrocarbons (eg, benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane, etc.), ethenore (jetino ethenole , Dibutynoate ethere, t-butyl methyl ether, tetrahydrofuran, dimethoxetane, etc.), nitrogen Solvent (Triethylamine, Tetramethylethylenediamine, Pyridine, N, N-Dimethylformamide, N, N-Dimethylacetamide, Acetonitrile, Benzonitrile, Hexamethylphosphoramide, etc.), Sulfur Containing solvent (dimethylsulfoxide, dimethylsulfide, carbon disulfide, etc.), fluorous solvent (benzotrifluoride, perfluorinated hexane, perfluorodecalin, etc.), ionic liquid (1-ethyl-3-methyltetrafluoro) Boroboric acid, 1-butyl-3-methylimidazole tetrafluoroboric acid, etc., alcohol (methanol, ethanol, isopropanol, butanol, ethylene glycol, etc.), water, or a combination of these Is used.

 The reaction temperature depends on the organic compound (A), organometallic compound or metal hydride compound (B), transition metal compound (C 1) and ligand (C 1 2) having the leaving group used. The temperature may be set as appropriate, for example — 100 ° C to 200 ° C, preferably — 50 to 1500 ° C, more preferably 0 to 100 ° C, and usually room temperature (about 25 ° C) The reaction time is not particularly limited, and is usually about several minutes to 100 hours, but the reaction time can be adjusted according to the reaction rate. The reaction pressure is not particularly limited but is usually carried out at atmospheric pressure. In order to prevent the catalyst from being deactivated by oxygen, the reaction is preferably carried out in an inert gas atmosphere such as nitrogen gas or argon gas.

 The amount of the organometallic compound or metal hydride compound (B) used may be appropriately set according to the number of leaving groups possessed by the organic compound (A) having a leaving group. With respect to 1 mol of the leaving group of the organic compound (A), for example, it is about 0.5 mol to 3 mol, preferably about 1 mol to 2 mol, and more preferably 1.1 mol to 1. About 5 moles. ·

The amount of the transition metal compound (C-11) used may be set as appropriate according to the reactivity of the organic compound (A) having a leaving group, but the elimination of the organic compound (A) having a leaving group. For example, 0.001 mol% or more and 100 mol based on the group. / ₀ or less, preferably 0.01 mol% or more and 20 mol% or less, more preferably 0.1 mol%. / ₀ or 1 0 mole _^0/0 or less, and particularly preferably 0.2 mol _^0/0 over 5 mole _^0/0 or less.

The amount of ligand (C 1-2) used is the same as the amount of transition metal compound (C 1 1) used. Configuration may be but, based on leaving group possessed by the organic compound (A) having a leaving group, for example, 0 - 0 0 1 mole _^0/0 or 1 0 0 mole _^0/0 or less, preferably 0 - 0 1 mole _^0/0 or 4 0 mol% or less, more preferably, 0. 0 5 mol% or more 2 0 mol% or less, particularly preferably 0. 2 mol% or more 1 0 mol% or less.

 The coupling reaction is not limited to this. For example, a transition metal compound (C

1), a ligand (C-12), an organic compound (A) having a leaving group, and a solvent as necessary, and mixed, and the resulting mixture is mixed with an organometallic compound or a metal hydride. This can be started by adding the compound (B). The organometallic compound or metal hydride compound (B) is usually added as a solution dissolved in an organic solvent, and is preferably added as a jetyl ether tetrahydrofuran solution. A coupling compound (D) can be obtained by stirring the obtained reaction mixture until the coupling reaction is completed.

 After the reaction, the generated coupling compound (D) is required after the reaction is stopped by adding an aqueous solution of an inorganic acid such as dilute hydrochloric acid, a saturated aqueous ammonium chloride solution or an alcohol such as methanol / re to the reaction mixture. Accordingly, extraction with an organic solvent and washing with water can be followed by purification by distilling off the solvent. The obtained coupling compound (D) can be further purified by means such as distillation, recrystallization, and various chromatographies, if necessary.

 The force pulling reaction of the present invention may be carried out in the presence of a base such as a metal carbonate, metal alkoxide, metal amide, or amine, a metal halide, or a metal oxide as an additive.

When R ¹ in the formula (A) is substituted with a halogen atom, the halogen atom is also reacted with an organometallic compound or a metal hydride compound (B) by the production method of the present invention. A coupling compound in which a halogen atom is also substituted with the group R ² of the organometallic compound or the metal hydride compound (B) can be obtained. In this case, the amount of the organometallic compound or metal hydride compound (B) used may be appropriately set according to the number of substitutions with halogen atoms in R ¹ . For example, when the number of substitutions by a hydrogen atom is 1, the amount of the organometallic compound or metal hydride compound (B) used is the leaving group 1 of the organic compound (A) having a leaving group. Mo The amount is preferably about 1.5 to 4 moles, more preferably about 2 to 3 moles. Example

 EXAMPLES Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

In the following examples, the obtained coupling compounds were all described in the literature except for the coupling compounds of Example 12 and were compared with the standard samples or described in the literature. Confirmed by comparison with spectroscopic data. Example 1 The coupling compound of Example 2 is Fourier transform infrared spectroscopy (measured with a React IR 1000 reaction analysis system (ASI Applied System) equipped with DuraSample IR (ASI Applied System)), proton nuclear magnetic resonance H NMR ) spectroscopy, and confirmed by carbon nuclear magnetic resonance ^{(1 3} CNMR) spectroscopy (JEOL ECX-400 (400 MHz ) measured by or JEOL ECA- 500 (500 MHz) NMR spectrometer) and elemental analysis.

 All reactions involving air and humidity sensitive compounds were performed in dry reactors under positive argon or nitrogen pressure. Air and humidity sensitive liquids and solutions were transferred using syringes or stainless steel force neuules. Analytical thin film chromatography was performed using glass plates pre-coated with 25-m, 230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin layer chromatography was detected by exposure to ultraviolet light (UV) and / or by immersing in an ethanolic solution of phosphomolybdic acid, followed by heating on a hot plate and coloring. The organic solution was concentrated by operating a rotary evaporator connected to a diaphragm pump at -15 torr. Flash column chromatography is based on Kanto Chemical Silica Gel 60 (spherical, neutral, 140-325 mesh), Still, WC; Klahn, M .; Mitra, AJ Org. Chem. 1978, 43, 2923. -Performed as described in -2924.

Materials: Reagents purchased from Tokyo Kasei, Aldrich, and other companies were used after being distilled or recrystallized. Anhydrous jetyl ether was purchased from Kanto Chemical, distilled from benzophenone ketyl at 760 Torr under an argon atmosphere and used immediately. It was. The water content in the solvent was confirmed to be less than 2 Oppra using a Karl Buischer moisture content titration apparatus. Nickel (II) acetylacetate was purchased from Aldrich. 2-Diphenylphosphinobenzil alcohol Other phosphine ligands synthesized by methods described in the literature were used. The aryl Grignard reagent was prepared from the corresponding aryl bromide and magnesium strips in anhydrous ether and used immediately after measuring the concentration by acid-base titration using methyl orange as an indicator.

Instrument: JEOL ECX-400 (400 MHz, JEOL Ltd.) or JEOL ECA-500 (500 MHz, JEOL Ltd.) Proton nuclear magnetic resonance (NMR) and carbon nuclear magnetic resonance using an NR spectrometer ( ¹³ C NMR) was recorded. The chemical shift of the hydrogen atom was recorded as 1 / 1,000,000 (ppm, δ scale) on the lower field side from tetramethylsilane, and the residual proton in the NMR solvent (CDC1 ₃ : ™ 7.26) was recorded. Referenced. The carbon nuclear magnetic resonance spectrum ( ¹³ C 匪 R) was recorded at 125 or 100 MHz. The chemical shift of carbon was recorded from tetramethylsilane as 1 / 1,000,000 on the low magnetic field side (ppm, δ scale) and referred to the carbon resonances in the NMR solvent (CDC1 ₃ : 5 77. 0). . The data are shown as follows: chemical shift, multiplicity (s = —double line, d = double line, t = triple line, c quadruple line, m = multiple line and / or multiple resonance, br = Broad band), coupling constant (Hertz: Hz), and integral.

Gas chromatographic (GC) analysis was performed with Shimadzu GC-14B equipped with a FID detector, a chiral ram, and HR-1 (25mx0.25 mm id, 0.25 μm film). Infrared spectra were recorded on a React IR 1000 reaction analysis system equipped with DuraSample IR (ASI Applied System) and indicated as cnf ¹ .

 Example 1

Nickel (II) Acetylacetonate (Ni (acac) ₂ ) (12.8 mg, 0.05 mmo) in a 2 OmL glass reaction vessel previously dried in an oven and containing a magnetic stir bar 1), 2-Diphenenorephosphinobenzinore alcohol (1 4.6 mg, 0.05 mm o 1), 4-Funoleoloanisonore (1 2 6. 1 mg, 1.0 0 mmo 1) and Jetyl ether (3.09 mL) were charged in an argon atmosphere. To this was added a solution of 1.65 mol ZL of phenylmagnesium bromide (0.91 mL, 1.50 mm o 1) in jetyl ether at room temperature. The resulting mixture was stirred for 4 hours, and 1 mL of methanol was added to stop the reaction. After adding dilute hydrochloric acid aqueous solution to the mixture, the resulting reaction solution was extracted with jetyl ether. The jetyl ether solution was passed through Florisil ^s (made by Yoneyama Pharmaceutical Co., Ltd.) and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: hexane) to give 4-methoxybiphenyl as a colorless solid (17.90 mg, yield 97%).

 In the following table, the yield was determined by isolating the coupling compound in the same manner as in Example 1 or by gas chromatograph (GC) analysis using tridecane as an internal standard.

 GC analysis was performed using a GC-1 4 B system (Shimadzu Corporation) equipped with an FID detector and HR-1 single-strength ram (25 m X 0.25 mm d., 0.25 μm film). Made). Example 2 and Comparative Examples 1-5

 In Example 1, 4-Furoreo Tonolene was used instead of 4-Fluoroa disole, and the ligands shown in the table were used instead of 2-Diphenylphosphinobendial alcohol, and the reaction times shown in the table And carried out according to Example 1. The yield of 4-methylbiphenyl was determined by GC analysis using tridecane as an internal standard.

 1] Reaction time Yield Ligand

(Time) (%) Example 2 0.5 6 5 Comparative Example 1 1 5 1 1 Comparative Example 2 1 5 0 Comparative Example 3 1 5 0 Comparative Example 4 1 5 7

Comparative Example 5 PPh ₃ 1 5 5

Examples 3-5

 In Example 1, .4-fluorotoluene was used instead of 4-fluoroa disole, and the ligand shown in the table was used instead of 2-diphenylphosphinobenzyl alcohol, and the reaction time was 30 minutes. It carried out according to Example 1. The yield of 4-methylbiphenyl and the production rate of by-product 4, 4, 1-dimethylbiphenyl were determined by GC analysis using tridecane as an internal standard.

 [Table 2]

Examples 6 to 1 0

 In Example 1, the organic halogenated compounds shown in the table were used instead of 4-fluoroanisole, and the reaction time was set to the time shown in the table. The ring compound was obtained in the yield shown in the table. The yield of the coupling compound in Example 6 was determined by GC analysis using tridecane as an internal standard. The yield of the coupling compound in Examples 7 to 10 was determined by isolating the coupling compound in the same manner as in Example 1.

 [Table 3]

Example 1 1

 In Example 1, the organic halides shown in the table were used instead of 4 fluoroanisole, phenyl magnesium bromide was used instead of 1.5 mmol, 2.5 mmol, and the reaction time was 2 hours. It carried out according to Example 1. The yields of the force coupling compounds shown in the table were determined by GC analysis using tridecane as an internal standard.

 [Table 4]

Example 1 2

 In Example 1, the organic halides shown in the table were used in place of 4 fluoroanisole, 4-methoxyphenyl magnesium promide was used in place of phenylmagnesium bromide, and the reaction time was 65 hours. Performed according to Example 1. The yield of the coupling compound shown in the table was determined by isolating the coupling compound in the same manner as in Example 1. .

 [Table 5]

Example 1 Data for coupling compound 2:

IR (powder) 3004 (w), 2958 (w), 2919 (w), 2838 (w), 1629 (w), 1602 (m), 1578 (w), 1520 (w), 1497 (ra), 1438 (w), 1399 (w), 1287 (m), 1248 (m), 1218 (m), 1183 (m), 1038 (m), 1011 (w), 992 (m), 905 (m), 824 (s), 814 (s), 750 (ra), 654 (m); 'Η NMR (400 MHz, CDC1 ₃ ): S 3.83 (s, 3H), 5.26 (dd, = 0.9, 11.0 Hz, 1H), 5.77 (dd, = 0.9, 17.6 Hz, 1H), 6.74 (dd, J = 11.0, 17.6 Hz, 1H), 6.96 (ra, 2H), 7.45 (m, 2 H), 7.52 (m, 4H); ¹³ C NMR (100 MHz, CDC1 ₃ ): δ 55.3, 113.5, 114.2, 126.6 , 126.7, 127.9, 133.2, 136.0, 136.4, 140.2, 159.2; Elemental analysis Calculated value: C, 85.68; 6., 6.71. Actual measurement: C, 85.47; Η, 6.92. Examples 13 and 14

 In Example 1, the organic halides shown in the table were used instead of 4 fluoroadisol, and the reaction time was set to the time shown in the table. The yield of the coupling compound shown in the table was determined by isolating the coupling compound in the same manner as in Example 1. [Table 6]

Example 15

Use 4-chloroanisole instead of 4-fluoroanisole, and charge nickel (II) acetylacetate and 2-diphenylphosphinobenzil alcohol from 0.05 051111110 1 to 0.002 mmo 1 (0.2 Monore _^0/0) to low Hesi, reducing the charge of bromide phenylpropyl magnesium 1. 5 mmo l 1. to 2 m mo 1, the reaction time was 24 hours, example 1 It carried out according to. cup The yield of the ring compound was found to be 61% when determined by a proton nuclear magnetic resonance spectrum using 1,1,2,2-tetrachlorophthane as an internal standard. Examples 1 6 to 3 4.

 In Example 1, an organic compound having a leaving group shown in the table was used instead of 4 fluoroadisol, and an organometallic compound shown in the table was used instead of phenylmagnesium bromide. Instead of phosphinobenzil alcohol 1—

 (2-Diphenylphosphinophenyl) Ethanol was used. Unless otherwise specified, the amount of organometallic compound charged is 1.1 equivalents, and the amount of nickel (II) acetylsulfate and 1- (2-diphenylphosphinophenyl) ethanol is listed in the table. The reaction was carried out in the same manner as in Example 1, with the amount shown in “Catalyst amount”. However, the amount of the organometallic compound charged was 1.2 equivalents in Examples 28 and 29 and 1.5 equivalents in Examples 30 and 31. In Example 30, the reaction temperature was 40 ° C. In Example 31, tetrahydrobran was used in place of jetyl ether, and the reaction temperature was 60. The yield of the coupling compound was determined by isolating the coupling compound in Examples 16 and 22 to 30 in the same manner as in Example 1. Examples 1 to 21 and 31 were determined by GC analysis using tridecane as an internal standard. Examples 3 2 to 3 4 were determined by a proton nuclear magnetic resonance spectrum using 1,1,2,2-tetrachloroethane as an internal standard.

 [Table 7]

 5υ'ί

 Yield Example Organic halide Organometallic compound Time Coupling compound

 (%) (Time)

1 6 BrMg— ^》 1 1 94

1 7 BrMg— ^ / J 1 1/3 97

Examples 35-43

 In Example 1, the organic halide shown in the table was used in place of 4 fluoroadisol, and the organometallic compound shown in the table was used in place of the phenyl bromide bromide. 1- (2-Diphenylphosphinophenyl) ethanol was used instead of alcohol. In addition, the amount of the organic halide charged is 0.5 to lmmo 1, the amount of the organometallic compound is the amount shown in the table, and nickel (II) acetyl cetate and 1- (2-diphenyl phosphate) are used. Inophenyl) Ethanol was charged in the amount shown in “Catalyst amount” in the table, and reaction time was shown in the table. However, Examples 41 and 43 were carried out at a reaction temperature of 45 ° C (bath temperature). The yield of the coupling compound was determined by isolating the coupling compound in the same manner as in Example 1.

[¾8]

Example 4 4 In Example 1, instead of 4 fluoroadisol, an equimolar mixture of 4 fluorotoluene and 1-ethyl-4_propylthiobenzene (each l mm o 1) was used, and 2-diphenylphosphinobenzil alcohol Instead, 1- (2-diphenylphosphinophenyl) ethanol was used, the reaction temperature was the temperature shown in the following formula, the reaction time was the time shown in the following formula, and nickel (II) acetylethylate ( It carried out according to Example 1 using the catalyst ligand shown in the table instead of Ni (acac) ₂ ) and 2-diphenylphosphinobenzil alcohol.

As shown in the following reaction formula 2, when 1- (2-diphenylphosphinophenyl) ethanol is used, it is different from the reaction of nickel catalyst (N i C 1 ₂ (dppp)) that is generally used. It was found to have chemical selectivity.

 [Reaction Formula 2].

Catalyst Ligand, reaction temperature, reaction time: Yield Yield

Ni (acac) ₂ /1-(2-Siphenylphenylphosphinophenyl) ethanol, 25 ° C, 4 hours 60% 0%

N l ₂ (dpp _P ), reflux, 22 hours 4% 34% Industrial applicability

 According to the production method of the present invention, the efficiency and selectivity of the coupling reaction are improved. Therefore, according to the present invention, the amount of catalyst used, the amount of organometallic compound or metal hydride compound used can be reduced, and the reaction time can be shortened. In addition, a coupling reaction of polyhalogenated aryl such as polychlorinated aryl and polyfluorinated reel which has not been generally used in the coupling reaction can be performed with high efficiency. In addition, according to a preferred embodiment of the present invention, the reaction can be carried out under mild reaction conditions, the generation of by-products (impurities) can be reduced, and the yield of the desired coupling compound can be improved. You can also

Therefore, for example, low-reactivity organics such as fluoride and chloride It is possible to efficiently produce a coupling compound using a halide as a starting material.

 Further, the production method of the present invention has chemical selectivity different from the reaction of nickel catalysts that are generally used, and therefore can be used to selectively produce the desired coupling compound.

Claims

The scope of the claims

1. In a method for producing a coupling compound (D) by subjecting an organic compound (A) having a leaving group to an organometallic compound or a metal hydride compound (B) to a coupling reaction, a transition metal A ligand (C-2) having a compound (C_l), a coordinating group and a protonic group, and the coordinating group and the protonic group are arranged adjacent to each other. ) In the presence of a catalyst composition (C) containing the organic compound (A) and the organometallic compound or metal hydride compound (B). how to.

2. Organic compound with leaving group (A) Force S, Formula (1)

R ¹ "H n

(In the formula, R ¹ represents a hydrocarbon group, X represents a leaving group, and n represents an integer of 1 or more.)

An organometallic compound or a metal hydride compound (B) ヽ Formula (2)

R ² —— m (2)

(Wherein R ² represents a hydrocarbon group or a hydrogen atom, m represents a metal element.), And the transition metal compound (C-1) is represented by the formula (3)

 M "(3)

It is a transition metal compound represented by the following formula: Ligand (C-2), Formula (4)

 □ 3

丫 \ _z (4)

(Wherein, Y represents a coordinating group, R ³ is optionally substituted alkyl, optionally substituted C ₆ _ ₁₂ Ariru group, optionally substituted § alkyl -C 6 ^ ₂ Ariru group, or an optionally substituted C ₆ - represents a ₁₂ Ariru Kiichi C alkyl group, Z is representative of a protic group).

Coupling compound (D) force formula (5)

R ¹ -("R ² ) n (5) (Wherein R 1 ² and 11 represent the same meaning as described above.)

 The method according to claim 1, wherein the compound is represented by:

3. In the formula (1), R ¹ is an alkyl group which may have a substituent, an aryl group which may have a substituent, a heterocyclic group which may have a substituent, An alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an acyl group which may have a substituent, and X is a halogen atom, a sulfonyloxy group, an alkylthio group The method according to claim 2, which is a group, an arylthio group or a diazonium group.

4. In formula (2), R ² is a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, or a hetero which may have a substituent. The method according to claim 2, which is a cyclic group, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or an acyl group which may have a substituent.

 5. Transition metal compound represented by M (C-1) force At least selected from Group 8 elements of the Periodic Table, Group 9 elements of the Periodic Table, Group 10 elements of the Periodic Table and Group 1 elements of the Periodic Table The method according to any one of claims 1 to 4, which also contains a kind of element.

 6. The method according to any one of claims 5 to 5, wherein the transition metal compound represented by M (C-1) comprises at least one element selected from Group 10 elements of the periodic table.

 7. Transition metal compounds represented by M (C-1), nickel halide, bis (cyclooctagen) nickel, nickel (II) acetyl cetate, nickel nitrate (1 1), nickel sulfate ( The method according to any one of claims 1 to 6, which is nickel acetate (II) or nickel hydroxide (II).

 8. The method according to claim 1, wherein the coordinating group and the protic group are bonded via 2 to 4 atoms.

 9. The method according to any one of claims 1 to 8, wherein the coordinating group is a group containing a trivalent phosphorus atom, a nitrogen atom, a sulfur atom or a carbon atom.

 10. The method according to any one of claims 1 to 9, wherein the protic group is a hydroxyl group, an amino group or a mercapto group.

1 1. The ligand (C-2) is 2-diphenylphosphinophenol, 2-diphenylphosphinobenzil alcohol, 1_ (2-diphenylphosphinophenol E) Ethanol, .2-Diphenylenophosphinocyclohexanol, 1 1 (2-Diphenylphosphinocyclohexenole) Ethanol, 2-diphenylphosphinoa dilin, 2-diphenylphosphinobenzyl 11. A process according to claims 1 to 10 selected from ammine, 2-diphenylphosphino hexylamine.

1 2. Catalyst composition (C) Force S, Nickel halide, Bis (cyclocactogen) Nickel, Nickel (II) Acetyl acetonate, Nickel nitrate (1 1), Nickel sulfate (1 1), Nickel acetate ( II) and transition metal compounds selected from nickel hydroxide (II) (C-1), 2-difunilylphosphinobenzyla noreconole, 1-i (2-dipheninorephosphinofenore) ethanol And a ligand selected from 2-diphenyl ninolephosphinocyclohexanol and 1- (2-diphenylphosphinocyclohexyl) ethanol (C1-2). ~ The method described in 1 1

 1 3. Catalyst composition (C) Force The method according to any one of claims 1 to 12, wherein the transition metal compound (C-1) and the ligand (C-2) are complexed.

14. The method according to any one of claims 1 to 13, which is a compound (A) having a leaving group, a halogenated aryl or a halogenated alkenyl.

 1 5. Organometallic compound or metal hydride compound (B) Force S, Periodic Table Group 1 element, Periodic Table Group 2 element, Periodic ¾ Group 4 element, Periodic Table Group 1 element, Periodic Table 1 The method according to claim 1, comprising a metal element selected from a Group 2 element, a Group 13 element of the Periodic Table, a Group 14 element of the Periodic Table, and a Group 15 element of the Periodic Table.

 1 6. Organometallic compound or metal hydride compound (B) Force Alkylmagnesium halide, ananol magnesium magnesium, alkynyl magnesium halide, allyl magnesium halide, dialkyl magnesium, dialkenyl magnesium, dialkynyl magnesium The method according to claim 15, wherein the method is a film or a gallium magnet.