JPH10204004A - Production of aryl-substituted aromatic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce, at a high efficiency and effectively, an aryl-substituted aromatic compound useful as an intermediate for production of pharmaceuticals and agrochemicals by reactions of aryl Grignard reagents and aryl triflates in the presence of a specific palladium catalyst. SOLUTION: This production of an aryl-substituted aromatic compound comprises making, for example, an aryl triflate of formula I (Tf is trifluorosulfonyl; R<6> -R<9> are each H, a halogen, alkyl, etc.) react with, for example, an aryl Grignard reagent of formula II (X is chlorine or bromine; R<10> -R<13> are the same as R<6> -R<9> ) by using, as a catalyst, a palladium-based catalyst having a diphosphine ligand of the formula: Ph2 P-(CH2 )n -P(R<1> )2 [(n) is 2-4; R<1> is (substituted) phenyl] and/or an aminoalkylphosphine ligand of the formula: R<3> R<4> N-CH(R<5> )CH2 -P(R<2> )2 [R<2> is a (substituted) phenyl; R<3> and R<4> are each a lower alkyl; R<5> is a lower alkyl, cycloalky, aralkyl or (substituted) phenyl].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing an aryl-substituted aromatic compound, and more particularly, to reacting an aryl triflate with an aryl Grignard reagent in the presence of a palladium-based catalyst having a specific ligand. And a method for producing an aryl-substituted aromatic compound.

[0002]

2. Description of the Related Art Aryl-substituted aromatics are important compounds as intermediates for pharmaceuticals, agricultural chemicals and the like. Production methods using Grignard reagents include, for example, nickel catalysts and palladium. Reaction with aryl halides in the presence of a catalyst (Synthesi
s, 147, 827 (1990), J. Am. Chem. Sos., 110 8153 (198
8)), a method of reacting with an aryl triflate in the presence of a nickel-based catalyst (J. Org. Chem., 57 4066 (1992)) and the like have been proposed. On the other hand, the present inventors have used Grignard reagents and aryl triflates as 1-ligands.
N, N-palladium having dimethylamino-2-diphenylphosphino ethane proposes a method of reacting in the presence of a catalyst (Tetrahedron Letters, 37 3161 (1996 ))
However, it is not satisfactory in terms of yield and the like, and improvement of this point has been desired.

[0003]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for producing an aryl-substituted aromatic by reacting a Grignard reagent with an aryl triflate in the presence of a palladium-based catalyst. As a result, when a specific palladium-based catalyst having a diphosphine-based ligand and / or an aminoalkylphosphine-based ligand in which the carbon to which an amino group is bonded is substituted is used as the palladium-based catalyst, the desired aryl can be obtained. The present inventors have found that substituted aromatics can be efficiently produced in high yield, and have completed the present invention.

That is, according to the present invention, when an aryl triflate is reacted with an aryl Grignard reagent to produce an aryl-substituted aromatic compound, the catalyst represented by the formula (I) Ph ₂ P- (CH ₂ ) _n -P (R ¹ ) ₂ (I) wherein n represents 2 to 4, R ¹ represents a phenyl group which may have a substituent, and / or a diphosphine ligand represented by the formula (II): R ³ R ⁴ N-CH (R ⁵ ) CH ₂ -P (R ² ) ₂ (II) (wherein, R ² represents a phenyl group which may have a substituent,
R ³ and R ⁴ each independently represent a lower alkyl group. R ⁵
Represents a lower alkyl group, a cycloalkyl group, an aralkyl group or a phenyl group which may have a substituent. The present invention provides an industrially excellent method for producing an aryl-substituted aromatic, which comprises using a palladium-based catalyst having an aminoalkylphosphine-based ligand represented by the formula (1).

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. The present invention is characterized by using a palladium-based catalyst having the above-mentioned diphosphine-based ligand (I) and / or β-aminoalkylphosphine-based ligand (II). In the ligand (I), n represents 2, 3, and 4, and R ¹ represents a phenyl group which may have a substituent. R ² in the aminoalkylphosphine ligand (II) is a phenyl group which may have a substituent, R ³ and R ⁴ are each independently a lower alkyl group, R ⁵ is a lower alkyl group, Represents a cycloalkyl group, an aralkyl group or a phenyl group which may have a substituent.

The lower alkyl group includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl,
Examples of i-butyl, sec-butyl, t-butyl, pentyl and the like, and examples of the cycloalkyl group include cyclopentyl, cyclohexyl, cycloheptyl and the like.
Examples of the aralkyl group include phenylmethyl, phenylethyl, phenylpropyl and the like. Examples of the phenyl group which may have a substituent include a phenyl group, a phenyl group substituted with a lower alkyl group as described above, a phenyl group substituted with a halogen atom such as a fluorine atom and a chlorine atom, methoxy, ethoxy, and propoxy. ,
And a phenyl group substituted by a lower alkoxy group such as butoxy and pentoxy.

Representative examples of the diphosphine ligand (I) include, for example, 1,2-bis (diphenylphosphino) ethane (hereinafter abbreviated as dppe) and 1,3-bis (diphenylphosphino) propane (hereinafter abbreviated as dppe). dppp), 1,4-bis (diphenylphosphino) butane (hereinafter abbreviated as dppb) and the like. Aminoalkylphosphine ligands
Representative examples of (II) include, for example, 1-diphenylphosphino-2-N, N-dimethylaminopropane (hereinafter abbreviated as alphos), 1-diphenylphosphino-2-N, N-dimethylamino-3 -Methylbutane (hereinafter abbreviated as valphos), 1-diphenylphosphino-2-N, N-dimethylamino-3-phenylpropane (hereinafter abbreviated as phephos) and the like. Aminophosphine ligand (II) is, for example, J. Org.Ch
em., 48 2195 (1983). Among the ligands, dppp, dppb, alphos and the like are preferable, and dppp is particularly preferably used.

The palladium-based catalyst used in the present invention comprises:
From the diphosphine-based ligand (I) and / or the aminoalkylphosphine-based ligand (II) and the palladium compound, for example, “Experimental Chemistry Course” edited by The Chemical Society of Japan 18 393
(1991). Examples of the palladium compound include tris (dibenzylideneacetone) palladium, allyl palladium dichloride,
Palladium acetate and the like can be mentioned. Palladium-based catalysts
Those prepared in advance may be used, or those prepared in a reaction system may be used.

In the present invention, an aryl triflate is reacted with an aryl Grignard reagent in the presence of such a palladium catalyst. As the aryl triflate, for example, a triflate represented by the formula (III) is used. No.

[0010] (In the formula, Tf represents a trifluorosulfonyl group, and R ⁶ and R ⁷ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group or an aralkyloxy group. R ⁸ and R ⁹ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom,
Represents an alkyl group, an aryl group, an aralkyl group, an alkoxy group or an aralkyloxy group, or represents a naphthyl group which may have a substituent together with a phenyl group. )

The aryl Grignard reagent includes:
For example, a Grignard reagent represented by the formula (IV) can be mentioned. (Wherein, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, an aryl group,
Represents an aralkyl group, an alkoxy group or an aralkyloxy group. R ¹² and R ¹³ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group or an aralkyloxy group, or a substituent together with a phenyl group; Represents a naphthyl group which may be present. x represents a chlorine atom or a bromine atom. )

The alkyl group in the triflate represented by the formula (III) and the Grignard reagent represented by the formula (IV) includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl -Butyl, sec-butyl, t-
Butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, myristyl, palmityl, chain alkyl groups such as stearyl, cyclopentyl, cycloalkyl groups such as cyclohexyl, trifluoromethyl, 2-chloroethyl, 2 And a halogenated alkyl group such as -bromoethyl. Examples of the alkoxy group include an alkoxy group in which the alkyl moiety is the above-described alkyl group or the like.

The aralkyl group includes, for example, benzyl, phenylethyl, naphthylmethyl, and a phenyl, naphthyl moiety having a fluorine atom, a chlorine atom, a bromine atom, an alkyl group as described above, an alkoxy group as described above. And the like are substituted. Examples of the aralkyloxy group include an aralkyloxy group in which the aralkyl moiety is the above-described aralkyl group or the like. Examples of the aryl group include phenyl and naphthyl substituted with a fluorine atom, a chlorine atom, a bromine atom, the aforementioned alkyl group, the aforementioned alkoxy group, the aforementioned aralkyl group, etc., in addition to phenyl and naphthyl. And the like. Further, as a naphthyl group in which R ¹⁰ and R ¹¹ may have a substituent together with a phenyl group,
In addition to naphthyl, a fluorine atom, a chlorine atom, a bromine atom, the above-mentioned alkyl group, the above-mentioned alkoxy group, the above-mentioned aralkyl group-substituted naphthyl and the like can be mentioned.

Representative examples of triflates include, for example,
1-methoxy-2-trifluoromethanesulfonyloxybenzene, 1-chloro-2-trifluoromethanesulfonyloxybenzene, 1-methyl-2-trifluoromethanesulfonyloxybenzene, 1,3-dimethyl-2-trifluoromethanesulfonyloxybenzene, 2-trifluoromethanesulfonyloxy-1,1′-biphenyl, 2-trifluoromethanesulfonyloxy-1,1′-binaphthyl and the like can be mentioned. Representative examples of the Grignard reagent include, for example, phenyl Grignard reagent, methylphenyl Grignard reagent, methoxyphenyl Grignard reagent, chlorophenyl Grignard reagent, naphthyl Grignard reagent, biphenyl Grignard reagent and the like.

In reacting the triflate with the Grignard reagent, the palladium-based catalyst is used in an amount of usually 0.1 to 20 mol%, preferably 0.5 to 10 mol%, based on the triflate.
Mol%, and the Grignard reagent is used usually at 1 to 5 mol times, preferably 1 to 3 mol times. In this reaction, ethers such as diethyl ether, aromatics such as benzene and toluene are usually used, and the reaction is carried out using a mixture of triflates, a palladium-based catalyst, and a solvent at -40 to 100 ° C, preferably- 20 to 80 ° C
By adding a mixture of a Grignard reagent and a solvent.

In the present invention, by performing the reaction in the presence of inorganic salts, the reaction can proceed efficiently and the yield of the desired product can be improved. In this case, the inorganic salts are preferably added in advance together with the palladium catalyst or the like. Examples of such inorganic salts include lithium bromide, lithium iodide, magnesium bromide, lithium chloride, sodium bromide, potassium bromide, cesium bromide,
Examples thereof include alkali metal halides such as sodium iodide, potassium iodide, cesium iodide, magnesium chloride, magnesium iodide, calcium chloride, calcium bromide, and calcium iodide, and alkaline earth metal halides. When an inorganic salt is used, it is usually 0.1 to
It is 10 equivalent times, preferably 1 to 5 equivalent times.

The resulting aryl-substituted aromatics are made acidic, for example, by adding an aqueous solution of a mineral acid such as dilute hydrochloric acid or dilute sulfuric acid to the reaction mass, and then, if necessary, extracted with an organic solvent, washed with water, and dried. The solvent can be removed from the reaction mass by distilling off the solvent. The obtained aryl-substituted aromatics can be further purified by performing means such as distillation, recrystallization, and various types of chromatography, if necessary.

[0018]

According to the present invention, an aryl-substituted aromatic compound which is an object of the present invention is obtained. According to the present invention, an aminoalkylphosphine having a diphosphine ligand and / or a carbon to which an amino group is bonded is substituted. By using a palladium-based catalyst having a specific ligand called a system ligand, the intended aryl-substituted aromatic compound can be efficiently produced in high yield from a Grignard reagent and aryl triflates.

[0019]

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

Reference Example 1 (Preparation example of catalyst) Under a nitrogen atmosphere, 5.64 mmol (1 g) of palladium chloride was added with 5 ml of acetonitrile, and the mixture was stirred at room temperature for 14 hours.
l Distilled off and filtered. The obtained solid was dried to obtain 1.39 g of a palladium chloride bisacetonitrile complex (95% yield). Under a nitrogen atmosphere, 0.385 mmol (100 mg) of palladium chloride bisacetonitrile complex in 3 ml of benzene
Benzene solution of 0.4 mmol (109 mg) of alaphos
ml was added and stirred at room temperature for 14 hours. The precipitated solid was filtered, washed with benzene, and dried under reduced pressure to obtain PdCl ₂ (al
aphos) 157 mg were obtained. Yield 91%. In addition, other ligands can be similarly prepared.

Example 1 Lithium bromide dried in 4 ml of ether under a nitrogen atmosphere
1 mmol (86 mg), PdCl ₂ (alaphos) 0.05 mmol (22.4 mg), 2-
1 mmol (305 mg) of trifluoromethanesulfonyloxy-1,1′-biphenyl was added and suspended. Next, 2 mmol (2 ml) of a 1 M phenylmagnesium bromide ether solution was added to the suspension under ice-cooling and stirring. After the temperature was raised to 30 ° C., the mixture was stirred at the same temperature for 3 hours, and a small amount of the sample was analyzed by gas chromatography. As a result, 2-trifluoromethanesulfonyloxy-1,1′-biphenyl had completely disappeared. After decomposing excess Grignard reagent with 1N hydrochloric acid, ether extraction, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off.The obtained crude product was subjected to silica gel chromatography (n-hexane). / Benzene = 20/1) to give 219 mg of 1,1 ': 2', 1 "-terphenyl. Yield 95%

Examples 2 to 4 and Comparative Examples 1 to 4 In Example 1, PdCl ₂ (alaphos) was replaced with PdCl _2.
2 (dppp), PdCl ₂ (dppb), PdCl ₂ (dppe), PdCl ₂ (glypho
s), PdCl ₂ (PPh ₃ ) ₂ , PdCl ₂ (dppf), and Pd (PPh ₃ ) ₄ each using 0.05 mmol, and stirring was performed for the time shown in Table 1, except that
It carried out based on Example 1. The results are shown in Table 1.

[0023]

TABLE 1 catalytic stirring time yield Example _{1 PdCl 2 (alaphos) 3h 95} % Example ₂ PdCl 2 (dppp) 1 97 Example 3 PdCl ₂ (dppb) 3 95 Example 4 PdCl ₂ (dppe) 14 93 Comparative Example 1 PdCl ₂ (glyphos) 20 54 Comparative Example 2 PdCl ₂ (PPh ₃ ) ₂ 24 25 Comparative Example 3 PdCl ₂ (dppf) 24 10 Comparative Example 4 Pd (PPh ₃ ) ₄ 24 2 glyphos: 1-N, N- dimethylamino-2-diphenylphosphino ethane PPh _3: triphenylphosphine dppf: 1,1'-bis (diphenylphosphino) ferrocene

Example 5 The procedure of Example 1 was repeated, except that 2 mmol of a 1M-4-chlorophenylmagnesium bromide ether solution was used instead of the 1M phenylmagnesium bromide ether solution, and the mixture was stirred for 2 hours. And 4-chloro-1,
1 ′: 2 ′, 1 ″ -terphenyl was obtained. The results are shown in Table 2. ¹ H-NMR (CDCl ₃ ): δ 7.03-7.43 (13H, m, aromatic)

Example 6, Comparative Example 5 In Example 5, PdCl ₂ (alaphos) was replaced with PdCl _2.
2 (dppp) and NiBr ₂ (PPh ₃ ) ₂ were used in the same manner as in Example 5 except that NiBr ₂ (PPh ₃ ) ₂ was used. The results are shown in Table 2.

[0026]

TABLE 2 catalytic stirring time yield Example _{5 PdCl 2 (alaphos) 2h 92} % Example 6 PdCl ₂ (dppp) 1 91 Comparative Example _{5 NiBr 2 (PPh 3) 2} 1 5

Example 7 In Example 1, 1 mmol of 1-methoxy-2-trifluoromethanesulfonyloxybenzene was used in place of 2-trifluoromethanesulfonyloxy-1,1'-biphenyl.
, And stirred according to Example 1 except for stirring for 5 hours to obtain 2-methoxy-1,1'-biphenyl. Table 3 shows the results
It was shown to. ¹ H-NMR (CDCl ₃ ): δ 6.97-7.54 (9H, m, aromatic), 3.80
(3H, s, CH ₃ )

Example 8, Comparative Example 6 In Example 7, PdCl ₂ (alaphos) was replaced with PdCl _2.
2 (dppp) and PdCl ₂ (PPh ₃ ) ₂ were used in the same manner as in Example 5 except for using PdCl ₂ (PPh ₃ ) ₂ . The results are shown in Table 3.

[0029]

TABLE 3 catalysts stirring time yield Example _{7 PdCl 2 (alaphos) 5h 95} % Example 8 PdCl ₂ (dppp) 1 97 Comparative Example _{6 PdCl 2 (PPh 3) 2} 24 12

Example 9 In Example 1, 1 mmol of 1-chloro-2-trifluoromethanesulfonyloxybenzene was used instead of 2-trifluoromethanesulfonyloxy-1,1'-biphenyl, and 1M-phenylmagnesium bromide ether was used. Instead of using a solution, 2 mmol of a 1 M-2-methylphenylmagnesium bromide ether solution was used, and stirring was performed for 4 hours.
Performed in accordance with Example 1 to give 2-chloro-2'-methyl-1,1'-
Biphenyl was obtained. The results are shown in Table 4.

Comparative Examples 7 and 8 In Example 9, PdCl ₂ (alaphos) was replaced with PdCl _2.
2 (PPh ₃ ) ₂ and Nibr ₂ (PPh ₃ ) ₂ were used in accordance with Example 9 except that Nibr ₂ (PPh ₃ ) ₂ was used. The results are shown in Table 4.

[0032]

TABLE 4 catalytic stirring time yield Example _{9 PdCl 2 (alaphos) 4h 84} % Comparative Example _{7 PdCl 2 (PPh 3) 24} 66 Comparative Example _{8 Nibr 2 (PPh 3) 1} 19

Example 10 The procedure of Example 1 was followed, except that 2 mmol of a 1M-2-methylphenylmagnesium bromide ether solution was used instead of the 1M phenylmagnesium bromide ether solution, and the mixture was stirred for 3 hours. Conducted, 2-methyl-1,
1 ′: 2 ′, 1 ″ -terphenyl was obtained. The results are shown in Table 5.

Example 11 In Example 10, PdCl ₂ (alaphos) was replaced with PdCl _2
The procedure was performed according to Example 10 except that ₂ (dppp) was used. Table 5 shows the results.

[0035]

TABLE 5 catalysts stirring time yield Example _{10 PdCl 2 (alaphos) 3h 92} % Example 11 PdCl ₂ (dppp) 1 93

Example 12 The procedure of Example 1 was repeated, except that 2 mmol of a 1M-4-methylphenylmagnesium bromide ether solution was used instead of the 1M phenylmagnesium bromide ether solution, and the mixture was stirred for 4 hours. Conducted, 4-methyl-1,
1 ′: 2 ′, 1 ″ -terphenyl was obtained. The results are shown in Table 6.

Example 13 In Example 12, PdCl ₂ (alaphos) was replaced with PdCl _2
The procedure was performed according to Example 12 except that ₂ (dppp) was used. The results are shown in Table 6.

[0038]

[Table 6] catalysts stirring time yield Example _{12 PdCl 2 (alaphos) 4h 93} % Example 13 PdCl ₂ (dppp) 1 92

Example 14 In Example 1, PdCl ₂ (alaphos) was replaced with PdCl _{2
2 Using} (dppp), 1 mmol of 1,3-dimethyl-2-trifluoromethanesulfonyloxybenzene was used instead of 2-trifluoromethanesulfonyloxy-1,1'-biphenyl.
And the procedure of Example 1, except that 2 mmol of a 1M 2-methylphenylmagnesium bromide ether solution was used instead of the 1M-phenylmagnesium bromide ether solution and stirring was performed for 18 hours. '-Trimethyl-
1,1'-biphenyl was obtained. The yield was 65%.

Example 15 In Example 1, PdCl ₂ (alaphos) was replaced with PdCl _{2.
2 Using} (dppp), 1 mmol of 1,3-dimethyl-2-trifluoromethanesulfonyloxybenzene was used instead of 2-trifluoromethanesulfonyloxy-1,1'-biphenyl.
And stirring was carried out in the same manner as in Example 1 except for stirring for 14 hours to obtain 2,6-dimethyl-1,1′-biphenyl. The yield is 94
%Met.

Example 16 In Example 1, PdCl ₂ (alaphos) was replaced with PdCl _{2
2 Using} (dppp), 1 mmol of 2-trifluoromethanesulfonyloxy-1,1'-binaphthyl instead of 2-trifluoromethanesulfonyloxy-1,1'-biphenyl, and It carried out according to Example 1 and obtained 2-phenyl-1,1'-binaphthyl. The yield was 91%.

Claims (6)

[Claims] In the production of an aryl-substituted aromatic compound by reacting an aryl triflate with an aryl Grignard reagent, a catalyst represented by the formula (I) (R ¹ ) ₂ P- (CH ₂ ) _n -P ( R ¹ ) ₂ (I) (wherein n represents 2 to 4 and R ¹ represents a phenyl group which may have a substituent) and / or a compound represented by the formula (II) R ³ R ⁴ N-CH (R ⁵ ) CH ₂ -P (R ² ) ₂ (II) (wherein, R ² represents a phenyl group which may have a substituent,
R ³ and R ⁴ each independently represent a lower alkyl group. R ⁵
Represents a lower alkyl group, a cycloalkyl group, an aralkyl group or a phenyl group which may have a substituent. A method for producing an aryl-substituted aromatic compound, comprising using a palladium-based catalyst having an aminoalkylphosphine-based ligand represented by the formula (1). 2. An aryltriflate of the formula (III) (Wherein Tf represents a trifluoromethanesulfonyl group,
R ⁶ and R ⁷ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group or an aralkyloxy group.
R ⁸ and R ⁹ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group or an aralkyloxy group, or a substituent together with a phenyl group; Represents a naphthyl group which may be present. The method according to claim 1, wherein the compound is represented by the formula: 3. The method according to claim 1, wherein the aryl Grignard reagent is of the formula (IV) (Wherein, R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, an aryl group,
Represents an aralkyl group, an alkoxy group or an aralkyloxy group. R ¹² and R ¹³ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group or an aralkyloxy group, or a substituent together with a phenyl group; Represents a naphthyl group which may be present. x represents a chlorine atom or a bromine atom. The method according to claim 1, wherein the compound is a compound represented by the formula: 4. The method according to claim 1, wherein the reaction is carried out in the presence of an inorganic salt. 5. The method according to claim 4, wherein the inorganic salt is at least one selected from an alkali metal halide and an alkaline earth metal halide. 6. The method according to claim 4, wherein the amount of the inorganic salt used is 0.1 to 10 equivalent times the amount of the aryl triflate.