WO2016093175A1 - Method for producing tri(hetero)arylacetonitrile compound - Google Patents

Method for producing tri(hetero)arylacetonitrile compound Download PDF

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WO2016093175A1
WO2016093175A1 PCT/JP2015/084181 JP2015084181W WO2016093175A1 WO 2016093175 A1 WO2016093175 A1 WO 2016093175A1 JP 2015084181 W JP2015084181 W JP 2015084181W WO 2016093175 A1 WO2016093175 A1 WO 2016093175A1
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group
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tri
substituted
compound
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正和 南保
ヤ― ムハンマド
キャサリン クラッデン
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国立大学法人名古屋大学
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Definitions

  • the present invention relates to a method for producing a tri (hetero) aryl acetonitrile compound.
  • Tri (hetero) aryl acetonitrile compounds and derivatives thereof are used in various fields such as organic dyes, fluorescent probes for bioimaging, and sensors for metal ions. Furthermore, application of these tri (hetero) arylacetonitrile compounds and derivatives thereof to pharmaceutical uses such as antituberculous agents and anticancer agents is also being studied.
  • a method for synthesizing such a tri (hetero) aryl acetonitrile compound for example, a method for obtaining a tri (hetero) aryl acetonitrile compound from a tri (hetero) aryl alcohol compound by a nitrile conversion reaction in the presence of a Lewis acid catalyst is known. ing. Also known is a method of obtaining a tri (hetero) aryl acetonitrile compound by nucleophilic substitution reaction of a cyanide anion with a tri (hetero) aryl halide. These synthesis methods are described, for example, in Non-Patent Documents 1 and 2.
  • the present invention is intended to solve the above-mentioned problems, and a main object is to provide a method for easily synthesizing various tri (hetero) arylacetonitrile compounds with few steps.
  • a tri (hetero) aryl acetonitrile compound was obtained by sequentially performing a reaction for introducing an aromatic group three times using a specific aromatic compound in the presence of a palladium catalyst using a halogenated acetonitrile compound. It was found that can be synthesized easily. In this method, any aromatic group can be introduced, and both the raw materials and the catalyst used are easy to handle in the atmosphere, and the number of steps is higher than that of the conventional method that required four or more steps.
  • the present invention includes the following configurations.
  • Item 2. The production method according to Item 1, wherein the step (III) is performed in the presence of a trialkylphosphine ligand.
  • Item 3. The production method according to Item 2, wherein the trialkylphosphine ligand is tri (t-butyl) phosphine or a salt thereof.
  • Item 4. The production method according to any one of Items 1 to 3, wherein the step (III) is performed in the presence of a base.
  • Item 5 The production method according to Item 4, wherein the base is at least one selected from the group consisting of cesium carbonate, cesium halides, and alkali metal phosphates.
  • Item 7. The production method according to Item 6, wherein the step (II) is performed in the presence of a phosphine ligand.
  • the phosphine ligand is tri (cycloalkyl) phosphine, alkyldi (cycloalkylphosphine), di (alkyl) cycloalkylphosphine, tri (alkyl) phosphine, tri (alkoxy) phosphine, alkyldiadamantylphosphine, or a general formula ( 6):
  • R 1 and R 2 are the same or different and each represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group.
  • R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or —PR 3 R 4 (R 3 and R 4 are the same or different, and are substituted or unsubstituted alkyl groups, or substituted or unsubstituted Represents a cycloalkyl group).
  • n represents an integer of 0 to 3.
  • Item 8 The production method according to Item 7, wherein the ligand is represented by the formula:
  • R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group or a cycloalkyl group. R 5 and R 6 may be bonded to each other to form a ring together with adjacent —O—B—O—.
  • Item 9 The production method according to any one of Items 6 to 8, further comprising a step of reacting the aromatic group-containing potassium trifluoroborate represented by the formula:
  • Ar ⁇ 1 >, Ar ⁇ 2 > and Ar ⁇ 3 > are the same or different, and show a substituted or unsubstituted aromatic group.
  • R represents a substituent.
  • a process for producing a compound represented by A production method comprising a step of substituting a cyano group of the tri (hetero) arylacetonitrile compound after the step (III) of the production method according to any one of Items 1 to 9.
  • R 10 represents an alkyl group or an alkoxycarbonyl group.
  • R 11 represents a substituted or unsubstituted alkyl group or an alkoxy group.
  • R 1b , R 1c , R 2b and R 2c are the same or different and each represents an alkyl group or a cycloalkyl group.
  • X 4 and X 5 are the same or different and each represents a halogen atom.
  • a di (hetero) arylacetonitrile compound is used to carry out a reaction for introducing an aromatic group using a specific aromatic compound in the presence of a palladium catalyst.
  • An arylacetonitrile compound can be easily synthesized in a high yield.
  • various tri (hetero) arylacetonitrile compounds that could not be synthesized conventionally can be synthesized.
  • a tri (hetero) arylacetonitrile compound is synthesized by reacting a specific di (hetero) arylacetonitrile compound with a specific halogenated aromatic compound (step (III)).
  • the di (hetero) aryl acetonitrile compound used as a raw material is not particularly limited.
  • it is synthesized by reacting a specific (hetero) aryl acetonitrile compound with a specific halogenated aromatic compound.
  • the specific (hetero) aryl acetonitrile compound is not particularly limited.
  • the specific halogenated acetonitrile compound, the specific aromatic group-containing compound (the aromatic group-containing boronic acid or its ester compound, the aromatic group) It can be synthesized by reacting (containing potassium trifluoroborate, halogenated aromatic compound, etc.) (step (I)).
  • the substituents Ar 1 and Ar 2 are synthesized. Since the selectivity and yield of introduction can be further improved, the di (hetero) arylacetonitrile compound used as a raw material in the present invention is prepared by using the halogenated acetonitrile compound as a raw material in the following steps (I) to (II). It is preferable to synthesize it through.
  • a tri (hetero) arylacetonitrile compound can be synthesized in only the shortest three steps, which is impossible with the conventional production method. At this time, the number and position of the introduced aromatic groups can be controlled in all reactions.
  • the above three-step reactions employed in the present invention can be carried out using only raw materials that are easy to obtain and prepare and easy to handle in the atmosphere. In addition, all of these three-stage reactions can proceed using a palladium catalyst that can be handled stably in the atmosphere. Also from this viewpoint, the production method of the present invention is a method for easily obtaining a tri (hetero) arylacetonitrile compound.
  • aromatic group possessed by the tri (hetero) aryl acetonitrile compound synthesized in the production method of the present invention various kinds of aromatic groups can be adopted.
  • aromatic group having a functional group such as an ester group, a formyl group, or a heteroaromatic ring can be easily introduced without impairing its structure.
  • the cyano group in the tri (hetero) arylacetonitrile compound obtained by the production method of the present invention can be easily substituted with various functional groups, which can lead to simple synthesis of various functional molecules. It is.
  • (hetero) aryl means aryl or heteroaryl.
  • (I) General formula (7): X—CH 2 —CN (7) [Wherein X represents a halogen atom. ]
  • R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group or a cycloalkyl group. R 5 and R 6 may be bonded to each other to form a ring together with adjacent —O—B—O—.
  • An aromatic group-containing boronic acid or an ester compound thereof hereinafter sometimes referred to as “compound (8A)”
  • compound (8B) An aromatic group-containing boronic acid or an ester compound thereof (hereinafter sometimes referred to as “compound (8A)”), or a general formula (8B): Ar 1 BF 3 K (8B) [Wherein Ar 1 is the same as defined above.
  • Aromatic group-containing potassium trifluoroborate represented by the formula (hereinafter also referred to as “compound (8B)”) are reacted in the presence of a palladium catalyst to synthesize a (hetero) arylacetonitrile compound.
  • examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • a chlorine atom is preferable from the viewpoints of selectivity and yield in this step.
  • the aromatic group in the substituted or unsubstituted aromatic group represented by the substituent Ar 1 is a (hetero) aryl group (aromatic) that the tri (hetero) arylacetonitrile compound as the final product has. Group), and various aromatic groups can be employed.
  • a monocyclic aromatic hydrocarbon group such as a phenyl group (especially a 6-membered monocyclic aromatic hydrocarbon group); a naphthyl group (1-naphthyl group, 2-naphthyl group, etc.), anthryl group (1-anthryl group, 2 -Anthryl group, 9-anthryl group, etc.), fluorenyl group (1-fluorenyl group, 2-fluorenyl group, 9-fluorenyl group, etc.), phenanthryl group, pyrenyl group (1-pyrenyl group, 2-pyrenyl group, 4-pyrenyl group) Groups), condensed ring aromatic hydrocarbon groups (especially bicyclic aromatic hydrocarbon groups) such as chrysenyl group, perylenyl group, and picenyl group; furyl groups (2-furyl group, 3-furyl group, etc.), thienyl groups ( 2-thienyl group, 3-thienyl group ( 2-
  • Ring aromatic heterocyclic group (especially bicyclic aromatic heterocyclic group) and the like.
  • a substituted or unsubstituted monocyclic aromatic hydrocarbon group a substituted or unsubstituted condensed ring aromatic hydrocarbon group, a 5-membered monocyclic aromatic heterocyclic group, and a 6-membered monocyclic aromatic heterocyclic ring Preferred are, for example, 6-membered monocyclic aromatic hydrocarbon group, bicyclic aromatic hydrocarbon group, 5-membered monocyclic aromatic heterocyclic group, 6-membered monocyclic aromatic heterocyclic group, etc.
  • a heterocyclic group is more preferred, and a phenyl group, a naphthyl group (1-naphthyl group, 2-naphthyl group, etc.), a thienyl group (2-thienyl group, 3-thienyl group, etc.) is more preferred.
  • examples of the substituent in the aromatic group include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n A C 1-6 -alkyl group or a C 3-8 -cycloalkyl group such as -pentyl group, isopentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; methoxy group, ethoxy group, n -Propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, cyclopropyloxy group, cyclobutyl group, cyclobut
  • Examples of the substituted aromatic group represented by the substituent Ar 1 satisfying such conditions include, for example, a tolyl group (o-tolyl group, m-tolyl group, p-tolyl group, etc.), an ethylphenyl group (4- Ethylphenyl group, 3-ethylphenyl group, 2-ethylphenyl group, etc.), 4-n-propylphenyl group, isopropylphenyl group (4-isopropylphenyl group, 2-isopropylphenyl group, etc.), 4-n-butylphenyl Group, 4-isobutylphenyl group, sec-butylphenyl group (4-sec-butylphenyl group, 2-sec-butylphenyl group, etc.), t-butylphenyl group (4-t-butylphenyl group, 3-t- Butylphenyl group, 2-t-butylphenyl group, etc.), 4-n-pent
  • the type of the substituent Ar 1 is not particularly limited, and may be any of the above-described substituted or unsubstituted aromatic groups, substituted or unsubstituted monocyclic aromatic hydrocarbon groups, substituted or unsubstituted condensed groups.
  • a ring aromatic hydrocarbon group a substituted or unsubstituted 5-membered monocyclic aromatic heterocyclic group, etc., a substituted or unsubstituted 6-membered monocyclic aromatic hydrocarbon group, a substituted or unsubstituted bicyclic aromatic group More preferred are a hydrocarbon group, a substituted or unsubstituted 5-membered monocyclic aromatic heterocyclic group, etc., a phenyl group, a tolyl group (such as an o-tolyl group, an m-tolyl group, a p-tolyl group), a methoxyphenyl group.
  • examples of the alkyl group and cycloalkyl group represented by R 5 and R 6 include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec- A C 1-8 -alkyl group such as a butyl group, a t-butyl group, a hexyl group or a cyclohexyl group, or a C 3-8 -cycloalkyl group can be employed.
  • Examples of the substituent that can be substituted on the alkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
  • R 5 and R 6 when R 5 and R 6 are both an alkyl group and / or a cycloalkyl group, they may be bonded to each other to form a ring with the adjacent —O—B—O—.
  • the aromatic group-containing boronic acid or its ester compound is, for example,
  • R 5 and R 6 are both hydrogen atoms from the viewpoint of product yield and economical viewpoint.
  • the compound (8A) specific examples thereof include, for example, dimethyl ester, diethyl ester, dipropyl ester, diisopropyl ester, dibutyl ester, dihexyl ester, dicyclohexyl ester, ethylene glycol ester, propylene glycol (1,2- Propanediol ester, 1,3-propanediol ester), trimethylene glycol ester, neopentyl glycol ester, pinacol ester, catechol ester, glycerin ester, trimethylolethane ester, N-methyliminodiacetic acid ester and the like.
  • aromatic group-containing boronic acids or ester compounds thereof it is preferable to use an aromatic group-containing boronic acid from the viewpoint of yield.
  • the substituent Ar 1 is a substituted or unsubstituted aromatic group, and the same as in the general formula (8A) can be adopted.
  • the above compound (8A) and compound (8B) can be used individually by 1 type, and can also be used in combination of 2 or more type. When two or more of these compounds are used, for example, two of the compounds (8A) can be used, two of the compounds (8B) can be used, and the compound (8A) and Compound (8B) can also be used. However, it is preferable to use only 1 type from a viewpoint of making a process simpler.
  • the amount of compound (8A) and compound (8B) to be used is generally preferably 0.2 to 3 mol per 1 mol of compound (7) from the viewpoints of selectivity and yield. More preferred is 3 to 2.5 mol.
  • the palladium catalyst used in this step is not particularly limited, and examples thereof include palladium acetate (Pd (OCOCH 3 ) 2 ; Pd (OAc) 2 ), palladium trifluoroacetate (Pd (OCOCF 3 ) 2 ), p-allyl palladium (II) chloride dimer ([PdCl (allyl)] 2 ), p-cinnamyl palladium (II) chloride dimer, di- ⁇ -chlorobis (2′-amino-1,1′-biphenyl-2-) C, N) dipalladium (II), palladium chloride (PdCl 2 ), palladium bromide (PdBr 2 ), palladium iodide (PdI 2 ), Pd (CH 2 COCH 2 COCH 3 ) 2 , K 2 PdCl 4 , K 2 PdCl 6, K 2 Pd ( NO 3) 4, tris (dibenzylideneacetone) dip
  • organic ligand complexes are preferable in this step from the viewpoint of selectivity, yield, and safety.
  • p-allyl palladium (II) chloride dimer trifluoroacetic acid Palladium, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like are more preferable, and palladium acetate (Pd (OCOCH 3 ) 2 ) is more preferable.
  • the amount of the palladium catalyst used is usually preferably 0.001 to 1 mol, preferably 0.01 to 0.25 mol, relative to 1 mol of the compound (7), from the viewpoints of selectivity and yield. Is more preferable.
  • This ligand can be introduced into the palladium catalyst in advance, or can be introduced into the system together with the palladium catalyst.
  • a phosphine ligand is preferable from a viewpoint of a selectivity and a yield.
  • the phosphine ligand that can be used in this step is not particularly limited.
  • a C 1-8 alkyl group (methyl group, ethyl group, t-butyl group etc.), C 1-4 alkoxy group (methoxy group, ethoxy group etc.), C 3-8 cycloalkyl group (cyclopropyl group) , cyclobutyl group, cyclopentyl group, cyclohexyl group), a phenyl group, a biphenyl group, a phenoxy group, or a furyl group.
  • the C 3-8 cycloalkyl group further C 1-4 alkyl group (methyl group, ethyl group, etc. ) may be substituted with.
  • the phenyl group may further methyl group, sulfonic acid or a salt thereof may be substituted.
  • the biphenyl group is independently further respectively, C 1-4 Alkyl group (methyl group, an ethyl group, an isopropyl group, etc.), C 1-4 alkoxy group (methoxy group, ethoxy group, etc.), dialkylamino groups (dimethylamino group, diethylamino group, etc.) may be substituted with.) Examples thereof include bis (diphenylphosphino) alkane, bis (dialkylphosphino) alkane, bis (diphenylphosphino) ferrocene and the like.
  • Examples of the phosphine ligand represented by PR 7 R 8 R 9 include t-butyldicyclohexylphosphine, isobutyldicyclohexylphosphine, (n-butyl) dicyclohexylphosphine, isopropyldicyclohexylphosphine, (n-propyl) dicyclohexylphosphine, and ethyl.
  • bis (diphenylphosphino) alkane examples include bis (diphenylphosphino) methane, 1,2-bis (diphenylphosphino) ethane (dppe), 1,3-bis (diphenylphosphino) propane, , 4-bis (diphenylphosphino) butane, 1,5-bis (diphenylphosphino) pentane, 1,6-bis (diphenylphosphino) hexane and the like.
  • Examples of the bis (dialkylphosphino) alkane include 1,2-bis (dimethylphosphino) ethane and the like, and examples of the bis (diphenylphosphino) ferrocene include 1,1′-bis (diphenylphosphino) ferrocene (dppf) and the like.
  • these phosphine ligands can also be used as ligand precursors which are salts with halogen atoms (such as chlorine atoms), HCl, HF, HBr, HI, HBF 4 and the like. These can be used alone or in combination.
  • the amount of ligand used is usually preferably 0.2 to 3 mol, and preferably 0.3 to 2.5 mol with respect to 1 mol of the palladium catalyst, from the viewpoints of selectivity and yield. More preferred.
  • step (I) is preferably performed in the presence of a base.
  • the base that can be used in this step include metal alkoxides such as potassium t-butoxide, sodium t-butoxide and lithium t-butoxide; alkali metal phosphates such as lithium phosphate, sodium phosphate and potassium phosphate; water Alkali metal hydroxides such as lithium oxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; Alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; Lithium diisopropylamide, lithium bis (trimethylsilyl) amide Metal amides such as sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide; amines such as triethylamine, diazabicycloundecene and 1,4-diazabicyclo [2.2.2] octane.
  • the amount of the base used is preferably 0.5 to 4 mol, preferably 1 to 3 mol per 1 mol of the compound (7) from the viewpoints of selectivity and yield. Mole is more preferred.
  • reaction solvents include, for example, ether solvents such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diisopropyl ether, diisobutyl ether, cyclopentyl methyl ether (CPME); benzene, toluene, It is preferable to use an organic solvent such as an aromatic hydrocarbon solvent such as o-xylene, m-xylene, p-xylene, mixed xylene, and mesitylene. These can be used alone or in combination.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diisopropyl ether, diisobutyl ether, cyclopentyl methyl ether (CPME);
  • a mixed solvent of an ether solvent and water is preferable, and a mixed solvent of 1,4-dioxane and water is more preferable.
  • the amount of these reaction solvents (organic solvents) used is not particularly limited as long as the reaction proceeds.
  • the reaction temperature in this step varies depending on the boiling point of the reaction solvent used. Usually, it is preferably carried out at a reaction temperature of about room temperature (25 ° C.) to about 300 ° C., particularly about 30 to 150 ° C., and further about 40 to 100 ° C. Moreover, it is preferable to implement this process normally under inert gas (for example, nitrogen, argon, helium etc.) airflow.
  • the reaction can be carried out at normal pressure, and can be carried out under reduced pressure or pressurized conditions as necessary. Among them, it is preferable to carry out under normal pressure.
  • the progress of the reaction can be followed by conventional methods such as chromatography. After completion of the reaction, the solvent is distilled off, and the product can be isolated and purified by the usual methods such as chromatography and recrystallization.
  • the structure of the product can be identified by elemental analysis, MS (FD-MS) analysis, IR analysis, 1 H-NMR, 13 C-NMR and the like.
  • the (hetero) aryl acetonitrile compound synthesized in this step can be used in the next step (step (II)) without being subjected to purification treatment, and if necessary, activated carbon treatment, recrystallization, column chromatography. It is also possible to purify by a usual purification method such as chromatography.
  • the (hetero) aryl acetonitrile compound thus obtained has the general formula (4): Ar 1 —CH 2 —CN (4) [Wherein Ar 1 is the same as defined above. ] It is a compound represented by these.
  • (II) General formula (4): Ar 1 —CH 2 —CN (4) [Wherein Ar 1 is the same as defined above. ]
  • a di (hetero) arylacetonitrile compound can be synthesized by a step of reacting a halogenated aromatic compound represented by the formula (hereinafter also referred to as “compound (5)”) in the presence of a palladium catalyst. it can.
  • Compound (4) is a compound that can be synthesized in the step (I), and various compounds can be employed.
  • Ar ⁇ 1 > in General formula (4) is a substituted or unsubstituted aromatic group, and can employ
  • the substituent Ar 2 is a substituted or unsubstituted aromatic group.
  • the substituted aromatic group if aromatic groups, the kind and number of substituents, if Ar 2 is substituted, Ar 2 is substituted in the substituent Ar 2, it can be employed the same ones as described in detail above Ar 1.
  • Substituent Ar 2 constitutes one of the (hetero) aryl groups (aromatic groups) of the tri (hetero) aryl acetonitrile compound that is the final product, and employs various aromatic groups. Can do. From the viewpoint of the selectivity and yield of this reaction, a substituted or unsubstituted monocyclic aromatic hydrocarbon group or a substituted or unsubstituted monocyclic aromatic heterocyclic group is preferred, and a substituted or unsubstituted six-membered single-membered aromatic group is preferred.
  • a cyclic aromatic hydrocarbon group or a substituted or unsubstituted 5-membered monocyclic aromatic heterocyclic group is more preferable, and a phenyl group, a tolyl group (o-tolyl group, m-tolyl group, p-tolyl group, etc.), Methoxyphenyl group (2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, etc.), fluorophenyl group (2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, etc.), trifluoro Oromethylphenyl group (2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, etc.), thienyl group (2-thienyl group, - a thienyl group, etc.) and the like are more preferred.
  • X 2 is a halogen atom, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a bromine atom and an iodine atom are preferable, and a bromine atom is particularly preferable.
  • the amount of compound (5) to be used is generally preferably 0.2 to 3 mol, preferably 1 to 2.5 mol, relative to 1 mol of compound (4), from the viewpoints of selectivity and yield. More preferred.
  • the palladium catalyst used in this step is not particularly limited, and examples thereof include palladium acetate (Pd (OCOCH 3 ) 2 ; Pd (OAc) 2 ), palladium trifluoroacetate (Pd (OCOCF 3 ) 2 ), p-allyl palladium (II) chloride dimer ([PdCl (allyl)] 2 ), p-cinnamyl palladium (II) chloride dimer, di- ⁇ -chlorobis (2′-amino-1,1′-biphenyl-2-) C, N) dipalladium (II), palladium chloride (PdCl 2 ), palladium bromide (PdBr 2 ), palladium iodide (PdI 2 ), Pd (CH 2 COCH 2 COCH 3 ) 2 , K 2 PdCl 4 , K 2 PdCl 6, K 2 Pd ( NO 3) 4, tris (dibenzylideneacetone) dip
  • organic ligand complexes are preferable in this step from the viewpoint of selectivity, yield, and safety, and palladium acetate (Pd (OCOCH 3 ) 2 ), p-allyl palladium (II) chloride dimer, trifluoro Palladium acetate, tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0) and the like are more preferable, and palladium acetate (Pd (OCOCH 3 ) 2 ) is more preferable.
  • the amount of the palladium catalyst used is usually preferably from 0.02 to 1 mol, preferably from 0.03 to 0.25 mol, based on 1 mol of the compound (4), from the viewpoints of selectivity and yield. Is more preferable.
  • This ligand can be introduced into the palladium catalyst in advance, or can be introduced into the system together with the palladium catalyst.
  • the ligand that can be used in this step is preferably a phosphine ligand from the viewpoint of selectivity and yield.
  • the phosphine ligand that can be used in this step is not particularly limited, and examples thereof include tri (cycloalkyl) phosphine, alkyldi (cycloalkylphosphine), di (alkyl) cycloalkylphosphine, tri (alkyl) phosphine, Tri (alkoxy) phosphine, alkyldiadamantylphosphine, general formula (6):
  • R 1 and R 2 are the same or different and each represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group.
  • R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or —PR 3 R 4 (R 3 and R 4 are the same or different, and are substituted or unsubstituted alkyl groups, or substituted or unsubstituted Represents a cycloalkyl group).
  • n represents an integer of 0 to 3.
  • the ligand etc. which are represented by these are mentioned.
  • a ligand having a biphenyl group or a derivative group thereof when used, the selectivity and yield are excellent. However, a ligand having a phenyl group or a derivative group thereof is inferior in the selectivity and yield, so it should not be used. preferable.
  • tri (cycloalkyl) phosphine examples include cyclopropyldicyclohexylphosphine, cyclobutyldicyclohexylphosphine, tri (cyclooctyl) phosphine, tri (cycloheptyl) phosphine, tri (cyclohexyl) phosphine, tri (cyclopentyl) phosphine, and tri (cyclobutyl).
  • Phosphine tri (cyclopropyl) phosphine, and the like.
  • alkyldi examples include t-butyldicyclohexylphosphine, isobutyldicyclohexylphosphine, (n-butyl) dicyclohexylphosphine, isopropyldicyclohexylphosphine, (n-propyl) dicyclohexylphosphine, ethyldicyclohexylphosphine, methyldicyclohexylphosphine, Examples thereof include t-butyldicyclooctylphosphine, t-butyldicycloheptylphosphine, t-butyldicyclopentylphosphine, t-butyldicyclobutylphosphine, t-butyldicyclopropylphosphine, and the like.
  • di (alkyl) cycloalkylphosphine examples include di (t-butyl) cyclohexylphosphine, di (isobutyl) cyclohexylphosphine, di (n-butyl) cyclohexylphosphine, di (isopropyl) cyclohexylphosphine, and di (n-propyl).
  • tri (alkyl) phosphine examples include triethylphosphine, tri (n-propyl) phosphine, tri (isopropyl) phosphine, tri (n-butyl) phosphine, tri (n-octyl) phosphine, and di (t-butyl) methyl.
  • Phosphine di (t-butyl) methylphosphine, di (t-butyl) ethylphosphine, di (t-butyl) n-propylphosphine, di (t-butyl) isopropylphosphine, di (t-butyl) n-butylphosphine , Di (t-butyl) isobutylphosphine, di (t-butyl) neopentylphosphine, and the like.
  • a tri (t-butyl) phosphine when tri (t-butyl) phosphine is used, a tri (hetero) arylacetonitrile compound is easily obtained as a by-product to the same extent as a di (hetero) arylacetonitrile compound. Therefore, a phosphine ligand other than tri (t-butyl) phosphine is preferable from the viewpoint of easier control of the aromatic group to be introduced.
  • tri (alkoxy) phosphine examples include trimethoxyphosphine, triethoxyphosphine, tri (n-propyloxy) phosphine, tri (isopropyloxy) phosphine, tri (n-butyloxy) phosphine, tri (isobutyloxy) phosphine, tri And (t-butyloxy) phosphine.
  • alkyldiadamantylphosphine examples include n-butyldiadamantylphosphine.
  • a ligand having a binaphthyl skeleton when used as a ligand, no by-product is produced when a phenyl group is to be introduced in this step, but an aromatic group other than a phenyl group is formed.
  • introduction a compound in which a target aromatic group is introduced and a by-product in which a phenyl group is introduced are likely to be produced. For this reason, it is preferable not to use a ligand having a binaphthyl skeleton.
  • examples of the alkyl group represented by R 1 and R 2 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, t
  • Examples of the substituent that can be substituted on the alkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
  • examples of the cycloalkyl group represented by R 1 and R 2 include C 3-8 -cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • Examples of the substituent that can be substituted on the cycloalkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
  • R 1 and R 2 a substituted or unsubstituted cycloalkyl group is preferable, an unsubstituted cycloalkyl group is more preferable, and a cyclohexyl group is more preferable from the viewpoint of selectivity and yield.
  • the same groups as those for R 1 and R 2 can be adopted.
  • the substituent that can be substituted on the alkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
  • examples of the alkoxy group represented by R include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a t-butoxy group. Further, a C 1-8 -alkoxy group such as a hexoxy group can be employed. Examples of the substituent that can be substituted on the alkoxy group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
  • the same groups as those for R 1 and R 2 can be adopted.
  • the substituent that can be substituted on the alkyl group and cycloalkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
  • R is preferably a group represented by —PR 3 R 4 from the viewpoint of selectivity and yield, and —PR 3 R 4 (R 3 and R 4 are the same or different and each represents a substituted or unsubstituted group. More preferably a group represented by -PR 3 R 4 (wherein R 3 and R 4 are the same or different, each being an unsubstituted cycloalkyl group), PCy 2 (Cy represents a cyclohexyl group; the same shall apply hereinafter) is particularly preferred.
  • n is the number of R, and any integer of 0 to 3 can be adopted. Especially, 1 or 2 is preferable from a viewpoint of a selectivity and a yield, and 1 is more preferable.
  • Examples of the ligand represented by the general formula (6) include XPhos (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl), t- Bu-XPhos (2-di-t-butylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl; L3 in Examples described later), JohnPhos (2- (di-t- Butylphosphino) biphenyl; L1) in the examples described later, Cy-JohnPhos (2- (dicyclohexylphosphino) biphenyl; L2 in the examples described later), MePhos (2-dicyclohexylphosphino-2′-methylbiphenyl), t-Bu-MePhos, SPhos (2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl;
  • R 1b , R 1c , R 2b and R 2c are the same or different and each represents an alkyl group or a cycloalkyl group (particularly a cycloalkyl group).
  • ligand (6a) can be used. A method for synthesizing this ligand (6a) will be described later.
  • tri (cycloalkyl) phosphine tri (alkyl) phosphine (except tri (t-butyl) phosphine), alkyldiadamantylphosphine, general A ligand represented by the formula (6) is preferable, and a tricycloalkylphosphine, di (t-butyl) methylphosphine, n-butyldiadamantylphosphine, a ligand represented by the general formula (6), and the like are more preferable.
  • tricyclohexylphosphine di (t-butyl) methylphosphine, t-Bu-XPhos (2-di-t-butylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl; L3) of Examples described later, John Phos (2- (di-t-butylphosphino) biphenyl; L1 of Examples described later), C -JohnPhos (2- (dicyclohexylphosphino) biphenyl; L2 in Examples below), SPhos (2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl; L4 in Examples below)
  • the ligand (6a) is more preferable, and tricyclohexylphosphine, di (t-butyl) methylphosphine, Cy-JohnPhos (2- (dicyclohexylphosphino
  • ligands di (t-butyl) methylphosphine, SPhos (2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl; L4 in Examples described later), A ligand (6a) etc. are preferable and a ligand (6a) is the most preferable.
  • the amount of ligand used is usually preferably from 0.01 to 3 mol, preferably from 0.1 to 2.5 mol, based on 1 mol of the palladium catalyst, from the viewpoints of selectivity and yield. More preferred.
  • step (II) is preferably performed in the presence of a base.
  • the base that can be used in this step include metal alkoxides such as potassium t-butoxide, sodium t-butoxide and lithium t-butoxide; alkali metal phosphates such as lithium phosphate, sodium phosphate and potassium phosphate; water Alkali metal hydroxides such as lithium oxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; Alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; Lithium diisopropylamide, lithium bis (trimethylsilyl) amide Metal amides such as sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide; amines such as triethylamine, diazabicycloundecene and 1,4-diazabicyclo [2.2.2] octane.
  • the amount of the base used is preferably 0.5 to 10 mol, preferably 1 to 5 mol per 1 mol of the compound (4) from the viewpoints of selectivity and yield. Mole is more preferred.
  • reaction solvents include, for example, ether solvents such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diisopropyl ether, diisobutyl ether, cyclopentyl methyl ether (CPME); benzene, toluene, It is preferable to use an organic solvent such as an aromatic hydrocarbon solvent such as o-xylene, m-xylene, p-xylene, mixed xylene, and mesitylene. These can be used alone or in combination. Of these, ether solvents are preferable and 1,4-dioxane is more preferable from the viewpoints of selectivity, yield, and safety.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol di
  • the amount of these reaction solvents (organic solvents) used is not particularly limited as long as the reaction proceeds.
  • the reaction temperature in this step varies depending on the boiling point of the reaction solvent used.
  • the reaction is preferably carried out at a reaction temperature of about room temperature (25 ° C.) to about 300 ° C., particularly about 40 to 150 ° C., and further about 60 to 120 ° C.
  • inert gas for example, nitrogen, argon, helium etc.
  • the reaction can be carried out at normal pressure, and can be carried out under reduced pressure or pressurized conditions as necessary. Among them, it is preferable to carry out under normal pressure.
  • limiting in particular in reaction time It can be set as time for reaction to fully advance.
  • the progress of the reaction can be followed by conventional methods such as chromatography. After completion of the reaction, the solvent is distilled off, and the product can be isolated and purified as a product di (hetero) arylacetonitrile compound by a usual method such as chromatography or recrystallization.
  • the structure of the product can be identified by elemental analysis, MS (FD-MS) analysis, IR analysis, 1 H-NMR, 13 C-NMR and the like.
  • the di (hetero) arylacetonitrile compound synthesized in this step can be used in the next step (step (III)) without performing purification treatment, and if necessary, activated carbon treatment, recrystallization, column It can also be purified by ordinary purification methods such as chromatography.
  • Compound (2) is a compound that can be synthesized in the step (II), and various compounds can be adopted. Further, Ar 1 and Ar 2 in the general formula (2) can include those described above. The same applies to preferred embodiments.
  • the substituent Ar 3 is a substituted or unsubstituted aromatic group.
  • the substituted aromatic group if aromatic groups, the kind and number of substituents, if Ar 3 is substituted, and Ar 3 is substituted in the substituent Ar 3
  • Ar 3 is substituted in the substituent Ar 3
  • Substituent Ar 3 constitutes one of the (hetero) aryl groups (aromatic groups) of the tri (hetero) aryl acetonitrile compound, which is the final product, and employs various aromatic groups. Can do. From the viewpoint of selectivity and yield of this reaction, a substituted or unsubstituted monocyclic aromatic hydrocarbon group, a substituted or unsubstituted monocyclic aromatic heterocyclic group, a substituted or unsubstituted condensed ring aromatic heterocyclic ring A substituted or unsubstituted 6-membered monocyclic aromatic hydrocarbon group, a substituted or unsubstituted 5- or 6-membered monocyclic aromatic heterocyclic group, a substituted or unsubstituted bicyclic aromatic heterocycle And more preferably a phenyl group, a tolyl group (o-tolyl group, m-tolyl group, p-tolyl group, etc.), a methoxyphenyl group
  • X 3 is a halogen atom, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a bromine atom and an iodine atom are preferable, and an iodine atom is particularly preferable.
  • the amount of compound (3) to be used is preferably 0.2 to 3 mol, preferably 1 to 2.5 mol, relative to 1 mol of compound (2), from the viewpoints of selectivity and yield. More preferred.
  • the palladium catalyst used in this step is not particularly limited, and examples thereof include palladium acetate (Pd (OCOCH 3 ) 2 ; Pd (OAc) 2 ), palladium trifluoroacetate (Pd (OCOCF 3 ) 2 ), p-allyl palladium (II) chloride dimer ([PdCl (allyl)] 2 ), p-cinnamyl palladium (II) chloride dimer, di- ⁇ -chlorobis (2′-amino-1,1′-biphenyl-2-) C, N) dipalladium (II), palladium chloride (PdCl 2 ), palladium bromide (PdBr 2 ), palladium iodide (PdI 2 ), Pd (CH 2 COCH 2 COCH 3 ) 2 , K 2 PdCl 4 , K 2 PdCl 6, K 2 Pd ( NO 3) 4, tris (dibenzylideneacetone) dip
  • organic ligand complexes are preferable in this step from the viewpoint of selectivity, yield, and safety.
  • p-allyl palladium (II) chloride dimer trifluoroacetic acid Palladium, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like are more preferable, and palladium acetate (Pd (OCOCH 3 ) 2 ) is more preferable.
  • the amount of the palladium catalyst used is usually preferably from 0.02 to 1 mol, preferably from 0.03 to 0.25 mol, based on 1 mol of the compound (2), from the viewpoints of selectivity and yield. Is more preferable.
  • This ligand can be introduced into the palladium catalyst in advance, or can be introduced into the system together with the palladium catalyst.
  • the ligand that can be used in this step is preferably a trialkylphosphine ligand from the viewpoint of selectivity and yield.
  • a trialkylphosphine ligand other than di (t-butyl) methylphosphine.
  • trialkylphosphine ligand examples include triethylphosphine, tri (n-propyl) phosphine, tri (isopropyl) phosphine, tri (t-butyl) phosphine, tri (n-butyl) phosphine, (N-octyl) phosphine, di (t-butyl) ethylphosphine, di (t-butyl) n-propylphosphine, di (t-butyl) isopropylphosphine, di (t-butyl) n-butylphosphine, di (t -Butyl) isobutylphosphine, di (t-butyl) neopentylphosphine and the like.
  • these phosphine ligands can also be used as ligand precursors which are salts with halogen atoms (such as chlorine atoms), HCl, HF, HBr, HI, HBF 4 and the like. These can be used alone or in combination. Among these, in this step, tri (t-butyl) phosphine is preferable from the viewpoints of selectivity, yield, and safety.
  • the amount of the ligand used is usually preferably 0.5 to 5 moles and more preferably 1 to 4 moles with respect to 1 mole of the palladium catalyst from the viewpoints of selectivity and yield.
  • step (III) is preferably performed in the presence of a base.
  • Bases that can be used in this step are cesium carbonate, cesium halides (cesium fluoride, cesium chloride, cesium bromide, cesium iodide, etc.), alkali metal phosphates (potassium phosphate) in terms of selectivity and yield.
  • cesium carbonate cesium halide (cesium fluoride, cesium chloride, cesium bromide, cesium iodide, etc.) and the like are more preferable, cesium carbonate, cesium fluoride and the like More preferably, cesium carbonate is particularly preferable. In particular, cesium carbonate can dramatically improve selectivity and yield even when compared with other bases.
  • the amount of the base used is preferably 0.5 to 10 mol, preferably 1 to 5 mol per 1 mol of the compound (2) from the viewpoints of selectivity and yield. Mole is more preferred.
  • reaction solvents include, for example, ether solvents such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diisopropyl ether, diisobutyl ether, cyclopentyl methyl ether (CPME); benzene, toluene, It is preferable to use an organic solvent such as an aromatic hydrocarbon solvent such as o-xylene, m-xylene, p-xylene, mixed xylene, and mesitylene. These can be used alone or in combination. Of these, ether solvents are preferable and 1,4-dioxane is more preferable from the viewpoints of selectivity, yield, and safety.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol di
  • the amount of these reaction solvents (organic solvents) used is not particularly limited as long as the reaction proceeds.
  • the reaction temperature in this step varies depending on the boiling point of the reaction solvent used. Usually, it is preferably carried out at a reaction temperature of about room temperature (25 ° C.) to about 300 ° C., particularly about 50 to 150 ° C., and further about 80 to 120 ° C. Moreover, it is preferable to implement this process normally under inert gas (for example, nitrogen, argon, helium etc.) airflow.
  • the reaction can be carried out at normal pressure, and if necessary, can be carried out under reduced pressure or pressurized conditions, but it is preferably carried out under normal pressure.
  • limiting in particular in reaction time It can be set as time for reaction to fully advance.
  • the progress of the reaction can be followed by conventional methods such as chromatography. After completion of the reaction, the solvent is distilled off, and the product can be isolated and purified by the usual method such as chromatography, recrystallization and the like as the product tri (hetero) arylacetonitrile compound.
  • the structure of the product can be identified by elemental analysis, MS (FD-MS) analysis, IR analysis, 1 H-NMR, 13 C-NMR and the like.
  • the tri (hetero) arylacetonitrile compound thus obtained has the general formula (1):
  • Tri (hetero) arylacetonitrile compound and derivatives thereof The tri (hetero) arylacetonitrile compound obtained as described above can easily substitute a cyano group with another functional group. For this reason, it is expected to easily connect to the synthesis of undeveloped tri (hetero) aryl compounds.
  • a tri (hetero) aryl aldehyde compound a tri (hetero) arylamine compound, a tri (hetero) arylamide compound, a tri (hetero) arylamide compound, (Hetero) arylmethane compounds, tri (hetero) aryloxadiazole compounds, tri (hetero) aryltriazine compounds and the like can be easily synthesized.
  • R 10 represents an alkyl group or an alkoxycarbonyl group.
  • R 11 represents a substituted or unsubstituted alkyl group or an alkoxy group.
  • the alkyl group and alkoxycarbonyl group represented by R 10 a substituted or unsubstituted alkyl group represented by R 11, and the alkoxy groups, can be employed the same as described above. The same applies to the type and number of substituents.
  • a ligand (6a) that can be used as a particularly preferred ligand in the step (II) is, for example, General formula (10):
  • X 4 and X 5 is a halogen atom, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a bromine atom, an iodine atom and the like are preferable, and a bromine atom is more preferable.
  • This compound (10) may be a commercially available product or may be synthesized according to a previously reported method.
  • examples of the leaving group represented by Y include a halogen atom (chlorine atom, bromine atom, iodine atom, etc.), alkyl sulfonate (methanesulfonate, etc.), haloalkylsulfonate (trifluoromethanesulfonate, etc.), Examples thereof include aryl sulfonates (p-toluene sulfonate, etc.). From the viewpoint of the yield of this reaction, a halogen atom (especially a chlorine atom) is preferred.
  • examples of the alkyl group represented by R 1b and R 2b include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t C 1-8 -alkyl groups such as -butyl group and n-hexyl group can be employed.
  • examples of the substituent that can be substituted on the alkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
  • examples of the cycloalkyl group represented by R 1b and R 2b include C 3-8 -cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • Examples of the substituent that can be substituted on the cycloalkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
  • the amount of compound (11) to be used is generally preferably 0.5 to 5 mol, more preferably 1 to 4 mol, relative to 1 mol of compound (10), from the viewpoint of yield.
  • the base examples include metal amides (particularly alkali metal amides) such as lithium diisopropylamide (LDA), lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium bistrimethylsilylamide; methyllithium, ethyllithium, n-butyllithium, s
  • metal amides particularly alkali metal amides
  • LDA lithium diisopropylamide
  • lithium bistrimethylsilylamide sodium bistrimethylsilylamide
  • potassium bistrimethylsilylamide methyllithium, ethyllithium, n-butyllithium, s
  • alkyllithium such as -butyllithium and t-butyllithium
  • aryllithium such as phenyllithium
  • Grignard reagent and the like. From the viewpoint of yield, alkyllithium is preferable, and n-butyllithium is more preferable.
  • This reaction can usually be carried out in a solvent.
  • the solvent include ether solvents such as diethyl ether, tetrahydrofuran, dioxane (1,4-dioxane), t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme; benzene, toluene, xylene, mesitylene And aromatic hydrocarbon solvents such as pentane, hexane, heptane, and cyclohexane.
  • ether solvents such as diethyl ether, tetrahydrofuran, dioxane (1,4-dioxane), t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme; benzene, toluene, xylene, mesitylene And aromatic hydrocarbon solvents such as pentane,
  • the amount of these solvents used is not particularly limited as long as the reaction proceeds.
  • reaction temperature of this reaction varies depending on the boiling point of the reaction solvent used. Usually, it is preferable to add the base in the solvent to the compound (10) at ⁇ 150 to 0 ° C., particularly at ⁇ 100 to ⁇ 50 ° C., and then add the compound compound (11).
  • this reaction is usually preferably carried out under an inert gas (for example, nitrogen, argon, helium, etc.) stream.
  • the reaction can be carried out at normal pressure, and if necessary, can be carried out under reduced pressure or pressurized conditions, but it is preferably carried out under normal pressure.
  • limiting in particular in reaction time It can be set as time for reaction to fully advance.
  • the progress of the reaction can be followed by conventional methods such as chromatography. After completion of the reaction, the solvent is distilled off, and the product, the ligand (6a), which is the product, can be isolated and purified by a usual method such as chromatography or recrystallization.
  • the structure of the product can be identified by elemental analysis, MS (FD-MS) analysis, IR analysis, 1 H-NMR, 13 C-NMR and the like.
  • Analytical thin layer chromatography was performed using E. Merck silica gel 60 F 254 precoated plates (0.25 mm). The developed chromatogram was analyzed with a UV lamp (254 nm) and a phosphomolybdic acid ethanol solution.
  • Preparative thin layer chromatography was performed using a pre-prepared Wakogel B5-F silica-coated plate (0.75 mm).
  • Recycle preparative high performance liquid chromatography (HPLC) was performed on a JAI LC-9204 equipped with a JAIGEL-1H / JAIGEL-2H column using chloroform as the eluent.
  • GC Gas chromatography
  • High resolution mass spectra were obtained from JMS-T100TD instrument (DART) and Thermo Fisher Scientific Exactive. Infrared (IR) spectra were recorded with FT / IR-6100.
  • Nuclear magnetic resonance (NMR) spectra were obtained from JEOL ECA-600 ( 1 H 600 MHz, 13 C 150 MHz) and JEOL A-100, JEOL ECS-400 and JEOL AL-400 ( 1 H 400 MHz, 13 C 100 MHz, 31 P 162 MHz). 1 H NMR chemical shift is relative to tetramethylsilane ( ⁇ 0.00 ppm), DMSO-d 6 residual proton signal ( ⁇ 2.50 ppm) or acetone-d 6 residual proton signal ( ⁇ 2.05 ppm).
  • n-Bu represents an n-butyl group.
  • THF represents tetrahydrofuran. The same applies hereinafter.
  • a magnetic stirring bar was accommodated in a two-necked flask having an internal volume of 100 mL, dried under a vacuum with a heat gun, cooled to room temperature, and filled with argon gas. Next, 2,2′-dibromobiphenyl (1,25 g, 4 mmol) and dry THF (15 mL) were added to the two-necked flask under a stream of argon.
  • n-butyllithium in n-hexane (1.6 M, 5.5 mL, 8.8 mmol) was slowly added at -78 ° C. After 15 minutes, at the same temperature, a solution of purified chlorodicyclohexylphosphine (1.95 mL, 8.8 mmol) in toluene (4 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was treated with NH 4 Cl salt (ca 15 mL) and extracted with CH 2 Cl 2 (3 times). The extract was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure.
  • Example 2 (Hetero) arylation of halogenated acetonitrile compound
  • a magnetic stir bar was housed in a sealed glass container having an internal volume of 10 mL, dried under a vacuum with a heat gun, cooled to room temperature, and filled with argon gas. Next, palladium acetate (Pd (OAc) 2 ; 1.7 mg, 7.5 ⁇ mol), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl (SPhos; 6.2 mg, 15 ⁇ mol) was placed in the glass container. ), And dry 1,4-dioxane (450 ⁇ L) were added at room temperature under a stream of argon.
  • Pd (OAc) 2 palladium acetate
  • SPhos 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl
  • Example 2-2 The same treatment as in Example 2-1 was performed, except that the type of boronic acid compound, the amount of palladium catalyst, the type and amount of ligand, the type of solvent, and the reaction temperature were variously changed. The results are shown in Table 1.
  • Example 2-3 The same treatment as in Example 2-1 was performed, except that the aromatic group (phenyl group) of the boronic acid compound was various groups. The results are shown in Table 2.
  • Binap represents 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl. The same applies hereinafter.
  • a magnetic stir bar was housed in a sealed glass container having an internal volume of 10 mL, dried under a vacuum with a heat gun, cooled to room temperature, and filled with argon gas. Next, palladium acetate (Pd (OAc) 2 ; 2.2 mg, 10 ⁇ mol), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (rac-BINAP2; 12.4 mg, 20 ⁇ mol) was placed in the glass container.
  • Pd (OAc) 2 palladium acetate
  • rac-BINAP2 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl
  • a phenyl substitution product was also produced as a by-product ((p-methoxyphenyl) (p-methyl (Spectral data of phenyl) acetonitrile (4bc) and (p-methylphenyl) phenylacetonitrile (4ba) will be described later).
  • a magnetic stir bar was housed in a sealed glass container having an internal volume of 10 mL, dried under a vacuum with a heat gun, cooled to room temperature, and filled with argon gas.
  • palladium acetate (Pd (OAc) 2 3.3 mg, 15 ⁇ mol
  • 2,2′-bis (dicyclohexylphosphino) -1,1′-bipyridyl (DCPB; 16.5) obtained in Example 1 was placed in the glass container.
  • mg, 30 ⁇ mol) and dry 1,4-dioxane (300 ⁇ L) were added at room temperature under a stream of argon.
  • Example 3-3 The same treatment as in Example 3-1 was performed, except that the amount of the palladium catalyst, the type and amount of the ligand, the reaction temperature, and the reaction time were variously changed. The results are shown in Table 3.
  • Example 3-4 The same treatment as in Example 3-2 was performed, except that the aromatic group (phenyl group) of the substrate and the halogenated aromatic compound was variously changed. The results are shown in Table 4.
  • a magnetic stir bar was housed in a sealed glass container having an internal volume of 10 mL, dried under a vacuum with a heat gun, cooled to room temperature, and filled with argon gas.
  • palladium acetate (Pd (OAc) 2 6.7 mg, 30 ⁇ mol
  • P (t-butyl) 3 .HBF 4 26.1 mg, 90 ⁇ mol
  • Cs 2 CO 3 195 mg, 0.6 mmol
  • Example 4-2 The same treatment as in Example 4-1 was performed, except that the halogen atom contained in the halogenated aromatic compound, the type and amount of ligand, and the type of base were variously changed. The results are shown in Table 5.
  • Example 4-3 The same treatment as in Example 4-1 was performed, except that the aromatic group (phenyl group) of the substrate and the halogenated aromatic compound was variously changed. The results are shown in Table 6.
  • DIBAL-H represents diisobutylaluminum hydride.
  • Example 5-2 The same treatment as in Example 5-1 was performed except that the substrate was changed. The results are shown below.
  • Example 6 Amination of tri (hetero) arylacetonitrile compound
  • a flame-dried Schlenk tube contains a magnetic stir bar, and triphenylacetonitrile (26.9 mg, 0.1 mmol) obtained in Example 4-1, 2-propanol (2 mL), Raney nickel catalyst (stored in 2-propanol) 0.2 g from Raney nickel) and KOH (100 mg) were added.
  • a condenser was placed on the Schlenk tube, and the mixture was refluxed with stirring at 100 ° C. for 48 hours. After cooling to room temperature, 1 M aqueous HCl (2 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes.
  • Example 6-2 The same treatment as in Example 6-1 was performed, except that the substrate was changed. The results are shown below.
  • Example 7 Amidation of tri (hetero) arylacetonitrile compound
  • a magnetic stirrer was housed in a sealed glass container with an internal volume of 10 mL, and triphenylacetonitrile (50 mg, 0.186 mmol), acetic acid (1.0 mL), H 2 SO 4 (1.5 mL) obtained in Example 4-1. And water (0.5 mL) were added and the vessel was sealed. The mixture was stirred at 135 ° C. for 48 hours. After cooling to room temperature, the acetic acid was removed under vacuum using a rotary evaporator, the mixture was diluted with water (1 mL), extracted with ethyl acetate (3 ⁇ 15 mL), and the organic layer was Na 2 SO 4 And concentrated under reduced pressure.
  • Example 8 Synthesis of tri (hetero) arylmethane using tri (hetero) arylacetonitrile compound
  • a magnetic stir bar was housed in a sealed glass container with an internal volume of 10 mL that was frame-dried, and triphenylacetonitrile (26.9 mg, 0.1 mmol) obtained in Example 4-1 and dry toluene (0.5 mL) under an argon atmosphere. ) was added. After cooling to 0 ° C., 3 M methylmagnesium chloride in THF (67 ⁇ L, 0.2 mmol) was added to the reaction mixture, and the vessel was sealed. The mixture was stirred at 135 ° C. for 24 hours. The reaction mixture was then cooled to 0 ° C. and then quenched with 1 M aqueous HCl (1 mL), and the reaction mixture was further stirred at room temperature for 30 minutes.
  • Example 8-2 The same treatment as in Example 8-1 was performed except that the substrate was changed. The results are shown below.
  • Example 9-2 The same treatment as in Example 9-1 was performed, except that the substrate was changed. The results are shown below.
  • Example 10 Triazination of tri (hetero) arylacetonitrile compound
  • a magnetic stir bar was housed in a sealed glass container with an internal volume of 10 mL that was frame-dried, and triphenylacetonitrile (26.9 mg, 0.1 mmol), cyanoguanidine (10.5 mg, 0.125 mmol), KOH (4 mg, 0.071 mmol), and ethanol (0.5 mL) were added and the vessel was sealed. The mixture was stirred at 140 ° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with water (1 mL) and extracted with ethyl acetate (3 ⁇ 15 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Example 10-2 The same treatment as in Example 10-1 was performed, except that the substrate was changed. The results are shown below.

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Abstract

According to the present invention, various tri(hetero)arylacetonitrile compounds are synthesized by reacting, in the presence of a palladium catalyst, a di(hetero)arylacetonitrile compound represented by the formula: CHAr1Ar2CN (Ar1 and Ar2 represent substituted or unsubstituted aromatic groups.) and a halogenated aromatic compound represented by the formula: Ar3X3 (Ar3 represents a substituted or unsubstituted aromatic group. X3 represents a halogen atom.) The di(hetero)arylacetonitrile compound used as a substrate can be synthesized in a two-stage reaction using a halogenated acetonitrile compound as a starting material. Due to this, various tri(hetero)arylacetonitrile compounds can be synthesized easily in a small number of steps.

Description

トリ（ヘテロ）アリールアセトニトリル化合物の製造方法Method for producing tri (hetero) arylacetonitrile compound
　本発明は、トリ（ヘテロ）アリールアセトニトリル化合物の製造方法に関する。 The present invention relates to a method for producing a tri (hetero) aryl acetonitrile compound.
　トリ（ヘテロ）アリールアセトニトリル化合物及びその誘導体は、有機色素、バイオイメージング用蛍光プローブ、金属イオンのセンサー等、種々様々な分野で使用されている。さらに、これらトリ（ヘテロ）アリールアセトニトリル化合物及びその誘導体は、抗結核剤、抗癌剤等の医薬用途への適用も検討されている。 Tri (hetero) aryl acetonitrile compounds and derivatives thereof are used in various fields such as organic dyes, fluorescent probes for bioimaging, and sensors for metal ions. Furthermore, application of these tri (hetero) arylacetonitrile compounds and derivatives thereof to pharmaceutical uses such as antituberculous agents and anticancer agents is also being studied.
　このため、トリ（ヘテロ）アリールアセトニトリル化合物をより簡便に合成することが重要である。 For this reason, it is important to synthesize a tri (hetero) arylacetonitrile compound more easily.
　このようなトリ（ヘテロ）アリールアセトニトリル化合物の合成方法としては、例えば、ルイス酸触媒の存在下、トリ（ヘテロ）アリールアルコール化合物からニトリル変換反応によりトリ（ヘテロ）アリールアセトニトリル化合物を得る方法が知られている。また、トリ（ヘテロ）アリールハロゲン化物に対してシアニドアニオンの求核置換反応によりトリ（ヘテロ）アリールアセトニトリル化合物を得る方法も知られている。これらの合成方法は、例えば、非特許文献１～２等に記載されている。 As a method for synthesizing such a tri (hetero) aryl acetonitrile compound, for example, a method for obtaining a tri (hetero) aryl acetonitrile compound from a tri (hetero) aryl alcohol compound by a nitrile conversion reaction in the presence of a Lewis acid catalyst is known. ing. Also known is a method of obtaining a tri (hetero) aryl acetonitrile compound by nucleophilic substitution reaction of a cyanide anion with a tri (hetero) aryl halide. These synthesis methods are described, for example, in Non-Patent Documents 1 and 2.
　しかしながら、これらの合成方法はいずれも、基質であるトリ（ヘテロ）アリールアルコール化合物又はトリ（ヘテロ）アリールハロゲン化物を得るためには多段階の合成が必要であり、合成経路が複雑にならざるを得ない（少なくとも４工程以上が必要である）ため、とても簡便な方法とは言えない。また、トリ（ヘテロ）アリールアセトニトリル化合物の合成の際に、空気や湿気に対して不安定な金属反応剤を使用する必要があるうえに、極めて毒性の高いシアン化物イオンを取り扱うために系中においてシアン酸等が発生することから、雰囲気制御が必要となり、装置が大掛かりにならざるを得ない。 However, in any of these synthesis methods, a multi-step synthesis is required to obtain a substrate tri (hetero) aryl alcohol compound or tri (hetero) aryl halide, and the synthesis route must be complicated. Since it cannot be obtained (at least 4 steps are required), it cannot be said that it is a very simple method. In addition, when synthesizing tri (hetero) arylacetonitrile compounds, it is necessary to use metal reactants that are unstable to air and moisture, and in the system to handle extremely toxic cyanide ions. Since cyanic acid and the like are generated, it is necessary to control the atmosphere, and the apparatus must be large.
　本発明は、上記のような課題を解決しようとするものであり、主な目的は、種々のトリ（ヘテロ）アリールアセトニトリル化合物を少ない工程で、簡便に合成できる方法を提供することである。 The present invention is intended to solve the above-mentioned problems, and a main object is to provide a method for easily synthesizing various tri (hetero) arylacetonitrile compounds with few steps.
　本発明者らは、上記課題に鑑み、鋭意研究を重ねた。その結果、ハロゲン化アセトニトリル化合物を使用して、パラジウム触媒の存在下に、特定の芳香族化合物を用いて、芳香族基を導入する反応を順次３回行うことにより、トリ（ヘテロ）アリールアセトニトリル化合物を簡便に合成することができることを見出した。この方法は、どのような芳香族基であっても導入することができるとともに、用いる原料及び触媒がいずれも大気中で取扱い容易であり、４工程以上要していた従来の方法よりも工程数を減らすことができる簡便な方法である。また、トリ（ヘテロ）アリールアセトニトリル化合物中のシアノ基は、様々な官能基に容易に置換することができ、様々な機能性分子の簡便な合成につなげることも可能である。本発明は、このような知見に基づき、さらに研究を重ね、完成したものである。すなわち、本発明は、以下の構成を包含する。 In view of the above problems, the present inventors have conducted extensive research. As a result, a tri (hetero) aryl acetonitrile compound was obtained by sequentially performing a reaction for introducing an aromatic group three times using a specific aromatic compound in the presence of a palladium catalyst using a halogenated acetonitrile compound. It was found that can be synthesized easily. In this method, any aromatic group can be introduced, and both the raw materials and the catalyst used are easy to handle in the atmosphere, and the number of steps is higher than that of the conventional method that required four or more steps. It is a simple method that can reduce In addition, the cyano group in the tri (hetero) arylacetonitrile compound can be easily substituted with various functional groups, which can lead to simple synthesis of various functional molecules. The present invention has been completed by further research based on such knowledge. That is, the present invention includes the following configurations.
　項１．一般式（１）： Item 1. General formula (1):
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
［式中、Ａｒ１、Ａｒ２及びＡｒ３は同一又は異なって、置換又は無置換の芳香族基を示す。］
で表されるトリ（ヘテロ）アリールアセトニトリル化合物の製造方法であって、
（III）一般式（２）： [In formula, Ar < 1 >, Ar < 2 > and Ar < 3 > are the same or different, and show a substituted or unsubstituted aromatic group. ]
A method for producing a tri (hetero) arylacetonitrile compound represented by
(III) General formula (2):
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
［式中、Ａｒ１及びＡｒ２は前記に同じである。］
で表されるジ（ヘテロ）アリールアセトニトリル化合物と、
一般式（３）：
Ａｒ３Ｘ３　　　（３）
［式中、Ａｒ３は前記に同じである。Ｘ３はハロゲン原子を示す。］
で表されるハロゲン化芳香族化合物とを、
パラジウム触媒の存在下に反応させる工程
を備える、製造方法。 [Wherein, Ar 1 and Ar 2 are the same as defined above. ]
A di (hetero) arylacetonitrile compound represented by:
General formula (3):
Ar 3 X 3 (3)
[Wherein Ar 3 is the same as defined above. X 3 represents a halogen atom. ]
A halogenated aromatic compound represented by
A production method comprising a step of reacting in the presence of a palladium catalyst.
　項２．前記工程（III）が、トリアルキルホスフィン配位子の存在下で行われる、項１に記載の製造方法。 Item 2. Item 2. The production method according to Item 1, wherein the step (III) is performed in the presence of a trialkylphosphine ligand.
　項３．前記トリアルキルホスフィン配位子が、トリ（ｔ－ブチル）ホスフィン又はその塩である、項２に記載の製造方法。 Item 3. Item 3. The production method according to Item 2, wherein the trialkylphosphine ligand is tri (t-butyl) phosphine or a salt thereof.
　項４．前記工程（III）が、塩基の存在下で行われる、項１～３のいずれかに記載の製造方法。 Item 4. Item 4. The production method according to any one of Items 1 to 3, wherein the step (III) is performed in the presence of a base.
　項５．前記塩基が、炭酸セシウム、ハロゲン化セシウム、及びリン酸アルカリ金属塩よりなる群から選ばれる少なくとも１種である、項４に記載の製造方法。 Item 5. Item 5. The production method according to Item 4, wherein the base is at least one selected from the group consisting of cesium carbonate, cesium halides, and alkali metal phosphates.
　項６．前記工程（III）の前に、
（II）一般式（４）：
Ａｒ１－ＣＨ２－ＣＮ　　　（４）
［式中、Ａｒ１は前記に同じである。］
で示される（ヘテロ）アリールアセトニトリル化合物と、
一般式（５）：
Ａｒ２Ｘ２　　　（５）
［式中、Ａｒ２は前記に同じである。Ｘ２はハロゲン原子を示す。］
で表されるハロゲン化芳香族化合物とを、パラジウム触媒の存在下で反応させる工程
を備える、項１～５のいずれかに記載の製造方法。 Item 6. Before the step (III),
(II) General formula (4):
Ar 1 —CH 2 —CN (4)
[Wherein Ar 1 is the same as defined above. ]
A (hetero) arylacetonitrile compound represented by:
General formula (5):
Ar 2 X 2 (5)
[Wherein Ar 2 is the same as defined above. X 2 represents a halogen atom. ]
Item 6. The production method according to any one of Items 1 to 5, further comprising a step of reacting the halogenated aromatic compound represented by the formula:
　項７．前記工程（II）が、ホスフィン配位子の存在下で行われる、項６に記載の製造方法。 Item 7. Item 7. The production method according to Item 6, wherein the step (II) is performed in the presence of a phosphine ligand.
　項８．前記ホスフィン配位子が、トリ（シクロアルキル）ホスフィン、アルキルジ（シクロアルキルホスフィン）、ジ（アルキル）シクロアルキルホスフィン、トリ（アルキル）ホスフィン、トリ（アルコキシ）ホスフィン、アルキルジアダマンチルホスフィン、又は一般式（６）： Item 8. The phosphine ligand is tri (cycloalkyl) phosphine, alkyldi (cycloalkylphosphine), di (alkyl) cycloalkylphosphine, tri (alkyl) phosphine, tri (alkoxy) phosphine, alkyldiadamantylphosphine, or a general formula ( 6):
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
［式中、Ｒ１及びＲ２は同一又は異なって、置換若しくは無置換のアルキル基、又は置換若しくは無置換のシクロアルキル基を示す。Ｒは置換若しくは無置換のアルキル基、置換若しくは無置換のアルコキシ基、又は－ＰＲ３Ｒ４（Ｒ３及びＲ４は同一又は異なって、置換若しくは無置換のアルキル基、又は置換若しくは無置換のシクロアルキル基を示す）で示される基を示す。ｎは０～３の整数を示す。］
で表される配位子である、項７に記載の製造方法。 [Wherein, R 1 and R 2 are the same or different and each represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group. R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or —PR 3 R 4 (R 3 and R 4 are the same or different, and are substituted or unsubstituted alkyl groups, or substituted or unsubstituted Represents a cycloalkyl group). n represents an integer of 0 to 3. ]
Item 8. The production method according to Item 7, wherein the ligand is represented by the formula:
　項９．前記工程（II）の前に、
（I）一般式（７）：
Ｘ－ＣＨ２－ＣＮ　　　（７）
［式中、Ｘはハロゲン原子を示す。］
で表されるハロゲン化アセトニトリル化合物と、
一般式（８Ａ）： Item 9. Before the step (II),
(I) General formula (7):
X—CH 2 —CN (7)
[Wherein X represents a halogen atom. ]
A halogenated acetonitrile compound represented by:
General formula (8A):
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
［式中、Ａｒ１は前記に同じである。Ｒ５及びＲ６は同一又は異なって、水素原子、アルキル基又はシクロアルキル基を示す。Ｒ５とＲ６とは互いに結合し、隣接する－Ｏ－Ｂ－Ｏ－とともに環を形成してもよい。］
で表される芳香族基含有ボロン酸若しくはそのエステル化合物、又は
一般式（８Ｂ）：
Ａｒ１ＢＦ３Ｋ　　　（８Ｂ）
［式中、Ａｒ１は前記に同じである。］
で表される芳香族基含有カリウムトリフルオロボレート
とを、パラジウム触媒の存在下で反応させる工程
を備える、項６～８のいずれかに記載の製造方法。 [Wherein Ar 1 is the same as defined above. R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group or a cycloalkyl group. R 5 and R 6 may be bonded to each other to form a ring together with adjacent —O—B—O—. ]
Or a boronic acid-containing boronic acid represented by the general formula (8B):
Ar 1 BF 3 K (8B)
[Wherein Ar 1 is the same as defined above. ]
Item 9. The production method according to any one of Items 6 to 8, further comprising a step of reacting the aromatic group-containing potassium trifluoroborate represented by the formula:
　項１０．一般式（９）： Item 10. General formula (9):
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
［式中、Ａｒ１、Ａｒ２及びＡｒ３は同一又は異なって、置換又は無置換の芳香族基を示す。Ｒは置換基を示す。］
で表される化合物の製造方法であって、
項１～９のいずれかに記載の製造方法の前記工程（III）の後、前記トリ（ヘテロ）アリールアセトニトリル化合物のシアノ基を置換する工程を備える、製造方法。 [In formula, Ar < 1 >, Ar < 2 > and Ar < 3 > are the same or different, and show a substituted or unsubstituted aromatic group. R represents a substituent. ]
A process for producing a compound represented by
A production method comprising a step of substituting a cyano group of the tri (hetero) arylacetonitrile compound after the step (III) of the production method according to any one of Items 1 to 9.
　項１１．式： Item 11. formula:
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
［式中、Ｍｅはメチル基を示す。Ｐｈはフェニル基を示す。］
のいずれか、又は、一般式（２ａ）： [Wherein, Me represents a methyl group. Ph represents a phenyl group. ]
Or the general formula (2a):
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
［式中、Ｒ１０はアルキル基又はアルコキシカルボニル基を示す。Ｒ１１は置換若しくは無置換のアルキル基、又はアルコキシ基を示す。］
で表される化合物。 [Wherein, R 10 represents an alkyl group or an alkoxycarbonyl group. R 11 represents a substituted or unsubstituted alkyl group or an alkoxy group. ]
A compound represented by
　項１２．一般式（６ａ）： Item 12. General formula (6a):
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
［式中、Ｒ１ｂ、Ｒ１ｃ、Ｒ２ｂ及びＲ２ｃは同一又は異なって、アルキル基又はシクロアルキル基を示す。］
で表される化合物の製造方法であって、
一般式（１０）： [Wherein, R 1b , R 1c , R 2b and R 2c are the same or different and each represents an alkyl group or a cycloalkyl group. ]
A process for producing a compound represented by
General formula (10):
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
［式中、Ｘ４及びＸ５は同一又は異なって、ハロゲン原子を示す。］
で表される化合物と、
一般式（１１）：
Ｙ－ＰＲ１ｂＲ２ｂ
［式中、Ｒ１ｂ及びＲ２ｂは前記に同じである。Ｙは脱離基を示す。］
で表される化合物とを、塩基の存在下に反応させる工程
を備える、製造方法。 [Wherein, X 4 and X 5 are the same or different and each represents a halogen atom. ]
A compound represented by
General formula (11):
Y-PR 1b R 2b
[Wherein, R 1b and R 2b are the same as defined above. Y represents a leaving group. ]
The manufacturing method provided with the process with which the compound represented by these is made to react in presence of a base.
　本発明によれば、ジ（ヘテロ）アリールアセトニトリル化合物を使用して、パラジウム触媒の存在下に、特定の芳香族化合物を用いて、芳香族基を導入する反応を行うことにより、トリ（ヘテロ）アリールアセトニトリル化合物を高収率且つ簡便に合成することができる。本発明では、従来は合成できなかった様々なトリ（ヘテロ）アリールアセトニトリル化合物を合成することができる。特に、合成が困難とされている、３個の芳香族基がいずれも異なるトリ（ヘテロ）アリールアセトニトリル化合物を合成することも可能である。また、本発明の好適な態様においては、高収率且つ簡便にトリ（ヘテロ）アリールアセトニトリル化合物を合成することも可能である。 According to the present invention, a di (hetero) arylacetonitrile compound is used to carry out a reaction for introducing an aromatic group using a specific aromatic compound in the presence of a palladium catalyst. An arylacetonitrile compound can be easily synthesized in a high yield. In the present invention, various tri (hetero) arylacetonitrile compounds that could not be synthesized conventionally can be synthesized. In particular, it is also possible to synthesize tri (hetero) aryl acetonitrile compounds in which all three aromatic groups are considered difficult to synthesize. In a preferred embodiment of the present invention, it is also possible to synthesize a tri (hetero) arylacetonitrile compound easily with a high yield.
　本発明の製造方法においては、特定のジ（ヘテロ）アリールアセトニトリル化合物と、特定のハロゲン化芳香族化合物とを反応させることにより、トリ（ヘテロ）アリールアセトニトリル化合物を合成する（工程（III））。 In the production method of the present invention, a tri (hetero) arylacetonitrile compound is synthesized by reacting a specific di (hetero) arylacetonitrile compound with a specific halogenated aromatic compound (step (III)).
　また、本発明において、原料として使用するジ（ヘテロ）アリールアセトニトリル化合物は、特に制限はなく、例えば、特定の（ヘテロ）アリールアセトニトリル化合物と、特定のハロゲン化芳香族化合物とを反応させることにより合成することができる（工程（II））。さらに、上記特定の（ヘテロ）アリールアセトニトリル化合物は、特に制限はなく、例えば、特定のハロゲン化アセトニトリル化合物と、特定の芳香族基含有化合物（芳香族基含有ボロン酸又はそのエステル化合物、芳香族基含有カリウムトリフルオロボレート、ハロゲン化芳香族化合物等）とを反応させることにより合成することができる（工程（I））。 In the present invention, the di (hetero) aryl acetonitrile compound used as a raw material is not particularly limited. For example, it is synthesized by reacting a specific (hetero) aryl acetonitrile compound with a specific halogenated aromatic compound. (Step (II)). Furthermore, the specific (hetero) aryl acetonitrile compound is not particularly limited. For example, the specific halogenated acetonitrile compound, the specific aromatic group-containing compound (the aromatic group-containing boronic acid or its ester compound, the aromatic group) It can be synthesized by reacting (containing potassium trifluoroborate, halogenated aromatic compound, etc.) (step (I)).
　このように、容易に入手可能なハロゲン化アセトニトリル化合物を原料として、後述の工程（I）～（II）を経てジ（ヘテロ）アリールアセトニトリル化合物を合成することにより、置換基Ａｒ１及びＡｒ２の導入の選択性及び収率をより向上させることができることから、本発明で原料として使用するジ（ヘテロ）アリールアセトニトリル化合物は、ハロゲン化アセトニトリル化合物を原料として、後述の工程（I）～（II）を経て合成することが好ましい。 Thus, by synthesizing a di (hetero) arylacetonitrile compound through the following steps (I) to (II) using a readily available halogenated acetonitrile compound as a raw material, the substituents Ar 1 and Ar 2 are synthesized. Since the selectivity and yield of introduction can be further improved, the di (hetero) arylacetonitrile compound used as a raw material in the present invention is prepared by using the halogenated acetonitrile compound as a raw material in the following steps (I) to (II). It is preferable to synthesize it through.
　このように、本発明においては、従来の製造方法では不可能であった最短の３段階のみでトリ（ヘテロ）アリールアセトニトリル化合物を合成することができる。この際、全ての反応において、導入される芳香族基の数及び位置を制御することが可能である。 Thus, in the present invention, a tri (hetero) arylacetonitrile compound can be synthesized in only the shortest three steps, which is impossible with the conventional production method. At this time, the number and position of the introduced aromatic groups can be controlled in all reactions.
　本発明において採用される上記３段階の反応は、いずれも入手及び調製が容易で、大気下で取扱い容易な原料のみを用いて行うことも可能である。また、この３段階の反応は、いずれも、大気下で安定に取り扱えるパラジウム触媒を使用して反応を進行させることもできる。この観点からも、本発明の製造方法は、簡便に、トリ（ヘテロ）アリールアセトニトリル化合物を得る方法である。 The above three-step reactions employed in the present invention can be carried out using only raw materials that are easy to obtain and prepare and easy to handle in the atmosphere. In addition, all of these three-stage reactions can proceed using a palladium catalyst that can be handled stably in the atmosphere. Also from this viewpoint, the production method of the present invention is a method for easily obtaining a tri (hetero) arylacetonitrile compound.
　本発明の製造方法において合成されるトリ（ヘテロ）アリールアセトニトリル化合物が有する芳香族基は、種々様々なものを採用することができる。例えば、エステル基、ホルミル基、ヘテロ芳香環等のように、官能基を有する芳香族基であっても、その構造を損なうことなく容易に導入することが可能である。上記３段階の全てにおいて、このような官能基を有する芳香族基を導入することも可能である。 As the aromatic group possessed by the tri (hetero) aryl acetonitrile compound synthesized in the production method of the present invention, various kinds of aromatic groups can be adopted. For example, even an aromatic group having a functional group such as an ester group, a formyl group, or a heteroaromatic ring can be easily introduced without impairing its structure. In all of the above three stages, it is also possible to introduce an aromatic group having such a functional group.
　さらに、本発明の製造方法で得られるトリ（ヘテロ）アリールアセトニトリル化合物中のシアノ基は、様々な官能基に容易に置換することができ、様々な機能性分子の簡便な合成につなげることも可能である。 Furthermore, the cyano group in the tri (hetero) arylacetonitrile compound obtained by the production method of the present invention can be easily substituted with various functional groups, which can lead to simple synthesis of various functional molecules. It is.
　なお、本明細書において、「（ヘテロ）アリール」とは、アリール又はヘテロアリールを意味する。 In the present specification, “(hetero) aryl” means aryl or heteroaryl.
　１．工程（I）：ハロゲン化アセトニトリル化合物の（ヘテロ）アリール化
　本工程では、
（I）一般式（７）：
Ｘ－ＣＨ２－ＣＮ　　　（７）
［式中、Ｘはハロゲン原子を示す。］
で表されるハロゲン化アセトニトリル化合物（以下、「化合物（７）」と言うこともある）と、
一般式（８Ａ）： 1. Step (I): (Hetero) arylation of halogenated acetonitrile compound In this step,
(I) General formula (7):
X—CH 2 —CN (7)
[Wherein X represents a halogen atom. ]
A halogenated acetonitrile compound represented by the formula (hereinafter also referred to as “compound (7)”),
General formula (8A):
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
［式中、Ａｒ１は前記に同じである。Ｒ５及びＲ６は同一又は異なって、水素原子、アルキル基又はシクロアルキル基を示す。Ｒ５とＲ６とは互いに結合し、隣接する－Ｏ－Ｂ－Ｏ－とともに環を形成してもよい。］
で表される芳香族基含有ボロン酸若しくはそのエステル化合物（以下、「化合物（８Ａ）と言うこともある」）、又は
一般式（８Ｂ）：
Ａｒ１ＢＦ３Ｋ　　　（８Ｂ）
［式中、Ａｒ１は前記に同じである。］
で表される芳香族基含有カリウムトリフルオロボレート（以下、「化合物（８Ｂ）」と言うこともある）
とを、パラジウム触媒の存在下で反応させる工程
により、（ヘテロ）アリールアセトニトリル化合物を合成する。 [Wherein Ar 1 is the same as defined above. R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group or a cycloalkyl group. R 5 and R 6 may be bonded to each other to form a ring together with adjacent —O—B—O—. ]
An aromatic group-containing boronic acid or an ester compound thereof (hereinafter sometimes referred to as “compound (8A)”), or a general formula (8B):
Ar 1 BF 3 K (8B)
[Wherein Ar 1 is the same as defined above. ]
Aromatic group-containing potassium trifluoroborate represented by the formula (hereinafter also referred to as “compound (8B)”)
Are reacted in the presence of a palladium catalyst to synthesize a (hetero) arylacetonitrile compound.
　一般式（７）において、Ｘで示されるハロゲン原子としては、フッ素原子、塩素原子、臭素原子及びヨウ素原子が挙げられる。これらのなかでも、本工程における選択性及び収率の観点から、塩素原子が好ましい。 In the general formula (7), examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, a chlorine atom is preferable from the viewpoints of selectivity and yield in this step.
　一般式（８Ａ）において、置換基Ａｒ１で示される置換又は無置換の芳香族基における芳香族基は、最終生成物であるトリ（ヘテロ）アリールアセトニトリル化合物が有する（ヘテロ）アリール基（芳香族基）のうち１つを構成しており、種々様々な芳香族基を採用することができる。例えば、フェニル基等の単環芳香族炭化水素基（特に六員単環芳香族炭化水素基）；ナフチル基（１－ナフチル基、２－ナフチル基等）、アントリル基（１－アントリル基、２－アントリル基、９－アントリル基等）、フルオレニル基（１－フルオレニル基、２－フルオレニル基、９－フルオレニル基等）、フェナントリル基、ピレニル基（１－ピレニル基、２－ピレニル基、４－ピレニル基等）、クリセニル基、ペリレニル基、ピセニル基等の縮合環芳香族炭化水素基（特に二環芳香族炭化水素基）；フリル基（２－フリル基、３－フリル基等）、チエニル基（２－チエニル基、３－チエニル基等）、ピロリル基（２－ピロリル基、３－ピロリル基等）、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、イミダゾリル基、ピラゾリル基、トリアゾリル基（１，２，３－トリアゾリル基、１，２，４－トリアゾリル基等）等の五員単環芳香族複素環式基；ピリジル基（２－ピリジル基、３－ピリジル基、４－ピリジル基等）、ピリミジニル基、ピリダジニル基、ピラジニル基等の六員単環芳香族複素環式基；キノリル基、イソキノリル基、インドリル基、ピリドチエノピリミジン環基等の縮合環芳香族複素環式基（特に二環芳香族複素環式基）等が挙げられる。これらのなかでも、置換又は無置換の単環芳香族炭化水素基、置換又は無置換の縮合環芳香族炭化水素基、五員単環芳香族複素環式基、六員単環芳香族複素環式基等が好ましく、六員単環芳香族炭化水素基、二環芳香族炭化水素基、五員単環芳香族複素環式基、六員単環芳香族複素環式基等、二環芳香族複素環式基等がより好ましく、フェニル基、ナフチル基（１－ナフチル基、２－ナフチル基等）、チエニル基（２－チエニル基、３－チエニル基等）等がさらに好ましい。 In the general formula (8A), the aromatic group in the substituted or unsubstituted aromatic group represented by the substituent Ar 1 is a (hetero) aryl group (aromatic) that the tri (hetero) arylacetonitrile compound as the final product has. Group), and various aromatic groups can be employed. For example, a monocyclic aromatic hydrocarbon group such as a phenyl group (especially a 6-membered monocyclic aromatic hydrocarbon group); a naphthyl group (1-naphthyl group, 2-naphthyl group, etc.), anthryl group (1-anthryl group, 2 -Anthryl group, 9-anthryl group, etc.), fluorenyl group (1-fluorenyl group, 2-fluorenyl group, 9-fluorenyl group, etc.), phenanthryl group, pyrenyl group (1-pyrenyl group, 2-pyrenyl group, 4-pyrenyl group) Groups), condensed ring aromatic hydrocarbon groups (especially bicyclic aromatic hydrocarbon groups) such as chrysenyl group, perylenyl group, and picenyl group; furyl groups (2-furyl group, 3-furyl group, etc.), thienyl groups ( 2-thienyl group, 3-thienyl group, etc.), pyrrolyl group (2-pyrrolyl group, 3-pyrrolyl group, etc.), oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazo A 5-membered monocyclic aromatic heterocyclic group such as a ru group, a pyrazolyl group, a triazolyl group (1,2,3-triazolyl group, 1,2,4-triazolyl group, etc.); a pyridyl group (2-pyridyl group, 3 -Pyridyl group, 4-pyridyl group, etc.), pyrimidinyl group, pyridazinyl group, pyrazinyl group and the like 6-membered monocyclic aromatic heterocyclic group; quinolyl group, isoquinolyl group, indolyl group, pyridothienopyrimidine ring group, etc. Ring aromatic heterocyclic group (especially bicyclic aromatic heterocyclic group) and the like. Among these, a substituted or unsubstituted monocyclic aromatic hydrocarbon group, a substituted or unsubstituted condensed ring aromatic hydrocarbon group, a 5-membered monocyclic aromatic heterocyclic group, and a 6-membered monocyclic aromatic heterocyclic ring Preferred are, for example, 6-membered monocyclic aromatic hydrocarbon group, bicyclic aromatic hydrocarbon group, 5-membered monocyclic aromatic heterocyclic group, 6-membered monocyclic aromatic heterocyclic group, etc. A heterocyclic group is more preferred, and a phenyl group, a naphthyl group (1-naphthyl group, 2-naphthyl group, etc.), a thienyl group (2-thienyl group, 3-thienyl group, etc.) is more preferred.
　置換基Ａｒ１において、芳香族基における置換基としては、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔ－ブチル基、ｎ－ペンチル基、イソペンチル基、ｎ－ヘキシル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等のＣ１－６－アルキル基又はＣ３－８－シクロアルキル基；メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔ－ブトキシ基、ｎ－ペンチルオキシ基、イソペンチルオキシ基、ｎ－ヘキシルオキシ基、シクロプロピルオキシ基、シクロブチルオキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基等のＣ１－６－アルコキシ基又はＣ３－８－シクロアルコキシ基；メトキシカルボニル基、エトキシカルボニル基、ｎ－プロポキシカルボニル基、イソプロポキシカルボニル基、ｎ－ブトキシカルボニル基、イソブトキシカルボニル基、ｓｅｃ－ブトキシカルボニル基、ｔ－ブトキシカルボニル基、ｎ－ペンチルオキシカルボニル基、イソペンチルオキシカルボニル基、シクロプロピルオキシカルボニル基、シクロブチルオキシカルボニル基、シクロペンチルオキシカルボニル基等のアルコキシカルボニル基又はシクロアルキルカルボニル基（特にＣ１－６－アルコキシカルボニル基又はＣ３－８－シクロアルコキシカルボニル基）；水酸基；フェニル基、トリル基、ナフチル基等の芳香族炭化水素基；フッ素原子、塩素原子、臭素原子、ヨウ素原子等のハロゲン原子；トリフルオロメチル基等のＣ１－６－ハロゲン化アルキル基；ベンジル基、フェネチル基等のアラルキル基；ホルミル基、アセチル基、ｎ－プロピオニル基（ｎ－プロパノイル基）、ｎ－ブチリル基（ｎ－ブタノイル基）、ｎ－バレリル基（ｎ－ペンタノイル基）、ｎ－ヘキサノイル基等のＣ１－６－脂肪族アシル基；ベンゾイル基、トルオイル基等の芳香族アシル基（アロイル基）；アラルキルオキシ基（ベンジルオキシ基、フェネチルオキシ基等）；カルボキシ基；Ｃ１－６－アルキルアミノ基（メチルアミノ基、エチルアミノ基等）；ジＣ１－６－アルキルアミノ基（ジメチルアミノ基、ジエチルアミノ基等）；アルコキシカルボニルアミノ基（メトキシカルボニルアミノ基、エトキシカルボニルアミノ基、ｔ－ブトキシカルボニルアミノ基等のＣ１－６－アルコキシカルボニルアミノ基等）；トリアルキルシリル基（トリメチルシリル基、トリエチルシリル基等）；ニトロ基等の１～６個が挙げられる。これらのなかでも、詳細には、Ｃ１－６－アルキル基、Ｃ３－８－シクロアルキル基、Ｃ１－６－アルコキシ基、Ｃ３－８－シクロアルコキシ基、Ｃ１－６－アルコキシカルボニル基、Ｃ３－８－シクロアルコキシカルボニル基、ハロゲン原子、Ｃ１－６－ハロゲン化アルキル基、Ｃ１－６－脂肪族アシル基、Ｃ１－６－アルコキシカルボニルアミノ基、ニトロ基等が好ましく、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔ－ブチル基、シクロペンチル基、シクロヘキシル基、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔ－ブトキシ基、シクロペンチルオキシ基、メトキシカルボニル基、エトキシカルボニル基、ｎ－プロポキシカルボニル基、イソプロポキシカルボニル基、ｎ－ブトキシカルボニル基、イソブトキシカルボニル基、ｓｅｃ－ブトキシカルボニル基、ｔ－ブトキシカルボニル基、シクロペンチルオキシカルボニル基、フッ素原子、塩素原子、臭素原子、ヨウ素原子、トリフルオロメチル基、ホルミル基、アセチル基、ｎ－プロピオニル基（ｎ－プロパノイル基）、ｎ－ブチリル基（ｎ－ブタノイル基）、ｎ－バレリル基（ｎ－ペンタノイル基）、ｎ－ヘキサノイル基、メトキシカルボニルアミノ基、エトキシカルボニルアミノ基、ｔ－ブトキシカルボニルアミノ基、ニトロ基等がより好ましく、メチル基、メトキシ基、メトキシカルボニル基、フッ素原子、トリフルオロメチル基、ホルミル基、ｔ－ブトキシカルボニルアミノ基、ニトロ基等がさらに好ましい。 In the substituent Ar 1 , examples of the substituent in the aromatic group include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n A C 1-6 -alkyl group or a C 3-8 -cycloalkyl group such as -pentyl group, isopentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; methoxy group, ethoxy group, n -Propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, cyclopropyloxy group, cyclobutyl A C 1-6 -alkoxy group such as an oxy group, a cyclopentyloxy group, a cyclohexyloxy group, or the like; C 3-8 -cycloalkoxy group; methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, t-butoxycarbonyl group N-pentyloxycarbonyl group, isopentyloxycarbonyl group, cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl group, cyclopentyloxycarbonyl group and the like alkoxycarbonyl group or cycloalkylcarbonyl group (especially C 1-6 -alkoxycarbonyl group) or C 3-8 - cycloalkoxy group), a hydroxyl group, a phenyl group, a tolyl group, an aromatic hydrocarbon group such as a naphthyl group; a fluorine atom, a chlorine atom, a bromine atom, a halogen atom such as an iodine atom; C 1-6, such as trifluoromethyl group - halogenated alkyl group; a benzyl group, aralkyl groups such as phenethyl group; formyl group, an acetyl group, n- propionyl group (n- propanoyl group), n- butyryl group (n- Butanoyl group), n-valeryl group (n-pentanoyl group), C 1-6 -aliphatic acyl group such as n-hexanoyl group; aromatic acyl group (aroyl group) such as benzoyl group and toluoyl group; aralkyloxy group (Benzyloxy group, phenethyloxy group, etc.); carboxy group; C 1-6 -alkylamino group (methylamino group, ethylamino group, etc.); di-C 1-6 -alkylamino group (dimethylamino group, diethylamino group, etc.) ); Alkoxycarbonylamino group (methoxycarbonylamino group, ethoxycarbonylamino group, t-butoxycarbonyl) A C 1-6 -alkoxycarbonylamino group such as a ruamino group); a trialkylsilyl group (trimethylsilyl group, triethylsilyl group, etc.); a nitro group and the like. Among these, in detail, a C 1-6 -alkyl group, a C 3-8 -cycloalkyl group, a C 1-6 -alkoxy group, a C 3-8 -cycloalkoxy group, a C 1-6 -alkoxycarbonyl Group, C 3-8 -cycloalkoxycarbonyl group, halogen atom, C 1-6 -halogenated alkyl group, C 1-6 -aliphatic acyl group, C 1-6 -alkoxycarbonylamino group, nitro group and the like are preferable. Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, cyclopentyl group, cyclohexyl group, methoxy group, ethoxy group, n-propoxy group, Isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group, cyclopentyloxy group, methoxycarbo Group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, t-butoxycarbonyl group, cyclopentyloxycarbonyl group, fluorine atom, chlorine Atom, bromine atom, iodine atom, trifluoromethyl group, formyl group, acetyl group, n-propionyl group (n-propanoyl group), n-butyryl group (n-butanoyl group), n-valeryl group (n-pentanoyl group) ), N-hexanoyl group, methoxycarbonylamino group, ethoxycarbonylamino group, t-butoxycarbonylamino group, nitro group, etc., more preferably methyl group, methoxy group, methoxycarbonyl group, fluorine atom, trifluoromethyl group, formyl Group, t-but Aryloxycarbonyl amino group, a nitro group are more preferable.
　このような条件を満たす置換基Ａｒ１で示される置換された芳香族基としては、例えば、トリル基（ｏ－トリル基、ｍ－トリル基、ｐ－トリル基等）、エチルフェニル基（４－エチルフェニル基、３－エチルフェニル基、２－エチルフェニル基等）、４－ｎ－プロピルフェニル基、イソプロピルフェニル基（４－イソプロピルフェニル基、２－イソプロピルフェニル基等）、４－ｎ－ブチルフェニル基、４－イソブチルフェニル基、ｓｅｃ－ブチルフェニル基（４－ｓｅｃ－ブチルフェニル基、２－ｓｅｃ－ブチルフェニル基等）、ｔ－ブチルフェニル基（４－ｔ－ブチルフェニル基、３－ｔ－ブチルフェニル基、２－ｔ－ブチルフェニル基等）、４－ｎ－ペンチルフェニル基、４－イソペンチルフェニル基、２－ネオペンチルフェニル基、４－ｔ－ペンチルフェニル基、４－ｎ－ヘキシルフェニル基、４－（２－エチルブチル）フェニル基、４－ｎ－ヘプチルフェニル基、４－ｎ－オクチルフェニル基、４－（２－エチルヘキシル）フェニル基、４－ｔ－オクチルフェニル基、４－ｎ－デシルフェニル基、４－ｎ－ドデシルフェニル基、４－ｎ－テトラデシルフェニル基、４－シクロペンチルフェニル基、シクロヘキシルフェニル基（４－シクロヘキシルフェニル基、３－シクロヘキシルフェニル基、２－シクロヘキシルフェニル基等）、４－（４－メチルシクロヘキシル）フェニル基、４－（４－ｔ－ブチルシクロヘキシル）フェニル基、４－エチル－１－ナフチル基、６－ｎ－ブチル－２－ナフチル基、ジメチルフェニル基（２，４－ジメチルフェニル基、２，５－ジメチルフェニル基、３，４－ジメチルフェニル基、３，５－ジメチルフェニル基、２，６－ジメチルフェニル基等）、トリメチルフェニル基（２，３，５－トリメチルフェニル基、２，３，６－トリメチルフェニル基、３，４，５－トリメチルフェニル基等）、ジエチルフェニル基（２，４－ジエチルフェニル基、２，６－ジエチルフェニル基等）、２，５－ジイソプロピルフェニル基、２，６－ジイソブチルフェニル基、ジ－ｔ－ブチルフェニル基（２，４－ジ－ｔ－ブチルフェニル基、２，５－ジ－ｔ－ブチルフェニル基等）、４，６－ジ－ｔ－ブチル－２－メチルフェニル基、５－ｔ－ブチル－２－メチルフェニル基、４－ｔ－ブチル－２，６－ジメチルフェニル基、９－メチル－２－フルオレニル基、９－エチル－２－フルオレニル基、９－ｎ－ヘキシル－２－フルオレニル基、９，９－ジメチル－２－フルオレニル基、９，９－ジエチル－２－フルオレニル基、９，９－ジ－ｎ－プロピル－２－フルオレニル基、メトキシフェニル基（４－メトキシフェニル基、３－メトキシフェニル基、２－メトキシフェニル基等）、エトキシフェニル基（４－エトキシフェニル基、３－エトキシフェニル基、２－エトキシフェニル基等）、ｎ－プロポキシフェニル基（４－ｎ－プロポキシフェニル基、３－ｎ－プロポキシフェニル基等）、イソプロポキシフェニル基（４－イソプロポキシフェニル基、２－イソプロポキシフェニル基等）、４－ｎ－ブトキシフェニル基、４－イソブトキシフェニル基、２－ｓｅｃ－ブトキシフェニル基、４－ｎ－ペンチルオキシフェニル基、イソペンチルオキシフェニル基（４－イソペンチルオキシフェニル基、２－イソペンチルオキシフェニル基等）、ネオペンチルオキシフェニル基（４－ネオペンチルオキシフェニル基、２－ネオペンチルオキシフェニル基等）、４－ｎ－ヘキシルオキシフェニル基、２－（２－エチルブチル）オキシフェニル基、４－ｎ－オクチルオキシフェニル基、４－ｎ－デシルオキシフェニル基、４－ｎ－ドデシルオキシフェニル基、４－ｎ－テトラデシルオキシフェニル基、シクロヘキシルオキシフェニル基（４－シクロヘキシルオキシフェニル基、２－シクロヘキシルオキシフェニル基等）、メトキシナフチル基（２－メトキシ－１－ナフチル基、４－メトキシ－１－ナフチル基、６－メトキシ－２－ナフチル基、７－メトキシ－２－ナフチル基等）、エトキシナフチル基（５－エトキシ－１－ナフチル基、６－エトキシ－２－ナフチル基等）、ｎ－ブトキシナフチル基（４－ｎ－ブトキシ－１－ナフチル基、６－ｎ－ブトキシ－２－ナフチル基、７－ｎ－ブトキシ－２－ナフチル基等）、６－ｎ－ヘキシルオキシ－２－ナフチル基、メチルメトキシフェニル基（２－メチル－４－メトキシフェニル基、２－メチル－５－メトキシフェニル基、３－メチル－４－メトキシフェニル基、３－メチル－５－メトキシフェニル基、２－メトキシ－４－メチルフェニル基、３－メトキシ－４－メチルフェニル基等）、３－エチル－５－メトキシフェニル基、ジメトキシフェニル基（２，４－ジメトキシフェニル基、２，５－ジメトキシフェニル基、２，６－ジメトキシフェニル基、３，４－ジメトキシフェニル基、３，５－ジメトキシフェニル基等）、３，５－ジエトキシフェニル基、３，５－ジ－ｎ－ブトキシフェニル基、メトキシエトキシフェニル基（２－メトキシ－４－エトキシフェニル基、２－メトキシ－６－エトキシフェニル基等）、３，４，５－トリメトキシフェニル基、ヒドロキシフェニル基（４－ヒドロキシフェニル基、３－ヒドロキシフェニル基、２－ヒドロキシフェニル基等）、ホルミルフェニル基（４－ホルミルフェニル基、３－ホルミルフェニル基、２－ホルミルフェニル基等）、メトキシカルボニルフェニル基（４－メトキシカルボニルフェニル基、３－メトキシカルボニルフェニル基、２－メトキシカルボニルフェニル基等）、ビフェニリル基（４－ビフェニリル基、３－ビフェニリル基、２－ビフェニリル基等）、トリルフェニル基（４－（ｐ－トリル）フェニル基、４－（ｍ－トリル）フェニル基、４－（ｐ－トリル）フェニル基、２－（ｏ－トリル）フェニル基等）、４－（４－ｎ－ブトキシフェニル）フェニル基、４－（４－クロロフェニル）フェニル基、３－メチル－４－フェニルフェニル基、３－メトキシ－４－フェニルフェニル基、ターフェニル基、３，５－ジフェニルフェニル基、１０－フェニル－９－アントリル基、１０－（３，５－ジフェニルフェニル）－９－アントリル基、９－フェニル－２－フルオレニル基、フルオロフェニル基（４－フルオロフェニル基、３－フルオロフェニル基、２－フルオロフェニル基等）、クロロフェニル基（４－クロロフェニル基、３－クロロフェニル基、２－クロロフェニル基等）、ブロモフェニル基（４－ブロモフェニル基、２－ブロモフェニル基等）、クロロナフチル基（４－クロロ－１－ナフチル基、４－クロロ－２－ナフチル基等）、６－ブロモ－２－ナフチル基、ジクロロフェニル基（２，３－ジクロロフェニル基、２，４－ジクロロフェニル基、２，５－ジクロロフェニル基、３，４－ジクロロフェニル基、３，５－ジクロロフェニル基等）、２，５－ジブロモフェニル基、２，４，６－トリクロロフェニル基、ジクロロナフチル基（２，４－ジクロロ－１－ナフチル基、１，６－ジクロロ－２－ナフチル基等）、クロロメチルフェニル基（２－クロロ－４－メチルフェニル基、２－クロロ－５－メチルフェニル基、２－クロロ－６－メチルフェニル基、３－クロロ－４－メチルフェニル基、２－メチル－３－クロロフェニル基、２－メチル－４－クロロフェニル基、３－メチル－４－クロロフェニル基等）、２－クロロ－４，６－ジメチルフェニル基、フルオロメトキシフェニル基（２－フルオロ－４－メトキシフェニル基、２－フルオロ－６－メトキシフェニル基、２－メトキシ－４－フルオロフェニル基等）、フルオロエトキシ基（２－フルオロ－４－エトキシフェニル基、３－フルオロ－４－エトキシフェニル基等）、クロロメトキシ基（３－クロロ－４－メトキシフェニル基、２－メトキシ－５－クロロフェニル基、３－メトキシ－６－クロロフェニル基等）、クロロジメトキシ基（５－クロロ－２，４－ジメトキシフェニル基等）、アセチルフェニル基（４－アセチルフェニル基等）、トリフルオロメチルフェニル基（４－トリフルオロメチルフェニル基等）、ジメチルアミノフェニル基（４－ジメチルアミノフェニル基等）、ｔ－ブトキシアミノフェニル基（４－（ｔ－ブトキシカルボニルアミノ）フェニル基等）、トリメチルシリルフェニル基（４－トリメチルシリルフェニル基等）、ベンジルオキシフェニル基（４－ベンジルオキシフェニル基等）、ニトロフェニル基（４－ニトロフェニル基等）等が挙げられるが、これらに限定されるものではない。 Examples of the substituted aromatic group represented by the substituent Ar 1 satisfying such conditions include, for example, a tolyl group (o-tolyl group, m-tolyl group, p-tolyl group, etc.), an ethylphenyl group (4- Ethylphenyl group, 3-ethylphenyl group, 2-ethylphenyl group, etc.), 4-n-propylphenyl group, isopropylphenyl group (4-isopropylphenyl group, 2-isopropylphenyl group, etc.), 4-n-butylphenyl Group, 4-isobutylphenyl group, sec-butylphenyl group (4-sec-butylphenyl group, 2-sec-butylphenyl group, etc.), t-butylphenyl group (4-t-butylphenyl group, 3-t- Butylphenyl group, 2-t-butylphenyl group, etc.), 4-n-pentylphenyl group, 4-isopentylphenyl group, 2-neopentylphenyl group, 4-t-pentylphenyl group, 4-n-hexylphenyl group, 4- (2-ethylbutyl) phenyl group, 4-n-heptylphenyl group, 4-n-octylphenyl group, 4- (2-ethylhexyl) phenyl Group, 4-t-octylphenyl group, 4-n-decylphenyl group, 4-n-dodecylphenyl group, 4-n-tetradecylphenyl group, 4-cyclopentylphenyl group, cyclohexylphenyl group (4-cyclohexylphenyl group) 3-cyclohexylphenyl group, 2-cyclohexylphenyl group, etc.), 4- (4-methylcyclohexyl) phenyl group, 4- (4-t-butylcyclohexyl) phenyl group, 4-ethyl-1-naphthyl group, 6- n-butyl-2-naphthyl group, dimethylphenyl group (2,4-dimethylphenyl group, 2,5-dimethyl group) Phenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 2,6-dimethylphenyl group, etc.), trimethylphenyl group (2,3,5-trimethylphenyl group, 2,3,6-trimethyl) Phenyl group, 3,4,5-trimethylphenyl group, etc.), diethylphenyl group (2,4-diethylphenyl group, 2,6-diethylphenyl group, etc.), 2,5-diisopropylphenyl group, 2,6-diisobutyl Phenyl group, di-t-butylphenyl group (2,4-di-t-butylphenyl group, 2,5-di-t-butylphenyl group, etc.), 4,6-di-t-butyl-2-methyl Phenyl group, 5-t-butyl-2-methylphenyl group, 4-t-butyl-2,6-dimethylphenyl group, 9-methyl-2-fluorenyl group, 9-ethyl-2-fluorenyl group, 9 n-hexyl-2-fluorenyl group, 9,9-dimethyl-2-fluorenyl group, 9,9-diethyl-2-fluorenyl group, 9,9-di-n-propyl-2-fluorenyl group, methoxyphenyl group ( 4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group, etc.), ethoxyphenyl group (4-ethoxyphenyl group, 3-ethoxyphenyl group, 2-ethoxyphenyl group, etc.), n-propoxyphenyl group ( 4-n-propoxyphenyl group, 3-n-propoxyphenyl group, etc.), isopropoxyphenyl group (4-isopropoxyphenyl group, 2-isopropoxyphenyl group, etc.), 4-n-butoxyphenyl group, 4-iso Butoxyphenyl group, 2-sec-butoxyphenyl group, 4-n-pentyloxyphenyl group, isopentyloxy Siphenyl group (4-isopentyloxyphenyl group, 2-isopentyloxyphenyl group, etc.), neopentyloxyphenyl group (4-neopentyloxyphenyl group, 2-neopentyloxyphenyl group, etc.), 4-n-hexyl Oxyphenyl group, 2- (2-ethylbutyl) oxyphenyl group, 4-n-octyloxyphenyl group, 4-n-decyloxyphenyl group, 4-n-dodecyloxyphenyl group, 4-n-tetradecyloxyphenyl Group, cyclohexyloxyphenyl group (4-cyclohexyloxyphenyl group, 2-cyclohexyloxyphenyl group, etc.), methoxynaphthyl group (2-methoxy-1-naphthyl group, 4-methoxy-1-naphthyl group, 6-methoxy-2) -Naphthyl group, 7-methoxy-2-naphthyl group, etc.), ethoxynaphth Group (5-ethoxy-1-naphthyl group, 6-ethoxy-2-naphthyl group, etc.), n-butoxynaphthyl group (4-n-butoxy-1-naphthyl group, 6-n-butoxy-2-naphthyl group) 7-n-butoxy-2-naphthyl group, etc.), 6-n-hexyloxy-2-naphthyl group, methylmethoxyphenyl group (2-methyl-4-methoxyphenyl group, 2-methyl-5-methoxyphenyl group) 3-methyl-4-methoxyphenyl group, 3-methyl-5-methoxyphenyl group, 2-methoxy-4-methylphenyl group, 3-methoxy-4-methylphenyl group, etc.), 3-ethyl-5-methoxy Phenyl group, dimethoxyphenyl group (2,4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group, 2,6-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, , 5-dimethoxyphenyl group, etc.), 3,5-diethoxyphenyl group, 3,5-di-n-butoxyphenyl group, methoxyethoxyphenyl group (2-methoxy-4-ethoxyphenyl group, 2-methoxy-6) -Ethoxyphenyl group, etc.), 3,4,5-trimethoxyphenyl group, hydroxyphenyl group (4-hydroxyphenyl group, 3-hydroxyphenyl group, 2-hydroxyphenyl group etc.), formylphenyl group (4-formylphenyl) Group, 3-formylphenyl group, 2-formylphenyl group, etc.), methoxycarbonylphenyl group (4-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 2-methoxycarbonylphenyl group, etc.), biphenylyl group (4-biphenylyl, etc.) Group, 3-biphenylyl group, 2-biphenylyl group, etc.), triruf Enyl groups (4- (p-tolyl) phenyl group, 4- (m-tolyl) phenyl group, 4- (p-tolyl) phenyl group, 2- (o-tolyl) phenyl group, etc.), 4- (4- n-butoxyphenyl) phenyl group, 4- (4-chlorophenyl) phenyl group, 3-methyl-4-phenylphenyl group, 3-methoxy-4-phenylphenyl group, terphenyl group, 3,5-diphenylphenyl group, 10-phenyl-9-anthryl group, 10- (3,5-diphenylphenyl) -9-anthryl group, 9-phenyl-2-fluorenyl group, fluorophenyl group (4-fluorophenyl group, 3-fluorophenyl group, 2-fluorophenyl group, etc.), chlorophenyl group (4-chlorophenyl group, 3-chlorophenyl group, 2-chlorophenyl group, etc.), bromophenyl group (4- Lomophenyl group, 2-bromophenyl group, etc.), chloronaphthyl group (4-chloro-1-naphthyl group, 4-chloro-2-naphthyl group, etc.), 6-bromo-2-naphthyl group, dichlorophenyl group (2,3 -Dichlorophenyl group, 2,4-dichlorophenyl group, 2,5-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group), 2,5-dibromophenyl group, 2,4,6-trichlorophenyl Group, dichloronaphthyl group (2,4-dichloro-1-naphthyl group, 1,6-dichloro-2-naphthyl group, etc.), chloromethylphenyl group (2-chloro-4-methylphenyl group, 2-chloro-5 -Methylphenyl group, 2-chloro-6-methylphenyl group, 3-chloro-4-methylphenyl group, 2-methyl-3-chlorophenyl group, 2- Til-4-chlorophenyl group, 3-methyl-4-chlorophenyl group, etc.), 2-chloro-4,6-dimethylphenyl group, fluoromethoxyphenyl group (2-fluoro-4-methoxyphenyl group, 2-fluoro-6) -Methoxyphenyl group, 2-methoxy-4-fluorophenyl group, etc.), fluoroethoxy group (2-fluoro-4-ethoxyphenyl group, 3-fluoro-4-ethoxyphenyl group etc.), chloromethoxy group (3-chloro -4-methoxyphenyl group, 2-methoxy-5-chlorophenyl group, 3-methoxy-6-chlorophenyl group, etc.), chlorodimethoxy group (5-chloro-2,4-dimethoxyphenyl group, etc.), acetylphenyl group (4 -Acetylphenyl group), trifluoromethylphenyl group (4-trifluoromethylphenyl group, etc.), di Methylaminophenyl group (such as 4-dimethylaminophenyl group), t-butoxyaminophenyl group (such as 4- (t-butoxycarbonylamino) phenyl group), trimethylsilylphenyl group (such as 4-trimethylsilylphenyl group), benzyloxyphenyl Examples include a group (such as 4-benzyloxyphenyl group) and a nitrophenyl group (such as 4-nitrophenyl group), but are not limited thereto.
　本発明において、置換基Ａｒ１の種類は特に制限はなく、前記の置換又は無置換の芳香族基のいずれでもよく、置換若しくは無置換の単環芳香族炭化水素基、置換若しくは無置換の縮合環芳香族炭化水素基、置換若しくは無置換の五員単環芳香族複素環式基等が好ましく、置換若しくは無置換の六員単環芳香族炭化水素基、置換若しくは無置換の二環芳香族炭化水素基、置換若しくは無置換の五員単環芳香族複素環式基等がより好ましく、フェニル基、トリル基（ｏ－トリル基、ｍ－トリル基、ｐ－トリル基等）、メトキシフェニル基（２－メトキシフェニル基、３－メトキシフェニル基、４－メトキシフェニル基等）、メトキシカルボニルフェニル基（４－メトキシカルボニルフェニル基、３－メトキシカルボニルフェニル基、２－メトキシカルボニルフェニル基等）、フルオロフェニル基（４－フルオロフェニル基、３－フルオロフェニル基、２－フルオロフェニル基等）、トリフルオロメチルフェニル基（４－トリフルオロメチルフェニル基等）、ｔ－ブトキシアミノフェニル基（４－（ｔ－ブトキシカルボニルアミノ）フェニル基等）、ニトロフェニル基（４－ニトロフェニル基等）、ナフチル基（１－ナフチル基、２－ナフチル基等）、チエニル基（２－チエニル基、３－チエニル基等）等がさらに好ましい。 In the present invention, the type of the substituent Ar 1 is not particularly limited, and may be any of the above-described substituted or unsubstituted aromatic groups, substituted or unsubstituted monocyclic aromatic hydrocarbon groups, substituted or unsubstituted condensed groups. Preferred are a ring aromatic hydrocarbon group, a substituted or unsubstituted 5-membered monocyclic aromatic heterocyclic group, etc., a substituted or unsubstituted 6-membered monocyclic aromatic hydrocarbon group, a substituted or unsubstituted bicyclic aromatic group More preferred are a hydrocarbon group, a substituted or unsubstituted 5-membered monocyclic aromatic heterocyclic group, etc., a phenyl group, a tolyl group (such as an o-tolyl group, an m-tolyl group, a p-tolyl group), a methoxyphenyl group. (2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, etc.), methoxycarbonylphenyl group (4-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 2-methoxy group) Sicarbonylphenyl group etc.), fluorophenyl group (4-fluorophenyl group, 3-fluorophenyl group, 2-fluorophenyl group etc.), trifluoromethylphenyl group (4-trifluoromethylphenyl group etc.), t-butoxy Aminophenyl group (4- (t-butoxycarbonylamino) phenyl group etc.), nitrophenyl group (4-nitrophenyl group etc.), naphthyl group (1-naphthyl group, 2-naphthyl group etc.), thienyl group (2- More preferred are thienyl group, 3-thienyl group and the like.
　一般式（８Ａ）において、Ｒ５及びＲ６で示されるアルキル基及びシクロアルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔ－ブチル基、ヘキシル基、シクロヘキシル基等のＣ１－８－アルキル基又はＣ３－８－シクロアルキル基等が採用できる。このアルキル基に置換し得る置換基としては、上記説明したＡｒ１に置換し得る置換基が挙げられる。置換基の数についても同様である。 In the general formula (8A), examples of the alkyl group and cycloalkyl group represented by R 5 and R 6 include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec- A C 1-8 -alkyl group such as a butyl group, a t-butyl group, a hexyl group or a cyclohexyl group, or a C 3-8 -cycloalkyl group can be employed. Examples of the substituent that can be substituted on the alkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
　また、一般式（８Ａ）において、Ｒ５及びＲ６がともにアルキル基及び／又はシクロアルキル基である場合、互いに結合して、隣接する－Ｏ－Ｂ－Ｏ－とともに環を形成してもよい。この場合、上記芳香族基含有ボロン酸又はそのエステル化合物は、例えば、 In the general formula (8A), when R 5 and R 6 are both an alkyl group and / or a cycloalkyl group, they may be bonded to each other to form a ring with the adjacent —O—B—O—. . In this case, the aromatic group-containing boronic acid or its ester compound is, for example,
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
［式中、Ａｒ１は前記に同じである。］
等が挙げられる。 [Wherein Ar 1 is the same as defined above. ]
Etc.
　なお、一般式（８Ａ）において、Ｒ５及びＲ６は、ともに水素原子であることが、生成物の収率及び経済的な観点から好ましい。 In the general formula (8A), it is preferable that R 5 and R 6 are both hydrogen atoms from the viewpoint of product yield and economical viewpoint.
　化合物（８Ａ）を使用する場合、その具体例としては、例えば、ジメチルエステル、ジエチルエステル、ジプロピルエステル、ジイソプロピルエステル、ジブチルエステル、ジヘキシルエステル、ジシクロヘキシルエステル、エチレングリコールエステル、プロピレングリコール（１，２－プロパンジオールエステル、１，３－プロパンジオールエステル）、トリメチレングリコールエステル、ネオペンチルグリコールエステル、ピナコールエステル、カテコールエステル、グリセリンエステル、トリメチロールエタンエステル、Ｎ－メチルイミノ二酢酸エステル等を挙げることができる。 When the compound (8A) is used, specific examples thereof include, for example, dimethyl ester, diethyl ester, dipropyl ester, diisopropyl ester, dibutyl ester, dihexyl ester, dicyclohexyl ester, ethylene glycol ester, propylene glycol (1,2- Propanediol ester, 1,3-propanediol ester), trimethylene glycol ester, neopentyl glycol ester, pinacol ester, catechol ester, glycerin ester, trimethylolethane ester, N-methyliminodiacetic acid ester and the like.
　芳香族基含有ボロン酸又はそのエステル化合物のなかでも、収率の観点から、芳香族基含有ボロン酸を使用することが好ましい。 Among the aromatic group-containing boronic acids or ester compounds thereof, it is preferable to use an aromatic group-containing boronic acid from the viewpoint of yield.
　一般式（８Ｂ）において、置換基Ａｒ１は、置換又は無置換の芳香族基であり、上記一般式（８Ａ）と同様のものを採用できる。置換基Ａｒ１における芳香族基、Ａｒ１が置換されている場合の置換基の種類及び数、Ａｒ１が置換されている場合の置換された芳香族基、それぞれの好ましい具体例等については、上記一般式（８Ａ）において詳述したものと同様のものを採用することができる。 In the general formula (8B), the substituent Ar 1 is a substituted or unsubstituted aromatic group, and the same as in the general formula (8A) can be adopted. Aromatic group in the substituent Ar 1, the type and number of substituents, if Ar 1 is substituted, the substituted aromatic group when Ar 1 is substituted, for each of the preferred embodiments or the like, The thing similar to what was explained in full detail in the said general formula (8A) is employable.
　以上の化合物（８Ａ）及び化合物（８Ｂ）は、１種単独で用いることができ、２種以上を組合せて用いることもできる。これらの化合物を２種以上使用する場合、例えば、化合物（８Ａ）のなかから２種を用いることもできるし、化合物（８Ｂ）のなかから２種を用いることもできるし、化合物（８Ａ）と化合物（８Ｂ）とを使用することもできる。ただし、工程をより簡便にする観点から、１種のみを使用することが好ましい。 The above compound (8A) and compound (8B) can be used individually by 1 type, and can also be used in combination of 2 or more type. When two or more of these compounds are used, for example, two of the compounds (8A) can be used, two of the compounds (8B) can be used, and the compound (8A) and Compound (8B) can also be used. However, it is preferable to use only 1 type from a viewpoint of making a process simpler.
　本工程において、化合物（８Ａ）及び化合物（８Ｂ）の使用量は、選択率及び収率の観点から、前記化合物（７）１モルに対して、通常、０．２～３モルが好ましく、０．３～２．５モルがより好ましい。なお、化合物（８Ａ）及び化合物（８Ｂ）のうち２種以上を使用する場合は、その合計量が上記範囲内となるように調整することが好ましい。 In this step, the amount of compound (8A) and compound (8B) to be used is generally preferably 0.2 to 3 mol per 1 mol of compound (7) from the viewpoints of selectivity and yield. More preferred is 3 to 2.5 mol. In addition, when using 2 or more types of a compound (8A) and a compound (8B), it is preferable to adjust so that the total amount may become in the said range.
　本工程で使用するパラジウム触媒としては、特に限定されるものではなく、例えば、酢酸パラジウム（Ｐｄ（ＯＣＯＣＨ３）２；Ｐｄ（ＯＡｃ）２）、トリフルオロ酢酸パラジウム（Ｐｄ（ＯＣＯＣＦ３）２）、ｐ－アリルパラジウム（II）クロリドダイマー（［ＰｄＣｌ（allyl）］２）、ｐ－シンナミルパラジウム（II）クロリドダイマー、ジ－μ－クロロビス（２’－アミノ－１，１’－ビフェニル－２－Ｃ，Ｎ）ジパラジウム（II）、塩化パラジウム（ＰｄＣｌ２）、臭化パラジウム（ＰｄＢｒ２）、ヨウ化パラジウム（ＰｄＩ２）、Ｐｄ（ＣＨ２ＣＯＣＨ２ＣＯＣＨ３）２、Ｋ２ＰｄＣｌ４、Ｋ２ＰｄＣｌ６、Ｋ２Ｐｄ（ＮＯ３）４、トリス（ジベンジリデンアセトン）ジパラジウム（0）、ビス（ジベンジリデンアセトン）パラジウム（0）、ジクロロビス（エチレン）パラジウム（ＰｄＣｌ２（Ｃ２Ｈ４）２）、ジクロロ（１，５－シクロオクタジエン）パラジウム（II）、２，５－ノルボルナジエンパラジウムジクロリド、ビス（アセトニトリル）パラジウムジクロリド、ビス（ベンゾニトリル）パラジウムジクロリド、Ｐｄ（π－Ｃ５Ｈ５）２等の有機配位子錯体；ＰｄＣｌ２（ＮＨ３）２、ＰｄＣｌ２［Ｎ（Ｃ２Ｈ５）３］ ２、Ｐｄ（ＮＯ３）２（ＮＨ３）６等のＮ－配位錯体等を挙げることができる。これらは単独で使用することができ、２種以上を組合せて用いることもできる。なかでも、本工程では、選択率、収率及び安全性の観点から、有機配位子錯体が好ましく、酢酸パラジウム（Ｐｄ（ＯＣＯＣＨ３）２）、ｐ－アリルパラジウム（II）クロリドダイマー、トリフロオロ酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム（0）、トリス(ジベンジリデンアセトン)ジパラジウム（0）等がより好ましく、酢酸パラジウム（Ｐｄ（ＯＣＯＣＨ３）２）がさらに好ましい。 The palladium catalyst used in this step is not particularly limited, and examples thereof include palladium acetate (Pd (OCOCH 3 ) 2 ; Pd (OAc) 2 ), palladium trifluoroacetate (Pd (OCOCF 3 ) 2 ), p-allyl palladium (II) chloride dimer ([PdCl (allyl)] 2 ), p-cinnamyl palladium (II) chloride dimer, di-μ-chlorobis (2′-amino-1,1′-biphenyl-2-) C, N) dipalladium (II), palladium chloride (PdCl 2 ), palladium bromide (PdBr 2 ), palladium iodide (PdI 2 ), Pd (CH 2 COCH 2 COCH 3 ) 2 , K 2 PdCl 4 , K 2 PdCl 6, K 2 Pd ( NO 3) 4, tris (dibenzylideneacetone) dipalladium (0), bis (Jibenjiri N'aseton) palladium (0), dichlorobis (ethylene) palladium (PdCl 2 (C 2 H 4 ) 2), dichloro (1,5-cyclooctadiene) palladium (II), 2,5-norbornadiene palladium dichloride, bis (acetonitrile ) Palladium dichloride, bis (benzonitrile) palladium dichloride, organic ligand complexes such as Pd (π-C 5 H 5 ) 2 ; PdCl 2 (NH 3 ) 2 , PdCl 2 [N (C 2 H 5 ) 3 ] 2 , N-coordination complexes such as Pd (NO 3 ) 2 (NH 3 ) 6 and the like. These can be used alone or in combination of two or more. Among these, organic ligand complexes are preferable in this step from the viewpoint of selectivity, yield, and safety. Palladium acetate (Pd (OCOCH 3 ) 2 ), p-allyl palladium (II) chloride dimer, trifluoroacetic acid Palladium, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like are more preferable, and palladium acetate (Pd (OCOCH 3 ) 2 ) is more preferable.
　本工程において、パラジウム触媒の使用量は、選択率及び収率の観点から、前記化合物（７）１モルに対して、通常、０．００１～１モルが好ましく、０．０１～０．２５モルがより好ましい。 In this step, the amount of the palladium catalyst used is usually preferably 0.001 to 1 mol, preferably 0.01 to 0.25 mol, relative to 1 mol of the compound (7), from the viewpoints of selectivity and yield. Is more preferable.
　本工程においては、選択率及び収率をより向上させる観点から、配位子を使用することが好ましい。この配位子は、あらかじめ上記パラジウム触媒に導入することもできるし、上記パラジウム触媒とともに系中に投入することもできる。 In this step, it is preferable to use a ligand from the viewpoint of further improving the selectivity and yield. This ligand can be introduced into the palladium catalyst in advance, or can be introduced into the system together with the palladium catalyst.
　本工程で使用し得る配位子としては、選択率及び収率の観点から、ホスフィン配位子が好ましい。本工程で使用できるホスフィン配位子としては、特に限定されるものではなく、例えば、次式：ＰＲ７Ｒ８Ｒ９で表されるホスフィン配位子（Ｒ７、Ｒ８及びＲ９は同一又は異なって、Ｃ１－８アルキル基（メチル基、エチル基、ｔ－ブチル基等）、Ｃ１－４アルコキシ基（メトキシ基、エトキシ基等）、Ｃ３－８シクロアルキル基（シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等）、フェニル基、ビフェニル基、フェノキシ基、又はフリル基を示す。前記Ｃ３－８シクロアルキル基は更にＣ１－４アルキル基（メチル基、エチル基等）で置換されていてもよい。前記フェニル基は更にメチル基、スルホン酸又はその塩で置換されていてもよい。前記ビフェニル基は更にそれぞれ独立して、Ｃ１－４アルキル基（メチル基、エチル基、イソプロピル基等）、Ｃ１－４アルコキシ基（メトキシ基、エトキシ基等）、ジアルキルアミノ基（ジメチルアミノ基、ジエチルアミノ基等）で置換されてもよい。）、ビス（ジフェニルホスフィノ）アルカン、ビス（ジアルキルホスフィノ）アルカン、ビス（ジフェニルホスフィノ）フェロセン等が挙げられる。 As a ligand which can be used at this process, a phosphine ligand is preferable from a viewpoint of a selectivity and a yield. The phosphine ligand that can be used in this step is not particularly limited. For example, the phosphine ligand represented by the following formula: PR 7 R 8 R 9 (R 7 , R 8, and R 9 are the same). Or, differently, a C 1-8 alkyl group (methyl group, ethyl group, t-butyl group etc.), C 1-4 alkoxy group (methoxy group, ethoxy group etc.), C 3-8 cycloalkyl group (cyclopropyl group) , cyclobutyl group, cyclopentyl group, cyclohexyl group), a phenyl group, a biphenyl group, a phenoxy group, or a furyl group. the C 3-8 cycloalkyl group further C 1-4 alkyl group (methyl group, ethyl group, etc. ) may be substituted with. the phenyl group may further methyl group, sulfonic acid or a salt thereof may be substituted. the biphenyl group is independently further respectively, C 1-4 Alkyl group (methyl group, an ethyl group, an isopropyl group, etc.), C 1-4 alkoxy group (methoxy group, ethoxy group, etc.), dialkylamino groups (dimethylamino group, diethylamino group, etc.) may be substituted with.) Examples thereof include bis (diphenylphosphino) alkane, bis (dialkylphosphino) alkane, bis (diphenylphosphino) ferrocene and the like.
　前記ＰＲ７Ｒ８Ｒ９で示されるホスフィン配位子としては、例えば、ｔ－ブチルジシクロヘキシルホスフィン、イソブチルジシクロヘキシルホスフィン、（ｎ－ブチル）ジシクロヘキシルホスフィン、イソプロピルジシクロヘキシルホスフィン、（ｎ－プロピル）ジシクロヘキシルホスフィン、エチルジシクロヘキシルホスフィン、メチルジシクロへキシルホスフィン、シクロプロピルジシクロヘキシルホスフィン、シクロブチルジシクロヘキシルホスフィン、ｔ－ブチルジシクロオクチルホスフィン、ｔ－ブチルジシクロヘプチルホスフィン、ｔ－ブチルジシクロペンチルホスフィン、ｔ－ブチルジシクロブチルホスフィン、ｔ－ブチルジシクロプロピルホスフィン、トリエチルホスフィン、トリ（ｎ－プロピル）ホスフィン、トリ（イソプロピル）ホスフィン、トリ（ｔ－ブチル）ホスフィン、トリ（ｎ－ブチル）ホスフィン、トリ（ｎ－オクチル）ホスフィン、トリ（シクロオクチル）ホスフィン、トリ（シクロヘプチル）ホスフィン、トリ（シクロヘキシル）ホスフィン、トリ（シクロペンチル）ホスフィン、トリ（シクロブチル）ホスフィン、トリ（シクロプロピル）ホスフィン、ジ（ｔ－ブチル）メチルホスフィン、ジ（ｔ－ブチル）エチルホスフィン、ジ（ｔ－ブチル）ｎ－プロピルホスフィン、ジ（ｔ－ブチル）イソプロピルホスフィン、ジ（ｔ－ブチル）ｎ－ブチルホスフィン、ジ（ｔ－ブチル）イソブチルホスフィン、ジ（ｔ－ブチル）ネオペンチルホスフィン、トリフェニルホスフィン、トリ（ｏ－トリル）ホスフィン、トリ－ｍ－トリルホスフィン、トリ－ｐ－トリルホスフィン、トリ（メシチル）ホスフィン、トリ（フェノキシ）ホスフイン、トリ－（２－フリル）ホスフィン、トリメトキシホスフィン、トリエトキシホスフィン、トリ（ｎ－プロピルオキシ）ホスフィン、トリ（イソプロピルオキシ）ホスフィン、トリ（ｎ－ブチルオキシ）ホスフィン、トリ（イソブチルオキシ）ホスフィン、トリ（ｔ－ブチルオキシ）ホスフィン、ジ（ｔ－ブチル）シクロヘキシルホスフィン、ジ（イソブチル）シクロヘキシルホスフィン、ジ（ｎ－ブチル）シクロヘキシルホスフィン、ジ（イソプロピル）シクロヘキシルホスフィン、ジ（ｎ－プロピル）シクロヘキシルホスフィン、ジエチルシクロヘキシルホスフィン、ジメチルシクロヘキシルホスフィン、ジ（ｔ－ブチル）シクロペンチルホスフィン、ジ（イソブチル）シクロペンチルホスフィン、ジ（ｎ－ブチル）シクロペンチルホスフィン、ジ（イソプロピル）シクロペンチルホスフィン、ジ（ｎ－プロピル）シクロペンチルホスフィン、ジエチルシクロペンチルホスフィン、ジメチルシクロペンチルホスフィン、ジ（ｔ－ブチル）シクロオクチルホスフィン、ジ（ｔ－ブチル）シクロヘプチルホスフィン、ジ（ｔ－ブチル）シクロペンチルホスフィン、ジ（ｔ－ブチル）シクロブチルホスフィン、ジ（ｔ－ブチル）シクロプロピルホスフィン、ジメチルフェニルホスフィン、ジエチルフェニルホスフィン、ジ（ｎ－プロピル）フェニルホスフィン、ジ（イソプロピル）フェニルホスフィン、ジ（ｎ－ブチル）フェニルホスフィン、ジ（イソブチル）フェニルホスフィン、ジ（ｔ－ブチル）フェニルホスフィン、ジシクロオクチルフェニルホスフィン、ジシクロヘプチルフェニルホスフィン、ジシクロヘキシルフェニルホスフィン、ジシクロペンチルフェニルホスフィン、ジシクロブチルフェニルホスフィン、ジシクロプロピルフェニルホスフィン、ジシクロヘキシル－（ｐ－トリル）－ホスフィン、ジシクロヘキシル－（ｏ－トリル）ホスフィン、ジシクロヘキシル－（ｐ－トリル）ホスフィン、ジシクロヘキシル－（２，４，６－トリメチルフェニル）ホスフィン、メチルジフェニルホスフィン、エチルジフェニルホスフィン、（ｎ－プロピル）ジフェニルホスフィン、イソプロピルジフェニルホスフィン、（ｎ－ブチル）ジフェニルホスフィン、イソブチルジフェニルホスフィン、（ｔ－ブチル）ジフェニルホスフィン、シクロオクチルジフェニルホスフィン、シクロヘプチルジフェニルホスフィン、シクロヘキシルジフェニルホスフィン、シクロペンチルジフェニルホスフィン、シクロブチルジフェニルホスフィン、シクロプロピルジフェニルホスフィン、ビス（ｐ－スルホナートフェニル）フェニルホスフィンカリウム、ｃＢＲＩＤＰ、ＢｉｐｐｙＰｈｏｓ、ＴｒｉｐｐｙＰｈｏｓ、ＸＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル；後述の実施例のＬ４）、ｔ－Ｂｕ－ＸＰｈｏｓ（２－ジ－ｔ－ブチルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル；後述の実施例のＬ３）、ＪｏｈｎＰｈｏｓ（２－（ジ－ｔ－ブチルホスフィノ）ビフェニル；後述の実施例のＬ１）、Ｃｙ－ＪｏｈｎＰｈｏｓ（２－（ジシクロヘキシルホスフィノ）ビフェニル；後述の実施例のＬ２）、ＭｅＰｈｏｓ、ｔ－Ｂｕ－ＭｅＰｈｏｓ、ＤａｖｅＰｈｏｓ、ｔ－Ｂｕ－ＤａｖｅＰｈｏｓ、ＳＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシ－１，１’－ビフェニル；後述の実施例のＬ５）、ＲｕＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，６’－ジイソプロポキシ－１，１’－ビフェニル）、ＣａｔａＣＸｉｕｍ　Ａ、ｃａｔａＣＸｉｕｍ　ＡＢｎ、ｃａｔａＣＸｉｕｍ　ＰｔＢ、ｃａｔａＣＸｉｕｍ　ＰＣｙ、ｃａｔａＣＸｉｕｍ　ＰＯＭｅｔＢ、ｃａｔａＣＸｉｕｍ　ＰＯＭｅＣｙ、ｃａｔａＣＸｉｕｍ　ＰＩｎｔＢ、ｃａｔａＣＸｉｕｍ　ＰＩｎＣｙ、ｃａｔａＣＸｉｕｍ　ＰＩＣｙ、Ｑ－Ｐｈｏｓ、ＪＯＳＩＰＨＯＳ等が挙げられる。 Examples of the phosphine ligand represented by PR 7 R 8 R 9 include t-butyldicyclohexylphosphine, isobutyldicyclohexylphosphine, (n-butyl) dicyclohexylphosphine, isopropyldicyclohexylphosphine, (n-propyl) dicyclohexylphosphine, and ethyl. Dicyclohexylphosphine, methyldicyclohexylphosphine, cyclopropyldicyclohexylphosphine, cyclobutyldicyclohexylphosphine, t-butyldicyclooctylphosphine, t-butyldicycloheptylphosphine, t-butyldicyclopentylphosphine, t-butyldicyclobutylphosphine, t -Butyldicyclopropylphosphine, triethylphosphine, tri (n-propyl) phosphine, tri ( Sopropyl) phosphine, tri (t-butyl) phosphine, tri (n-butyl) phosphine, tri (n-octyl) phosphine, tri (cyclooctyl) phosphine, tri (cycloheptyl) phosphine, tri (cyclohexyl) phosphine, tri ( Cyclopentyl) phosphine, tri (cyclobutyl) phosphine, tri (cyclopropyl) phosphine, di (t-butyl) methylphosphine, di (t-butyl) ethylphosphine, di (t-butyl) n-propylphosphine, di (t- Butyl) isopropylphosphine, di (t-butyl) n-butylphosphine, di (t-butyl) isobutylphosphine, di (t-butyl) neopentylphosphine, triphenylphosphine, tri (o-tolyl) phosphine, tri-m -Tolylphosphine, To Ri-p-tolylphosphine, tri (mesityl) phosphine, tri (phenoxy) phosphine, tri- (2-furyl) phosphine, trimethoxyphosphine, triethoxyphosphine, tri (n-propyloxy) phosphine, tri (isopropyloxy) Phosphine, tri (n-butyloxy) phosphine, tri (isobutyloxy) phosphine, tri (t-butyloxy) phosphine, di (t-butyl) cyclohexylphosphine, di (isobutyl) cyclohexylphosphine, di (n-butyl) cyclohexylphosphine, Di (isopropyl) cyclohexylphosphine, di (n-propyl) cyclohexylphosphine, diethylcyclohexylphosphine, dimethylcyclohexylphosphine, di (t-butyl) cyclopentylphosphine , Di (isobutyl) cyclopentylphosphine, di (n-butyl) cyclopentylphosphine, di (isopropyl) cyclopentylphosphine, di (n-propyl) cyclopentylphosphine, diethylcyclopentylphosphine, dimethylcyclopentylphosphine, di (t-butyl) cyclooctyl Phosphine, di (t-butyl) cycloheptylphosphine, di (t-butyl) cyclopentylphosphine, di (t-butyl) cyclobutylphosphine, di (t-butyl) cyclopropylphosphine, dimethylphenylphosphine, diethylphenylphosphine, di (N-propyl) phenylphosphine, di (isopropyl) phenylphosphine, di (n-butyl) phenylphosphine, di (isobutyl) phenylphosphine, di (t- Til) phenylphosphine, dicyclooctylphenylphosphine, dicycloheptylphenylphosphine, dicyclohexylphenylphosphine, dicyclopentylphenylphosphine, dicyclobutylphenylphosphine, dicyclopropylphenylphosphine, dicyclohexyl- (p-tolyl) -phosphine, dicyclohexyl- (O-tolyl) phosphine, dicyclohexyl- (p-tolyl) phosphine, dicyclohexyl- (2,4,6-trimethylphenyl) phosphine, methyldiphenylphosphine, ethyldiphenylphosphine, (n-propyl) diphenylphosphine, isopropyldiphenylphosphine, (N-butyl) diphenylphosphine, isobutyldiphenylphosphine, (t-butyl) diphenylphosphite , Cyclooctyldiphenylphosphine, cycloheptyldiphenylphosphine, cyclohexyldiphenylphosphine, cyclopentyldiphenylphosphine, cyclobutyldiphenylphosphine, cyclopropyldiphenylphosphine, bis (p-sulfonatephenyl) phenylphosphine potassium, cBRIDP, BippyPhos, TrippyPhos, XPhos ( 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl; L4 in Examples described later), t-Bu-XPhos (2-di-t-butylphosphino-2) ', 4', 6'-Triisopropyl-1,1'-biphenyl; L3) of Examples described later, John Phos (2- (di-t-butylphosphino) biphenyl; L1 of Examples described later), C -JohnPhos (2- (dicyclohexylphosphino) biphenyl; L2 in Examples described later), MePhos, t-Bu-MePhos, DavePhos, t-Bu-DavePhos, SPhos (2-dicyclohexylphosphino-2 ', 6'- Dimethoxy-1,1′-biphenyl; L5) of Examples described later, RuPhos (2-dicyclohexylphosphino-2 ′, 6′-diisopropoxy-1,1′-biphenyl), CataCXium A, cataCXium ABn, cataCXium PtB, dataCXium PCy, dataCXium POMeetB, dataCXium POMeCy, dataCXium PIntB, dataCXium PInCy, dataCXium PIcy, Q-Phos, JOSIPHOS, etc. Is mentioned.
　また、ビス（ジフェニルホスフィノ）アルカンとしては、例えば、ビス（ジフェニルホスフィノ）メタン、１，２－ビス（ジフェニルホスフィノ）エタン（ｄｐｐｅ）、１，３－ビス（ジフェニルホスフィノ）プロパン、１，４－ビス（ジフェニルホスフィノ）ブタン、１，５－ビス（ジフェニルホスフィノ）ペンタン、１，６－ビス（ジフェニルホスフィノ）ヘキサン等が挙げられ、ビス（ジアルキルホスフィノ）アルカンとしては、例えば、１，２－ビス（ジメチルホスフィノ）エタン等が挙げられ、ビス（ジフェニルホスフィノ）フェロセンとしては、例えば、１，１’－ビス（ジフェニルホスフィノ）フェロセン（ｄｐｐｆ）等が挙げられる。 Examples of the bis (diphenylphosphino) alkane include bis (diphenylphosphino) methane, 1,2-bis (diphenylphosphino) ethane (dppe), 1,3-bis (diphenylphosphino) propane, , 4-bis (diphenylphosphino) butane, 1,5-bis (diphenylphosphino) pentane, 1,6-bis (diphenylphosphino) hexane and the like. Examples of the bis (dialkylphosphino) alkane include 1,2-bis (dimethylphosphino) ethane and the like, and examples of the bis (diphenylphosphino) ferrocene include 1,1′-bis (diphenylphosphino) ferrocene (dppf) and the like.
　さらに、これらのホスフィン配位子は、ハロゲン原子（塩素原子等）、ＨＣｌ、ＨＦ、ＨＢｒ、ＨＩ、ＨＢＦ４等との塩である配位子前駆体として用いることもできる。これらは単独で使用することもでき、また、複数併用することもできる。 Furthermore, these phosphine ligands can also be used as ligand precursors which are salts with halogen atoms (such as chlorine atoms), HCl, HF, HBr, HI, HBF 4 and the like. These can be used alone or in combination.
　なかでも、本工程では、選択率、収率及び安全性の観点から、ＸＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル；後述の実施例のＬ４）、ＪｏｈｎＰｈｏｓ（２－（ジ－ｔ－ブチルホスフィノ）ビフェニル；後述の実施例のＬ１）、Ｃｙ－ＪｏｈｎＰｈｏｓ（２－（ジシクロヘキシルホスフィノ）ビフェニル；後述の実施例のＬ２）、ＳＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシ－１，１’－ビフェニル；後述の実施例のＬ５）等が好ましく、ＪｏｈｎＰｈｏｓ（２－（ジ－ｔ－ブチルホスフィノ）ビフェニル；後述の実施例のＬ１）、ＳＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシ－１，１’－ビフェニル；後述の実施例のＬ５）等がより好ましく、ＳＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシ－１，１’－ビフェニル；後述の実施例のＬ５）等がさらに好ましい。 In particular, in this step, XPhos (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl; examples described later) from the viewpoints of selectivity, yield and safety L4), JohnPhos (2- (di-t-butylphosphino) biphenyl; L1 in Examples described later), Cy-JohnPhos (2- (dicyclohexylphosphino) biphenyl; L2 in Examples described later), SPhos ( 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl; L5) of the examples described later is preferable, and JohnPhos (2- (di-t-butylphosphino) biphenyl; Example L1), SPhos (2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl; L5) and the like are more preferred for, SPhos (2-dicyclohexyl phosphino-2 ', 6'-dimethoxy-1,1'-biphenyl; L5) and the like described later in the Examples are more preferred.
　本工程において、配位子の使用量は、選択率及び収率の観点から、前記パラジウム触媒１モルに対して、通常、０．２～３モルが好ましく、０．３～２．５モルがより好ましい。 In this step, the amount of ligand used is usually preferably 0.2 to 3 mol, and preferably 0.3 to 2.5 mol with respect to 1 mol of the palladium catalyst, from the viewpoints of selectivity and yield. More preferred.
　本工程では、塩基を使用することが好ましい。つまり、工程（I）は、塩基の存在下で行われることが好ましい。本工程で使用できる塩基としては、例えば、カリウムｔ－ブトキシド、ナトリウムｔ－ブトキシド、リチウムｔ－ブトキシド等の金属アルコキシド；リン酸リチウム、リン酸ナトリウム、リン酸カリウム等のリン酸アルカリ金属塩；水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化セシウム等のアルカリ金属水酸化物；炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属塩；リチウムジイソプロピルアミド、リチウムビス（トリメチルシリル）アミド、ナトリウムビス（トリメチルシリル）アミド、カリウムビス（トリメチルシリル）アミド等の金属アミド；トリエチルアミン、ジアザビシクロウンデセン、１，４－ジアザビシクロ［２．２．２］オクタン等のアミン等が挙げられる。これらは単独で使用することもできるし、２種以上を組合せて使用することもできる。なかでも、本工程では、選択率、収率及び安全性の観点から、炭酸アルカリ金属塩が好ましく、炭酸ナトリウムがより好ましい。 In this step, it is preferable to use a base. That is, step (I) is preferably performed in the presence of a base. Examples of the base that can be used in this step include metal alkoxides such as potassium t-butoxide, sodium t-butoxide and lithium t-butoxide; alkali metal phosphates such as lithium phosphate, sodium phosphate and potassium phosphate; water Alkali metal hydroxides such as lithium oxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; Alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; Lithium diisopropylamide, lithium bis (trimethylsilyl) amide Metal amides such as sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide; amines such as triethylamine, diazabicycloundecene and 1,4-diazabicyclo [2.2.2] octane. These can be used alone or in combination of two or more. Among these, in this step, an alkali metal carbonate is preferable and sodium carbonate is more preferable from the viewpoints of selectivity, yield, and safety.
　本工程において、塩基を使用する場合、塩基の使用量は、選択率及び収率の観点から、前記化合物（７）１モルに対して、通常、０．５～４モルが好ましく、１～３モルがより好ましい。 In this step, when a base is used, the amount of the base used is preferably 0.5 to 4 mol, preferably 1 to 3 mol per 1 mol of the compound (7) from the viewpoints of selectivity and yield. Mole is more preferred.
　本工程は、通常、反応溶媒下で行われる。使用できる反応溶媒としては、例えば、１，４－ジオキサン、テトラヒドロフラン、エチレングリコールジメチルエーテル、エチレングリコールジエチルエーテル、ジエチレングリコールジメチルエーテル、ジイソプロピルエーテル、ジイソブチルエーテル、シクロペンチルメチルエーテル（ＣＰＭＥ）等のエーテル溶媒；ベンゼン、トルエン、ｏ－キシレン、ｍ－キシレン、ｐ－キシレン、混合キシレン、メシチレン等の芳香族炭化水素溶媒等の有機溶媒を用いることが好ましい。これらは単独で使用することもでき、また、複数併用することもできる。また、これらの有機溶媒と、水との混合溶媒（混合比は有機溶媒：水＝１：９９～９９：１が好ましい）を用いることもできる。なかでも、選択率、収率及び安全性の観点から、エーテル溶媒と水との混合溶媒が好ましく、１，４－ジオキサンと水との混合溶媒がより好ましい。 This step is usually performed in a reaction solvent. Usable reaction solvents include, for example, ether solvents such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diisopropyl ether, diisobutyl ether, cyclopentyl methyl ether (CPME); benzene, toluene, It is preferable to use an organic solvent such as an aromatic hydrocarbon solvent such as o-xylene, m-xylene, p-xylene, mixed xylene, and mesitylene. These can be used alone or in combination. A mixed solvent of these organic solvents and water (mixing ratio is preferably organic solvent: water = 1: 99 to 99: 1) can also be used. Among these, from the viewpoint of selectivity, yield, and safety, a mixed solvent of an ether solvent and water is preferable, and a mixed solvent of 1,4-dioxane and water is more preferable.
　これらの反応溶媒（有機溶媒）の使用量は、反応が進行する限り特に限定されるものではない。 The amount of these reaction solvents (organic solvents) used is not particularly limited as long as the reaction proceeds.
　本工程の反応温度は、使用する反応溶媒の沸点等によっても異なる。通常室温（２５℃）～３００℃程度、特に３０～１５０℃程度、さらに４０～１００℃程度の反応温度で実施することが好ましい。また、本工程は通常、不活性ガス（例えば、窒素、アルゴン、ヘリウム等）気流下で実施することが好ましい。また、反応は、常圧で実施することもでき、また、必要に応じて、減圧又は加圧条件下で実施することも可能であり、なかでも、常圧下で実施することが好ましい。反応時間は、特に制限はなく、反応が十分に進行する時間とすることができる。 The reaction temperature in this step varies depending on the boiling point of the reaction solvent used. Usually, it is preferably carried out at a reaction temperature of about room temperature (25 ° C.) to about 300 ° C., particularly about 30 to 150 ° C., and further about 40 to 100 ° C. Moreover, it is preferable to implement this process normally under inert gas (for example, nitrogen, argon, helium etc.) airflow. In addition, the reaction can be carried out at normal pressure, and can be carried out under reduced pressure or pressurized conditions as necessary. Among them, it is preferable to carry out under normal pressure. There is no restriction | limiting in particular in reaction time, It can be set as time for reaction to fully advance.
　反応の進行は、クロマトグラフィーのような通常の方法で追跡することができる。反応終了後、溶媒を留去し、生成物はクロマトグラフィー法、再結晶法等の通常の方法で生成物である（ヘテロ）アリールアセトニトリル化合物を単離精製することができる。また、生成物の構造は、元素分析、ＭＳ（ＦＤ－ＭＳ）分析、ＩＲ分析、１Ｈ－ＮＭＲ、１３Ｃ－ＮＭＲ等により同定することができる。 The progress of the reaction can be followed by conventional methods such as chromatography. After completion of the reaction, the solvent is distilled off, and the product can be isolated and purified by the usual methods such as chromatography and recrystallization. The structure of the product can be identified by elemental analysis, MS (FD-MS) analysis, IR analysis, 1 H-NMR, 13 C-NMR and the like.
　また、本工程で合成される（ヘテロ）アリールアセトニトリル化合物は、精製処理を施さずに次の工程（工程（II））に用いることもでき、必要に応じて、活性炭処理、再結晶、カラムクロマトグラフィー等の通常の精製方法により精製することも可能である。 In addition, the (hetero) aryl acetonitrile compound synthesized in this step can be used in the next step (step (II)) without being subjected to purification treatment, and if necessary, activated carbon treatment, recrystallization, column chromatography. It is also possible to purify by a usual purification method such as chromatography.
　このようにして得られる（ヘテロ）アリールアセトニトリル化合物は、一般式（４）：
Ａｒ１－ＣＨ２－ＣＮ　　　（４）
［式中、Ａｒ１は前記に同じである。］
で表される化合物である。 The (hetero) aryl acetonitrile compound thus obtained has the general formula (4):
Ar 1 —CH 2 —CN (4)
[Wherein Ar 1 is the same as defined above. ]
It is a compound represented by these.
　２．工程（II）：（ヘテロ）アリールアセトニトリル化合物の（ヘテロ）アリール化
　本工程では、
（II）一般式（４）：
Ａｒ１－ＣＨ２－ＣＮ　　　（４）
［式中、Ａｒ１は前記に同じである。］
で表される（ヘテロ）アリールアセトニトリル化合物（以下、「化合物（４）」と言うこともある）と、
一般式（５）：
Ａｒ２Ｘ２　　　（５）
［式中、Ａｒ２は置換又は無置換の芳香族基を示す。Ｘ２はハロゲン原子を示す。］
で表されるハロゲン化芳香族化合物（以下、「化合物（５）」と言うこともある）とを、パラジウム触媒の存在下で反応させる工程
により、ジ（ヘテロ）アリールアセトニトリル化合物を合成することができる。 2. Step (II): (Hetero) arylation of (hetero) arylacetonitrile compound In this step,
(II) General formula (4):
Ar 1 —CH 2 —CN (4)
[Wherein Ar 1 is the same as defined above. ]
A (hetero) arylacetonitrile compound represented by the formula (hereinafter also referred to as “compound (4)”),
General formula (5):
Ar 2 X 2 (5)
[Wherein Ar 2 represents a substituted or unsubstituted aromatic group. X 2 represents a halogen atom. ]
A di (hetero) arylacetonitrile compound can be synthesized by a step of reacting a halogenated aromatic compound represented by the formula (hereinafter also referred to as “compound (5)”) in the presence of a palladium catalyst. it can.
　化合物（４）は、前記工程（I）で合成することができる化合物であり、種々様々な化合物を採用することができる。また、一般式（４）におけるＡｒ１は、置換又は無置換の芳香族基であり、上記一般式（８Ａ）と同様のものを採用できる。置換基Ａｒ１における芳香族基、Ａｒ１が置換されている場合の置換基の種類及び数、Ａｒ１が置換されている場合の置換された芳香族基、それぞれの好ましい具体例等については、上記一般式（８Ａ）において詳述したものと同様のものを採用することができる。 Compound (4) is a compound that can be synthesized in the step (I), and various compounds can be employed. Moreover, Ar < 1 > in General formula (4) is a substituted or unsubstituted aromatic group, and can employ | adopt the thing similar to the said general formula (8A). Aromatic group in the substituent Ar 1, the type and number of substituents, if Ar 1 is substituted, the substituted aromatic group when Ar 1 is substituted, for each of the preferred embodiments or the like, The thing similar to what was explained in full detail in the said general formula (8A) is employable.
　一般式（５）において、置換基Ａｒ２は、置換又は無置換の芳香族基である。一般式（５）において、置換基Ａｒ２における芳香族基、Ａｒ２が置換されている場合の置換基の種類及び数、Ａｒ２が置換されている場合の置換された芳香族基としては、上記Ａｒ１について詳述したものと同様のものを採用することができる。 In the general formula (5), the substituent Ar 2 is a substituted or unsubstituted aromatic group. In the general formula (5), as the substituted aromatic group if aromatic groups, the kind and number of substituents, if Ar 2 is substituted, Ar 2 is substituted in the substituent Ar 2, it can be employed the same ones as described in detail above Ar 1.
　置換基Ａｒ２は、最終生成物であるトリ（ヘテロ）アリールアセトニトリル化合物が有する（ヘテロ）アリール基（芳香族基）のうち１つを構成しており、種々様々な芳香族基を採用することができる。本反応の選択率及び収率の観点から、置換若しくは無置換の単環芳香族炭化水素基、又は置換若しくは無置換の単環芳香族複素環式基が好ましく、置換若しくは無置換の六員単環芳香族炭化水素基、又は置換若しくは無置換の五員単環芳香族複素環式基がより好ましく、フェニル基、トリル基（ｏ－トリル基、ｍ－トリル基、ｐ－トリル基等）、メトキシフェニル基（２－メトキシフェニル基、３－メトキシフェニル基、４－メトキシフェニル基等）、フルオロフェニル基（２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基等）、トリフロオロメチルフェニル基（２－トリフロオロメチルフェニル基、３－トリフロオロメチルフェニル基、４－トリフロオロメチルフェニル基等）、チエニル基（２－チエニル基、３－チエニル基等）等がさらに好ましい。 Substituent Ar 2 constitutes one of the (hetero) aryl groups (aromatic groups) of the tri (hetero) aryl acetonitrile compound that is the final product, and employs various aromatic groups. Can do. From the viewpoint of the selectivity and yield of this reaction, a substituted or unsubstituted monocyclic aromatic hydrocarbon group or a substituted or unsubstituted monocyclic aromatic heterocyclic group is preferred, and a substituted or unsubstituted six-membered single-membered aromatic group is preferred. A cyclic aromatic hydrocarbon group or a substituted or unsubstituted 5-membered monocyclic aromatic heterocyclic group is more preferable, and a phenyl group, a tolyl group (o-tolyl group, m-tolyl group, p-tolyl group, etc.), Methoxyphenyl group (2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, etc.), fluorophenyl group (2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, etc.), trifluoro Oromethylphenyl group (2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, etc.), thienyl group (2-thienyl group, - a thienyl group, etc.) and the like are more preferred.
　一般式（５）において、Ｘ２はハロゲン原子であり、フッ素原子、塩素原子、臭素原子及びヨウ素原子が挙げられる。これらのなかでも、本工程における選択性及び収率の観点から、臭素原子及びヨウ素原子が好ましく、特に臭素原子が好ましい。 In the general formula (5), X 2 is a halogen atom, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among these, from the viewpoint of selectivity and yield in this step, a bromine atom and an iodine atom are preferable, and a bromine atom is particularly preferable.
　本工程において、化合物（５）の使用量は、選択率及び収率の観点から、化合物（４）１モルに対して、通常、０．２～３モルが好ましく、１～２．５モルがより好ましい。 In this step, the amount of compound (5) to be used is generally preferably 0.2 to 3 mol, preferably 1 to 2.5 mol, relative to 1 mol of compound (4), from the viewpoints of selectivity and yield. More preferred.
　本工程で使用するパラジウム触媒としては、特に限定されるものではなく、例えば、酢酸パラジウム（Ｐｄ（ＯＣＯＣＨ３）２；Ｐｄ（ＯＡｃ）２）、トリフルオロ酢酸パラジウム（Ｐｄ（ＯＣＯＣＦ３）２）、ｐ－アリルパラジウム（II）クロリドダイマー（［ＰｄＣｌ（allyl）］２）、ｐ－シンナミルパラジウム（II）クロリドダイマー、ジ－μ－クロロビス（２’－アミノ－１，１’－ビフェニル－２－Ｃ，Ｎ）ジパラジウム（II）、塩化パラジウム（ＰｄＣｌ２）、臭化パラジウム（ＰｄＢｒ２）、ヨウ化パラジウム（ＰｄＩ２）、Ｐｄ（ＣＨ２ＣＯＣＨ２ＣＯＣＨ３）２、Ｋ２ＰｄＣｌ４、Ｋ２ＰｄＣｌ６、Ｋ２Ｐｄ（ＮＯ３）４、トリス（ジベンジリデンアセトン）ジパラジウム（0）、ビス（ジベンジリデンアセトン）パラジウム（0）、ジクロロビス（エチレン）パラジウム（ＰｄＣｌ２（Ｃ２Ｈ４）２）、ジクロロ（１，５－シクロオクタジエン）パラジウム（II）、２，５－ノルボルナジエンパラジウムジクロリド、ビス（アセトニトリル）パラジウムジクロリド、ビス（ベンゾニトリル）パラジウムジクロリド、Ｐｄ（π－Ｃ５Ｈ５）２等の有機配位子錯体；ＰｄＣｌ２（ＮＨ３）２、ＰｄＣｌ２［Ｎ（Ｃ２Ｈ５）３］ ２、Ｐｄ（ＮＯ３）２（ＮＨ３）６等のＮ－配位錯体等を挙げることができる。これらは単独で使用することもでき、２種以上を組合せて用いることもできる。 The palladium catalyst used in this step is not particularly limited, and examples thereof include palladium acetate (Pd (OCOCH 3 ) 2 ; Pd (OAc) 2 ), palladium trifluoroacetate (Pd (OCOCF 3 ) 2 ), p-allyl palladium (II) chloride dimer ([PdCl (allyl)] 2 ), p-cinnamyl palladium (II) chloride dimer, di-μ-chlorobis (2′-amino-1,1′-biphenyl-2-) C, N) dipalladium (II), palladium chloride (PdCl 2 ), palladium bromide (PdBr 2 ), palladium iodide (PdI 2 ), Pd (CH 2 COCH 2 COCH 3 ) 2 , K 2 PdCl 4 , K 2 PdCl 6, K 2 Pd ( NO 3) 4, tris (dibenzylideneacetone) dipalladium (0), bis (Jibenjiri N'aseton) palladium (0), dichlorobis (ethylene) palladium (PdCl 2 (C 2 H 4 ) 2), dichloro (1,5-cyclooctadiene) palladium (II), 2,5-norbornadiene palladium dichloride, bis (acetonitrile ) Palladium dichloride, bis (benzonitrile) palladium dichloride, organic ligand complexes such as Pd (π-C 5 H 5 ) 2 ; PdCl 2 (NH 3 ) 2 , PdCl 2 [N (C 2 H 5 ) 3 ] 2 , N-coordination complexes such as Pd (NO 3 ) 2 (NH 3 ) 6 and the like. These can be used alone or in combination of two or more.
　なかでも、本工程では、選択率、収率及び安全性の観点から、有機配位子錯体が好ましく、酢酸パラジウム（Ｐｄ（ＯＣＯＣＨ３）２）、ｐ－アリルパラジウム（II）クロリドダイマー、トリフルオロ酢酸パラジウム、トリス(ジベンジリデンアセトン)ジパラジウム（0）、ビス（ジベンジリデンアセトン）パラジウム（0）等がより好ましく、酢酸パラジウム（Ｐｄ（ＯＣＯＣＨ３）２）がさらに好ましい。 Among these, organic ligand complexes are preferable in this step from the viewpoint of selectivity, yield, and safety, and palladium acetate (Pd (OCOCH 3 ) 2 ), p-allyl palladium (II) chloride dimer, trifluoro Palladium acetate, tris (dibenzylideneacetone) dipalladium (0), bis (dibenzylideneacetone) palladium (0) and the like are more preferable, and palladium acetate (Pd (OCOCH 3 ) 2 ) is more preferable.
　本工程において、パラジウム触媒の使用量は、選択率及び収率の観点から、前記化合物（４）１モルに対して、通常、０．０２～１モルが好ましく、０．０３～０．２５モルがより好ましい。 In this step, the amount of the palladium catalyst used is usually preferably from 0.02 to 1 mol, preferably from 0.03 to 0.25 mol, based on 1 mol of the compound (4), from the viewpoints of selectivity and yield. Is more preferable.
　本工程においては、選択率及び収率をより向上させる観点から、配位子を使用することが好ましい。この配位子は、あらかじめ上記パラジウム触媒に導入することもできるし、上記パラジウム触媒とともに系中に投入することもできる。 In this step, it is preferable to use a ligand from the viewpoint of further improving the selectivity and yield. This ligand can be introduced into the palladium catalyst in advance, or can be introduced into the system together with the palladium catalyst.
　本工程で使用し得る配位子としては、選択率及び収率の観点から、ホスフィン配位子が好ましい。本工程で使用できるホスフィン配位子としては、特に限定されるものではなく、例えば、トリ（シクロアルキル）ホスフィン、アルキルジ（シクロアルキルホスフィン）、ジ（アルキル）シクロアルキルホスフィン、トリ（アルキル）ホスフィン、トリ（アルコキシ）ホスフィン、アルキルジアダマンチルホスフィン、一般式（６）： The ligand that can be used in this step is preferably a phosphine ligand from the viewpoint of selectivity and yield. The phosphine ligand that can be used in this step is not particularly limited, and examples thereof include tri (cycloalkyl) phosphine, alkyldi (cycloalkylphosphine), di (alkyl) cycloalkylphosphine, tri (alkyl) phosphine, Tri (alkoxy) phosphine, alkyldiadamantylphosphine, general formula (6):
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
［式中、Ｒ１及びＲ２は同一又は異なって、置換若しくは無置換のアルキル基、又は置換若しくは無置換のシクロアルキル基を示す。Ｒは置換若しくは無置換のアルキル基、置換若しくは無置換のアルコキシ基、又は－ＰＲ３Ｒ４（Ｒ３及びＲ４は同一又は異なって、置換若しくは無置換のアルキル基、又は置換若しくは無置換のシクロアルキル基を示す）で示される基を示す。ｎは０～３の整数を示す。］
で表される配位子等が挙げられる。なお、ビフェニル基又はその誘導体基を有する配位子を使用すると、選択率及び収率に優れるが、フェニル基又はその誘導体基を有する配位子は選択率及び収率に劣るため使用しないことが好ましい。 [Wherein, R 1 and R 2 are the same or different and each represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group. R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or —PR 3 R 4 (R 3 and R 4 are the same or different, and are substituted or unsubstituted alkyl groups, or substituted or unsubstituted Represents a cycloalkyl group). n represents an integer of 0 to 3. ]
The ligand etc. which are represented by these are mentioned. In addition, when a ligand having a biphenyl group or a derivative group thereof is used, the selectivity and yield are excellent. However, a ligand having a phenyl group or a derivative group thereof is inferior in the selectivity and yield, so it should not be used. preferable.
　トリ（シクロアルキル）ホスフィンとしては、例えば、シクロプロピルジシクロヘキシルホスフィン、シクロブチルジシクロヘキシルホスフィン、トリ（シクロオクチル）ホスフィン、トリ（シクロヘプチル）ホスフィン、トリ（シクロヘキシル）ホスフィン、トリ（シクロペンチル）ホスフィン、トリ（シクロブチル）ホスフィン、トリ（シクロプロピル）ホスフィン等が挙げられる。 Examples of tri (cycloalkyl) phosphine include cyclopropyldicyclohexylphosphine, cyclobutyldicyclohexylphosphine, tri (cyclooctyl) phosphine, tri (cycloheptyl) phosphine, tri (cyclohexyl) phosphine, tri (cyclopentyl) phosphine, and tri (cyclobutyl). ) Phosphine, tri (cyclopropyl) phosphine, and the like.
　アルキルジ（シクロアルキルホスフィン）としては、例えば、ｔ－ブチルジシクロヘキシルホスフィン、イソブチルジシクロヘキシルホスフィン、（ｎ－ブチル）ジシクロヘキシルホスフィン、イソプロピルジシクロヘキシルホスフィン、（ｎ－プロピル）ジシクロヘキシルホスフィン、エチルジシクロヘキシルホスフィン、メチルジシクロへキシルホスフィン、ｔ－ブチルジシクロオクチルホスフィン、ｔ－ブチルジシクロヘプチルホスフィン、ｔ－ブチルジシクロペンチルホスフィン、ｔ－ブチルジシクロブチルホスフィン、ｔ－ブチルジシクロプロピルホスフィン等が挙げられる。 Examples of the alkyldi (cycloalkylphosphine) include t-butyldicyclohexylphosphine, isobutyldicyclohexylphosphine, (n-butyl) dicyclohexylphosphine, isopropyldicyclohexylphosphine, (n-propyl) dicyclohexylphosphine, ethyldicyclohexylphosphine, methyldicyclohexylphosphine, Examples thereof include t-butyldicyclooctylphosphine, t-butyldicycloheptylphosphine, t-butyldicyclopentylphosphine, t-butyldicyclobutylphosphine, t-butyldicyclopropylphosphine, and the like.
　ジ（アルキル）シクロアルキルホスフィンとしては、例えば、ジ（ｔ－ブチル）シクロヘキシルホスフィン、ジ（イソブチル）シクロヘキシルホスフィン、ジ（ｎ－ブチル）シクロヘキシルホスフィン、ジ（イソプロピル）シクロヘキシルホスフィン、ジ（ｎ－プロピル）シクロヘキシルホスフィン、ジエチルシクロヘキシルホスフィン、ジメチルシクロヘキシルホスフィン、ジ（ｔ－ブチル）シクロペンチルホスフィン、ジ（イソブチル）シクロペンチルホスフィン、ジ（ｎ－ブチル）シクロペンチルホスフィン、ジ（イソプロピル）シクロペンチルホスフィン、ジ（ｎ－プロピル）シクロペンチルホスフィン、ジエチルシクロペンチルホスフィン、ジメチルシクロペンチルホスフィン、ジ（ｔ－ブチル）シクロオクチルホスフィン、ジ（ｔ－ブチル）シクロヘプチルホスフィン、ジ（ｔ－ブチル）シクロペンチルホスフィン、ジ（ｔ－ブチル）シクロブチルホスフィン、ジ（ｔ－ブチル）シクロプロピルホスフィン等が挙げられる。 Examples of di (alkyl) cycloalkylphosphine include di (t-butyl) cyclohexylphosphine, di (isobutyl) cyclohexylphosphine, di (n-butyl) cyclohexylphosphine, di (isopropyl) cyclohexylphosphine, and di (n-propyl). Cyclohexylphosphine, diethylcyclohexylphosphine, dimethylcyclohexylphosphine, di (t-butyl) cyclopentylphosphine, di (isobutyl) cyclopentylphosphine, di (n-butyl) cyclopentylphosphine, di (isopropyl) cyclopentylphosphine, di (n-propyl) cyclopentyl Phosphine, diethylcyclopentylphosphine, dimethylcyclopentylphosphine, di (t-butyl) cyclooctylphosphine, di t-butyl) cycloheptyl phosphine, di (t-butyl) cyclopentyl phosphine, di (t-butyl) cycloalkyl-butylphosphine, di (t-butyl) cyclopropyl phosphine, and the like.
　トリ（アルキル）ホスフィンとしては、例えば、トリエチルホスフィン、トリ（ｎ－プロピル）ホスフィン、トリ（イソプロピル）ホスフィン、トリ（ｎ－ブチル）ホスフィン、トリ（ｎ－オクチル）ホスフィン、ジ（ｔ－ブチル）メチルホスフィン、ジ（ｔ－ブチル）メチルホスフィン、ジ（ｔ－ブチル）エチルホスフィン、ジ（ｔ－ブチル）ｎ－プロピルホスフィン、ジ（ｔ－ブチル）イソプロピルホスフィン、ジ（ｔ－ブチル）ｎ－ブチルホスフィン、ジ（ｔ－ブチル）イソブチルホスフィン、ジ（ｔ－ブチル）ネオペンチルホスフィン等が挙げられる。ただし、トリ（ｔ－ブチル）ホスフィンを使用した場合、副生成物としてトリ（ヘテロ）アリールアセトニトリル化合物も、ジ（ヘテロ）アリールアセトニトリル化合物と同程度得られやすい。このため、導入する芳香族基の制御をより容易にする観点からは、トリ（ｔ－ブチル）ホスフィン以外のホスフィン配位子が好ましい。 Examples of tri (alkyl) phosphine include triethylphosphine, tri (n-propyl) phosphine, tri (isopropyl) phosphine, tri (n-butyl) phosphine, tri (n-octyl) phosphine, and di (t-butyl) methyl. Phosphine, di (t-butyl) methylphosphine, di (t-butyl) ethylphosphine, di (t-butyl) n-propylphosphine, di (t-butyl) isopropylphosphine, di (t-butyl) n-butylphosphine , Di (t-butyl) isobutylphosphine, di (t-butyl) neopentylphosphine, and the like. However, when tri (t-butyl) phosphine is used, a tri (hetero) arylacetonitrile compound is easily obtained as a by-product to the same extent as a di (hetero) arylacetonitrile compound. Therefore, a phosphine ligand other than tri (t-butyl) phosphine is preferable from the viewpoint of easier control of the aromatic group to be introduced.
　トリ（アルコキシ）ホスフィンとしては、例えば、トリメトキシホスフィン、トリエトキシホスフィン、トリ（ｎ－プロピルオキシ）ホスフィン、トリ（イソプロピルオキシ）ホスフィン、トリ（ｎ－ブチルオキシ）ホスフィン、トリ（イソブチルオキシ）ホスフィン、トリ（ｔ－ブチルオキシ）ホスフィン等が挙げられる。 Examples of the tri (alkoxy) phosphine include trimethoxyphosphine, triethoxyphosphine, tri (n-propyloxy) phosphine, tri (isopropyloxy) phosphine, tri (n-butyloxy) phosphine, tri (isobutyloxy) phosphine, tri And (t-butyloxy) phosphine.
　アルキルジアダマンチルホスフィンとしては、例えば、ｎ－ブチルジアダマンチルホスフィン等が挙げられる。 Examples of the alkyldiadamantylphosphine include n-butyldiadamantylphosphine.
　なお、配位子として、ビナフチル骨格を有する配位子を使用した場合には、本工程でフェニル基を導入しようとする場合には副生成物は生成しないが、フェニル基以外の芳香族基を導入しようとする場合には、目的の芳香族基が導入された化合物と、フェニル基が導入された副生成物とが生成されやすい。このため、ビナフチル骨格を有する配位子は使用しないことが好ましい。 In addition, when a ligand having a binaphthyl skeleton is used as a ligand, no by-product is produced when a phenyl group is to be introduced in this step, but an aromatic group other than a phenyl group is formed. In the case of introduction, a compound in which a target aromatic group is introduced and a by-product in which a phenyl group is introduced are likely to be produced. For this reason, it is preferable not to use a ligand having a binaphthyl skeleton.
　一般式（６）において、Ｒ１及びＲ２で示されるアルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔ－ブチル基、ヘキシル基等のＣ１－８－アルキル基等が採用できる。このアルキル基に置換し得る置換基としては、上記説明したＡｒ１に置換し得る置換基が挙げられる。置換基の数についても同様である。 In the general formula (6), examples of the alkyl group represented by R 1 and R 2 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, t A C 1-8 -alkyl group such as -butyl group or hexyl group can be employed. Examples of the substituent that can be substituted on the alkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
　一般式（６）において、Ｒ１及びＲ２で示されるシクロアルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等のＣ３－８－シクロアルキル基等が採用できる。このシクロアルキル基に置換し得る置換基としては、上記説明したＡｒ１に置換し得る置換基が挙げられる。置換基の数についても同様である。 In the general formula (6), examples of the cycloalkyl group represented by R 1 and R 2 include C 3-8 -cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the substituent that can be substituted on the cycloalkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
　なかでも、Ｒ１及びＲ２としては、選択率及び収率の観点から、置換又は無置換のシクロアルキル基が好ましく、無置換のシクロアルキル基がより好ましく、シクロヘキシル基がさらに好ましい。 Among these, as R 1 and R 2 , a substituted or unsubstituted cycloalkyl group is preferable, an unsubstituted cycloalkyl group is more preferable, and a cyclohexyl group is more preferable from the viewpoint of selectivity and yield.
　一般式（６）において、Ｒで示されるアルキル基としては、上記Ｒ１及びＲ２と同様の基を採用し得る。このアルキル基に置換し得る置換基としては、上記説明したＡｒ１に置換し得る置換基が挙げられる。置換基の数についても同様である。 In the general formula (6), as the alkyl group represented by R, the same groups as those for R 1 and R 2 can be adopted. Examples of the substituent that can be substituted on the alkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
　一般式（６）において、Ｒで示されるアルコキシ基としては、例えば、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔ－ブトキシ基、ヘキトキシ基等のＣ１－８－アルコキシ基等が採用できる。このアルコキシ基に置換し得る置換基としては、上記説明したＡｒ１に置換し得る置換基が挙げられる。置換基の数についても同様である。 In the general formula (6), examples of the alkoxy group represented by R include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a t-butoxy group. Further, a C 1-8 -alkoxy group such as a hexoxy group can be employed. Examples of the substituent that can be substituted on the alkoxy group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
　一般式（６）の－ＰＲ３Ｒ４で表される基において、Ｒ３及びＲ４で示されるアルキル基及びシクロアルキル基としては、上記Ｒ１及びＲ２と同様の基を採用し得る。このアルキル基及びシクロアルキル基に置換し得る置換基としては、上記説明したＡｒ１に置換し得る置換基が挙げられる。置換基の数についても同様である。 In the group represented by —PR 3 R 4 in the general formula (6), as the alkyl group and cycloalkyl group represented by R 3 and R 4 , the same groups as those for R 1 and R 2 can be adopted. Examples of the substituent that can be substituted on the alkyl group and cycloalkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
　なかでも、Ｒとしては、選択率及び収率の観点から、－ＰＲ３Ｒ４で表される基が好ましく、－ＰＲ３Ｒ４（Ｒ３及びＲ４は同一又は異なって、それぞれ置換又は無置換のシクロアルキル基）で表される基がより好ましく、－ＰＲ３Ｒ４（Ｒ３及びＲ４は同一又は異なって、それぞれ無置換のシクロアルキル基）で表される基がさらに好ましく、－ＰＣｙ２（Ｃｙはシクロヘキシル基を示す。以下同様である）が特に好ましい。 Among them, R is preferably a group represented by —PR 3 R 4 from the viewpoint of selectivity and yield, and —PR 3 R 4 (R 3 and R 4 are the same or different and each represents a substituted or unsubstituted group. More preferably a group represented by -PR 3 R 4 (wherein R 3 and R 4 are the same or different, each being an unsubstituted cycloalkyl group), PCy 2 (Cy represents a cyclohexyl group; the same shall apply hereinafter) is particularly preferred.
　一般式（６）において、ｎはＲの数であり、０～３の整数のいずれも採用し得る。なかでも、選択率及び収率の観点から、１又は２が好ましく、１がより好ましい。 In the general formula (6), n is the number of R, and any integer of 0 to 3 can be adopted. Especially, 1 or 2 is preferable from a viewpoint of a selectivity and a yield, and 1 is more preferable.
　このような一般式（６）で表される配位子としては、例えば、ＸＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル）、ｔ－Ｂｕ－ＸＰｈｏｓ（２－ジ－ｔ－ブチルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル；後述の実施例のＬ３）、ＪｏｈｎＰｈｏｓ（２－（ジ－ｔ－ブチルホスフィノ）ビフェニル；後述の実施例のＬ１）、Ｃｙ－ＪｏｈｎＰｈｏｓ（２－（ジシクロヘキシルホスフィノ）ビフェニル；後述の実施例のＬ２）、ＭｅＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’－メチルビフェニル）、ｔ－Ｂｕ－ＭｅＰｈｏｓ、ＳＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシ－１，１’－ビフェニル；後述の実施例のＬ４）、ＲｕＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，６’－ジイソプロポキシ－１，１’－ビフェニル）等が挙げられる。 Examples of the ligand represented by the general formula (6) include XPhos (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl), t- Bu-XPhos (2-di-t-butylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl; L3 in Examples described later), JohnPhos (2- (di-t- Butylphosphino) biphenyl; L1) in the examples described later, Cy-JohnPhos (2- (dicyclohexylphosphino) biphenyl; L2 in the examples described later), MePhos (2-dicyclohexylphosphino-2′-methylbiphenyl), t-Bu-MePhos, SPhos (2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl; Of L4), RuPhos (2- dicyclohexyl phosphino-2 ', include 6'-diisopropoxy-1,1'-biphenyl) or the like.
　また、一般式（６）で表される配位子としては、一般式（６ａ）： Moreover, as a ligand represented by the general formula (6), the general formula (6a):
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
［式中、Ｒ１ｂ、Ｒ１ｃ、Ｒ２ｂ及びＲ２ｃは同一又は異なって、アルキル基又はシクロアルキル基（特にシクロアルキル基）を示す。］
で表される配位子（以下、「配位子（６ａ）」と言うこともある）を使用することもできる。この配位子（６ａ）の合成方法は後述する。 [Wherein, R 1b , R 1c , R 2b and R 2c are the same or different and each represents an alkyl group or a cycloalkyl group (particularly a cycloalkyl group). ]
(Hereinafter, also referred to as “ligand (6a)”) can be used. A method for synthesizing this ligand (6a) will be described later.
　これらの配位子のなかでも、選択性及び収率の観点から、トリ（シクロアルキル）ホスフィン、トリ（アルキル）ホスフィン（ただし、トリ（ｔ－ブチル）ホスフィンは除く）、アルキルジアダマンチルホスフィン、一般式（６）で表される配位子等が好ましく、トリシクロアルキルホスフィン、ジ（ｔ－ブチル）メチルホスフィン、ｎ－ブチルジアダマンチルホスフィン、一般式（６）で示される配位子等がより好ましく、トリシクロヘキシルホスフィン、ジ（ｔ－ブチル）メチルホスフィン、ｔ－Ｂｕ－ＸＰｈｏｓ（２－ジ－ｔ－ブチルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル；後述の実施例のＬ３）、ＪｏｈｎＰｈｏｓ（２－（ジ－ｔ－ブチルホスフィノ）ビフェニル；後述の実施例のＬ１）、Ｃｙ－ＪｏｈｎＰｈｏｓ（２－（ジシクロヘキシルホスフィノ）ビフェニル；後述の実施例のＬ２）、ＳＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシ－１，１’－ビフェニル；後述の実施例のＬ４）、配位子（６ａ）がさらに好ましく、トリシクロヘキシルホスフィン、ジ（ｔ－ブチル）メチルホスフィン、Ｃｙ－ＪｏｈｎＰｈｏｓ（２－（ジシクロヘキシルホスフィノ）ビフェニル；後述の実施例のＬ２）、ＳＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシ－１，１’－ビフェニル；後述の実施例のＬ４）、等配位子（６ａ）が特に好ましい。前記特に好ましい配位子のなかでも、ジ（ｔ－ブチル）メチルホスフィン、ＳＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシ－１，１’－ビフェニル；後述の実施例のＬ４）、配位子（６ａ）等が好ましく、配位子（６ａ）が最も好ましい。 Among these ligands, from the viewpoint of selectivity and yield, tri (cycloalkyl) phosphine, tri (alkyl) phosphine (except tri (t-butyl) phosphine), alkyldiadamantylphosphine, general A ligand represented by the formula (6) is preferable, and a tricycloalkylphosphine, di (t-butyl) methylphosphine, n-butyldiadamantylphosphine, a ligand represented by the general formula (6), and the like are more preferable. Preferably, tricyclohexylphosphine, di (t-butyl) methylphosphine, t-Bu-XPhos (2-di-t-butylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl; L3) of Examples described later, John Phos (2- (di-t-butylphosphino) biphenyl; L1 of Examples described later), C -JohnPhos (2- (dicyclohexylphosphino) biphenyl; L2 in Examples below), SPhos (2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl; L4 in Examples below) Further, the ligand (6a) is more preferable, and tricyclohexylphosphine, di (t-butyl) methylphosphine, Cy-JohnPhos (2- (dicyclohexylphosphino) biphenyl; L2 in Examples described later), SPhos (2-dicyclohexyl) Phosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl; L4) in the examples described later, and equiligand (6a) are particularly preferred. Among the particularly preferred ligands, di (t-butyl) methylphosphine, SPhos (2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl; L4 in Examples described later), A ligand (6a) etc. are preferable and a ligand (6a) is the most preferable.
　本工程において、配位子の使用量は、選択率及び収率の観点から、前記パラジウム触媒１モルに対して、通常、０．０１～３モルが好ましく、０．１～２．５モルがより好ましい。 In this step, the amount of ligand used is usually preferably from 0.01 to 3 mol, preferably from 0.1 to 2.5 mol, based on 1 mol of the palladium catalyst, from the viewpoints of selectivity and yield. More preferred.
　本工程では、塩基を使用することが好ましい。つまり、工程（II）は、塩基の存在下で行われることが好ましい。本工程で使用できる塩基としては、例えば、カリウムｔ－ブトキシド、ナトリウムｔ－ブトキシド、リチウムｔ－ブトキシド等の金属アルコキシド；リン酸リチウム、リン酸ナトリウム、リン酸カリウム等のリン酸アルカリ金属塩；水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化セシウム等のアルカリ金属水酸化物；炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の炭酸アルカリ金属塩；リチウムジイソプロピルアミド、リチウムビス（トリメチルシリル）アミド、ナトリウムビス（トリメチルシリル）アミド、カリウムビス（トリメチルシリル）アミド等の金属アミド；トリエチルアミン、ジアザビシクロウンデセン、１，４－ジアザビシクロ［２．２．２］オクタン等のアミン等が挙げられる。これらは単独で使用することもできるし、２種以上を組合せて使用することもできる。なかでも、本工程では、選択率、収率及び安全性の観点から、リン酸アルカリ金属塩が好ましく、リン酸カリウムがより好ましい。 In this step, it is preferable to use a base. That is, step (II) is preferably performed in the presence of a base. Examples of the base that can be used in this step include metal alkoxides such as potassium t-butoxide, sodium t-butoxide and lithium t-butoxide; alkali metal phosphates such as lithium phosphate, sodium phosphate and potassium phosphate; water Alkali metal hydroxides such as lithium oxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; Alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; Lithium diisopropylamide, lithium bis (trimethylsilyl) amide Metal amides such as sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide; amines such as triethylamine, diazabicycloundecene and 1,4-diazabicyclo [2.2.2] octane. These can be used alone or in combination of two or more. Among these, in this step, from the viewpoints of selectivity, yield, and safety, an alkali metal phosphate is preferable, and potassium phosphate is more preferable.
　本工程において、塩基を使用する場合、塩基の使用量は、選択率及び収率の観点から、前記化合物（４）１モルに対して、通常、０．５～１０モルが好ましく、１～５モルがより好ましい。 In this step, when a base is used, the amount of the base used is preferably 0.5 to 10 mol, preferably 1 to 5 mol per 1 mol of the compound (4) from the viewpoints of selectivity and yield. Mole is more preferred.
　本工程は、通常、反応溶媒下で行われる。使用できる反応溶媒としては、例えば、１，４－ジオキサン、テトラヒドロフラン、エチレングリコールジメチルエーテル、エチレングリコールジエチルエーテル、ジエチレングリコールジメチルエーテル、ジイソプロピルエーテル、ジイソブチルエーテル、シクロペンチルメチルエーテル（ＣＰＭＥ）等のエーテル溶媒；ベンゼン、トルエン、ｏ－キシレン、ｍ－キシレン、ｐ－キシレン、混合キシレン、メシチレン等の芳香族炭化水素溶媒等の有機溶媒を用いることが好ましい。これらは単独で使用することもでき、また、複数併用することもできる。なかでも、選択率、収率及び安全性の観点から、エーテル溶媒が好ましく、１，４－ジオキサンがより好ましい。 This step is usually performed in a reaction solvent. Usable reaction solvents include, for example, ether solvents such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diisopropyl ether, diisobutyl ether, cyclopentyl methyl ether (CPME); benzene, toluene, It is preferable to use an organic solvent such as an aromatic hydrocarbon solvent such as o-xylene, m-xylene, p-xylene, mixed xylene, and mesitylene. These can be used alone or in combination. Of these, ether solvents are preferable and 1,4-dioxane is more preferable from the viewpoints of selectivity, yield, and safety.
　これらの反応溶媒（有機溶媒）の使用量は、反応が進行する限り特に限定されるものではない。 The amount of these reaction solvents (organic solvents) used is not particularly limited as long as the reaction proceeds.
　本工程の反応温度は、使用する反応溶媒の沸点等によっても異なる。通常室温（２５℃）～３００℃程度、特に４０～１５０℃程度、さらに６０～１２０℃程度の反応温度で実施することが好ましい。また、本工程は通常、不活性ガス（例えば、窒素、アルゴン、ヘリウム等）気流下で実施することが好ましい。また、反応は、常圧で実施することもでき、また、必要に応じて、減圧又は加圧条件下で実施することも可能であり、なかでも、常圧下で実施することが好ましい。反応時間は、特に制限はなく、反応が十分に進行する時間とすることができる。 The reaction temperature in this step varies depending on the boiling point of the reaction solvent used. Usually, the reaction is preferably carried out at a reaction temperature of about room temperature (25 ° C.) to about 300 ° C., particularly about 40 to 150 ° C., and further about 60 to 120 ° C. Moreover, it is preferable to implement this process normally under inert gas (for example, nitrogen, argon, helium etc.) airflow. In addition, the reaction can be carried out at normal pressure, and can be carried out under reduced pressure or pressurized conditions as necessary. Among them, it is preferable to carry out under normal pressure. There is no restriction | limiting in particular in reaction time, It can be set as time for reaction to fully advance.
　反応の進行は、クロマトグラフィーのような通常の方法で追跡することができる。反応終了後、溶媒を留去し、生成物はクロマトグラフィー法、再結晶法等の通常の方法で生成物であるジ（ヘテロ）アリールアセトニトリル化合物を単離精製することができる。また、生成物の構造は、元素分析、ＭＳ（ＦＤ－ＭＳ）分析、ＩＲ分析、１Ｈ－ＮＭＲ、１３Ｃ－ＮＭＲ等により同定することができる。 The progress of the reaction can be followed by conventional methods such as chromatography. After completion of the reaction, the solvent is distilled off, and the product can be isolated and purified as a product di (hetero) arylacetonitrile compound by a usual method such as chromatography or recrystallization. The structure of the product can be identified by elemental analysis, MS (FD-MS) analysis, IR analysis, 1 H-NMR, 13 C-NMR and the like.
　また、本工程で合成されるジ（ヘテロ）アリールアセトニトリル化合物は、精製処理を施さずに次の工程（工程（III））に用いることもでき、必要に応じて、活性炭処理、再結晶、カラムクロマトグラフィー等の通常の精製方法により精製することも可能である。 In addition, the di (hetero) arylacetonitrile compound synthesized in this step can be used in the next step (step (III)) without performing purification treatment, and if necessary, activated carbon treatment, recrystallization, column It can also be purified by ordinary purification methods such as chromatography.
　このようにして得られる（ヘテロ）アリールアセトニトリル化合物は、一般式（２）： The (hetero) arylacetonitrile compound thus obtained has the general formula (2):
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
［式中、Ａｒ１及びＡｒ２は前記に同じである。］
で表される化合物である。 [Wherein, Ar 1 and Ar 2 are the same as defined above. ]
It is a compound represented by these.
　３．工程（III）：ジ（ヘテロ）アリールアセトニトリル化合物の（ヘテロ）アリール化
　本工程では、
（III）一般式（２）： 3. Step (III): (Hetero) arylation of di (hetero) arylacetonitrile compound In this step,
(III) General formula (2):
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
［式中、Ａｒ１及びＡｒ２は前記に同じである。］
で示されるジ（ヘテロ）アリールアセトニトリル化合物（以下、「化合物（２）」と言うこともある）と、
一般式（３）：
Ａｒ３Ｘ３　　　（３）
［式中、Ａｒ３は置換又は無置換の芳香族基を示す。Ｘ３はハロゲン原子を示す。］
で表されるハロゲン化芳香族化合物（以下、「化合物（３）」と言うこともある）とを、
パラジウム触媒の存在下に反応させる工程
により、目的化合物であるトリ（ヘテロ）アリールアセトニトリル化合物を合成する。 [Wherein, Ar 1 and Ar 2 are the same as defined above. ]
A di (hetero) arylacetonitrile compound represented by formula (hereinafter also referred to as “compound (2)”),
General formula (3):
Ar 3 X 3 (3)
[Wherein Ar 3 represents a substituted or unsubstituted aromatic group. X 3 represents a halogen atom. ]
A halogenated aromatic compound represented by the following (hereinafter also referred to as “compound (3)”),
The target compound, tri (hetero) arylacetonitrile compound, is synthesized by the reaction in the presence of a palladium catalyst.
　化合物（２）は、前記工程（II）で合成することができる化合物であり、種々様々な化合物を採用することができる。また、一般式（２）におけるＡｒ１及びＡｒ２は、前記説明したものを挙げることができる。好ましい具体例も同様である。 Compound (2) is a compound that can be synthesized in the step (II), and various compounds can be adopted. Further, Ar 1 and Ar 2 in the general formula (2) can include those described above. The same applies to preferred embodiments.
　一般式（３）において、置換基Ａｒ３は、置換又は無置換の芳香族基である。一般式（３）において、置換基Ａｒ３における芳香族基、Ａｒ３が置換されている場合の置換基の種類及び数、並びにＡｒ３が置換されている場合の置換された芳香族基としては、上記Ａｒ１について詳述したものと同様のものを採用することができる。 In the general formula (3), the substituent Ar 3 is a substituted or unsubstituted aromatic group. In the general formula (3), as the substituted aromatic group if aromatic groups, the kind and number of substituents, if Ar 3 is substituted, and Ar 3 is substituted in the substituent Ar 3 A thing similar to that described in detail for Ar 1 can be employed.
　置換基Ａｒ３は、最終生成物であるトリ（ヘテロ）アリールアセトニトリル化合物が有する（ヘテロ）アリール基（芳香族基）のうち１つを構成しており、種々様々な芳香族基を採用することができる。本反応の選択率及び収率の観点から、置換若しくは無置換の単環芳香族炭化水素基、置換若しくは無置換の単環芳香族複素環式基、置換若しくは無置換の縮合環芳香族複素環式基等が好ましく、置換若しくは無置換の六員単環芳香族炭化水素基、置換若しくは無置換の五又は六員単環芳香族複素環式基、置換若しくは無置換の二環芳香族複素環式基等がより好ましく、フェニル基、トリル基（ｏ－トリル基、ｍ－トリル基、ｐ－トリル基等）、メトキシフェニル基（２－メトキシフェニル基、３－メトキシフェニル基、４－メトキシフェニル基等）、ホルミルフェニル基（４－ホルミルフェニル基、３－ホルミルフェニル基、２－ホルミルフェニル基等）、メトキシカルボニルフェニル基（４－メトキシカルボニルフェニル基、３－メトキシカルボニルフェニル基、２－メトキシカルボニルフェニル基等）、フルオロフェニル基（２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基等）、トリフロオロメチルフェニル基（２－トリフロオロメチルフェニル基、３－トリフロオロメチルフェニル基、４－トリフロオロメチルフェニル基等）、ジメチルアミノフェニル基（４－ジメチルアミノフェニル基等）、チエニル基（２－チエニル基、３－チエニル基等）、ピリジル基（２－ピリジル基、３－ピリジル基、４－ピリジル基等）、インドリル基等がさらに好ましい。 Substituent Ar 3 constitutes one of the (hetero) aryl groups (aromatic groups) of the tri (hetero) aryl acetonitrile compound, which is the final product, and employs various aromatic groups. Can do. From the viewpoint of selectivity and yield of this reaction, a substituted or unsubstituted monocyclic aromatic hydrocarbon group, a substituted or unsubstituted monocyclic aromatic heterocyclic group, a substituted or unsubstituted condensed ring aromatic heterocyclic ring A substituted or unsubstituted 6-membered monocyclic aromatic hydrocarbon group, a substituted or unsubstituted 5- or 6-membered monocyclic aromatic heterocyclic group, a substituted or unsubstituted bicyclic aromatic heterocycle And more preferably a phenyl group, a tolyl group (o-tolyl group, m-tolyl group, p-tolyl group, etc.), a methoxyphenyl group (2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl) Group), formylphenyl group (4-formylphenyl group, 3-formylphenyl group, 2-formylphenyl group, etc.), methoxycarbonylphenyl group (4-methoxycarbonylphenyl group, 3-methoxy). Sulfonylphenyl group, 2-methoxycarbonylphenyl group, etc.), fluorophenyl group (2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, etc.), trifluoromethylphenyl group (2-trifluoromethyl group, etc.) Phenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, etc.), dimethylaminophenyl group (4-dimethylaminophenyl group, etc.), thienyl group (2-thienyl group, 3-thienyl group, etc.) ), A pyridyl group (2-pyridyl group, 3-pyridyl group, 4-pyridyl group, etc.), an indolyl group, and the like are more preferable.
　一般式（３）において、Ｘ３はハロゲン原子であり、フッ素原子、塩素原子、臭素原子及びヨウ素原子が挙げられる。これらのなかでも、本工程における選択性及び収率の観点から、臭素原子及びヨウ素原子が好ましく、特にヨウ素原子が好ましい。 In the general formula (3), X 3 is a halogen atom, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among these, from the viewpoints of selectivity and yield in this step, a bromine atom and an iodine atom are preferable, and an iodine atom is particularly preferable.
　本工程において、化合物（３）の使用量は、選択率及び収率の観点から、化合物（２）１モルに対して、通常、０．２～３モルが好ましく、１～２．５モルがより好ましい。 In this step, the amount of compound (3) to be used is preferably 0.2 to 3 mol, preferably 1 to 2.5 mol, relative to 1 mol of compound (2), from the viewpoints of selectivity and yield. More preferred.
　本工程で使用するパラジウム触媒としては、特に限定されるものではなく、例えば、酢酸パラジウム（Ｐｄ（ＯＣＯＣＨ３）２；Ｐｄ（ＯＡｃ）２）、トリフルオロ酢酸パラジウム（Ｐｄ（ＯＣＯＣＦ３）２）、ｐ－アリルパラジウム（II）クロリドダイマー（［ＰｄＣｌ（allyl）］２）、ｐ－シンナミルパラジウム（II）クロリドダイマー、ジ－μ－クロロビス（２’－アミノ－１，１’－ビフェニル－２－Ｃ，Ｎ）ジパラジウム（II）、塩化パラジウム（ＰｄＣｌ２）、臭化パラジウム（ＰｄＢｒ２）、ヨウ化パラジウム（ＰｄＩ２）、Ｐｄ（ＣＨ２ＣＯＣＨ２ＣＯＣＨ３）２、Ｋ２ＰｄＣｌ４、Ｋ２ＰｄＣｌ６、Ｋ２Ｐｄ（ＮＯ３）４、トリス（ジベンジリデンアセトン）ジパラジウム（0）、ビス（ジベンジリデンアセトン）パラジウム（0）、ジクロロビス（エチレン）パラジウム（ＰｄＣｌ２（Ｃ２Ｈ４）２）、ジクロロ（１，５－シクロオクタジエン）パラジウム（II）、２，５－ノルボルナジエンパラジウムジクロリド、ビス（アセトニトリル）パラジウムジクロリド、ビス（ベンゾニトリル）パラジウムジクロリド、Ｐｄ（π－Ｃ５Ｈ５）２等の有機配位子錯体；ＰｄＣｌ２（ＮＨ３）２、ＰｄＣｌ２［Ｎ（Ｃ２Ｈ５）３］ ２、Ｐｄ（ＮＯ３）２（ＮＨ３）６等のＮ－配位錯体等を挙げることができる。これらは単独で使用することもでき、２種以上を組合せて用いることもできる。なかでも、本工程では、選択率、収率及び安全性の観点から、有機配位子錯体が好ましく、酢酸パラジウム（Ｐｄ（ＯＣＯＣＨ３）２）、ｐ－アリルパラジウム（II）クロリドダイマー、トリフロオロ酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム（0）、トリス(ジベンジリデンアセトン)ジパラジウム（0）等がより好ましく、酢酸パラジウム（Ｐｄ（ＯＣＯＣＨ３）２）がさらに好ましい。 The palladium catalyst used in this step is not particularly limited, and examples thereof include palladium acetate (Pd (OCOCH 3 ) 2 ; Pd (OAc) 2 ), palladium trifluoroacetate (Pd (OCOCF 3 ) 2 ), p-allyl palladium (II) chloride dimer ([PdCl (allyl)] 2 ), p-cinnamyl palladium (II) chloride dimer, di-μ-chlorobis (2′-amino-1,1′-biphenyl-2-) C, N) dipalladium (II), palladium chloride (PdCl 2 ), palladium bromide (PdBr 2 ), palladium iodide (PdI 2 ), Pd (CH 2 COCH 2 COCH 3 ) 2 , K 2 PdCl 4 , K 2 PdCl 6, K 2 Pd ( NO 3) 4, tris (dibenzylideneacetone) dipalladium (0), bis (Jibenjiri N'aseton) palladium (0), dichlorobis (ethylene) palladium (PdCl 2 (C 2 H 4 ) 2), dichloro (1,5-cyclooctadiene) palladium (II), 2,5-norbornadiene palladium dichloride, bis (acetonitrile ) Palladium dichloride, bis (benzonitrile) palladium dichloride, organic ligand complexes such as Pd (π-C 5 H 5 ) 2 ; PdCl 2 (NH 3 ) 2 , PdCl 2 [N (C 2 H 5 ) 3 ] 2 , N-coordination complexes such as Pd (NO 3 ) 2 (NH 3 ) 6 and the like. These can be used alone or in combination of two or more. Among these, organic ligand complexes are preferable in this step from the viewpoint of selectivity, yield, and safety. Palladium acetate (Pd (OCOCH 3 ) 2 ), p-allyl palladium (II) chloride dimer, trifluoroacetic acid Palladium, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like are more preferable, and palladium acetate (Pd (OCOCH 3 ) 2 ) is more preferable.
　本工程において、パラジウム触媒の使用量は、選択率及び収率の観点から、前記化合物（２）１モルに対して、通常、０．０２～１モルが好ましく、０．０３～０．２５モルがより好ましい。 In this step, the amount of the palladium catalyst used is usually preferably from 0.02 to 1 mol, preferably from 0.03 to 0.25 mol, based on 1 mol of the compound (2), from the viewpoints of selectivity and yield. Is more preferable.
　本工程においては、選択率及び収率をより向上させる観点から、配位子を使用することが好ましい。この配位子は、あらかじめ上記パラジウム触媒に導入することもできるし、上記パラジウム触媒とともに系中に投入することもできる。 In this step, it is preferable to use a ligand from the viewpoint of further improving the selectivity and yield. This ligand can be introduced into the palladium catalyst in advance, or can be introduced into the system together with the palladium catalyst.
　本工程で使用し得る配位子としては、選択率及び収率の観点から、トリアルキルホスフィン配位子が好ましい。ただし、ジ（ｔ－ブチル）メチルホスフィンは、反応が進行しにくいため、ジ（ｔ－ブチル）メチルホスフィン以外のトリアルキルホスフィン配位子を使用することが好ましい。本工程で使用できるトリアルキルホスフィン配位子としては、例えば、トリエチルホスフィン、トリ（ｎ－プロピル）ホスフィン、トリ（イソプロピル）ホスフィン、トリ（ｔ－ブチル）ホスフィン、トリ（ｎ－ブチル）ホスフィン、トリ（ｎ－オクチル）ホスフィン、ジ（ｔ－ブチル）エチルホスフィン、ジ（ｔ－ブチル）ｎ－プロピルホスフィン、ジ（ｔ－ブチル）イソプロピルホスフィン、ジ（ｔ－ブチル）ｎ－ブチルホスフィン、ジ（ｔ－ブチル）イソブチルホスフィン、ジ（ｔ－ブチル）ネオペンチルホスフィン等が挙げられる。 The ligand that can be used in this step is preferably a trialkylphosphine ligand from the viewpoint of selectivity and yield. However, since the reaction of di (t-butyl) methylphosphine is difficult to proceed, it is preferable to use a trialkylphosphine ligand other than di (t-butyl) methylphosphine. Examples of the trialkylphosphine ligand that can be used in this step include triethylphosphine, tri (n-propyl) phosphine, tri (isopropyl) phosphine, tri (t-butyl) phosphine, tri (n-butyl) phosphine, (N-octyl) phosphine, di (t-butyl) ethylphosphine, di (t-butyl) n-propylphosphine, di (t-butyl) isopropylphosphine, di (t-butyl) n-butylphosphine, di (t -Butyl) isobutylphosphine, di (t-butyl) neopentylphosphine and the like.
　さらに、これらのホスフィン配位子は、ハロゲン原子（塩素原子等）、ＨＣｌ、ＨＦ、ＨＢｒ、ＨＩ、ＨＢＦ４等との塩である配位子前駆体として用いることもできる。これらは単独で使用することもでき、また、複数併用することもできる。なかでも、本工程では、選択率、収率及び安全性の観点から、トリ（ｔ－ブチル）ホスフィンが好ましい。 Furthermore, these phosphine ligands can also be used as ligand precursors which are salts with halogen atoms (such as chlorine atoms), HCl, HF, HBr, HI, HBF 4 and the like. These can be used alone or in combination. Among these, in this step, tri (t-butyl) phosphine is preferable from the viewpoints of selectivity, yield, and safety.
　本工程において、配位子の使用量は、選択率及び収率の観点から、前記パラジウム触媒１モルに対して、通常、０．５～５モルが好ましく、１～４モルがより好ましい。 In this step, the amount of the ligand used is usually preferably 0.5 to 5 moles and more preferably 1 to 4 moles with respect to 1 mole of the palladium catalyst from the viewpoints of selectivity and yield.
　本工程では、塩基を使用することが好ましい。つまり、工程（III）は、塩基の存在下で行われることが好ましい。本工程で使用できる塩基は、選択率及び収率の観点から、炭酸セシウム、ハロゲン化セシウム（フッ化セシウム、塩化セシウム、臭化セシウム、ヨウ化セシウム等）、リン酸アルカリ金属塩（リン酸カリウム、リン酸ナトリウム、リン酸リチウム等）等が好ましく、炭酸セシウム、ハロゲン化セシウム（フッ化セシウム、塩化セシウム、臭化セシウム、ヨウ化セシウム等）等がより好ましく、炭酸セシウム、フッ化セシウム等がさらに好ましく、炭酸セシウムが特に好ましい。特に、炭酸セシウムは、他の塩基と比較しても、選択率及び収率を飛躍的に向上させることができる。 In this step, it is preferable to use a base. That is, step (III) is preferably performed in the presence of a base. Bases that can be used in this step are cesium carbonate, cesium halides (cesium fluoride, cesium chloride, cesium bromide, cesium iodide, etc.), alkali metal phosphates (potassium phosphate) in terms of selectivity and yield. , Sodium phosphate, lithium phosphate and the like), cesium carbonate, cesium halide (cesium fluoride, cesium chloride, cesium bromide, cesium iodide, etc.) and the like are more preferable, cesium carbonate, cesium fluoride and the like More preferably, cesium carbonate is particularly preferable. In particular, cesium carbonate can dramatically improve selectivity and yield even when compared with other bases.
　本工程において、塩基を使用する場合、塩基の使用量は、選択率及び収率の観点から、前記化合物（２）１モルに対して、通常、０．５～１０モルが好ましく、１～５モルがより好ましい。 In this step, when a base is used, the amount of the base used is preferably 0.5 to 10 mol, preferably 1 to 5 mol per 1 mol of the compound (2) from the viewpoints of selectivity and yield. Mole is more preferred.
　本工程は、通常、反応溶媒下で行われる。使用できる反応溶媒としては、例えば、１，４－ジオキサン、テトラヒドロフラン、エチレングリコールジメチルエーテル、エチレングリコールジエチルエーテル、ジエチレングリコールジメチルエーテル、ジイソプロピルエーテル、ジイソブチルエーテル、シクロペンチルメチルエーテル（ＣＰＭＥ）等のエーテル溶媒；ベンゼン、トルエン、ｏ－キシレン、ｍ－キシレン、ｐ－キシレン、混合キシレン、メシチレン等の芳香族炭化水素溶媒等の有機溶媒を用いることが好ましい。これらは単独で使用することもでき、また、複数併用することもできる。なかでも、選択率、収率及び安全性の観点から、エーテル溶媒が好ましく、１，４－ジオキサンがより好ましい。 This step is usually performed in a reaction solvent. Usable reaction solvents include, for example, ether solvents such as 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diisopropyl ether, diisobutyl ether, cyclopentyl methyl ether (CPME); benzene, toluene, It is preferable to use an organic solvent such as an aromatic hydrocarbon solvent such as o-xylene, m-xylene, p-xylene, mixed xylene, and mesitylene. These can be used alone or in combination. Of these, ether solvents are preferable and 1,4-dioxane is more preferable from the viewpoints of selectivity, yield, and safety.
　これらの反応溶媒（有機溶媒）の使用量は、反応が進行する限り特に限定されるものではない。 The amount of these reaction solvents (organic solvents) used is not particularly limited as long as the reaction proceeds.
　本工程の反応温度は、使用する反応溶媒の沸点等によっても異なる。通常室温（２５℃）～３００℃程度、特に５０～１５０℃程度、さらに８０～１２０℃程度の反応温度で実施することが好ましい。また、本工程は通常、不活性ガス（例えば、窒素、アルゴン、ヘリウム等）気流下で実施することが好ましい。また、反応は、常圧で実施することもでき、また、必要に応じて、減圧又は加圧条件下で実施することも可能であるが、常圧下で実施することが好ましい。反応時間は、特に制限はなく、反応が十分に進行する時間とすることができる。 The reaction temperature in this step varies depending on the boiling point of the reaction solvent used. Usually, it is preferably carried out at a reaction temperature of about room temperature (25 ° C.) to about 300 ° C., particularly about 50 to 150 ° C., and further about 80 to 120 ° C. Moreover, it is preferable to implement this process normally under inert gas (for example, nitrogen, argon, helium etc.) airflow. In addition, the reaction can be carried out at normal pressure, and if necessary, can be carried out under reduced pressure or pressurized conditions, but it is preferably carried out under normal pressure. There is no restriction | limiting in particular in reaction time, It can be set as time for reaction to fully advance.
　反応の進行は、クロマトグラフィーのような通常の方法で追跡することができる。反応終了後、溶媒を留去し、生成物はクロマトグラフィー法、再結晶法等の通常の方法で生成物であるトリ（ヘテロ）アリールアセトニトリル化合物を単離精製することができる。また、生成物の構造は、元素分析、ＭＳ（ＦＤ－ＭＳ）分析、ＩＲ分析、１Ｈ－ＮＭＲ、１３Ｃ－ＮＭＲ等により同定することができる。 The progress of the reaction can be followed by conventional methods such as chromatography. After completion of the reaction, the solvent is distilled off, and the product can be isolated and purified by the usual method such as chromatography, recrystallization and the like as the product tri (hetero) arylacetonitrile compound. The structure of the product can be identified by elemental analysis, MS (FD-MS) analysis, IR analysis, 1 H-NMR, 13 C-NMR and the like.
　このようにして得られるトリ（ヘテロ）アリールアセトニトリル化合物は、一般式（１）： The tri (hetero) arylacetonitrile compound thus obtained has the general formula (1):
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
［式中、Ａｒ１、Ａｒ２及びＡｒ３は前記に同じである。］
で表される化合物である。 [Wherein, Ar 1 , Ar 2 and Ar 3 are the same as defined above. ]
It is a compound represented by these.
　４．トリ（ヘテロ）アリールアセトニトリル化合物及びその誘導体
　以上のようにして得られるトリ（ヘテロ）アリールアセトニトリル化合物は、シアノ基を容易に他の官能基に置換することが可能である。このため、未開拓のトリ（ヘテロ）アリール化合物の合成へと容易につなげることが期待される。例えば、後述の実施例のように、本発明のトリ（ヘテロ）アリールアセトニトリル化合物を出発物質として、トリ（ヘテロ）アリールアルデヒド化合物、トリ（ヘテロ）アリールアミン化合物、トリ（ヘテロ）アリールアミド化合物、トリ（ヘテロ）アリールメタン化合物、トリ（ヘテロ）アリールオキサジアゾール化合物、トリ（ヘテロ）アリールトリアジン化合物等を容易に合成することが可能である。 4). Tri (hetero) arylacetonitrile compound and derivatives thereof The tri (hetero) arylacetonitrile compound obtained as described above can easily substitute a cyano group with another functional group. For this reason, it is expected to easily connect to the synthesis of undeveloped tri (hetero) aryl compounds. For example, as in the examples described below, a tri (hetero) aryl aldehyde compound, a tri (hetero) arylamine compound, a tri (hetero) arylamide compound, a tri (hetero) arylamide compound, (Hetero) arylmethane compounds, tri (hetero) aryloxadiazole compounds, tri (hetero) aryltriazine compounds and the like can be easily synthesized.
　また、本発明の製造方法により得られるトリ（ヘテロ）アセトニトリル化合物、及び該トリ（ヘテロ）アセトニトリル化合物を出発物質とする化合物のうち、式： Among the tri (hetero) acetonitrile compounds obtained by the production method of the present invention and compounds starting from the tri (hetero) acetonitrile compounds, the formula:
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
［式中、Ｍｅはメチル基を示す。Ｐｈはフェニル基を示す。以下同様である。］
のいずれか、又は、一般式（２ａ）： [Wherein, Me represents a methyl group. Ph represents a phenyl group. The same applies hereinafter. ]
Or the general formula (2a):
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
［式中、Ｒ１０はアルキル基又はアルコキシカルボニル基を示す。Ｒ１１は置換若しくは無置換のアルキル基、又はアルコキシ基を示す。］
で表される化合物は、文献未記載の新規化合物である。 [Wherein, R 10 represents an alkyl group or an alkoxycarbonyl group. R 11 represents a substituted or unsubstituted alkyl group or an alkoxy group. ]
Is a novel compound not described in any literature.
　なお、一般式（２ａ）において、Ｒ１０で示されるアルキル基及びアルコキシカルボニル基、Ｒ１１で示される置換若しくは無置換のアルキル基、及びアルコキシ基としては、上記と同様のものを採用できる。置換基の種類及び数についても同様である。 Incidentally, in the general formula (2a), the alkyl group and alkoxycarbonyl group represented by R 10, a substituted or unsubstituted alkyl group represented by R 11, and the alkoxy groups, can be employed the same as described above. The same applies to the type and number of substituents.
　このように、本発明の製造方法を採用すれば、新規化合物も含めて、様々な機能を有する多種多様な化合物を合成することが可能であるため、未開拓の化合物の合成にもつながることが期待される。 As described above, if the production method of the present invention is employed, it is possible to synthesize a wide variety of compounds having various functions including new compounds, which may lead to synthesis of unexplored compounds. Be expected.
　５．工程（II）で使用できる配位子（６ａ）の合成方法
　本発明において、工程（II）において、特に好ましい配位子として使用できる配位子（６ａ）は、例えば、
一般式（１０）： 5). In the present invention, a ligand (6a) that can be used as a particularly preferred ligand in the step (II) is, for example,
General formula (10):
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
［式中、Ｘ４及びＸ５は同一又は異なって、ハロゲン原子を示す。］
で表される化合物（以下、「化合物（１０）」と言うこともある）と、
一般式（１１）：
Ｙ－ＰＲ１ｂＲ２ｂ
［式中、Ｒ１ｂ及びＲ２ｂは同一又は異なって、それぞれアルキル基又はシクロアルキル基を示す。Ｙは脱離基を示す。］
で表される化合物（以下、「化合物（１１）」と言うこともある）とを、塩基の存在下に反応させる工程
により合成することができる。 [Wherein, X 4 and X 5 are the same or different and each represents a halogen atom. ]
(Hereinafter also referred to as “compound (10)”),
General formula (11):
Y-PR 1b R 2b
[Wherein, R 1b and R 2b are the same or different and each represents an alkyl group or a cycloalkyl group. Y represents a leaving group. ]
Can be synthesized by a step of reacting a compound represented by the formula (hereinafter also referred to as “compound (11)”) in the presence of a base.
　一般式（１０）において、Ｘ４及びＸ５はハロゲン原子であり、フッ素原子、塩素原子、臭素原子及びヨウ素原子が挙げられる。これらのなかでも、本工程における選択性及び収率の観点から、臭素原子、ヨウ素原子等が好ましく、臭素原子がより好ましい。 In the general formula (10), X 4 and X 5 is a halogen atom, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among these, from the viewpoints of selectivity and yield in this step, a bromine atom, an iodine atom and the like are preferable, and a bromine atom is more preferable.
　この化合物（１０）は、市販品を使用してもよいし、既報の方法にしたがって合成してもよい。 This compound (10) may be a commercially available product or may be synthesized according to a previously reported method.
　一般式（１１）において、Ｙで示される脱離基としては、例えば、ハロゲン原子（塩素原子、臭素原子、ヨウ素原子等）、アルキルスルホネート（メタンスルホネート等）、ハロアルキルスルホネート（トリフルオロメタンスルホネート等）、アリールスルホネート（ｐ－トルエンスルホネート等）等が挙げられる。本反応の収率の観点から、ハロゲン原子（特に塩素原子）が好ましい。 In the general formula (11), examples of the leaving group represented by Y include a halogen atom (chlorine atom, bromine atom, iodine atom, etc.), alkyl sulfonate (methanesulfonate, etc.), haloalkylsulfonate (trifluoromethanesulfonate, etc.), Examples thereof include aryl sulfonates (p-toluene sulfonate, etc.). From the viewpoint of the yield of this reaction, a halogen atom (especially a chlorine atom) is preferred.
　一般式（１１）において、Ｒ１ｂ及びＲ２ｂで示されるアルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔ－ブチル基、ｎ－ヘキシル基等のＣ１－８－アルキル基等が採用できる。このアルキル基に置換し得る置換基としては、上記説明したＡｒ１に置換し得る置換基が挙げられる。置換基の数についても同様である。 In the general formula (11), examples of the alkyl group represented by R 1b and R 2b include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t C 1-8 -alkyl groups such as -butyl group and n-hexyl group can be employed. Examples of the substituent that can be substituted on the alkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
　一般式（１１）において、Ｒ１ｂ及びＲ２ｂで示されるシクロアルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等のＣ３－８－シクロアルキル基等が採用できる。このシクロアルキル基に置換し得る置換基としては、上記説明したＡｒ１に置換し得る置換基が挙げられる。置換基の数についても同様である。 In the general formula (11), examples of the cycloalkyl group represented by R 1b and R 2b include C 3-8 -cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the substituent that can be substituted on the cycloalkyl group include the substituent that can be substituted on Ar 1 described above. The same applies to the number of substituents.
　本反応において、化合物（１１）の使用量は、収率の観点から、化合物（１０）１モルに対して、通常、０．５～５モルが好ましく、１～４モルがより好ましい。 In this reaction, the amount of compound (11) to be used is generally preferably 0.5 to 5 mol, more preferably 1 to 4 mol, relative to 1 mol of compound (10), from the viewpoint of yield.
　塩基としては、例えば、リチウムジイソプロピルアミド（ＬＤＡ）、リチウムビストリメチルシリルアミド、ナトリウムビストリメチルシリルアミド、カリウムビストリメチルシリルアミド等の金属アミド（特にアルカリ金属アミド）；メチルリチウム、エチルリチウム、ｎ－ブチルリチウム、ｓ－ブチルリチウム、ｔ－ブチルリチウム等のアルキルリチウム；フェニルリチウム等のアリールリチウム；グリニヤール反応剤等が挙げられ、収率の観点から、アルキルリチウムが好ましく、ｎ－ブチルリチウムがより好ましい。 Examples of the base include metal amides (particularly alkali metal amides) such as lithium diisopropylamide (LDA), lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium bistrimethylsilylamide; methyllithium, ethyllithium, n-butyllithium, s Examples thereof include alkyllithium such as -butyllithium and t-butyllithium; aryllithium such as phenyllithium; Grignard reagent and the like. From the viewpoint of yield, alkyllithium is preferable, and n-butyllithium is more preferable.
　本反応は、通常溶媒中で実施することができる。溶媒としては、例えば、ジエチルエーテル、テトラヒドロフラン、ジオキサン（１，４－ジオキサン）、ｔ－ブチルメチルエーテル、シクロペンチルメチルエーテル、１，２－ジメトキシエタン、ジグライム等のエーテル溶媒；ベンゼン、トルエン、キシレン、メシチレン等の芳香族炭化水素溶媒；ペンタン、ヘキサン、ヘプタン、シクロヘキサン等の脂肪族炭化水素溶媒等が挙げられる。これらの溶媒は単独で又は２種以上を組み合わせて使用できる。なかでも、収率の観点から、エーテル溶媒が好ましく、テトラヒドロフランがより好ましい。 This reaction can usually be carried out in a solvent. Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, dioxane (1,4-dioxane), t-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme; benzene, toluene, xylene, mesitylene And aromatic hydrocarbon solvents such as pentane, hexane, heptane, and cyclohexane. These solvents can be used alone or in combination of two or more. Among these, from the viewpoint of yield, an ether solvent is preferable, and tetrahydrofuran is more preferable.
　これらの溶媒の使用量は、反応が進行する限り特に限定されるものではない。 The amount of these solvents used is not particularly limited as long as the reaction proceeds.
　本反応の反応温度は、使用する反応溶媒の沸点等によっても異なる。通常、－１５０～０℃、特に－１００～－５０℃において、化合物（１０）に対して前記溶媒中で前記塩基を添加し、その後、前記化合物化合物（１１）を添加することが好ましい。また、本反応は通常、不活性ガス（例えば、窒素、アルゴン、ヘリウム等）気流下で実施することが好ましい。また、反応は、常圧で実施することもでき、また、必要に応じて、減圧又は加圧条件下で実施することも可能であるが、常圧下で実施することが好ましい。反応時間は、特に制限はなく、反応が十分に進行する時間とすることができる。 The reaction temperature of this reaction varies depending on the boiling point of the reaction solvent used. Usually, it is preferable to add the base in the solvent to the compound (10) at −150 to 0 ° C., particularly at −100 to −50 ° C., and then add the compound compound (11). In addition, this reaction is usually preferably carried out under an inert gas (for example, nitrogen, argon, helium, etc.) stream. In addition, the reaction can be carried out at normal pressure, and if necessary, can be carried out under reduced pressure or pressurized conditions, but it is preferably carried out under normal pressure. There is no restriction | limiting in particular in reaction time, It can be set as time for reaction to fully advance.
　反応の進行は、クロマトグラフィーのような通常の方法で追跡することができる。反応終了後、溶媒を留去し、生成物はクロマトグラフィー法、再結晶法等の通常の方法で生成物である配位子（６ａ）を単離精製することができる。また、生成物の構造は、元素分析、ＭＳ（ＦＤ－ＭＳ）分析、ＩＲ分析、１Ｈ－ＮＭＲ、１３Ｃ－ＮＭＲ等により同定することができる。 The progress of the reaction can be followed by conventional methods such as chromatography. After completion of the reaction, the solvent is distilled off, and the product, the ligand (6a), which is the product, can be isolated and purified by a usual method such as chromatography or recrystallization. The structure of the product can be identified by elemental analysis, MS (FD-MS) analysis, IR analysis, 1 H-NMR, 13 C-NMR and the like.
　以下、実施例により本発明を更に具体的に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described more specifically with reference to examples, but the scope of the present invention is not limited thereto.
　特に制約しない限り、乾燥溶媒を含む全ての材料は、市販品をそのまま使用した。また、５－ブロモ－Ｎ－メチルインドールは、既報（Eur. J. Org. Chem. 2011, 3781.）にしたがって合成した。特に断りのない限り、すべての反応は、標準的な真空ライン技法を用いて乾燥したガラス容器中でアルゴン雰囲気下に乾燥溶媒を用いて行った。すべての処理及び精製は、空気中で試薬グレードの溶媒を用いて行った。 Unless otherwise specified, all materials including the dry solvent were used as they were on the market. In addition, 5-bromo-N-methylindole was synthesized according to a previous report (Eur. J. Org. Chem. 2011, 3781.). Unless otherwise noted, all reactions were performed using a dry solvent under an argon atmosphere in a glass container dried using standard vacuum line techniques. All treatments and purifications were performed in air using reagent grade solvents.
　分析用薄層クロマトグラフィー（TLC）は、E. Merckシリカゲル60 F254プレコートプレート（0.25 mm）を用いて行った。開発したクロマトグラムは、UVランプ（254 nm）及びリンモリブデン酸エタノール溶液で分析した。分取薄層クロマトグラフィー（PTLC）はあらかじめ準備したワコーゲルB5-Fのシリカ被覆プレート（0.75 mm）を用いて行った。リサイクル分取高速液体クロマトグラフィー（HPLC）は、溶離液としてクロロホルムを用い、JAIGEL-1H/JAIGEL-2Hカラムを備えたJAI LC-9204で行った。ガスクロマトグラフィー（GC）は、HP-5カラム（30 m×0.25 mm、ヒューレット－パッカード社）を備えた島津GC-2010計器で行った。GCMS分析は、HP-5カラム（30 m×0.25 mm、ヒューレット－パッカード社）を備えた島津GCMS-QP2010で行った。 Analytical thin layer chromatography (TLC) was performed using E. Merck silica gel 60 F 254 precoated plates (0.25 mm). The developed chromatogram was analyzed with a UV lamp (254 nm) and a phosphomolybdic acid ethanol solution. Preparative thin layer chromatography (PTLC) was performed using a pre-prepared Wakogel B5-F silica-coated plate (0.75 mm). Recycle preparative high performance liquid chromatography (HPLC) was performed on a JAI LC-9204 equipped with a JAIGEL-1H / JAIGEL-2H column using chloroform as the eluent. Gas chromatography (GC) was performed on a Shimadzu GC-2010 instrument equipped with an HP-5 column (30 m × 0.25 mm, Hewlett-Packard). GCMS analysis was performed on a Shimadzu GCMS-QP2010 equipped with an HP-5 column (30 m × 0.25 mm, Hewlett-Packard).
　高分解能質量スペクトル（HRMS）は、JMS-T100TD計器（DART）及びThermo Fisher Scientific Exactiveから得た。赤外（IR）スペクトルはFT/IR-6100で記録した。核磁気共鳴（NMR）スペクトルは、JEOL ECA-600（1H 600 MHz、13C 150MHz）とJEOL A-100、JEOL ECS-400及びJEOL AL-400（1H 400 MHz、13C 100 MHz、31P 162 MHz）で記録した。1H NMRの化学シフトはテトラメチルシラン（δ0.00 ppm）、DMSO-d6の残留プロトンシグナル（δ2.50 ppm）又はアセトン-d6の残留プロトンシグナル（δ2.05 ppm）の相対的な百万分率（ppm）で表した。13C NMRの化学シフトはCDCl3（δ77.0 ppm）、DMSO-d6（δ39.5 ppm）又はアセトン-d6（δ29.8 ppm）の相対的な百万分率（ppm）で表した。31P NMRの化学シフトはH3PO4（δ0.00 ppm）の相対的な百万分率（ppm）で表した。データは、化学シフト、多重度（s =シングレット、d =ダブレット、dd =ッダブルダブレット、dt =ダブルトリプレット、t =トリプレット、q =カルテット、m=マルチプレット、br =ブロードシグナル）、結合定数（Hz）、及び統合の順に報告する。 High resolution mass spectra (HRMS) were obtained from JMS-T100TD instrument (DART) and Thermo Fisher Scientific Exactive. Infrared (IR) spectra were recorded with FT / IR-6100. Nuclear magnetic resonance (NMR) spectra were obtained from JEOL ECA-600 ( 1 H 600 MHz, 13 C 150 MHz) and JEOL A-100, JEOL ECS-400 and JEOL AL-400 ( 1 H 400 MHz, 13 C 100 MHz, 31 P 162 MHz). 1 H NMR chemical shift is relative to tetramethylsilane (δ0.00 ppm), DMSO-d 6 residual proton signal (δ2.50 ppm) or acetone-d 6 residual proton signal (δ2.05 ppm). Expressed in parts per million (ppm). 13 C NMR chemical shifts are expressed in relative parts per million (ppm) of CDCl 3 (δ77.0 ppm), DMSO-d 6 (δ39.5 ppm) or acetone-d 6 (δ29.8 ppm). did. 31 P NMR chemical shifts were expressed in relative parts per million (ppm) of H 3 PO 4 (δ0.00 ppm). Data are chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet, dt = doublet, t = triplet, q = quartet, m = multiplet, br = broad signal), binding constant ( Hz), then report in order of integration.
　［実施例１：２，２’－ビス（ジシクロヘキシルホスフィノ）－１，１’－ビピリジル（DCPB）の合成］ [Example 1: Synthesis of 2,2'-bis (dicyclohexylphosphino) -1,1'-bipyridyl (DCPB)]
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
［式中、n-Buはn-ブチル基を示す。THFはテトラヒドロフランを示す。以下同様である。］
　内容積100 mLの二口フラスコに、磁気撹拌子を収容し、真空下、ヒートガンで乾燥させた後、室温に冷却し、アルゴンガスを満たした。次いで、前記二口フラスコに、2,2’-ジブロモビフェニル（1,25 g, 4 mmol）及び乾燥THF（15 mL）をアルゴン気流下で添加した。この溶液に、-78℃において、n-ブチルリチウムのn-ヘキサン溶液（1.6 M, 5.5 mL, 8.8 mmol）をゆっくりと添加した。15分後、同じ温度で、精製したクロロジシクロヘキシルホスフィン（1.95 mL, 8.8 mmol）のトルエン（4 mL）溶液を添加し、混合物を室温で2時間攪拌した。混合物をNH4Cl塩（約15 mL）で処理し、CH2Cl2（3回）で抽出した。抽出物をNa2SO4で乾燥し、溶媒を減圧下に蒸発させた。粗生成物にアルゴンを30分間吹き込んだCH2Cl2に溶解させ、シリカゲルのパッドでろ過し、CH2Cl2で繰り返し洗浄した。溶媒を蒸発させたところ、目的物である2,2’-ビス（ジシクロヘキシルホスフィノ）-1,1’-ビピリジル（DCPB）を白色固体として得た（1.48 g, 68％）。
1H NMR (400 MHz, CDCl3) δ 1.06-1,32 (m, 20H), 1.53-1.91 (m, 24H), 7.11-7.13 (m, 2H), 7.28-7.36 (m, 4H), 7.53 (d, J = 7.2 Hz, 2H). 13C NMR (150 MHz, CDCl3) δ 26.4, 26.7, 27.19, 27.23, 27.27, 27.32, 27.35, 27.53, 27.56, 27.61, 27.63, 29.64, 29.67, 29.70, 30.59, 30.66, 30.72, 30.88, 30.93, 30.98, 34.46, 34.55, 36.70, 36.80, (Observed complexity due to C-P splitting), 126.3, 127.0, 132.1 (virtual t, J = 4.4 Hz), 132.5, 135.0 (d, J = 18.8 Hz), 132.1 (virtual t, J = 18.6 Hz). 31P NMR (162 MHz, CDCl3) δ -12.7. HRMS (ESI) m/z calcd for C36H53P2 [M+H]+: 547.3617, found 547.3618。 [Wherein n-Bu represents an n-butyl group. THF represents tetrahydrofuran. The same applies hereinafter. ]
A magnetic stirring bar was accommodated in a two-necked flask having an internal volume of 100 mL, dried under a vacuum with a heat gun, cooled to room temperature, and filled with argon gas. Next, 2,2′-dibromobiphenyl (1,25 g, 4 mmol) and dry THF (15 mL) were added to the two-necked flask under a stream of argon. To this solution, n-butyllithium in n-hexane (1.6 M, 5.5 mL, 8.8 mmol) was slowly added at -78 ° C. After 15 minutes, at the same temperature, a solution of purified chlorodicyclohexylphosphine (1.95 mL, 8.8 mmol) in toluene (4 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was treated with NH 4 Cl salt (ca 15 mL) and extracted with CH 2 Cl 2 (3 times). The extract was dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure. The crude product was dissolved in CH 2 Cl 2 blown with argon for 30 minutes, filtered through a pad of silica gel and washed repeatedly with CH 2 Cl 2 . When the solvent was evaporated, the desired product 2,2′-bis (dicyclohexylphosphino) -1,1′-bipyridyl (DCPB) was obtained as a white solid (1.48 g, 68%).
1 H NMR (400 MHz, CDCl 3 ) δ 1.06-1,32 (m, 20H), 1.53-1.91 (m, 24H), 7.11-7.13 (m, 2H), 7.28-7.36 (m, 4H), 7.53 (d, J = 7.2 Hz, 2H). 13 C NMR (150 MHz, CDCl 3) δ 26.4, 26.7, 27.19, 27.23, 27.27, 27.32, 27.35, 27.53, 27.56, 27.61, 27.63, 29.64, 29.67, 29.70, 30.59, 30.66, 30.72, 30.88, 30.93, 30.98, 34.46, 34.55, 36.70, 36.80, (Observed complexity due to CP splitting), 126.3, 127.0, 132.1 (virtual t, J = 4.4 Hz), 132.5, 135.0 (d, J = 18.8 Hz), 132.1 ( virtual t, J = 18.6 Hz). 31 P NMR (162 MHz, CDCl 3) δ -12.7. HRMS (ESI) m / z calcd for C 36 H 53 P 2 [M + H ] + : 547.3617, found 547.3618.
　［実施例２：ハロゲン化アセトニトリル化合物の（ヘテロ）アリール化］
　実施例２－１ [Example 2: (Hetero) arylation of halogenated acetonitrile compound]
Example 2-1
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
［式中、Acはアセチル基を示す。以下同様である。］
　内容積10 mLの密閉ガラス容器に、磁気撹拌子を収容し、真空下、ヒートガンで乾燥させた後、室温に冷却し、アルゴンガスを満たした。次いで、前記ガラス容器に、酢酸パラジウム（Pd(OAc)2; 1.7 mg, 7.5μmol）、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシ-1,1’-ビフェニル（SPhos; 6.2 mg, 15μmol）、及び乾燥1,4-ジオキサン（450μL）をアルゴン気流下に室温で添加した。同じ温度で30分間攪拌した後、クロロアセトニトリル（19.0μL, 0.3 mmol）、フェニルボロン酸（54.9 mg, 0.45 mmol）、Na2CO3（47.7 mg, 0.45 mmol）、乾燥1,4-ジオキサン（450μL）、及び水（90μL）を添加し、ガラス容器を密封した。混合物を60℃で12時間攪拌した。混合物を室温まで冷却した後、シリカゲルのパッドでろ過し、酢酸エチル（EtOAc; 約15 mL）で繰り返し洗浄した。ろ液を減圧下に濃縮した。粗生成物をPTLC（酢酸エチル／n-ヘキサン=1: 20）により精製し、フェニルアセトニトリル（2a）を無色油として得た（30.0 mg, 85％）。この結果は、後述の表２のentry 1に相当する。
フェニルアセトニトリル（2a）
1H NMR (400 MHz, CDCl3) δ 3.76 (s, 2H), 7.32-7.40 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 23.6, 117.8, 127.9, 128.0, 129.1, 129.8. HRMS (DART) m/z calcd for C8H7N [M]+: 117.0579, found 117.0582。 [In the formula, Ac represents an acetyl group. The same applies hereinafter. ]
A magnetic stir bar was housed in a sealed glass container having an internal volume of 10 mL, dried under a vacuum with a heat gun, cooled to room temperature, and filled with argon gas. Next, palladium acetate (Pd (OAc) 2 ; 1.7 mg, 7.5 μmol), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl (SPhos; 6.2 mg, 15 μmol) was placed in the glass container. ), And dry 1,4-dioxane (450 μL) were added at room temperature under a stream of argon. After stirring at the same temperature for 30 minutes, chloroacetonitrile (19.0μL, 0.3 mmol), phenylboronic acid (54.9 mg, 0.45 mmol), Na 2 CO 3 (47.7 mg, 0.45 mmol), dry 1,4-dioxane (450 μL) ) And water (90 μL) were added and the glass container was sealed. The mixture was stirred at 60 ° C. for 12 hours. After the mixture was cooled to room temperature, it was filtered through a pad of silica gel and washed repeatedly with ethyl acetate (EtOAc; ca. 15 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by PTLC (ethyl acetate / n-hexane = 1: 20) to obtain phenylacetonitrile (2a) as a colorless oil (30.0 mg, 85%). This result corresponds to entry 1 in Table 2 described later.
Phenylacetonitrile (2a)
1 H NMR (400 MHz, CDCl 3 ) δ 3.76 (s, 2H), 7.32-7.40 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 23.6, 117.8, 127.9, 128.0, 129.1, 129.8. HRMS (DART) m / z calcd for C 8 H 7 N [M] + : 117.0579, found 117.0582.
　実施例２－２
　ボロン酸化合物の種類、パラジウム触媒の量、配位子の種類及び量、溶媒の種類、反応温度を種々変更する他は実施例２－１と同様の処理を行った。結果を表１に示す。 Example 2-2
The same treatment as in Example 2-1 was performed, except that the type of boronic acid compound, the amount of palladium catalyst, the type and amount of ligand, the type of solvent, and the reaction temperature were variously changed. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
　実施例２－３
　ボロン酸化合物が有する芳香族基（フェニル基）を種々の基とする他は実施例２－１と同様の処理を行った。結果を表２に示す。 Example 2-3
The same treatment as in Example 2-1 was performed, except that the aromatic group (phenyl group) of the boronic acid compound was various groups. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
4-メチルフェニルアセトニトリル（2b）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 20)
1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.66 (s, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 20.9, 23.0, 118.0, 126.7, 127.6, 129.6, 137.6. HRMS (DART) m/z calcd for C9H9N [M]+: 131.0735, found 131.0737。
4-メトキシフェニルアセトニトリル（2c）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 15)
1H NMR (400 MHz, CDCl3) δ 3.65 (s, 2H), 3.78 (s, 3H), 6.88 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 22.8, 55.3, 114.5, 118.2, 121.7, 129.0, 159.3. HRMS (DART) m/z calcd for C9H9NO [M]+: 147.0684, found 147.0689。
4-フルオロフェニルアセトニトリル（2d）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 20)
1H NMR (400 MHz, CDCl3) δ 3.73 (s, 2H), 7.04-7.10 (m, 2H), 7.28-7.33 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 22,9, 116.1 (d, J = 22 Hz), 117.7, 125.6, 129.6 (d, J = 8.6 Hz), 162.4 (d, J = 248 Hz). HRMS (DART) m/z calcd for C8H6NF [M]+: 135.0484, found 135.0484。
(4-トリフルオロメチル)フェニルアセトニトリル（2e）
反応温度：100℃、PTLCによる精製（酢酸エチル/ヘキサン= 1: 15)
1H NMR (400 MHz, CDCl3) δ 3.83 (s, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 23.5, 117.0, 123.7 (q, J = 273 Hz), 126.1 (q, J = 3.9 Hz), 128.3, 130.5 (q, J = 33 Hz), 133.9. HRMS (DART) m/z calcd for C9H7NF3 [M+H]+: 186.0525, found 186.0525。
4-メトキシカルボニルフェニルアセトニトリル（2f）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 4)
1H NMR (400 MHz, CDCl3) δ 3.82 (s, 2H), 3.93 (s, 3H), 7.42 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 23.6, 52.2, 117.1, 127.9, 130.0, 130.3, 134.8, 166.3. IR (Neat) v 684, 833, 921, 959, 1020, 1109, 1189, 1280, 1415, 1429, 1613, 1725, 2248, 3018, 3063 cm-1. HRMS (DART) m/z calcd for C10H10NO2 [M+H]+: 176.0706, found 176.0706。
4-(N-Boc-アミノ)フェニルアセトニトリル（2g）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 10)
1H NMR (400 MHz, CDCl3) δ 1.52 (s, 9H), 3.69 (s, 2H), 6.62 (br.s, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 22.9, 28.3, 80.7, 118.0, 118.9, 124.0, 128.5, 138.3, 152.6. IR (Neat) v 771, 819, 840, 912, 1018, 1055, 1156, 1234, 1315, 1365, 1416, 1509, 1523, 1596, 1698, 2245, 2986 cm-1. HRMS (DART) m/z calcd for C13H17N2O2 [M+H]+: 233.1285, found 233.1296。
4-ニトロフェニルアセトニトリル（2h）
反応温度：100℃、PTLCによる精製（酢酸エチル/ヘキサン= 1: 10)
1H NMR (400 MHz, CDCl3) δ 3.91 (s, 2H), 7.56 (d, J = 8.8 Hz, 2H), 8.26 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 23.5, 116.4, 124.3, 128.9, 137.0, 147.7. HRMS (DART) m/z calcd for C8H7N2O2 [M+H]+: 163.0502, found 163.0509。
1-ナフチルアセトニトリル（2i）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 20)
1H NMR (400 MHz, CDCl3) δ 4.11 (s, 2H), 7.44-7.48 (m, 1H), 7.53-7.62 (m, 3H), 7.85 (d, J = 8.0 Hz, 2H), 7.91 (dd, J = 8.0, 1.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 21.7, 117.6, 122.4, 125.4, 125.7, 126.3, 126.4, 127.0, 129.0, 129.1, 130.7, 133.7. HRMS (DART) m/z calcd for C12H9N [M]+: 167.0735, found 167.0727。
1-メチルフェニルアセトニトリル（2j）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 20)
1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.65 (s, 2H), 7.19-7.27 (m, 3H), 7.34 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 19.2, 21.8, 117.5, 126.7, 128.3, 128.4, 128.5, 130.6, 136.0. HRMS (DART) m/z calcd for C9H9N [M]+: 131.0735, found 131.0738。
3-チエニルアセトニトリル（2k）
反応温度：100℃、PTLCによる精製（酢酸エチル/ヘキサン= 1: 15)
1H NMR (400 MHz, CDCl3) δ 3.74 (d, J = 1.2 Hz, 2H), 7.03 (dd, J = 5.2, 1.2 Hz, 1H), 7.25-7.27 (m, 1H), 7.36 (dd, J = 5.2, 2.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 18.8, 117.6, 123.1, 127.0, 127.2, 129.4. HRMS (DART) m/z calcd for C6H5NS [M]+: 123.0143, found 123.0147。 4-Methylphenylacetonitrile (2b)
Purification by PTLC (ethyl acetate / hexane = 1: 20)
1 H NMR (400 MHz, CDCl 3 ) δ 2.33 (s, 3H), 3.66 (s, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 20.9, 23.0, 118.0, 126.7, 127.6, 129.6, 137.6. HRMS (DART) m / z calcd for C 9 H 9 N [M] + : 131.0735, found 131.0737.
4-Methoxyphenylacetonitrile (2c)
Purification by PTLC (ethyl acetate / hexane = 1: 15)
1 H NMR (400 MHz, CDCl 3 ) δ 3.65 (s, 2H), 3.78 (s, 3H), 6.88 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 22.8, 55.3, 114.5, 118.2, 121.7, 129.0, 159.3. HRMS (DART) m / z calcd for C 9 H 9 NO [M] + : 147.0684, found 147.0689.
4-Fluorophenylacetonitrile (2d)
Purification by PTLC (ethyl acetate / hexane = 1: 20)
1 H NMR (400 MHz, CDCl 3 ) δ 3.73 (s, 2H), 7.04-7.10 (m, 2H), 7.28-7.33 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 22,9 , 116.1 (d, J = 22 Hz), 117.7, 125.6, 129.6 (d, J = 8.6 Hz), 162.4 (d, J = 248 Hz). HRMS (DART) m / z calcd for C 8 H 6 NF [ M] + : 135.0484, found 135.0484.
(4-Trifluoromethyl) phenylacetonitrile (2e)
Reaction temperature: 100 ° C, purification by PTLC (ethyl acetate / hexane = 1: 15)
1 H NMR (400 MHz, CDCl 3 ) δ 3.83 (s, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 23.5, 117.0, 123.7 (q, J = 273 Hz), 126.1 (q, J = 3.9 Hz), 128.3, 130.5 (q, J = 33 Hz), 133.9.HRMS (DART) m / z calcd for C 9 H 7 NF 3 [M + H] + : 186.0525, found 186.0525.
4-Methoxycarbonylphenylacetonitrile (2f)
Purification by PTLC (ethyl acetate / hexane = 1: 4)
1 H NMR (400 MHz, CDCl 3 ) δ 3.82 (s, 2H), 3.93 (s, 3H), 7.42 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 23.6, 52.2, 117.1, 127.9, 130.0, 130.3, 134.8, 166.3. IR (Neat) v 684, 833, 921, 959, 1020, 1109, 1189, 1280, 1415, 1429 , 1613, 1725, 2248, 3018, 3063 cm −1 . HRMS (DART) m / z calcd for C 10 H 10 NO 2 [M + H] + : 176.0706, found 176.0706.
4- (N-Boc-amino) phenylacetonitrile (2g)
Purification by PTLC (ethyl acetate / hexane = 1: 10)
1 H NMR (400 MHz, CDCl 3 ) δ 1.52 (s, 9H), 3.69 (s, 2H), 6.62 (br.s, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 22.9, 28.3, 80.7, 118.0, 118.9, 124.0, 128.5, 138.3, 152.6. IR (Neat) v 771, 819, 840, 912, 1018, 1055, 1156, 1234, 1315, 1365, 1416, 1509, 1523, 1596, 1698, 2245, 2986 cm -1 .HRMS (DART) m / z calcd for C 13 H 17 N 2 O 2 [M + H ] + : 233.1285, found 233.1296.
4-Nitrophenylacetonitrile (2h)
Reaction temperature: 100 ° C, purification by PTLC (ethyl acetate / hexane = 1: 10)
1 H NMR (400 MHz, CDCl 3 ) δ 3.91 (s, 2H), 7.56 (d, J = 8.8 Hz, 2H), 8.26 (d, J = 8.8 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 23.5, 116.4, 124.3, 128.9, 137.0, 147.7. HRMS (DART) m / z calcd for C 8 H 7 N 2 O 2 [M + H] + : 163.0502, found 163.0509.
1-naphthylacetonitrile (2i)
Purification by PTLC (ethyl acetate / hexane = 1: 20)
1 H NMR (400 MHz, CDCl 3 ) δ 4.11 (s, 2H), 7.44-7.48 (m, 1H), 7.53-7.62 (m, 3H), 7.85 (d, J = 8.0 Hz, 2H), 7.91 ( dd, J = 8.0, 1.2 Hz , 1H). 13 C NMR (100 MHz, CDCl 3) δ 21.7, 117.6, 122.4, 125.4, 125.7, 126.3, 126.4, 127.0, 129.0, 129.1, 130.7, 133.7. HRMS (DART ) m / z calcd for C 12 H 9 N [M] + : 167.0735, found 167.0727.
1-Methylphenylacetonitrile (2j)
Purification by PTLC (ethyl acetate / hexane = 1: 20)
1 H NMR (400 MHz, CDCl 3 ) δ 2.33 (s, 3H), 3.65 (s, 2H), 7.19-7.27 (m, 3H), 7.34 (d, J = 8.0 Hz, 1H). 13 C NMR ( 100 MHz, CDCl 3 ) δ 19.2, 21.8, 117.5, 126.7, 128.3, 128.4, 128.5, 130.6, 136.0. HRMS (DART) m / z calcd for C 9 H 9 N [M] + : 131.0735, found 131.0738.
3-Thienylacetonitrile (2k)
Reaction temperature: 100 ° C, purification by PTLC (ethyl acetate / hexane = 1: 15)
1 H NMR (400 MHz, CDCl 3 ) δ 3.74 (d, J = 1.2 Hz, 2H), 7.03 (dd, J = 5.2, 1.2 Hz, 1H), 7.25-7.27 (m, 1H), 7.36 (dd, J = 5.2, 2.8 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 18.8, 117.6, 123.1, 127.0, 127.2, 129.4. HRMS (DART) m / z calcd for C 6 H 5 NS [M] + : 123.0143, found 123.0147.
　［実施例３：（ヘテロ）アリールアセトニトリル化合物のアリール化］
　実施例３－１ [Example 3: Arylation of (hetero) arylacetonitrile compound]
Example 3-1
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
［式中、Binapは2,2’-ビス（ジフェニルホスフィノ）-1,1’-ビナフチルを示す。以下同様である。］
　内容積10 mLの密閉ガラス容器に、磁気撹拌子を収容し、真空下、ヒートガンで乾燥させた後、室温に冷却し、アルゴンガスを満たした。次いで、前記ガラス容器に、酢酸パラジウム（Pd(OAc)2; 2.2 mg, 10μmol）、2,2’-ビス（ジフェニルホスフィノ）-1,1’-ビナフチル（rac-BINAP2; 12.4 mg, 20μmol）、及び乾燥1,4-ジオキサン（150μL）をアルゴン気流下に室温で添加した。同じ温度で30分間攪拌した後、p-メチルフェニルアセトニトリル（13.2μL, 0.1 mmol）、p-ブロモアニソール（18.7μL, 0.15 mmol）、K3PO4（63.7 mg, 0.3 mmol）、及び乾燥1,4-ジオキサン（150μL）を添加し、ガラス容器を密封した。混合物を100℃で12時間攪拌した。混合物を室温まで冷却した後、NH4Cl水溶液（100μL）、CH2Cl2（500μL）、及びドデカン（内部標準）を添加し、混合物をシリカゲルのパッドでろ過し、酢酸エチル（EtOAc; 約5 mL）で繰り返し洗浄した。ドデカンを内部標準とする粗生成物のGC分析の結果、（p-メトキシフェニル）（p-メチルフェニル）アセトニトリル（4bc）の収率は34 %、（p-メチルフェニル）フェニルアセトニトリル（4ba）の収率は13 %であった。このように、メトキシフェニル基を導入しようとする場合に、ビナフチル骨格を有する配位子を使用すると、副生成物として、フェニル置換物も生成していた（（p-メトキシフェニル）（p-メチルフェニル）アセトニトリル（4bc）及び（p-メチルフェニル）フェニルアセトニトリル（4ba）のスペクトルデータは後述する）。 [Wherein Binap represents 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl. The same applies hereinafter. ]
A magnetic stir bar was housed in a sealed glass container having an internal volume of 10 mL, dried under a vacuum with a heat gun, cooled to room temperature, and filled with argon gas. Next, palladium acetate (Pd (OAc) 2 ; 2.2 mg, 10 μmol), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (rac-BINAP2; 12.4 mg, 20 μmol) was placed in the glass container. , And dry 1,4-dioxane (150 μL) was added at room temperature under a stream of argon. After stirring at the same temperature for 30 minutes, p-methylphenylacetonitrile (13.2 μL, 0.1 mmol), p-bromoanisole (18.7 μL, 0.15 mmol), K 3 PO 4 (63.7 mg, 0.3 mmol), and dry 1, 4-Dioxane (150 μL) was added and the glass container was sealed. The mixture was stirred at 100 ° C. for 12 hours. After the mixture was cooled to room temperature, aqueous NH 4 Cl (100 μL), CH 2 Cl 2 (500 μL), and dodecane (internal standard) were added and the mixture was filtered through a pad of silica gel and ethyl acetate (EtOAc; approx. 5 mL). As a result of GC analysis of the crude product using dodecane as an internal standard, the yield of (p-methoxyphenyl) (p-methylphenyl) acetonitrile (4bc) was 34%, and that of (p-methylphenyl) phenylacetonitrile (4ba) The yield was 13%. Thus, when a methoxyphenyl group is to be introduced and a ligand having a binaphthyl skeleton is used, a phenyl substitution product was also produced as a by-product ((p-methoxyphenyl) (p-methyl (Spectral data of phenyl) acetonitrile (4bc) and (p-methylphenyl) phenylacetonitrile (4ba) will be described later).
　実施例３－２ Example 3-2
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　内容積10 mLの密閉ガラス容器に、磁気撹拌子を収容し、真空下、ヒートガンで乾燥させた後、室温に冷却し、アルゴンガスを満たした。次いで、前記ガラス容器に、酢酸パラジウム（Pd(OAc)2; 3.3 mg, 15μmol）、実施例１で得た2,2’-ビス（ジシクロヘキシルホスフィノ）-1,1’-ビピリジル（DCPB; 16.5 mg, 30μmol）、及び乾燥1,4-ジオキサン（300μL）をアルゴン気流下に室温で添加した。同じ温度で30分間攪拌した後、実施例２－１で得たフェニルアセトニトリル（34.5μL, 0.3 mmol）、ブロモベンゼン（47.7 mg, 0.45 mmol）、K3PO4（191 mg, 0.9 mmol）、及び乾燥1,4-ジオキサン（300μL）を添加し、ガラス容器を密封した。混合物を80℃で24時間攪拌した。混合物を室温まで冷却した後、シリカゲルのパッドでろ過し、酢酸エチル（EtOAc; 約15 mL）で繰り返し洗浄した。ろ液を減圧下に濃縮した。粗生成物をPTLC（酢酸エチル／n-ヘキサン=1: 20）により精製し、ジフェニルアセトニトリル（4aa）を白色固体として得た（51.6 mg, 89％）。この結果は、後述の表４のentry 1に相当する。 A magnetic stir bar was housed in a sealed glass container having an internal volume of 10 mL, dried under a vacuum with a heat gun, cooled to room temperature, and filled with argon gas. Next, palladium acetate (Pd (OAc) 2 ; 3.3 mg, 15 μmol), 2,2′-bis (dicyclohexylphosphino) -1,1′-bipyridyl (DCPB; 16.5) obtained in Example 1 was placed in the glass container. mg, 30 μmol) and dry 1,4-dioxane (300 μL) were added at room temperature under a stream of argon. After stirring at the same temperature for 30 minutes, phenylacetonitrile (34.5 μL, 0.3 mmol), bromobenzene (47.7 mg, 0.45 mmol), K 3 PO 4 (191 mg, 0.9 mmol) obtained in Example 2-1 and Dry 1,4-dioxane (300 μL) was added and the glass container was sealed. The mixture was stirred at 80 ° C. for 24 hours. After the mixture was cooled to room temperature, it was filtered through a pad of silica gel and washed repeatedly with ethyl acetate (EtOAc; ca. 15 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by PTLC (ethyl acetate / n-hexane = 1: 20) to obtain diphenylacetonitrile (4aa) as a white solid (51.6 mg, 89%). This result corresponds to entry 1 in Table 4 described later.
　なお、ブロモベンゼン（Ph-Br）ではなく、クロロベンゼン（Ph-Cl）を用いた他は上記と同様に実験を行った場合、ジフェニルアセトニトリル（4aa）の収率は11%であった。
ジフェニルアセトニトリル（4aa）
1H NMR (400 MHz, CDCl3) δ 5.13 (s, 1H), 7.29-7.39 (m, 10H). 13C NMR (100 MHz, CDCl3) δ 42.5, 119.6, 127.7, 128.2, 129.2, 135.9. HRMS (DART) m/z calcd for C14H11N [M]+: 193.0892, found 193.0898。 When the experiment was performed in the same manner as above except that chlorobenzene (Ph-Cl) was used instead of bromobenzene (Ph-Br), the yield of diphenylacetonitrile (4aa) was 11%.
Diphenylacetonitrile (4aa)
1 H NMR (400 MHz, CDCl 3) δ 5.13 (s, 1H), 7.29-7.39 (m, 10H). 13 C NMR (100 MHz, CDCl 3) δ 42.5, 119.6, 127.7, 128.2, 129.2, 135.9. HRMS (DART) m / z calcd for C 14 H 11 N [M] + : 193.0892, found 193.0898.
　実施例３－３
　パラジウム触媒の量、配位子の種類及び量、反応温度、反応時間を種々変更する他は実施例３－１と同様の処理を行った。結果を表３に示す。 Example 3-3
The same treatment as in Example 3-1 was performed, except that the amount of the palladium catalyst, the type and amount of the ligand, the reaction temperature, and the reaction time were variously changed. The results are shown in Table 3.
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
　実施例３－４
　基質及びハロゲン化芳香族化合物が有する芳香族基（フェニル基）を種々変更する他は実施例３－２と同様の処理を行った。結果を表４に示す。 Example 3-4
The same treatment as in Example 3-2 was performed, except that the aromatic group (phenyl group) of the substrate and the halogenated aromatic compound was variously changed. The results are shown in Table 4.
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
 (4-メトキシフェニル)フェニルアセトニトリル（4ac）
分取HPLCによる精製。
1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 5.10 (s, 1H), 6.89 (dm, J = 8.8 Hz, 2H), 7.23-7.26 (m, 2H), 7.30-7.39 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 41.7, 55.3, 114.5, 119.9, 127.6, 127.9, 128.1, 128.8, 129.1, 136.2, 159.4. HRMS (DART) m/z calcd for C15H13NO [M]+: 223.0997, found 223.1008。
(4-フルオロフェニル)フェニルアセトニトリル（4ad）
分取HPLCによる精製。
1H NMR (400 MHz, CDCl3) δ 5.13 (s, 1H), 7.03-7.09 (m, 2H), 7.29-7.40 (m, 7H). 13C NMR (100 MHz, CDCl3) δ 41.8, 116.1 (d, J = 22.9 Hz), 119.5, 127.6, 128.4, 129.3, 129.4 (d, J = 8.6 Hz), 131.7 (d, J = 2.8 Hz), 135.6 (d, J = 251 Hz). HRMS (DART) m/z calcd for C14H10NF [M]+: 211.0797, found 211.0802。
(4-メトキシフェニル)フェニルアセトニトリル（4ba）
分取HPLCによる精製。
1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 5.09 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.29-7.30 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 21.0, 42.2, 119.8, 127.5, 127.6, 128.1, 129.1, 129.8, 132.9, 136.1, 138.0. HRMS (FAB) m/z calcd for C15H13N [M]+: 207.1048, found 207.1038。
(4-メトキシフェニル)(4-メトキシフェニル)アセトニトリル（4bc）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 10)。
1H NMR (400 MHz, CDCl3) δ 2.32 (s, 3H), 3.77 (s, 3H), 5.04 (s, 1H), 6.86 (dm, J = 8.8 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.19-7.24 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 21.0, 41.4, 55.2, 114.4, 120.0, 127.4, 128.1, 128.8, 129.7, 133.2, 137.9, 159.3. HRMS (DART) m/z calcd for C16H15NO [M]+: 237.1154, found 237.1150。
(4-メチルフェニル)(4-トリフルオロメチルフェニル)アセトニトリル（4be）
分取HPLCによる精製。
1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 5.15 (s, 1H), 7.18-7.23 (m, 4H), 7.47 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.0, 42.0, 119.1, 123.7 (q, J = 274 Hz), 126.2 (q, J = 3.8 Hz), 127.6, 128.1, 130.1, 130.5 (q, J = 32.5 Hz), 132.0, 138.6, 140.0. HRMS (DART) m/z calcd for C16H12NF3 [M]+: 275.0922, found 275.0921。
ジ-(4-メトキシフェニル)アセトニトリル（4cc）
分取HPLCによる精製。
1H NMR (400 MHz, CDCl3) δ 3.79 (s, 6H), 5.05 (s, 1H), 6.88 (d, J = 9.2 Hz, 4H), 7.23 (d, J = 9.2 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 41.0, 55.3, 114.5, 120.1, 128.3, 128.8, 159.4. HRMS (DART) m/z calcd for C16H15NO2 [M]+: 253.1103, found 253.1101。
(4-フルオロフェニル)(3-チエニル)アセトニトリル（4dk）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 20)。
1H NMR (400 MHz, CDCl3) δ 5.17 (s, 1H), 6.95 (dd, J = 5.2, 1.6 Hz, 1H), 7.06-7.11 (m, 2H), 7.23-7.25 (m, 1H), 7.31-7.36 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 37.4, 116.2 (d, J = 22.1 Hz), 119.2, 123.2, 126.5, 127.6, 129.4 (d, J = 8.6 Hz), 131.1 (d, J = 2.9 Hz), 135.6, 162.5 (d, J = 243 Hz). HRMS (DART) m/z calcd for C12H8NFS [M]+: 217.0362, found 217.0358。
フェニル(4-トリフルオロメチルフェニル)アセトニトリル（4ea）
分取HPLCによる精製。
1H NMR (400 MHz, CDCl3) δ 5.20 (s, 1H), 7.33-7.42 (m, 5H), 7.48 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 42.4, 118.9, 123.7 (q, J = 274 Hz), 126.2 (q, J = 3.8 Hz), 127.7, 128.1, 128.6, 129.4, 130.6 (q, J = 33.4 Hz), 134.9, 139.8. HRMS (DART) m/z calcd for C15H10NF3 [M]+: 261.0765, found 261.0764。
(4-メトキシカルボニルフェニル)(4-メチルフェニル)アセトニトリル（4fb）
分取HPLCによる精製。
1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 3.91 (s, 3H), 5.15 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.0, 42.2, 52.2, 119.2, 127.6, 127.7, 130.0, 130.1, 130.4, 132.2, 138.5, 140.9, 166.3. IR (Neat) v 699, 774, 796, 1020, 1045, 1108, 1184, 1246, 1279, 1416, 1434, 1512, 1610, 1720, 2246, 3004, 3025 cm-1. HRMS (DART) m/z calcd for C17H15NO2 [M]+: 265.1103, found 265.1106。
フェニル(3-チエニル)アセトニトリル（4ka）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 20)。
1H NMR (400 MHz, CDCl3) δ 5.19 (s, 1H), 6.97 (dd, J = 5.6, 1.2 Hz, 1H), 7.24-7.25 (m, 1H), 7.33-7.40 (m, 6H), 13C NMR (100 MHz, CDCl3) δ 38.1, 119.4, 123.2, 126.6, 127.3, 127.6, 128.4, 129.2, 135.2, 135.8. HRMS (DART) m/z calcd for C12H9NS [M]+: 199.0456, found 199.0447。 (4-Methoxyphenyl) phenylacetonitrile (4ac)
Purification by preparative HPLC.
1 H NMR (400 MHz, CDCl 3 ) δ 3.80 (s, 3H), 5.10 (s, 1H), 6.89 (dm, J = 8.8 Hz, 2H), 7.23-7.26 (m, 2H), 7.30-7.39 ( 13 C NMR (100 MHz, CDCl 3 ) δ 41.7, 55.3, 114.5, 119.9, 127.6, 127.9, 128.1, 128.8, 129.1, 136.2, 159.4.HRMS (DART) m / z calcd for C 15 H 13 NO [M] + : 223.0997, found 223.1008.
(4-Fluorophenyl) phenylacetonitrile (4ad)
Purification by preparative HPLC.
1 H NMR (400 MHz, CDCl 3 ) δ 5.13 (s, 1H), 7.03-7.09 (m, 2H), 7.29-7.40 (m, 7H). 13 C NMR (100 MHz, CDCl 3 ) δ 41.8, 116.1 (d, J = 22.9 Hz), 119.5, 127.6, 128.4, 129.3, 129.4 (d, J = 8.6 Hz), 131.7 (d, J = 2.8 Hz), 135.6 (d, J = 251 Hz). HRMS (DART ) m / z calcd for C 14 H 10 NF [M] + : 211.0797, found 211.0802.
(4-Methoxyphenyl) phenylacetonitrile (4ba)
Purification by preparative HPLC.
1 H NMR (400 MHz, CDCl 3 ) δ 2.33 (s, 3H), 5.09 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.29 -7.30 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 21.0, 42.2, 119.8, 127.5, 127.6, 128.1, 129.1, 129.8, 132.9, 136.1, 138.0.HRMS (FAB) m / z calcd for C 15 H 13 N [M] + : 207.1048, found 207.1038.
(4-Methoxyphenyl) (4-methoxyphenyl) acetonitrile (4bc)
Purification by PTLC (ethyl acetate / hexane = 1: 10).
1 H NMR (400 MHz, CDCl 3 ) δ 2.32 (s, 3H), 3.77 (s, 3H), 5.04 (s, 1H), 6.86 (dm, J = 8.8 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.19-7.24 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 21.0, 41.4, 55.2, 114.4, 120.0, 127.4, 128.1, 128.8, 129.7, 133.2, 137.9, 159.3.HRMS (DART) m / z calcd for C 16 H 15 NO [M] + : 237.1154, found 237.1150.
(4-Methylphenyl) (4-trifluoromethylphenyl) acetonitrile (4be)
Purification by preparative HPLC.
1 H NMR (400 MHz, CDCl 3 ) δ 2.34 (s, 3H), 5.15 (s, 1H), 7.18-7.23 (m, 4H), 7.47 (d, J = 8.4 Hz, 2H), 7.63 (d, 13 C NMR (100 MHz, CDCl3) δ 21.0, 42.0, 119.1, 123.7 (q, J = 274 Hz), 126.2 (q, J = 3.8 Hz), 127.6, 128.1, 130.1, 130.5 (q, J = 32.5 Hz), 132.0, 138.6, 140.0. HRMS (DART) m / z calcd for C 16 H 12 NF 3 [M] + : 275.0922, found 275.0921.
Di- (4-methoxyphenyl) acetonitrile (4cc)
Purification by preparative HPLC.
1 H NMR (400 MHz, CDCl 3 ) δ 3.79 (s, 6H), 5.05 (s, 1H), 6.88 (d, J = 9.2 Hz, 4H), 7.23 (d, J = 9.2 Hz, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 41.0, 55.3, 114.5, 120.1, 128.3, 128.8, 159.4. HRMS (DART) m / z calcd for C 16 H 15 NO 2 [M] + : 253.1103, found 253.1101.
(4-Fluorophenyl) (3-thienyl) acetonitrile (4dk)
Purification by PTLC (ethyl acetate / hexane = 1: 20).
1 H NMR (400 MHz, CDCl 3 ) δ 5.17 (s, 1H), 6.95 (dd, J = 5.2, 1.6 Hz, 1H), 7.06-7.11 (m, 2H), 7.23-7.25 (m, 1H), 7.31-7.36 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 37.4, 116.2 (d, J = 22.1 Hz), 119.2, 123.2, 126.5, 127.6, 129.4 (d, J = 8.6 Hz), 131.1 (d, J = 2.9 Hz), 135.6, 162.5 (d, J = 243 Hz). HRMS (DART) m / z calcd for C 12 H 8 NFS [M] + : 217.0362, found 217.0358.
Phenyl (4-trifluoromethylphenyl) acetonitrile (4ea)
Purification by preparative HPLC.
1 H NMR (400 MHz, CDCl 3 ) δ 5.20 (s, 1H), 7.33-7.42 (m, 5H), 7.48 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H) 13 C NMR (100 MHz, CDCl 3 ) δ 42.4, 118.9, 123.7 (q, J = 274 Hz), 126.2 (q, J = 3.8 Hz), 127.7, 128.1, 128.6, 129.4, 130.6 (q, J = 33.4 Hz), 134.9, 139.8. HRMS (DART) m / z calcd for C 15 H 10 NF 3 [M] + : 261.0765, found 261.0764.
(4-Methoxycarbonylphenyl) (4-methylphenyl) acetonitrile (4fb)
Purification by preparative HPLC.
1 H NMR (400 MHz, CDCl 3 ) δ 2.34 (s, 3H), 3.91 (s, 3H), 5.15 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 21.0, 42.2, 52.2, 119.2, 127.6 , 127.7, 130.0, 130.1, 130.4, 132.2, 138.5, 140.9, 166.3. IR (Neat) v 699, 774, 796, 1020, 1045, 1108, 1184, 1246, 1279, 1416, 1434, 1512, 1610, 1720, 2246, 3004, 3025 cm −1 .HRMS (DART) m / z calcd for C 17 H 15 NO 2 [M] + : 265.1103, found 265.1106.
Phenyl (3-thienyl) acetonitrile (4ka)
Purification by PTLC (ethyl acetate / hexane = 1: 20).
1 H NMR (400 MHz, CDCl 3 ) δ 5.19 (s, 1H), 6.97 (dd, J = 5.6, 1.2 Hz, 1H), 7.24-7.25 (m, 1H), 7.33-7.40 (m, 6H), 13 C NMR (100 MHz, CDCl 3 ) δ 38.1, 119.4, 123.2, 126.6, 127.3, 127.6, 128.4, 129.2, 135.2, 135.8. HRMS (DART) m / z calcd for C 12 H 9 NS [M] + : 199.0456, found 199.0447.
　［実施例４：ジ（ヘテロ）アリールアセトニトリル化合物の（ヘテロ）アリール化］
　実施例４－１ [Example 4: (Hetero) arylation of di (hetero) arylacetonitrile compound]
Example 4-1
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　内容積10 mLの密閉ガラス容器に、磁気撹拌子を収容し、真空下、ヒートガンで乾燥させた後、室温に冷却し、アルゴンガスを満たした。次いで、前記ガラス容器に、酢酸パラジウム（Pd(OAc)2; 6.7 mg, 30μmol）、P(t-ブチル)3・HBF4（26.1 mg, 90μmol）、Cs2CO3（195 mg, 0.6 mmol）、及び乾燥1,4-ジオキサン（300μL）をアルゴン気流下に室温で添加した。同じ温度で10分間攪拌した後、実施例３－２で得たジフェニルアセトニトリル（58.0 mg, 0.3 mmol）、ヨードベンゼン（50.3μL, 0.45 mmol）、及び乾燥1,4-ジオキサン（300μL）を添加し、ガラス容器を密封した。混合物を105℃で20時間攪拌した。混合物を室温まで冷却した後、混合物をシリカゲルのパッドでろ過し、酢酸エチル（EtOAc; 約30 mL）で繰り返し洗浄した。ろ液を減圧下に濃縮した。粗生成物をPTLC（酢酸エチル／n-ヘキサン=5: 95）により精製し、トリフェニルアセトニトリル（6aaa）を白色固体として得た（76.1 mg, 94％）。この結果は、後述の表６のentry 1に相当する。
トリフェニルアセトニトリル（6aaa）
1H NMR (400 MHz, CDCl3) δ 7.21-7.26 (m, 6H), 7.33-7.36 (m, 9H). 13C NMR (100 MHz, CDCl3) δ 57.4, 123.5, 128.1, 128.7, 128.8, 140.2. HRMS (DART) m/z calcd for C20H15N [M]+: 269.1205, found 269.1217。 A magnetic stir bar was housed in a sealed glass container having an internal volume of 10 mL, dried under a vacuum with a heat gun, cooled to room temperature, and filled with argon gas. Next, palladium acetate (Pd (OAc) 2 ; 6.7 mg, 30 μmol), P (t-butyl) 3 .HBF 4 (26.1 mg, 90 μmol), Cs 2 CO 3 (195 mg, 0.6 mmol) is placed in the glass container. , And dry 1,4-dioxane (300 μL) was added at room temperature under a stream of argon. After stirring at the same temperature for 10 minutes, diphenylacetonitrile (58.0 mg, 0.3 mmol) obtained in Example 3-2, iodobenzene (50.3 μL, 0.45 mmol), and dry 1,4-dioxane (300 μL) were added. The glass container was sealed. The mixture was stirred at 105 ° C. for 20 hours. After the mixture was cooled to room temperature, the mixture was filtered through a pad of silica gel and washed repeatedly with ethyl acetate (EtOAc; about 30 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by PTLC (ethyl acetate / n-hexane = 5: 95) to obtain triphenylacetonitrile (6aaa) as a white solid (76.1 mg, 94%). This result corresponds to entry 1 in Table 6 described later.
Triphenylacetonitrile (6aaa)
1 H NMR (400 MHz, CDCl 3 ) δ 7.21-7.26 (m, 6H), 7.33-7.36 (m, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 57.4, 123.5, 128.1, 128.7, 128.8, 140.2. HRMS (DART) m / z calcd for C 20 H 15 N [M] + : 269.1205, found 269.1217.
　実施例４－２
　ハロゲン化芳香族化合物が有するハロゲン原子、配位子の種類及び量、塩基の種類を種々変更する他は実施例４－１と同様の処理を行った。結果を表５に示す。 Example 4-2
The same treatment as in Example 4-1 was performed, except that the halogen atom contained in the halogenated aromatic compound, the type and amount of ligand, and the type of base were variously changed. The results are shown in Table 5.
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
　実施例４－３
　基質及びハロゲン化芳香族化合物が有する芳香族基（フェニル基）を種々変更する他は実施例４－１と同様の処理を行った。結果を表６に示す。 Example 4-3
The same treatment as in Example 4-1 was performed, except that the aromatic group (phenyl group) of the substrate and the halogenated aromatic compound was variously changed. The results are shown in Table 6.
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
ジフェニル(4-メチルフェニル)アセトニトリル（6aab）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 7.09 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 7.21-7.23 (m, 4H), 7.31-7.36 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 21.0, 57.1, 123.6, 128.0, 128.6, 128.7, 128.8, 129.3, 137.2, 138.0, 140.3. HRMS (DART) m/z calcd for C21H17N [M]+: 283.1361, found 283.1368。
ジフェニル(4-メトキシフェニル)アセトニトリル（6aac）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, CDCl3) δ 3.81 (s, 3H), 6.87 (dm, J = 8.8 Hz, 2H), 7.12 (dm, J = 8.8 Hz, 2H), 7.21-7.23 (m, 4H), 7.31-7.38 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 55.3, 56.7, 113.9, 123.6, 128.0, 128.6, 128.7, 130.0, 132.2, 140.5, 159.2. HRMS (DART) m/z calcd for C21H17NO [M]+: 299.1310, found 299.1310。
[4-(N, N-ジメチルアミノ)フェニル]ジフェニルアセトニトリル（6aao）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 4)。ハロゲン化芳香族化合物として4-ブロモ-N, N-ジメチルアニリンを使用した。
1H NMR (400 MHz, CDCl3) δ 2.94 (s, 6H), 6.65 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.23-7.25 (m, 4H), 7.30-7.33 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 40.3, 56.6, 111.9, 123.9, 127.3, 127.8, 128.5, 128.7, 129.5, 140.9, 149.9. HRMS (DART) m/z calcd for C22H20N2 [M]+: 312.1627, found 312.1636。
ジフェニル(4-フルオロフェニル)アセトニトリル（6aad）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, CDCl3) δ 7.02-7.06 (m, 2H), 7.17-7.22 (m, 6H), 7.34-7.39 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 56.8, 115.6 (d, J = 21.5 Hz), 123.3, 128.3, 128.7, 128.8, 130.6 (d, J = 8.2 Hz), 136.1 (d, J = 3.3 Hz), 140.0, 162.3 (d, J = 248 Hz). HRMS (DART) m/z calcd for C20H14NF [M]+: 287.1110, found 287.1116。
ジフェニル[4-(トリフルオロメチル)フェニル]アセトニトリル（6aae）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, CDCl3) δ 7.20-7.22 (m, 4H), 7.37-7.40 (m, 8H), 7.63 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 57.3, 122.8, 123.7 (q, J = 271 Hz), 125.7 (q, J = 3.3 Hz), 128.5, 128.7, 128.9, 129.3, 130.5 (q, J = 33.0 Hz), 139.3, 144.2. HRMS (DART) m/z calcd for C21H14NF3 [M]+: 337.1078, found 337.1075。
ジフェニル(2-メチルフェニル)アセトニトリル（6aaj）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, CDCl3) δ 2.24 (s, 3H), 6.48 (d, J = 8.4 Hz, 1H), 7.05-7.08 (m, 1H), 7.23-7.26 (m, 6H), 7.34-7.38 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 21.6, 56.3, 122.5, 125.8, 128.1, 128.5, 128.7, 128.8, 129.6, 132.5, 137.9, 138.2, 139.6. HRMS (DART) m/z calcd for C21H17N [M]+: 283.1361, found 283.1374。
ジフェニル(4-メトキシカルボニルフェニル)アセトニトリル（6aaf）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, CDCl3) δ 3.92 (s, 3H), 7.20-7.22 (m, 4H), 7.32-7.38 (m, 8H), 8.03 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 52.3, 57.4, 122.9, 128.4, 128.7, 128.8, 128.9, 129.9, 130.0, 139.5, 145.0, 166.3. IR (Neat) v 695, 753, 850, 1019, 1109, 1189, 1278, 1409, 1435, 1447, 1492, 1599, 1610, 1721, 2238, 3027, 3062 cm-1. HRMS (DART) m/z calcd for C22H17NO2 [M]+: 327.1259, found 327.1263。 Diphenyl (4-methylphenyl) acetonitrile (6aab)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, CDCl 3 ) δ 2.35 (s, 3H), 7.09 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 7.6 Hz, 2H), 7.21-7.23 (m, 4H) , 7.31-7.36 (m, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 21.0, 57.1, 123.6, 128.0, 128.6, 128.7, 128.8, 129.3, 137.2, 138.0, 140.3.HRMS (DART) m / z calcd for C 21 H 17 N [M] + : 283.1361, found 283.1368.
Diphenyl (4-methoxyphenyl) acetonitrile (6aac)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, CDCl 3 ) δ 3.81 (s, 3H), 6.87 (dm, J = 8.8 Hz, 2H), 7.12 (dm, J = 8.8 Hz, 2H), 7.21-7.23 (m, 4H) , 7.31-7.38 (m, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 55.3, 56.7, 113.9, 123.6, 128.0, 128.6, 128.7, 130.0, 132.2, 140.5, 159.2.HRMS (DART) m / z calcd for C 21 H 17 NO [M] + : 299.1310, found 299.1310.
[4- (N, N-dimethylamino) phenyl] diphenylacetonitrile (6aao)
Purification by PTLC (ethyl acetate / hexane = 1: 4). 4-Bromo-N, N-dimethylaniline was used as the halogenated aromatic compound.
1 H NMR (400 MHz, CDCl 3 ) δ 2.94 (s, 6H), 6.65 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.23-7.25 (m, 4H) , 7.30-7.33 (m, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 40.3, 56.6, 111.9, 123.9, 127.3, 127.8, 128.5, 128.7, 129.5, 140.9, 149.9.HRMS (DART) m / z calcd for C 22 H 20 N 2 [M] + : 312.1627, found 312.1636.
Diphenyl (4-fluorophenyl) acetonitrile (6aad)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, CDCl 3 ) δ 7.02-7.06 (m, 2H), 7.17-7.22 (m, 6H), 7.34-7.39 (m, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 56.8 , 115.6 (d, J = 21.5 Hz), 123.3, 128.3, 128.7, 128.8, 130.6 (d, J = 8.2 Hz), 136.1 (d, J = 3.3 Hz), 140.0, 162.3 (d, J = 248 Hz) HRMS (DART) m / z calcd for C 20 H 14 NF [M] + : 287.1110, found 287.1116.
Diphenyl [4- (trifluoromethyl) phenyl] acetonitrile (6aae)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, CDCl 3 ) δ 7.20-7.22 (m, 4H), 7.37-7.40 (m, 8H), 7.63 (d, J = 8.4 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 57.3, 122.8, 123.7 (q, J = 271 Hz), 125.7 (q, J = 3.3 Hz), 128.5, 128.7, 128.9, 129.3, 130.5 (q, J = 33.0 Hz), 139.3, 144.2.HRMS ( DART) m / z calcd for C 21 H 14 NF 3 [M] + : 337.1078, found 337.1075.
Diphenyl (2-methylphenyl) acetonitrile (6aaj)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, CDCl 3 ) δ 2.24 (s, 3H), 6.48 (d, J = 8.4 Hz, 1H), 7.05-7.08 (m, 1H), 7.23-7.26 (m, 6H), 7.34- 7.38 (m, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 21.6, 56.3, 122.5, 125.8, 128.1, 128.5, 128.7, 128.8, 129.6, 132.5, 137.9, 138.2, 139.6.HRMS (DART) m / z calcd for C 21 H 17 N [M] + : 283.1361, found 283.1374.
Diphenyl (4-methoxycarbonylphenyl) acetonitrile (6aaf)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, CDCl 3 ) δ 3.92 (s, 3H), 7.20-7.22 (m, 4H), 7.32-7.38 (m, 8H), 8.03 (d, J = 8.0 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 52.3, 57.4, 122.9, 128.4, 128.7, 128.8, 128.9, 129.9, 130.0, 139.5, 145.0, 166.3. IR (Neat) v 695, 753, 850, 1019, 1109, 1189, 1278, 1409, 1435, 1447, 1492, 1599, 1610, 1721, 2238, 3027, 3062 cm −1 .HRMS (DART) m / z calcd for C 22 H 17 NO 2 [M] + : 327.1259, found 327.1263.
ジフェニル(4-ホルムルフェニル)アセトニトリル（6aam）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, CDCl3) δ 7.20-7.23 (m, 4H), 7.37-7.39 (m, 6H), 7.44 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 10.04 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 57.5, 122.7, 128.5, 128.7, 128.9, 129.6, 130.0, 135.9, 139.3, 146.6, 191.4. IR (Neat) v 689, 724, 755, 822, 1014, 1174, 1187, 1210, 1393, 1446, 1490, 1577, 1596, 1695, 2239, 3033, 3062 cm-1. HRMS (DART) m/z calcd for C21H16NO [M+H]+: 298.1232, found 298.1237。
ジフェニル(3-チエニル)アセトニトリル（6aak）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.25-7.28 (m, 4H), 7.32-7.39 (m, 7H). 13C NMR (100 MHz, CDCl3) δ 53.8, 122.6, 125.0, 126.9, 128.0, 128.19, 128.25, 128.7, 140.1, 140.8. HRMS (DART) m/z calcd for C18H13NS [M]+: 275.0769, found 275.0763。
ジフェニル(N-メチル-5-インドリル)アセトニトリル（6aan）
PTLCによる精製（酢酸エチル/ヘキサン= 10: 90)。
ハロゲン化芳香族化合物として5-ブロモ-N-メチルインドールを使用した。
1H NMR (400 MHz, CDCl3) δ 3.78 (s, 3H), 6.39-6.40 (m, 1H), 7.06 (d, J = 3.2 Hz, 1H), 7.16 (dd, J = 8.8, 2.0 Hz, 1H), 7.23-7.33 (m, 12H). 13C NMR (100 MHz, CDCl3) δ 32.9, 57.5, 101.5, 109.5, 121.4, 122.6, 124.2, 127.9, 128.1, 128.5, 128.9, 129.8, 131.2, 136.0, 141.0. HRMS (DART) m/z calcd for C23H18N2 [M]+: 322.1470, found 322.1480。
ジフェニル(4-ピリジル)アセトニトリル（6aal）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 4)。
1H NMR (400 MHz, CDCl3) δ 7.18-7.22 (m, 6H), 7.37-7.40 (m, 6H), 8.64 (dd, J = 4.4, 2.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 57.0, 122.2, 123.5, 128.6, 128.7, 129.0, 138.5, 149.0, 150.4. HRMS (DART) m/z calcd for C19H15N2 [M+H]+: 271.1235, found 271.1238。
(4-ホルミルフェニル)(4-メトキシフェニル)フェニルアセトニトリル（6acm）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 6.89 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.20-7.23 (m, 2H), 7.37-7.38 (m, 3H), 7.43 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 10.04 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 55.4, 56.8, 114.2, 122.9, 128.5, 128.6, 128.9, 129.5, 129.87, 129.92, 131.2, 135.9, 139.6, 147.0, 159.5, 191.4. IR (Neat) v 681, 698, 757, 817, 1030, 1181, 1213, 1253, 1308, 1462, 1492, 1508, 1605, 1701, 2238, 3031, 3055 cm-1. HRMS (DART) m/z calcd for C22H17NO2 [M]+: 327.1259, found 327.1268。
(4-フルオロフェニル)(4-メトキシカルボニルフェニル)フェニルアセトニトリル（6adf）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, アセトン-d6) δ 3.90 (s, 3H), 7.21-7.30 (m, 6H), 7.38-7.49 (m, 5H), 8.08 (dm, J = 8.8 Hz, 2H). 13C NMR (100 MHz, アセトン-d6) δ 52.5, 57.6, 116.7 (d, J = 22.3 Hz), 123.3, 129.3, 129.5, 129.6, 129.9, 130.7, 131.2, 131.6 (d, J = 8.2 Hz), 136.7 (d, J = 3.3 Hz), 140.4, 145.8, 163.3 (d, J = 246 Hz), 166.5. IR (Neat) v 697, 760, 825, 1018, 1113, 1167, 1187, 1226, 1280, 1411, 1446, 1507, 1603, 1720, 2240, 3027, 3062 cm-1. HRMS (DART) m/z calcd for C22H16NO2F [M]+: 345.1165, found 345.1174。
(4-メトキシフェニル)(4-メチルフェニル)フェニルアセトニトリル（6bac）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 3.79 (s, 3H), 6.85 (dm, J = 8.8 Hz, 2H), 7.08-7.15 (m, 6H), 7.21-7.23 (m, 2H), 7.30-7.36 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 21.0, 55.3, 56.4, 113.9, 123.7, 127.9, 128.55, 128.56, 128.66, 129.3, 129.9, 132.4, 137.5, 137.9, 140.7, 159.2. HRMS (DART) m/z calcd for C22H18NO [M]+: 313.1467, found 313.1475。 Diphenyl (4-formylphenyl) acetonitrile (6aam)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, CDCl 3 ) δ 7.20-7.23 (m, 4H), 7.37-7.39 (m, 6H), 7.44 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 10.04 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 57.5, 122.7, 128.5, 128.7, 128.9, 129.6, 130.0, 135.9, 139.3, 146.6, 191.4.IR (Neat) v 689, 724, 755, 822, 1014, 1174, 1187, 1210, 1393, 1446, 1490, 1577, 1596, 1695, 2239, 3033, 3062 cm -1 .HRMS (DART) m / z calcd for C 21 H 16 NO [ M + H] + : 298.1232, found 298.1237.
Diphenyl (3-thienyl) acetonitrile (6aak)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, CDCl 3 ) δ 7.44 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.25-7.28 (m, 4H), 7.32-7.39 (m, 13 C NMR (100 MHz, CDCl 3 ) δ 53.8, 122.6, 125.0, 126.9, 128.0, 128.19, 128.25, 128.7, 140.1, 140.8.HRMS (DART) m / z calcd for C 18 H 13 NS [M ] + : 275.0769, found 275.0763.
Diphenyl (N-methyl-5-indolyl) acetonitrile (6aan)
Purification by PTLC (ethyl acetate / hexane = 10: 90).
5-Bromo-N-methylindole was used as the halogenated aromatic compound.
1 H NMR (400 MHz, CDCl 3 ) δ 3.78 (s, 3H), 6.39-6.40 (m, 1H), 7.06 (d, J = 3.2 Hz, 1H), 7.16 (dd, J = 8.8, 2.0 Hz, 1H), 7.23-7.33 (m, 12H). 13 C NMR (100 MHz, CDCl 3 ) δ 32.9, 57.5, 101.5, 109.5, 121.4, 122.6, 124.2, 127.9, 128.1, 128.5, 128.9, 129.8, 131.2, 136.0 HRMS (DART) m / z calcd for C 23 H 18 N 2 [M] + : 322.1470, found 322.1480.
Diphenyl (4-pyridyl) acetonitrile (6aal)
Purification by PTLC (ethyl acetate / hexane = 1: 4).
1 H NMR (400 MHz, CDCl 3 ) δ 7.18-7.22 (m, 6H), 7.37-7.40 (m, 6H), 8.64 (dd, J = 4.4, 2.0 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 57.0, 122.2, 123.5, 128.6, 128.7, 129.0, 138.5, 149.0, 150.4. HRMS (DART) m / z calcd for C 19 H 15 N 2 [M + H] + : 271.1235, found 271.1238.
(4-Formylphenyl) (4-methoxyphenyl) phenylacetonitrile (6acm)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, CDCl 3 ) δ 3.82 (s, 3H), 6.89 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.20-7.23 (m, 2H) , 7.37-7.38 (m, 3H), 7.43 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 10.04 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 55.4, 56.8, 114.2, 122.9, 128.5, 128.6, 128.9, 129.5, 129.87, 129.92, 131.2, 135.9, 139.6, 147.0, 159.5, 191.4.IR (Neat) v 681, 698, 757, 817, 1030, 1181 , 1213, 1253, 1308, 1462, 1492, 1508, 1605, 1701, 2238, 3031, 3055 cm -1 .HRMS (DART) m / z calcd for C 22 H 17 NO 2 [M] + : 327.1259, found 327.1268 .
(4-Fluorophenyl) (4-methoxycarbonylphenyl) phenylacetonitrile (6adf)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, acetone-d 6 ) δ 3.90 (s, 3H), 7.21-7.30 (m, 6H), 7.38-7.49 (m, 5H), 8.08 (dm, J = 8.8 Hz, 2H). 13 C NMR (100 MHz, acetone-d 6 ) δ 52.5, 57.6, 116.7 (d, J = 22.3 Hz), 123.3, 129.3, 129.5, 129.6, 129.9, 130.7, 131.2, 131.6 (d, J = 8.2 Hz) , 136.7 (d, J = 3.3 Hz), 140.4, 145.8, 163.3 (d, J = 246 Hz), 166.5. IR (Neat) v 697, 760, 825, 1018, 1113, 1167, 1187, 1226, 1280, 1411, 1446, 1507, 1603, 1720, 2240, 3027, 3062 cm −1 .HRMS (DART) m / z calcd for C 22 H 16 NO 2 F [M] + : 345.1165, found 345.1174.
(4-Methoxyphenyl) (4-methylphenyl) phenylacetonitrile (6bac)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
1 H NMR (400 MHz, CDCl 3 ) δ 2.34 (s, 3H), 3.79 (s, 3H), 6.85 (dm, J = 8.8 Hz, 2H), 7.08-7.15 (m, 6H), 7.21-7.23 ( m, 2H), 7.30-7.36 (m , 3H). 13 C NMR (100 MHz, CDCl 3) δ 21.0, 55.3, 56.4, 113.9, 123.7, 127.9, 128.55, 128.56, 128.66, 129.3, 129.9, 132.4, 137.5 , 137.9, 140.7, 159.2. HRMS (DART) m / z calcd for C 22 H 18 NO [M] + : 313.1467, found 313.1475.
(2-メチルフェニル)(4-メチルフェニル)(4-トリフルオロメチルフェニル)アセトニトリル（6bej）
PTLCによる精製（酢酸エチル/ヘキサン= 4: 96)。
1H NMR (400 MHz, CDCl3) δ 2.24 (s, 3H), 2.38 (s, 3H), 6.47 (d, J = 8.0 Hz, 1H), 7.06-7.10 (m, 3H), 7.19 (d, J = 8.8 Hz, 2H), 7.24-7.30 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.0, 21.6, 55.9, 122.0, 123.8, (q, J = 271 Hz), 125.7, (q, J = 3.3 Hz), 126.0, 128.5, 128.8, 129.1, 129.4, 129.7, 130.3 (q, J = 31.7 Hz), 132.7, 135.8, 137.5, 137.8, 138.4, 144.0. HRMS (DART) m/z calcd for C23H18NF3 [M]+: 365.1391, found 365.1387。
(4-メトキシフェニル)(4-メチルフェニル)(4-トリフルオロメチルフェニル)アセトニトリル（6bce）
分取HPLCによる精製。
1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 3.81 (s, 3H), 6.88 (d, J = 8.8 Hz, 2H), 7.07-7.11 (m, 4H), 7.17 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.0, 55.3, 56.3, 114.1, 123.1, 123.8, (q, J = 274 Hz), 125.6, (q, J = 2.8 Hz), 128.5, 129.2, 129.5, 129.9, 130.3 (q, J = 32.6 Hz), 131.5, 136.7, 138.4, 144.7, 159.5. HRMS (DART) m/z calcd for C23H18NOF3 [M]+: 381.1341, found 381.1356。
トリス(4-メトキシフェニル)アセトニトリル（6ccc）
分取HPLCによる精製。
1H NMR (400 MHz, CDCl3) δ 3.80 (s, 9H), 6.86 (dm, J = 8.8 Hz, 6H), 7.12 (dm, J = 8.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 55.3, 55.4, 113.8, 123.9, 129.8, 132.8, 159.1. HRMS (DART) m/z calcd for C23H21NO3 [M]+: 359.1521, found 359.1524。
(4-フルオロフェニル)(4-メチルフェニル)(3-チエニル)アセトニトリル（6dkb）
分取HPLCによる精製。
1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 6.87 (dd, J = 3.2, 1.6 Hz, 1H), 6.98 (dd, J = 5.2, 1.6 Hz, 1H), 7.02-7.07 (m, 2H), 7.11-7.18 (m, 4H), 7.21-7.25 (m, 2H), 7.36 (dd, J = 5.2, 3.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 21.0, 52.9, 115.6 (d, J = 21.9 Hz), 122.5, 124.9, 127.0, 127.8, 127.9, 129.5, 130.0 (d, J = 7.6 Hz), 136.2 (d, J = 2.8 Hz), 137.0, 138.3, 140.9, 162.3 (d, J = 253 Hz). HRMS (DART) m/z calcd for C19H14NFS [M]+: 307.0831, found 307.0841。
(N-メチル-5-インドリル)フェニル(4-トリフルオロメチルフェニル)アセトニトリル（6ean）
PTLCによる精製（酢酸エチル/ヘキサン= 10: 90)。
ハロゲン化芳香族化合物として5-ブロモ-N-メチルインドールを使用した。
1H NMR (400 MHz, CDCl3) δ 3.79 (s, 3H), 6.42 (d, J = 3.2 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H), 7.13 (dd, J = 8.8, 1.6 Hz, 1H), 7.23-7.26 (m, 2H), 7.30-7.38 (m, 5H), 7.41 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 33.0, 57.4, 101.6, 109.7, 121.3, 122.4, 123.5, 123.9, (q, J = 274 Hz), 125.5, (q, J = 3.8 Hz), 128.23, 128.25, 128.7, 128.8, 129.4, 130.1, 130.2 (q, J = 32.5 Hz), 130.4, 136.1, 140.2, 145.1. HRMS (DART) m/z calcd for C24H17N2F3 [M]+: 390.1344, found 390.1341。
[4-(N, N-ジメチルアミノ)フェニル](4-メトキシカルボニルフェニル)(4-メチルフェニル)アセトニトリル（6fbo）
PTLCによる精製（酢酸エチル/ヘキサン= 10: 90)。
ハロゲン化芳香族化合物として4-ブロモ-N, N-ジメチルアニリンを使用した。
1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.96 (s, 6H), 3.91 (s, 3H), 6.65 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.0, 40.2, 52.2, 56.3, 112.0, 123.4, 126.7, 128.5, 128.8, 129.3, 129.4, 129.66, 129.70, 137.3, 138.0, 146.1, 150.0, 166.5. IR (Neat) v 704, 750, 768, 809, 947, 1019, 1109, 1187, 1277, 1358, 1435, 1519, 1609, 1721, 2237, 3025, 3062 cm-1. HRMS (DART) m/z calcd for C25H24N2O2 [M]+: 384.1838, found 384.1834。
フェニル(4-ピリジル)(3-チエニル)アセトニトリル（6kal）
PTLCによる精製（酢酸エチル/ヘキサン= 1: 15)。
1H NMR (400 MHz, CDCl3) δ 6.92 (dd, J = 3.2, 1.2 Hz, 1H), 6.98 (dd, J = 5.2, 1.2 Hz, 1H), 7.21-7.26 (m, 4H), 7.36-7.43 (m, 4H), 8.64 (dm, J = 6.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 53.3, 121.3, 122.9, 125.4, 127.5, 127.6, 128.0, 128.8, 129.0, 138.5, 139.0, 148.8, 150.4. HRMS (DART) m/z calcd for C17H13N2S [M+H]+: 277.0794, found 277.0794。 (2-Methylphenyl) (4-methylphenyl) (4-trifluoromethylphenyl) acetonitrile (6bej)
Purification by PTLC (ethyl acetate / hexane = 4: 96).
1 H NMR (400 MHz, CDCl 3 ) δ 2.24 (s, 3H), 2.38 (s, 3H), 6.47 (d, J = 8.0 Hz, 1H), 7.06-7.10 (m, 3H), 7.19 (d, J = 8.8 Hz, 2H), 7.24-7.30 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 21.0, 21.6, 55.9, 122.0, 123.8, (q, J = 271 Hz), 125.7, (q, J = 3.3 Hz), 126.0, 128.5, 128.8, 129.1, 129.4, 129.7, 130.3 (q, J = 31.7 Hz), 132.7, 135.8, 137.5, 137.8, 138.4, 144.0. HRMS (DART) m / z calcd for C 23 H 18 NF 3 [M] + : 365.1391, found 365.1387.
(4-Methoxyphenyl) (4-methylphenyl) (4-trifluoromethylphenyl) acetonitrile (6bce)
Purification by preparative HPLC.
1 H NMR (400 MHz, CDCl 3 ) δ 2.36 (s, 3H), 3.81 (s, 3H), 6.88 (d, J = 8.8 Hz, 2H), 7.07-7.11 (m, 4H), 7.17 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 21.0, 55.3, 56.3, 114.1, 123.1, 123.8, (q, J = 274 Hz), 125.6, (q, J = 2.8 Hz), 128.5, 129.2, 129.5, 129.9, 130.3 (q, J = 32.6 Hz), 131.5, 136.7, 138.4, 144.7, 159.5. HRMS (DART) m / z calcd for C 23 H 18 NOF 3 [M] + : 381.1341, found 381.1356.
Tris (4-methoxyphenyl) acetonitrile (6ccc)
Purification by preparative HPLC.
1 H NMR (400 MHz, CDCl 3 ) δ 3.80 (s, 9H), 6.86 (dm, J = 8.8 Hz, 6H), 7.12 (dm, J = 8.8 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 55.3, 55.4, 113.8, 123.9, 129.8, 132.8, 159.1. HRMS (DART) m / z calcd for C 23 H 21 NO 3 [M] + : 359.1521, found 359.1524.
(4-Fluorophenyl) (4-methylphenyl) (3-thienyl) acetonitrile (6dkb)
Purification by preparative HPLC.
1 H NMR (400 MHz, CDCl 3 ) δ 2.36 (s, 3H), 6.87 (dd, J = 3.2, 1.6 Hz, 1H), 6.98 (dd, J = 5.2, 1.6 Hz, 1H), 7.02-7.07 ( m, 2H), 7.11-7.18 (m , 4H), 7.21-7.25 (m, 2H), 7.36 (dd, J = 5.2, 3.2 Hz, 1H). 13 C NMR (100 MHz, CDCl 3) δ 21.0, 52.9, 115.6 (d, J = 21.9 Hz), 122.5, 124.9, 127.0, 127.8, 127.9, 129.5, 130.0 (d, J = 7.6 Hz), 136.2 (d, J = 2.8 Hz), 137.0, 138.3, 140.9, 162.3 (d, J = 253 Hz). HRMS (DART) m / z calcd for C 19 H 14 NFS [M] + : 307.0831, found 307.0841.
(N-Methyl-5-indolyl) phenyl (4-trifluoromethylphenyl) acetonitrile (6ean)
Purification by PTLC (ethyl acetate / hexane = 10: 90).
5-Bromo-N-methylindole was used as the halogenated aromatic compound.
1 H NMR (400 MHz, CDCl 3 ) δ 3.79 (s, 3H), 6.42 (d, J = 3.2 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H), 7.13 (dd, J = 8.8, 1.6 Hz, 1H), 7.23-7.26 (m, 2H), 7.30-7.38 (m, 5H), 7.41 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 33.0, 57.4, 101.6, 109.7, 121.3, 122.4, 123.5, 123.9, (q, J = 274 Hz), 125.5, (q, J = 3.8 Hz), 128.23, 128.25, 128.7 , 128.8, 129.4, 130.1, 130.2 (q, J = 32.5 Hz), 130.4, 136.1, 140.2, 145.1.HRMS (DART) m / z calcd for C 24 H 17 N 2 F 3 [M] + : 390.1344, found 390.1341.
[4- (N, N-dimethylamino) phenyl] (4-methoxycarbonylphenyl) (4-methylphenyl) acetonitrile (6fbo)
Purification by PTLC (ethyl acetate / hexane = 10: 90).
4-Bromo-N, N-dimethylaniline was used as the halogenated aromatic compound.
1 H NMR (400 MHz, CDCl 3 ) δ 2.35 (s, 3H), 2.96 (s, 6H), 3.91 (s, 3H), 6.65 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz 13 C NMR (100 MHz, CDCl 3 ) δ 21.0, 40.2, 52.2, 56.3, 112.0, 123.4, 126.7, 128.5, 128.8, 129.3, 129.4, 129.66, 129.70, 137.3, 138.0, 146.1, 150.0, 166.5 IR (Neat) v 704, 750, 768, 809, 947, 1019, 1109, 1187, 1277, 1358, 1435, 1519, 1609, 1721, 2237, 3025, 3062 cm -1 .HRMS (DART) m / z calcd for C 25 H 24 N 2 O 2 [M] + : 384.1838, found 384.1834.
Phenyl (4-pyridyl) (3-thienyl) acetonitrile (6kal)
Purification by PTLC (ethyl acetate / hexane = 1: 15).
1 H NMR (400 MHz, CDCl 3 ) δ 6.92 (dd, J = 3.2, 1.2 Hz, 1H), 6.98 (dd, J = 5.2, 1.2 Hz, 1H), 7.21-7.26 (m, 4H), 7.36- 7.43 (m, 4H), 8.64 (dm, J = 6.4 Hz, 2H). 13 C NMR (100 MHz, CDCl 3) δ 53.3, 121.3, 122.9, 125.4, 127.5, 127.6, 128.0, 128.8, 129.0, 138.5, 139.0, 148.8, 150.4. HRMS (DART) m / z calcd for C 17 H 13 N 2 S [M + H] + : 277.0794, found 277.0794.
　［実施例５：トリ（ヘテロ）アリールアセトニトリル化合物のアルデヒド化］
　実施例５－１ [Example 5: Aldehydation of tri (hetero) arylacetonitrile compound]
Example 5-1
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
［式中、DIBAL-Hはジイソブチルアルミニルムハイドライドを示す。以下同様である。］
　実施例４－１で得たトリフェニルアセトニトリル（26.9 mg, 0.1 mmol）の乾燥トルエン（0.4 mL）溶液をアルゴン雰囲気下、0℃で攪拌し、ジイソブチルアルミニルムハイドライド（0.4 mL, ヘキサン中1 M）を添加した。この混合物を、高真空下で数秒かけて慎重に蒸発させ、ほとんどのn-ヘキサンを除去した。その後、反応混合物を室温まで昇温した。混合物を24時間攪拌した後、0℃まで冷却し、1 M HCl水溶液（1 mL）で反応をクエンチし、さらに室温下で30分間攪拌した。酢酸エチル（EtOAc; 3回×15 mL）で抽出し、有機層をNa2SO4で乾燥し、減圧下に濃縮した。粗生成物をPTLC（酢酸エチル／n-ヘキサン=10: 90）により精製し、トリフェニルアセトアルデヒド（7aaa）を白色固体として得た（22.5 mg, 83％）。
1H NMR (400 MHz, CDCl3) δ 7.06-7.08 (m, 6H), 7.29-7.37 (m, 9H), 10.29 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 69.9, 127.4, 128.4, 130.4, 140.5, 198.2. IR (Neat) v 663, 696, 752, 1013, 1036, 1083, 1443, 1490, 1718, 3048, 3087 cm-1. HRMS (DART) m/z calcd for C20H17O [M+H]+: 273.1274, found 273.1282。 [Wherein, DIBAL-H represents diisobutylaluminum hydride. The same applies hereinafter. ]
A solution of triphenylacetonitrile (26.9 mg, 0.1 mmol) obtained in Example 4-1 in dry toluene (0.4 mL) was stirred at 0 ° C. under an argon atmosphere, and diisobutylaluminum hydride (0.4 mL, 1 M in hexane). Was added. The mixture was carefully evaporated under high vacuum over a few seconds to remove most of the n-hexane. Thereafter, the reaction mixture was warmed to room temperature. The mixture was stirred for 24 hours, then cooled to 0 ° C., quenched with 1 M aqueous HCl (1 mL), and further stirred at room temperature for 30 minutes. Extraction with ethyl acetate (EtOAc; 3 × 15 mL), the organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by PTLC (ethyl acetate / n-hexane = 10: 90) to obtain triphenylacetaldehyde (7aaa) as a white solid (22.5 mg, 83%).
1 H NMR (400 MHz, CDCl 3 ) δ 7.06-7.08 (m, 6H), 7.29-7.37 (m, 9H), 10.29 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 69.9, 127.4 , 128.4, 130.4, 140.5, 198.2. IR (Neat) v 663, 696, 752, 1013, 1036, 1083, 1443, 1490, 1718, 3048, 3087 cm -1 .HRMS (DART) m / z calcd for C 20 H 17 O [M + H] + : 273.1274, found 273.1282.
　実施例５－２
　基質を変更する他は実施例５－１と同様の処理を行った。結果を以下に示す。 Example 5-2
The same treatment as in Example 5-1 was performed except that the substrate was changed. The results are shown below.
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
 (4-メトキシフェニル)(4-メチルフェニル)フェニルアセトアルデヒド（7bac）
25.0 mg, 79%（単離収率）；白色固体。
1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 3.81 (s, 3H), 6.87 (d, J = 8.8 Hz, 2H), 6.94-6.98 (m, 4H), 7.07 (d, J = 6.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.30-7.36 (m, 3H), 10.23 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 21.0, 55.2, 69.0, 113.7, 127.2, 128.3, 129.1, 130.2, 130.3, 131.5, 132.4, 137.1, 137.7, 140.9, 158.7, 198.3. IR (Neat) v 662, 700, 722, 813, 829, 1033, 1120, 1183, 1253, 1297, 1445, 1464, 1608, 1726, 2926, 2951 cm-1. HRMS (DART) m/z calcd for C22H21O2 [M+H]+: 317.1536, found 317.1548。 (4-Methoxyphenyl) (4-methylphenyl) phenylacetaldehyde (7bac)
25.0 mg, 79% (isolated yield); white solid.
1 H NMR (400 MHz, CDCl 3 ) δ 2.35 (s, 3H), 3.81 (s, 3H), 6.87 (d, J = 8.8 Hz, 2H), 6.94-6.98 (m, 4H), 7.07 (d, J = 6.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.30-7.36 (m, 3H), 10.23 (s, 1H). 13 C NMR (100 MHz, CDCl 3) δ 21.0, 55.2 , 69.0, 113.7, 127.2, 128.3, 129.1, 130.2, 130.3, 131.5, 132.4, 137.1, 137.7, 140.9, 158.7, 198.3. IR (Neat) v 662, 700, 722, 813, 829, 1033, 1120, 1183, 1253, 1297, 1445, 1464, 1608, 1726, 2926, 2951 cm −1 .HRMS (DART) m / z calcd for C 22 H 21 O 2 [M + H] + : 317.1536, found 317.1548.
　［実施例６：トリ（ヘテロ）アリールアセトニトリル化合物のアミン化］
　実施例６－１ [Example 6: Amination of tri (hetero) arylacetonitrile compound]
Example 6-1
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　フレームドライしたシュレンク管に、磁気撹拌子を収容し、実施例４－１で得たトリフェニルアセトニトリル（26.9 mg, 0.1 mmol）、2-プロパノール（2 mL）、ラネーニッケル触媒（2-プロパノール中に保存されたラネーニッケルから0.2 g取得した）、及びKOH（100 mg）を添加した。シュレンク管上にコンデンサーを設置し、混合物を、100℃で48時間攪拌しながら還流した。室温まで冷却した後、1 M HCl水溶液（2 mL）を添加し、反応混合物を室温で30分間攪拌した。次に、5 M NaOH水溶液（3 mL）及びベンゾイルクロライド（58.6μL, 0.5 mmol）を反応混合物に添加し、得られた混合物を室温下で6時間攪拌した。混合物を水（2 mL）で希釈し、酢酸エチル（3回×15 mL）で抽出した。有機層をNa2SO4で乾燥し、減圧下に濃縮した。粗生成物をPTLC（酢酸エチル／n-ヘキサン=5: 95）により精製し、N-(2,2,2-トリフェニルエチル)ベンズアミド（8aaa）を白色固体として得た（29 mg, 77％）。
1H NMR (400 MHz, CDCl3) δ 4.64 (d, J = 5.6 Hz, 2H), 5.74 (br.s, 1H), 7.23-7.42 (m, 20H). 13C NMR (100 MHz, CDCl3) δ 48.2, 57.1, 126.6, 126.8, 128.4, 128.5, 129.0, 131.4, 134.4, 145.1, 166.9. IR (Neat) v 671, 698, 714, 751, 759, 801, 1029, 1272, 1444, 1482, 1510, 1659, 3047, 3059 cm-1. HRMS (DART) m/z calcd for C27H24NO [M+H]+: 378.1852, found 378.1850。 A flame-dried Schlenk tube contains a magnetic stir bar, and triphenylacetonitrile (26.9 mg, 0.1 mmol) obtained in Example 4-1, 2-propanol (2 mL), Raney nickel catalyst (stored in 2-propanol) 0.2 g from Raney nickel) and KOH (100 mg) were added. A condenser was placed on the Schlenk tube, and the mixture was refluxed with stirring at 100 ° C. for 48 hours. After cooling to room temperature, 1 M aqueous HCl (2 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes. Next, 5 M NaOH aqueous solution (3 mL) and benzoyl chloride (58.6 μL, 0.5 mmol) were added to the reaction mixture, and the resulting mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 × 15 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by PTLC (ethyl acetate / n-hexane = 5: 95) to obtain N- (2,2,2-triphenylethyl) benzamide (8aaa) as a white solid (29 mg, 77% ).
1 H NMR (400 MHz, CDCl 3 ) δ 4.64 (d, J = 5.6 Hz, 2H), 5.74 (br.s, 1H), 7.23-7.42 (m, 20H). 13 C NMR (100 MHz, CDCl 3 ) δ 48.2, 57.1, 126.6, 126.8, 128.4, 128.5, 129.0, 131.4, 134.4, 145.1, 166.9.IR (Neat) v 671, 698, 714, 751, 759, 801, 1029, 1272, 1444, 1482, 1510 , 1659, 3047, 3059 cm-1. HRMS (DART) m / z calcd for C27H24NO [M + H] +: 378.1852, found 378.1850.
　実施例６－２
　基質を変更する他は実施例６－１と同様の処理を行った。結果を以下に示す。 Example 6-2
The same treatment as in Example 6-1 was performed, except that the substrate was changed. The results are shown below.
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
N-[2-(4-メトキシフェニル)-2-(4-メチルフェニル)-2-フェニルエチル]ベンズアミド（8bac）
PTLCによる精製（酢酸エチル/ヘキサン= 10: 90)。
28.2 mg, 67%（単離収率）；白色固体。
1H NMR (400 MHz, CDCl3) δ 2.32 (s, 3H), 3.79 (s, 3H), 4.58 (d, J = 5.6 Hz, 2H), 5.77 (br.s, 1H), 6.84 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.17-7.25 (m, 5H), 7.28-7.34 (m, 6H), 7.40-7.43 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 20.9, 48.3, 55.2, 56.0, 113.7, 126.60, 126.65, 128.4, 128.5, 128.8, 128.9, 129.1, 130.1, 131.4, 134.5, 136.3, 137.2, 142.4, 145.6, 158.1, 166.9. IR (Neat) v 660, 670, 716, 767, 783, 794, 808, 841, 1040, 1180, 1252, 1282, 1480, 1508, 1667, 3028, 3055 cm-1. HRMS (DART) m/z calcd for C29H28NO2 [M+H]+: 422.2115, found 422.2121。 N- [2- (4-Methoxyphenyl) -2- (4-methylphenyl) -2-phenylethyl] benzamide (8bac)
Purification by PTLC (ethyl acetate / hexane = 10: 90).
28.2 mg, 67% (isolated yield); white solid.
1 H NMR (400 MHz, CDCl 3 ) δ 2.32 (s, 3H), 3.79 (s, 3H), 4.58 (d, J = 5.6 Hz, 2H), 5.77 (br.s, 1H), 6.84 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.17-7.25 (m, 5H), 7.28-7.34 (m, 6H), 7.40-7.43 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 20.9, 48.3, 55.2, 56.0, 113.7, 126.60, 126.65, 128.4, 128.5, 128.8, 128.9, 129.1, 130.1, 131.4, 134.5, 136.3, 137.2, 142.4, 145.6, 158.1, 166.9. IR (Neat) v 660, 670, 716, 767, 783, 794, 808, 841, 1040, 1180, 1252, 1282, 1480, 1508, 1667, 3028, 3055 cm-1.HRMS (DART) m / z calcd for C 29 H 28 NO 2 [M + H] + : 422.2115, found 422.2121.
　［実施例７：トリ（ヘテロ）アリールアセトニトリル化合物のアミド化］
　実施例７－１ [Example 7: Amidation of tri (hetero) arylacetonitrile compound]
Example 7-1
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　内容積10 mLの密閉ガラス容器に、磁気撹拌子を収容し、実施例４－１で得たトリフェニルアセトニトリル（50 mg, 0.186 mmol）、酢酸（1.0 mL）、H2SO4（1.5 mL）、及び水（0.5 mL）を添加し、容器を密閉した。混合物を135℃で48時間攪拌した。室温まで冷却した後、ロータリーエバポレーターを用いて真空下に酢酸を除去し、混合物を水（1 mL）で希釈し、酢酸エチル（3回×15 mL）で抽出し、有機層をNa2SO4で乾燥し、減圧下に濃縮した。粗生成物をn-ヘキサン（5 mL）及びジクロロメタン（5 mL）で洗浄することで精製し、トリフェニルアセトアミド（9aaa）を白色固体として得た（46.9 mg, 88％）。
1H NMR (400 MHz, DMSO) δ 6.60 (br.s, 1H), 7.21-7.24 (m, 9H), 7.28-7.32 (m, 6H), 7.51 (br.s, 1H). 13C NMR (100 MHz, DMSO) δ 67.2, 126.4, 127.6, 130.1, 143.9, 174.0. IR (Neat) v 675, 699, 748, 767, 790, 809, 841, 903, 999, 1035, 1086, 1185, 1337, 1441, 1492, 1602, 1678 cm-1. HRMS (DART) m/z calcd for C20H18NO [M+H]+: 288.1383, found 288.1388。 A magnetic stirrer was housed in a sealed glass container with an internal volume of 10 mL, and triphenylacetonitrile (50 mg, 0.186 mmol), acetic acid (1.0 mL), H 2 SO 4 (1.5 mL) obtained in Example 4-1. And water (0.5 mL) were added and the vessel was sealed. The mixture was stirred at 135 ° C. for 48 hours. After cooling to room temperature, the acetic acid was removed under vacuum using a rotary evaporator, the mixture was diluted with water (1 mL), extracted with ethyl acetate (3 × 15 mL), and the organic layer was Na 2 SO 4 And concentrated under reduced pressure. The crude product was purified by washing with n-hexane (5 mL) and dichloromethane (5 mL) to obtain triphenylacetamide (9aaa) as a white solid (46.9 mg, 88%).
1 H NMR (400 MHz, DMSO) δ 6.60 (br.s, 1H), 7.21-7.24 (m, 9H), 7.28-7.32 (m, 6H), 7.51 (br.s, 1H). 13 C NMR ( 100 MHz, DMSO) δ 67.2, 126.4, 127.6, 130.1, 143.9, 174.0. IR (Neat) v 675, 699, 748, 767, 790, 809, 841, 903, 999, 1035, 1086, 1185, 1337, 1441 , 1492, 1602, 1678 cm −1 . HRMS (DART) m / z calcd for C 20 H 18 NO [M + H] + : 288.1383, found 288.1388.
　実施例７－２ Example 7-2
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　内容積10 mLの密閉ガラス容器に、磁気撹拌子を収容し、実施例４－３のentry 15で得た(p-メトキシフェニル)(p-メチルフェニル)フェニルアセトニトリル（31.3 mg, 0.1 mmol）、KOH（30.5 mg, 0.54 mmol）、及びt-アミルアルコール（300μL）をアルゴン気流下で添加した。容器を密閉し、混合物を105℃で24時間攪拌した。室温まで冷却した後、シリカゲルのパッドでろ過し、酢酸エチル（約15 mL）で繰り返し洗浄した。ろ液を減圧下に濃縮した。粗生成物をPTLC（酢酸エチル／n-ヘキサン=1: 3）により精製し、(p-メトキシフェニル)(p-メチルフェニル)フェニルアセトアミド（9bac）を白色固体として得た（25.6 mg, 77％）。
1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.79 (s, 3H), 5.78 (br.s, 1H), 6.21 (br.s, 1H), 6.82 (d, J = 9.2 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 9.2 Hz, 2H), 7.23-7.29 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 20.9, 55.2, 66.6, 113.2, 126.9, 127.9, 128.6, 130.2, 130.3, 131.5, 135.4, 136.6, 140.5, 143.6, 158.3, 176.3. IR (Neat) v 699, 684, 705, 757, 775, 795, 812, 1035, 1184, 1254, 1292, 1338, 1441, 1459, 1488, 1508, 1602, 1684, 3460 cm-1.HRMS (DART) m/z calcd for C22H22NO2 [M+H]+: 3322.1645, found 3322.1644。 In a sealed glass container having an internal volume of 10 mL, a magnetic stir bar was accommodated, and (p-methoxyphenyl) (p-methylphenyl) phenylacetonitrile (31.3 mg, 0.1 mmol) obtained in entry 15 of Example 4-3, KOH (30.5 mg, 0.54 mmol) and t-amyl alcohol (300 μL) were added under a stream of argon. The vessel was sealed and the mixture was stirred at 105 ° C. for 24 hours. After cooling to room temperature, the mixture was filtered through a pad of silica gel and washed repeatedly with ethyl acetate (about 15 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by PTLC (ethyl acetate / n-hexane = 1: 3) to give (p-methoxyphenyl) (p-methylphenyl) phenylacetamide (9bac) as a white solid (25.6 mg, 77% ).
1 H NMR (400 MHz, CDCl 3 ) δ 2.33 (s, 3H), 3.79 (s, 3H), 5.78 (br.s, 1H), 6.21 (br.s, 1H), 6.82 (d, J = 9.2 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 9.2 Hz, 2H), 7.23-7.29 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 20.9, 55.2, 66.6, 113.2, 126.9, 127.9, 128.6, 130.2, 130.3, 131.5, 135.4, 136.6, 140.5, 143.6, 158.3, 176.3. IR (Neat) v 699, 684, 705, 757, 775, 795, 812, 1035, 1184, 1254, 1292, 1338, 1441, 1459, 1488, 1508, 1602, 1684, 3460 cm-1.HRMS (DART) m / z calcd for C 22 H 22 NO 2 [M + H] + : 3322.1645, found 3322.1644.
　［実施例８：トリ（ヘテロ）アリールアセトニトリル化合物を用いたトリ（ヘテロ）アリールメタンの合成］
　実施例８－１ [Example 8: Synthesis of tri (hetero) arylmethane using tri (hetero) arylacetonitrile compound]
Example 8-1
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　フレームドライした内容積10 mLの密閉ガラス容器に、磁気撹拌子を収容し、アルゴン雰囲気下で、実施例４－１で得たトリフェニルアセトニトリル（26.9 mg, 0.1 mmol）、及び乾燥トルエン（0.5 mL）を添加した。0℃まで冷却し、反応混合物に3 MメチルマグネシウムクロライドのTHF溶液（67μL, 0.2 mmol）を添加し、容器を密閉した。混合物を135℃で24時間攪拌した。次に、反応混合物を0℃まで冷却した後、1 M HCl水溶液（1 mL）でクエンチし、さらに反応混合物を室温下で30分間攪拌した。酢酸エチル（3回×15 mL）で抽出した後、有機層をNa2SO4で乾燥し、減圧下に濃縮した。粗生成物をPTLC（酢酸エチル／n-ヘキサン=3: 97）により精製し、トリフェニルメタン（10aaa）を白色固体として得た（22.9 mg, 94％）。
1H NMR (400 MHz, CDCl3) δ 5.55 (s, 1H), 7.11-7.13 (m, 6H), 7.19-7.30 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 56.8, 126.3, 128.3, 129.4, 143.9. HRMS (DART) m/z calcd for C19H15 [M-H]+: 243.1174, found 243.1179。 A magnetic stir bar was housed in a sealed glass container with an internal volume of 10 mL that was frame-dried, and triphenylacetonitrile (26.9 mg, 0.1 mmol) obtained in Example 4-1 and dry toluene (0.5 mL) under an argon atmosphere. ) Was added. After cooling to 0 ° C., 3 M methylmagnesium chloride in THF (67 μL, 0.2 mmol) was added to the reaction mixture, and the vessel was sealed. The mixture was stirred at 135 ° C. for 24 hours. The reaction mixture was then cooled to 0 ° C. and then quenched with 1 M aqueous HCl (1 mL), and the reaction mixture was further stirred at room temperature for 30 minutes. After extraction with ethyl acetate (3 × 15 mL), the organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by PTLC (ethyl acetate / n-hexane = 3: 97) to obtain triphenylmethane (10aaa) as a white solid (22.9 mg, 94%).
1 H NMR (400 MHz, CDCl 3 ) δ 5.55 (s, 1H), 7.11-7.13 (m, 6H), 7.19-7.30 (m, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 56.8, 126.3 , 128.3, 129.4, 143.9. HRMS (DART) m / z calcd for C 19 H 15 [MH] + : 243.1174, found 243.1179.
　実施例８－２
　基質を変更する他は実施例８－１と同様の処理を行った。結果を以下に示す。 Example 8-2
The same treatment as in Example 8-1 was performed except that the substrate was changed. The results are shown below.
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
 (4-メトキシフェニル)(4-メチルフェニル)フェニルメタン（10bac）
PTLCによる精製（酢酸エチル/ヘキサン= 5: 95)。
27.0 mg, 93%（単離収率）；白色固体。
1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 3.77 (s, 3H), 5.46 (s, 1H), 6.81 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 7.08-7.11 (m, 4H), 7.17-7.21 (m, 1H), 7.24-7.29 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 21.0, 55.2, 55.6, 113.6, 126.1, 128.2, 129.0, 129.2, 129.3, 130.3, 135.7, 136.3, 141.3, 144.4, 157.9. HRMS (DART) m/z calcd for C21H19O [M-H]+: 289.1436, found 289.1440。 (4-Methoxyphenyl) (4-methylphenyl) phenylmethane (10bac)
Purification by PTLC (ethyl acetate / hexane = 5: 95).
27.0 mg, 93% (isolated yield); white solid.
1 H NMR (400 MHz, CDCl 3 ) δ 2.31 (s, 3H), 3.77 (s, 3H), 5.46 (s, 1H), 6.81 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 7.08-7.11 (m, 4H), 7.17-7.21 (m, 1H), 7.24-7.29 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 21.0, 55.2, 55.6, 113.6, 126.1, 128.2, 129.0, 129.2, 129.3, 130.3, 135.7, 136.3, 141.3, 144.4, 157.9.HRMS (DART) m / z calcd for C 21 H 19 O [MH] + : 289.1436, found 289.1440.
　［実施例９：トリ（ヘテロ）アリールアセトニトリル化合物のオキサジアゾール化］
　実施例９－１ [Example 9: Oxadiazolation of tri (hetero) arylacetonitrile compound]
Example 9-1
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
［式中、Etはエチル基を示す。以下同様である。］
　フレームドライした内容積10 mLの密閉ガラス容器に、磁気撹拌子を収容し、アルゴン雰囲気下で、実施例４－１で得たトリフェニルアセトニトリル（26.9 mg, 0.1 mmol）、NH2OH（66μL, 50 %水溶液）、及びエタノール（0.5 mL）を添加し、容器を密封した。混合物を140℃で24時間攪拌した。室温まで冷却した後、反応混合物を水（1 mL）で希釈し、酢酸エチル（3回×15 mL）で抽出した。有機層をNa2SO4で乾燥し、減圧下に濃縮した。粗生成物を酢酸無水物（0.5 mL）で処理し、反応混合物を140℃で24時間攪拌した。室温まで冷却した後、反応混合物を水（5 mL）で希釈し、酢酸エチル（3回×20 mL）で抽出した。有機層をNa2SO4で乾燥し、減圧下に濃縮した。粗生成物をPTLC（酢酸エチル／n-ヘキサン=10: 90）により精製し、5-メチル-3-トリチル-1,2,4-オキサジアゾール（11aaa）を白色固体として得た（17 mg, 52％）。
1H NMR (400 MHz, CDCl3) δ 2.59 (s, 3H), 7.17-7.21 (m, 6H), 7.26-7.32 (m, 9H). 13C NMR (100 MHz, CDCl3) δ 12.5, 59.8, 127.1, 127.8, 130.4, 143.3, 175.2, 175.7. HRMS (DART) m/z calcd for C22H19N2O [M+H]+: 327.1492, found 327.1489。 [Wherein Et represents an ethyl group. The same applies hereinafter. ]
A magnetic stir bar was housed in a sealed glass container having an internal volume of 10 mL that was frame-dried, and triphenylacetonitrile (26.9 mg, 0.1 mmol), NH 2 OH (66 μL, obtained in Example 4-1) was obtained under an argon atmosphere. 50% aqueous solution) and ethanol (0.5 mL) were added and the vessel was sealed. The mixture was stirred at 140 ° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with water (1 mL) and extracted with ethyl acetate (3 × 15 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was treated with acetic anhydride (0.5 mL) and the reaction mixture was stirred at 140 ° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by PTLC (ethyl acetate / n-hexane = 10: 90) to obtain 5-methyl-3-trityl-1,2,4-oxadiazole (11aaa) as a white solid (17 mg , 52%).
1 H NMR (400 MHz, CDCl 3 ) δ 2.59 (s, 3H), 7.17-7.21 (m, 6H), 7.26-7.32 (m, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 12.5, 59.8 127.1, 127.8, 130.4, 143.3, 175.2, 175.7. HRMS (DART) m / z calcd for C 22 H 19 N 2 O [M + H] + : 327.1492, found 327.1489.
　実施例９－２
　基質を変更する他は実施例９－１と同様の処理を行った。結果を以下に示す。 Example 9-2
The same treatment as in Example 9-1 was performed, except that the substrate was changed. The results are shown below.
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
3-[(4-メトキシフェニル)(4-メチルフェニル)フェニルメチル]-5-メチル-1,2,4-オキサジアゾール（11bac）
PTLCによる精製（酢酸エチル/ヘキサン= 10: 90)。
21.0 mg, 57%（単離収率）；白色固体。
1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 2.59 (s, 3H), 3.79 (s, 3H), 6.81 (dm, J = 8.8 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 7.08-7.10 (m, 4H), 7.16-7.18 (m, 2H), 7.27-7.30 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 12.5, 21.0, 55.2, 58.8, 113.0, 126.9, 127.7, 128.5, 130.2, 130.3, 131.5, 135.6, 136.6, 140.7, 143.8, 158.3, 175.5, 175.7. HRMS (DART) m/z calcd for C24H23N2O2 [M+H]+: 371.1754, found 371.1754。 3-[(4-Methoxyphenyl) (4-methylphenyl) phenylmethyl] -5-methyl-1,2,4-oxadiazole (11bac)
Purification by PTLC (ethyl acetate / hexane = 10: 90).
21.0 mg, 57% (isolated yield); white solid.
1 H NMR (400 MHz, CDCl 3 ) δ 2.33 (s, 3H), 2.59 (s, 3H), 3.79 (s, 3H), 6.81 (dm, J = 8.8 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 7.08-7.10 (m, 4H), 7.16-7.18 (m, 2H), 7.27-7.30 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 12.5, 21.0, 55.2, 58.8, 113.0, 126.9, 127.7, 128.5, 130.2, 130.3, 131.5, 135.6, 136.6, 140.7, 143.8, 158.3, 175.5, 175.7.HRMS (DART) m / z calcd for C 24 H 23 N 2 O 2 [M + H] + : 371.1754, found 371.1754.
　［実施例１０：トリ（ヘテロ）アリールアセトニトリル化合物のトリアジン化］
　実施例１０－１ [Example 10: Triazination of tri (hetero) arylacetonitrile compound]
Example 10-1
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　フレームドライした内容積10 mLの密閉ガラス容器に、磁気撹拌子を収容し、アルゴン雰囲気下で、実施例４－１で得たトリフェニルアセトニトリル（26.9 mg, 0.1 mmol）、シアノグアニジン（10.5 mg, 0.125 mmol）、KOH（4 mg, 0.071 mmol）、及びエタノール（0.5 mL）を添加し、容器を密封した。混合物を140℃で24時間攪拌した。室温まで冷却した後、反応混合物を水（1 mL）で希釈し、酢酸エチル（3回×15 mL）で抽出した。有機層をNa2SO4で乾燥し、減圧下に濃縮した。粗生成物をPTLC（酢酸エチル／n-ヘキサン=1: 1）により精製し、2,4-ジアミノ-6-トリチル-1,3,5-トリアジン（12aaa）を白色固体として得た（16 mg, 45％）。
1H NMR (400 MHz, DMSO-d6) δ 6.58 (br.s, 4H), 7.12-7.18 (m, 3H), 7.22-7.23 (m, 12H). 13C NMR (100 MHz, DMSO-d6) δ 66.9, 125.6, 127.1, 130.7, 145.8, 166.7, 180.4. HRMS (DART) m/z calcd for C22H20N5 [M+H]+: 354.1713, found 354.1719。 A magnetic stir bar was housed in a sealed glass container with an internal volume of 10 mL that was frame-dried, and triphenylacetonitrile (26.9 mg, 0.1 mmol), cyanoguanidine (10.5 mg, 0.125 mmol), KOH (4 mg, 0.071 mmol), and ethanol (0.5 mL) were added and the vessel was sealed. The mixture was stirred at 140 ° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with water (1 mL) and extracted with ethyl acetate (3 × 15 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by PTLC (ethyl acetate / n-hexane = 1: 1) to give 2,4-diamino-6-trityl-1,3,5-triazine (12aaa) as a white solid (16 mg , 45%).
1 H NMR (400 MHz, DMSO-d 6 ) δ 6.58 (br.s, 4H), 7.12-7.18 (m, 3H), 7.22-7.23 (m, 12H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 66.9, 125.6, 127.1, 130.7, 145.8, 166.7, 180.4. HRMS (DART) m / z calcd for C 22 H 20 N 5 [M + H] + : 354.1713, found 354.1719.
　実施例１０－２
　基質を変更する他は実施例１０－１と同様の処理を行った。結果を以下に示す。 Example 10-2
The same treatment as in Example 10-1 was performed, except that the substrate was changed. The results are shown below.
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
2,4-ジアミノ-6-[(4-メトキシフェニル)(4-メチルフェニル)フェニルメチル]-1,3,5-トリアジン（12bac）
PTLCによる精製（エタノール/ヘキサン= 6: 4)。
21.0 mg, 53%（単離収率）；白色固体。
1H NMR (400 MHz, DMSO-d6) δ 2.24 (s, 3H), 3.71 (s, 3H), 6.56 (br.s, 4H), 6.78 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 7.07-7.12 (m, 5H), 7.19-7.21 (m, 4H). 13C NMR (100 MHz, DMSO-d6) δ 20.5, 54.9, 65.9, 112.4, 125.4, 127.0, 127.6, 130.5, 130.6, 131.7, 134.5, 143.2, 146.3, 157.0, 166.7, 180.7. HRMS (DART) m/z calcd for C24H24N5O [M+H]+: 398.1975, found 398.1976。
  2,4-Diamino-6-[(4-methoxyphenyl) (4-methylphenyl) phenylmethyl] -1,3,5-triazine (12bac)
Purification by PTLC (ethanol / hexane = 6: 4).
21.0 mg, 53% (isolated yield); white solid.
1 H NMR (400 MHz, DMSO-d 6 ) δ 2.24 (s, 3H), 3.71 (s, 3H), 6.56 (br.s, 4H), 6.78 (d, J = 8.8 Hz, 2H), 7.01 ( d, J = 8.4 Hz, 2H), 7.07-7.12 (m, 5H), 7.19-7.21 (m, 4H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 20.5, 54.9, 65.9, 112.4, 125.4 , 127.0, 127.6, 130.5, 130.6, 131.7, 134.5, 143.2, 146.3, 157.0, 166.7, 180.7.HRMS (DART) m / z calcd for C 24 H 24 N 5 O [M + H] + : 398.1975, found 398.1976 .

Claims (12)

  1. 一般式（１）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、Ａｒ１、Ａｒ２及びＡｒ３は同一又は異なって、置換又は無置換の芳香族基を示す。］
    で表されるトリ（ヘテロ）アリールアセトニトリル化合物の製造方法であって、
    （III）一般式（２）：
    Figure JPOXMLDOC01-appb-C000002
     ［式中、Ａｒ１及びＡｒ２は前記に同じである。］
    で表されるジ（ヘテロ）アリールアセトニトリル化合物と、
    一般式（３）：
    Ａｒ３Ｘ３　　　（３）
    ［式中、Ａｒ３は前記に同じである。Ｘ３はハロゲン原子を示す。］
    で表されるハロゲン化芳香族化合物とを、
    パラジウム触媒の存在下に反応させる工程
    を備える、製造方法。     General formula (1):
    Figure JPOXMLDOC01-appb-C000001
     [In formula, Ar < 1 >, Ar < 2 > and Ar < 3 > are the same or different, and show a substituted or unsubstituted aromatic group. ]
    A method for producing a tri (hetero) arylacetonitrile compound represented by
    (III) General formula (2):
    Figure JPOXMLDOC01-appb-C000002
     [Wherein, Ar 1 and Ar 2 are the same as defined above. ]
    A di (hetero) arylacetonitrile compound represented by:
    General formula (3):
    Ar 3 X 3 (3)
    [Wherein Ar 3 is the same as defined above. X 3 represents a halogen atom. ]
    A halogenated aromatic compound represented by
    A production method comprising a step of reacting in the presence of a palladium catalyst.
  2. 前記工程（III）が、トリアルキルホスフィン配位子の存在下で行われる、請求項１に記載の製造方法。 The production method according to claim 1, wherein the step (III) is performed in the presence of a trialkylphosphine ligand.
  3. 前記トリアルキルホスフィン配位子が、トリ（ｔ－ブチル）ホスフィン又はその塩である、請求項２に記載の製造方法。 The production method according to claim 2, wherein the trialkylphosphine ligand is tri (t-butyl) phosphine or a salt thereof.
  4. 前記工程（III）が、塩基の存在下で行われる、請求項１～３のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 3, wherein the step (III) is carried out in the presence of a base.
  5. 前記塩基が、炭酸セシウム、ハロゲン化セシウム、及びリン酸アルカリ金属塩よりなる群から選ばれる少なくとも１種である、請求項４に記載の製造方法。 The manufacturing method according to claim 4, wherein the base is at least one selected from the group consisting of cesium carbonate, cesium halides, and alkali metal phosphates.
  6. 前記工程（III）の前に、
    （II）一般式（４）：
    Ａｒ１－ＣＨ２－ＣＮ　　　（４）
    ［式中、Ａｒ１は前記に同じである。］
    で表される（ヘテロ）アリールアセトニトリル化合物と、
    一般式（５）：
    Ａｒ２Ｘ２　　　（５）
    ［式中、Ａｒ２は前記に同じである。Ｘ２はハロゲン原子を示す。］
    で表されるハロゲン化芳香族化合物とを、パラジウム触媒の存在下で反応させる工程
    を備える、請求項１～５のいずれかに記載の製造方法。     Before the step (III),
    (II) General formula (4):
    Ar 1 —CH 2 —CN (4)
    [Wherein Ar 1 is the same as defined above. ]
    A (hetero) arylacetonitrile compound represented by:
    General formula (5):
    Ar 2 X 2 (5)
    [Wherein Ar 2 is the same as defined above. X 2 represents a halogen atom. ]
    The production method according to any one of claims 1 to 5, further comprising a step of reacting the halogenated aromatic compound represented by the formula (1) in the presence of a palladium catalyst.
  7. 前記工程（II）が、ホスフィン配位子の存在下で行われる、請求項６に記載の製造方法。 The production method according to claim 6, wherein the step (II) is performed in the presence of a phosphine ligand.
  8. 前記ホスフィン配位子が、トリ（シクロアルキル）ホスフィン、アルキルジ（シクロアルキルホスフィン）、ジ（アルキル）シクロアルキルホスフィン、トリ（アルキル）ホスフィン、トリ（アルコキシ）ホスフィン、アルキルジアダマンチルホスフィン、又は一般式（６）：
    Figure JPOXMLDOC01-appb-C000003
     ［式中、Ｒ１及びＲ２は同一又は異なって、置換若しくは無置換のアルキル基、又は置換若しくは無置換のシクロアルキル基を示す。Ｒは置換若しくは無置換のアルキル基、置換若しくは無置換のアルコキシ基、又は－ＰＲ３Ｒ４（Ｒ３及びＲ４は同一又は異なって、置換若しくは無置換のアルキル基、又は置換若しくは無置換のシクロアルキル基を示す）で示される基を示す。ｎは０～３の整数を示す。］
    で表される配位子である、請求項７に記載の製造方法。     The phosphine ligand is tri (cycloalkyl) phosphine, alkyldi (cycloalkylphosphine), di (alkyl) cycloalkylphosphine, tri (alkyl) phosphine, tri (alkoxy) phosphine, alkyldiadamantylphosphine, or a general formula ( 6):
    Figure JPOXMLDOC01-appb-C000003
     [Wherein, R 1 and R 2 are the same or different and each represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted cycloalkyl group. R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or —PR 3 R 4 (R 3 and R 4 are the same or different, and are substituted or unsubstituted alkyl groups, or substituted or unsubstituted Represents a cycloalkyl group). n represents an integer of 0 to 3. ]
    The manufacturing method of Claim 7 which is a ligand represented by these.
  9. 前記工程（II）の前に、
    （I）一般式（７）：
    Ｘ－ＣＨ２－ＣＮ　　　（７）
    ［式中、Ｘはハロゲン原子を示す。］
    で表されるハロゲン化アセトニトリル化合物と、
    一般式（８Ａ）：
    Figure JPOXMLDOC01-appb-C000004
     ［式中、Ａｒ１は前記に同じである。Ｒ５及びＲ６は同一又は異なって、水素原子、アルキル基又はシクロアルキル基を示す。Ｒ５とＲ６とは互いに結合し、隣接する－Ｏ－Ｂ－Ｏ－とともに環を形成してもよい。］
    で表される芳香族基含有ボロン酸若しくはそのエステル化合物、又は
    一般式（８Ｂ）：
    Ａｒ１ＢＦ３Ｋ　　　（８Ｂ）
    ［式中、Ａｒ１は前記に同じである。］
    で表される芳香族基含有カリウムトリフルオロボレート
    とを、パラジウム触媒の存在下で反応させる工程
    を備える、請求項６～８のいずれかに記載の製造方法。     Before the step (II),
    (I) General formula (7):
    X—CH 2 —CN (7)
    [Wherein X represents a halogen atom. ]
    A halogenated acetonitrile compound represented by:
    General formula (8A):
    Figure JPOXMLDOC01-appb-C000004
     [Wherein Ar 1 is the same as defined above. R 5 and R 6 are the same or different and each represents a hydrogen atom, an alkyl group or a cycloalkyl group. R 5 and R 6 may be bonded to each other to form a ring together with adjacent —O—B—O—. ]
    Or a boronic acid-containing boronic acid represented by the general formula (8B):
    Ar 1 BF 3 K (8B)
    [Wherein Ar 1 is the same as defined above. ]
    The production method according to any one of claims 6 to 8, further comprising a step of reacting the aromatic group-containing potassium trifluoroborate represented by the formula:
  10. 一般式（９）：
    Figure JPOXMLDOC01-appb-C000005
     ［式中、Ａｒ１、Ａｒ２及びＡｒ３は同一又は異なって、置換又は無置換の芳香族基を示す。Ｒは置換基を示す。］
    で表される化合物の製造方法であって、
    請求項１～９のいずれかに記載の製造方法の前記工程（III）の後、前記トリ（ヘテロ）アリールアセトニトリル化合物のシアノ基を置換する工程を備える、製造方法。     General formula (9):
    Figure JPOXMLDOC01-appb-C000005
     [In formula, Ar < 1 >, Ar < 2 > and Ar < 3 > are the same or different, and show a substituted or unsubstituted aromatic group. R represents a substituent. ]
    A process for producing a compound represented by
    A production method comprising a step of substituting a cyano group of the tri (hetero) arylacetonitrile compound after the step (III) of the production method according to any one of claims 1 to 9.
  11. 式：
    Figure JPOXMLDOC01-appb-C000006
     ［式中、Ｍｅはメチル基を示す。Ｐｈはフェニル基を示す。］
    のいずれか、又は、一般式（２ａ）：
    Figure JPOXMLDOC01-appb-C000007
     ［式中、Ｒ１０はアルキル基又はアルコキシカルボニル基を示す。Ｒ１１は置換若しくは無置換のアルキル基、又はアルコキシ基を示す。］
    で表される化合物。     formula:
    Figure JPOXMLDOC01-appb-C000006
     [Wherein, Me represents a methyl group. Ph represents a phenyl group. ]
    Or the general formula (2a):
    Figure JPOXMLDOC01-appb-C000007
     [Wherein, R 10 represents an alkyl group or an alkoxycarbonyl group. R 11 represents a substituted or unsubstituted alkyl group or an alkoxy group. ]
    A compound represented by
  12. 一般式（６ａ）：
    Figure JPOXMLDOC01-appb-C000008
     ［式中、Ｒ１ｂ、Ｒ１ｃ、Ｒ２ｂ及びＲ２ｃは同一又は異なって、アルキル基又はシクロアルキル基を示す。］
    で表される化合物の製造方法であって、
    一般式（１０）：
    Figure JPOXMLDOC01-appb-C000009
     ［式中、Ｘ４及びＸ５は同一又は異なって、ハロゲン原子を示す。］
    で表される化合物と、
    一般式（１１）：
    Ｙ－ＰＲ１ｂＲ２ｂ
    ［式中、Ｒ１ｂ及びＲ２ｂは前記に同じである。Ｙは脱離基を示す。］
    で表される化合物とを、塩基の存在下に反応させる工程
    を備える、製造方法。
          General formula (6a):
    Figure JPOXMLDOC01-appb-C000008
     [Wherein, R 1b , R 1c , R 2b and R 2c are the same or different and each represents an alkyl group or a cycloalkyl group. ]
    A process for producing a compound represented by
    General formula (10):
    Figure JPOXMLDOC01-appb-C000009
     [Wherein, X 4 and X 5 are the same or different and each represents a halogen atom. ]
    A compound represented by
    General formula (11):
    Y-PR 1b R 2b
    [Wherein, R 1b and R 2b are the same as defined above. Y represents a leaving group. ]
    The manufacturing method provided with the process with which the compound represented by these is made to react in presence of a base.
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