JPWO2016093175A1 - Method for producing tri (hetero) arylacetonitrile compound - Google Patents

Abstract

A di (hetero) arylacetonitrile compound represented by the formula: CHAr1Ar2CN (Ar1 and Ar2 represent a substituted or unsubstituted aromatic group) and a formula: Ar3X3 (Ar3 represents a substituted or unsubstituted aromatic group). X3 represents a halogen atom.) Various tri (hetero) arylacetonitrile compounds are synthesized by reacting with a halogenated aromatic compound represented by the formula (3) in the presence of a palladium catalyst. The di (hetero) aryl acetonitrile compound used as a substrate can be synthesized by a two-step reaction using a halogenated acetonitrile compound as a starting material. Therefore, various tri (hetero) arylacetonitrile compounds can be easily synthesized with few steps.

Description

  The present invention relates to a method for producing a tri (hetero) arylacetonitrile 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.

  For this reason, it is important to synthesize a tri (hetero) arylacetonitrile compound more easily.

  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 in, for example, Non-Patent Documents 1-2.

  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.

McClelland, R. A .; Kanagasabapathy, V. M .; Banait, N. S .; Steenken, S. J. Am. Chem. Soc. 1989, 111, 3966. Kimura, K .; Mizutani, R .; Yokoyama, M .; Arakawa, R .; Sakurai, Y. J. Am. Chem. Soc. 2000, 122, 5448.

  The present invention is intended to solve the above-described problems, and a main object is to provide a method for easily synthesizing various tri (hetero) arylacetonitrile compounds with few steps.

  In view of the above problems, the present inventors have made extensive studies. 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.

  Item 1. General formula (1):

[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):

[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.

  Item 2. Item 2. The production method according to Item 1, wherein the step (III) is performed in the presence of a trialkylphosphine ligand.

  Item 3. Item 3. The production method according to Item 2, wherein the trialkylphosphine ligand is tri (t-butyl) phosphine or a salt thereof.

  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.

  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.

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 formula (I) with a palladium catalyst.

  Item 7. Item 7. The production method according to Item 6, wherein the step (II) is performed in the presence of a phosphine ligand.

  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):

[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:

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):

[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 manufacturing method in any one of claim | item 6 -8 provided with the process with which the aromatic group containing potassium trifluoroborate represented by these is made to react in presence of a palladium catalyst.

  Item 10. General formula (9):

[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
Item 10. 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.

  Item 11. formula:

[Wherein, Me represents a methyl group. Ph represents a phenyl group. ]
Or the general formula (2a):

[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

  Item 12. General formula (6a):

[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):

[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.

  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.

  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)).

  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)).

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, which will be described later in steps (I) to (II). It is preferable to synthesize it through.

  Thus, in the present invention, a tri (hetero) arylacetonitrile compound can be synthesized in only the shortest three steps, which was 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 three-stage reaction 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.

  A variety of aromatic groups can be employed as the aromatic group of the tri (hetero) aryl acetonitrile compound synthesized in the production method of the present invention. 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.

  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.

  In the present specification, “(hetero) aryl” means aryl or heteroaryl.

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):

[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.

  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.

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) Group), condensed ring aromatic hydrocarbon groups (especially bicyclic aromatic hydrocarbon groups) such as chrysenyl group, perylenyl group, and picenyl group; furyl group (2-furyl group, 3-furyl group, etc.), thienyl group ( 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 5-membered monocyclic aromatic heterocyclic groups such as a ru group, pyrazolyl group and triazolyl group (1,2,3-triazolyl group, 1,2,4-triazolyl group, etc.); 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 group heterocyclic group is more preferable, and a phenyl group, a naphthyl group (1-naphthyl group, 2-naphthyl group, etc.), a thienyl group (2-thienyl group, 3-thienyl group, etc.) and the like are more preferable.

In the substituent Ar ¹ , examples of the substituent in the aromatic group include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n -C _1-6 -alkyl group or 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- C _1-6 -aliphatic acyl group such as butanoyl group), n-valeryl group (n-pentanoyl group) and n-hexanoyl group; aromatic acyl group such as benzoyl group and toluoyl group (aroyl 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) C _1-6 -alkoxycarbonylamino group such as ruamino group); _1-6 such as trialkylsilyl group (trimethylsilyl group, triethylsilyl group, etc.); 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 and the like are more preferable, methyl group, methoxy group, methoxycarbonyl group, fluorine atom, trifluoromethyl group, formyl Group, t-but Aryloxycarbonyl amino group, a nitro group are more preferable.

Examples of the substituted aromatic group represented by the substituent Ar ¹ that satisfies such conditions include a tolyl group (such as an o-tolyl group, an m-tolyl group, and a p-tolyl group), 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 group (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, etc.), 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, etc.) -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, etc.), trifluoromethylphenyl group (4-trifluoromethylphenyl group, etc.), di Methylaminophenyl group (4-dimethylaminophenyl group etc.), t-butoxyaminophenyl group (4- (t-butoxycarbonylamino) phenyl group etc.), trimethylsilylphenyl group (4-trimethylsilylphenyl group etc.), benzyloxyphenyl Examples include a group (such as 4-benzyloxyphenyl group) and a nitrophenyl group (such as 4-nitrophenyl group), but are not limited thereto.

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, 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, etc.), methoxycarbonylphenyl group (4-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 2-methoxy group) Cicarbonylphenyl 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- Thienyl group, 3-thienyl group and the like are more preferable.

In the general formula (8A), examples of the alkyl group and cycloalkyl group represented by R ⁵ and R ⁶ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an 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.

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 adjacent —O—B—O—. . In this case, the aromatic group-containing boronic acid or its ester compound is, for example,

[Wherein Ar ¹ is the same as defined above. ]
Etc.

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.

  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.

  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.

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.

  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.

  In this step, the amount of compound (8A) and compound (8B) used is usually preferably 0.2 to 3 moles per mole of compound (7) from the viewpoints of selectivity and yield. .3 to 2.5 mol is more preferable. 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.

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. Above all, in this process, the selectivity, in terms of yield and safety, organic ligand complexes are preferred, 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.

  In this step, the amount of the palladium catalyst used is usually preferably 0.001 to 1 mol, and 0.01 to 0.25 mol with respect to 1 mol of the compound (7) from the viewpoints of selectivity and yield. Is more preferable.

  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.

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. 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.

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.

  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, and examples of the bis (dialkylphosphino) alkane include 1,2-bis (dimethylphosphino) ethane and the like, and examples of bis (diphenylphosphino) ferrocene include 1,1′-bis (diphenylphosphino) ferrocene (dppf) and the like.

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.

  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; Examples described below L5) and the like are more preferable, SPhos (2-dicyclohexyl phosphino-2 ', 6'-dimethoxy-1,1'-biphenyl; L5) and the like described later in the Examples are more preferred.

  In this step, the amount of the 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.

  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, 1,4-diazabicyclo [2.2.2] octane, and the like. 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.

  In this step, when a base is used, the amount of the base used is usually preferably 0.5 to 4 mol with respect to 1 mol of the compound (7) from the viewpoints of selectivity and yield. Mole is more preferred.

  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 (the mixing ratio is preferably organic solvent: water = 1: 99 to 99: 1) can also be used. Among these, from the viewpoints 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.

  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. 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.

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.

  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.

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. 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 following (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 is 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. 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.

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.

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 ring 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.

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.

  In this step, the amount of the compound (5) used is usually preferably 0.2 to 3 mol, and preferably 1 to 2.5 mol with respect to 1 mol of the 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-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.

Above all, in this process, the selectivity, in terms of yield and safety, organic ligand complexes are preferred, palladium acetate _{(Pd (OCOCH 3) 2)} , p- allyl palladium (II) chloride dimer, trifluoroacetic 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.

  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.

  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.

  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, and examples thereof include tri (cycloalkyl) phosphine, alkyldi (cycloalkylphosphine), di (alkyl) cycloalkylphosphine, tri (alkyl) phosphine, Tri (alkoxy) phosphine, alkyldiadamantylphosphine, general formula (6):

[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. preferable.

  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.

  Examples of the alkyldi (cycloalkylphosphine) include t-butyldicyclohexylphosphine, isobutyldicyclohexylphosphine, (n-butyl) dicyclohexylphosphine, isopropyldicyclohexylphosphine, (n-propyl) dicyclohexylphosphine, ethyldicyclohexylphosphine, methyldicyclohexylphosphine, Examples include t-butyldicyclooctylphosphine, t-butyldicycloheptylphosphine, t-butyldicyclopentylphosphine, t-butyldicyclobutylphosphine, t-butyldicyclopropylphosphine, and the like.

  Examples of the 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 ( - butyl) cycloheptyl phosphine, di (t-butyl) cyclopentyl phosphine, di (t-butyl) cycloalkyl-butylphosphine, di (t-butyl) cyclopropyl phosphine, and the like.

  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. For this reason, a phosphine ligand other than tri (t-butyl) phosphine is preferable from the viewpoint of easier control of the aromatic group to be introduced.

  Examples of tri (alkoxy) phosphine include trimethoxyphosphine, triethoxyphosphine, tri (n-propyloxy) phosphine, tri (isopropyloxy) phosphine, tri (n-butyloxy) phosphine, tri (isobutyloxy) phosphine, tri (T-Butyloxy) phosphine and the like.

  Examples of the alkyldiadamantylphosphine include n-butyldiadamantylphosphine.

  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.

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 a butyl group or a 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.

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.

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.

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.

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. C _1-8 -alkoxy groups 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.

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.

Among these, as R, in terms of selectivity and yield, preferably a group represented by ^{-PR 3 R 4, -PR 3 R} 4 (R 3 and ^{R 4} are the same or different, each represents a substituted or unsubstituted More preferably a group represented by -PR ³ R ⁴ (wherein R ³ and R ⁴ are the same or different and each is an unsubstituted cycloalkyl group), PCy ₂ (Cy represents a cyclohexyl group; the same shall apply hereinafter) is particularly preferred.

  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.

  Examples of such a 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; Examples described later) L4), RuPhos (2- dicyclohexyl phosphino-2 ', include 6'-diisopropoxy-1,1'-biphenyl) or the like.

  Moreover, as a ligand represented by General formula (6), General formula (6a):

[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.

  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), Cy John Phos (2- (dicyclohexylphosphino) biphenyl; L2 in Examples described later), SPhos (2-dicyclohexylphosphino-2 ′, 6′-dimethoxy-1,1′-biphenyl; L4 in Examples described later), The ligand (6a) is more preferable, and tricyclohexylphosphine, di (t-butyl) methylphosphine, Cy-JohnPhos (2- (dicyclohexylphosphino) biphenyl; L2 in Examples described later), SPhos (2-dicyclohexylphosphine) Fino-2 ′, 6′-dimethoxy-1,1′-biphenyl; L4) in the examples described later, and the 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.

  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.

  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, 1,4-diazabicyclo [2.2.2] octane, and the like. 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.

  In this step, when a base is used, the amount of the base used is usually preferably 0.5 to 10 moles with respect to 1 mole of the compound (4) from the viewpoints of selectivity and yield. Mole is more preferred.

  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. Especially, from a viewpoint of a selectivity, a yield, and safety | security, an ether solvent is preferable and 1, 4- dioxane 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 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.

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.

  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.

  The (hetero) arylacetonitrile compound thus obtained has the general formula (2):

[Wherein, Ar ¹ and Ar ² are the same as defined above. ]
It is a compound represented by these.

3. Step (III): (Hetero) arylation of di (hetero) arylacetonitrile compound In this step,
(III) General formula (2):

[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.

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.

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.

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 Formula groups and the like are more preferable. Phenyl group, tolyl group (o-tolyl group, m-tolyl group, p-tolyl group, etc.), 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.

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.

  In this step, the amount of compound (3) used is usually preferably 0.2 to 3 mol, and preferably 1 to 2.5 mol, based on 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-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. Above all, in this process, the selectivity, in terms of yield and safety, organic ligand complexes are preferred, 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.

  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.

  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.

  The ligand that can be used in this step is preferably a trialkylphosphine ligand from the viewpoints of selectivity and yield. However, since di (t-butyl) methylphosphine does not easily react, 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.

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.

  In this step, the amount of the ligand used is usually preferably 0.5 to 5 mol, more preferably 1 to 4 mol with respect to 1 mol of the palladium catalyst, from the viewpoints of selectivity and yield.

  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.

  In this step, when a base is used, the amount of the base used is usually preferably 0.5 to 10 mol with respect to 1 mol of the compound (2) from the viewpoints of selectivity and yield, and 1 to 5 Mole is more preferred.

  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. Especially, from a viewpoint of a selectivity, a yield, and safety | security, an ether solvent is preferable and 1, 4- dioxane 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 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.

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):

[Wherein, Ar ¹ , Ar ² and Ar ³ are the same as defined above. ]
It is a compound represented by these.

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.

  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:

[Wherein, Me represents a methyl group. Ph represents a phenyl group. The same applies hereinafter. ]
Or the general formula (2a):

[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.

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.

  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. In the present invention, the ligand (6a) that can be used as a particularly preferred ligand in the step (II) is, for example,
General formula (10):

[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.

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 viewpoint 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.

  This compound (10) may be a commercially available product or may be synthesized according to a previously reported method.

  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.), Aryl sulfonates (p-toluene sulfonate etc.) etc. are mentioned. From the viewpoint of the yield of this reaction, a halogen atom (especially a chlorine atom) is preferred.

In the general formula (11), examples of the alkyl group represented by R ^1b and R ^2b 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 a -butyl group and an 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.

In the general formula (11), examples of the cycloalkyl group represented by R ^1b and R ^2b include a C _3-8 -cycloalkyl group 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.

  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.

  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 -Althyllithium such as butyllithium and t-butyllithium; Aryllithium such as phenyllithium; Grignard reactant and the like. Alkyllithium is preferable and n-butyllithium is more preferable in terms of yield.

  This reaction can be normally implemented 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.

  The amount of these solvents used is not particularly limited as long as the reaction proceeds.

  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.

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.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the scope of the present invention is not limited thereto.

  Unless otherwise specified, all the materials including the dry solvent were used as they were on the market. Further, 5-bromo-N-methylindole was synthesized according to a 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.

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).

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.

  Example 1: Synthesis of 2,2'-bis (dicyclohexylphosphino) -1,1'-bipyridyl (DCPB)

[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 with a heat gun under vacuum, 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.

[Example 2: (Hetero) arylation of halogenated acetonitrile compound]
Example 2-1

[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.

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.

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.

[Example 3: Arylation of (hetero) arylacetonitrile compound]
Example 3-1.

[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).

Example 3-2

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.

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.

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.

(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.

[Example 4: (Hetero) arylation of di (hetero) arylacetonitrile compound]
Example 4-1

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.

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 the ligand, and the type of the 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.

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.

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-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.

[Example 5: Aldehydation of tri (hetero) arylacetonitrile compound]
Example 5-1

[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.

Example 5-2
The same treatment as in Example 5-1 was performed except that the substrate was changed. The results are shown below.

(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.

[Example 6: Amination of tri (hetero) arylacetonitrile compound]
Example 6-1

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.

Example 6-2
The same treatment as in Example 6-1 was performed except that the substrate was changed. The results are shown below.

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.

[Example 7: Amidation of tri (hetero) arylacetonitrile compound]
Example 7-1

A magnetic stir bar was accommodated 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 was obtained. 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.

Example 7-2

(P-methoxyphenyl) (p-methylphenyl) phenylacetonitrile (31.3 mg, 0.1 mmol) obtained in entry 15 of Example 4-3, in a sealed glass container with an internal volume of 10 mL, 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.

[Example 8: Synthesis of tri (hetero) arylmethane using tri (hetero) arylacetonitrile compound]
Example 8-1

A magnetic stirrer was housed in a sealed glass container having an internal volume of 10 mL that had been frame-dried, and under an argon atmosphere, triphenylacetonitrile (26.9 mg, 0.1 mmol) obtained in Example 4-1 and dry toluene (0.5 mL). ) 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.

Example 8-2
The same treatment as in Example 8-1 was performed except that the substrate was changed. The results are shown below.

(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.

[Example 9: Oxadiazolation of tri (hetero) arylacetonitrile compound]
Example 9-1

[Wherein Et represents an ethyl group. The same applies hereinafter. ]
A magnetic stirrer was housed in a sealed glass container having an internal volume of 10 mL that was frame-dried, and under an argon atmosphere, triphenylacetonitrile (26.9 mg, 0.1 mmol) obtained in Example 4-1 and NH ₂ OH (66 μL, 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.

Example 9-2
The same treatment as in Example 9-1 was performed except that the substrate was changed. The results are shown below.

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.

[Example 10: Triazination of tri (hetero) arylacetonitrile compound]
Example 10-1

A magnetic stirrer was housed in a sealed glass container having an internal volume of 10 mL that was frame-dried, and under an argon atmosphere, triphenylacetonitrile (26.9 mg, 0.1 mmol) obtained in Example 4-1 and 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.

Example 10-2
The same treatment as in Example 10-1 was performed except that the substrate was changed. The results are shown below.

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)

General formula (1):

[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):

[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. The production method according to claim 1, wherein the step (III) is performed in the presence of a trialkylphosphine ligand. The production method according to claim 2, wherein the trialkylphosphine ligand is tri (t-butyl) phosphine or a salt thereof. The manufacturing method in any one of Claims 1-3 with which the said process (III) is performed in presence of a base. 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. 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 manufacturing method in any one of Claims 1-5 provided with the process with which the halogenated aromatic compound represented by these is made to react in presence of a palladium catalyst. The production method according to claim 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):

[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. 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):

[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 manufacturing method in any one of Claims 6-8 provided with the process with which the aromatic group containing potassium trifluoroborate represented by these is made to react in presence of a palladium catalyst. General formula (9):

[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 manufacturing method comprising a step of substituting a cyano group of the tri (hetero) arylacetonitrile compound after the step (III) of the manufacturing method according to claim 1. formula:

[Wherein, Me represents a methyl group. Ph represents a phenyl group. ]
Or the general formula (2a):

[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 General formula (6a):

[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):

[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.