JP2018138534A - Method for producing aromatic nitrile - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an aromatic nitrile compound from an aromatic halide or an aromatic pseudohalide without using a highly toxic cyanide compound or an expensive catalyst.SOLUTION: An aromatic nitrile compound is produced by cyanating an aromatic halide or an aromatic pseudohalide using acetonitrile as a cyanide source in the presence of a nickel catalyst and an organosilicon compound.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing an aromatic nitrile. More specifically, the present invention relates to a method for producing an aromatic nitrile in high yield by a catalytic cyanation reaction using an aromatic halide or an aromatic pseudohalide as a raw material and using acetonitrile as a cyanide source in the presence of a nickel catalyst.

  As a method of cyanating an aromatic halide or aromatic pseudohalide to obtain an aromatic nitrile, for example, an alkali metal cyanide (Patent Document 1) or nickel cyanide (Non-Patent Document 1) in the presence of a palladium catalyst. A method using zinc cyanide (Non-patent Document 2) is known. However, these metal cyanides are highly toxic and are not excellent methods. In contrast, cyanation reactions of aromatic halides using a low toxicity cyanide source have been reported. For example, a method using a palladium catalyst with trimethylsilyl cyanide as a cyanide source (Non-patent Document 3) and a method using a palladium or nickel catalyst with acetone cyanohydrin as a cyanide source are known (Non-Patent Documents 4 and 5). However, these cyanide sources have a risk of generating toxic hydrogen cyanide during or after the reaction, and it is necessary to take safety measures for industrial use. As a non-toxic and easy-to-handle cyanide source, a method of cyanating an aromatic halide in the presence of a palladium catalyst using potassium hexacyanoferrate (II) is known, but expensive palladium was required as a catalyst. (Patent Document 2). Further, a method for obtaining an aromatic nitrile by reacting an aromatic halide with a formamide compound and aqueous ammonia is known, but since it is necessary to use a molar equivalent of an expensive organometallic reagent, a practical method and (Patent Document 3).

  On the other hand, if an organic nitrile compound can be used as a cyanide source, it is industrially useful because it has little toxicity and there is no fear of decomposing to produce toxic hydrogen cyanide. For example, a method of cyanating an aromatic halide with a palladium catalyst using benzyl cyanide as a cyanide source is known, but benzyl cyanide is relatively expensive as an organic nitrile compound (Non-patent Document 6). As a cheaper organic nitrile compound, a method of carrying out a cyanation reaction in the presence of a palladium catalyst using acetonitrile as a cyanide source is known. However, it is necessary to use an excessive amount of zinc powder as a reducing agent, and a temperature of 160 ° C. High temperature conditions are required (Non-patent Document 7). In addition, any method needs to use expensive palladium as a catalyst.

  Therefore, it is desired to develop a method for efficiently converting an aromatic halide to an aromatic nitrile under mild conditions using a non-toxic cyanide source, using an inexpensive catalyst and a small amount of additives.

JP 2003-64040 A JP 2008-189656 A JP 2011-241196 A

J. Org. Chem. 2003, 68, 9122. Tetrahedron.Lett. 2006, 47, 3303. J. Organomet. Chem. 2003, 684, 50. Angew.Chem.Int.Ed.2003, 42, 1661. Org.Process.Rec.Dev.2016, 20, 1540. RSC.Adv.2012, 2, 6167. Organometallics, 1998, 17, 1025.

  The present invention has been made in order to overcome the above-described problems of the prior art, and without using an expensive catalyst such as a metal cyanide or palladium, an aromatic halide or an aromatic pseudo compound can be efficiently used. It is an object to provide a method for producing an aromatic nitrile from a halide.

  As a result of diligent research to solve the above problems, the present inventors have used a nickel compound as a catalyst and an organosilicon compound as a reducing agent, thereby using acetonitrile as a cyanide source and an aromatic halide or aromatic pseudohalide. From this, it was found that aromatic nitriles can be produced efficiently, and the present invention has been completed.

(一般式(１)中、Ａｒは場合により置換された芳香族または複素芳香族基であり、Ｘは塩素、臭素、ヨウ素、トリフラート、メシラートまたはトシラートを表す。)
〈２〉前記ニッケル化合物として、ニッケル(ＩＩ)アセチルアセトナートを用いることを特徴とする〈１〉に記載の芳香族ニトリルの製造方法。
〈３〉前記有機ケイ素化合物として、以下の一般式(２)で示される構造を有する化合物を使用することを特徴とする〈１〉または〈２〉に記載の芳香族ニトリルの製造方法。

(一般式(２)中、ＸはＣＨまたはＮを表し、Ｒ¹〜Ｒ⁴はＨまたはメチル基を表す。)
〈４〉前記一般式(１)において、Ｘが臭素であることを特徴とする、〈１〉-〈３〉のいずれかに記載の芳香族ニトリルの製造方法。
〈５〉前記一般式(１)において、Ｘがトリフラートであることを特徴とする、〈１〉-〈３〉のいずれかに記載の芳香族ニトリルの製造方法。
〈６〉さらなる添加剤として、配位原子となる中性の窒素原子を少なくとも一つ有する二座配位子を用いることを特徴とする、〈１〉-〈５〉のいずれかに記載の芳香族ニトリルの製造方法。
〈７〉前記二座配位子として、２，２’−ビピリジル誘導体または１，１０−フェナントロリン誘導体を用いることを特徴とする、〈６〉に記載の芳香族ニトリルの製造方法。
〈８〉さらなる添加剤として、金属塩化物を用いることを特徴とする〈１〉-〈７〉のいずれかに記載の芳香族ニトリルの製造方法。
〈９〉前記添加剤として塩化亜鉛、または塩化マンガンを用いることを特徴とする、〈８〉に記載の芳香族ニトリルの製造方法。 That is, this application provides the following invention.
<1> Aromatics characterized by reacting an aromatic halide or aromatic pseudohalide represented by the following general formula with acetonitrile as a cyanide source, a nickel compound as a catalyst, and an organosilicon compound as a reducing agent. Nitrile production method.

(In the general formula (1), Ar represents an optionally substituted aromatic or heteroaromatic group, and X represents chlorine, bromine, iodine, triflate, mesylate or tosylate.)
<2> The method for producing an aromatic nitrile according to <1>, wherein nickel (II) acetylacetonate is used as the nickel compound.
<3> The method for producing an aromatic nitrile according to <1> or <2>, wherein a compound having a structure represented by the following general formula (2) is used as the organosilicon compound.

(In general formula (2), X represents CH or N, and R ^{1 to} R ⁴ represent H or a methyl group.)
<4> The method for producing an aromatic nitrile according to any one of <1> to <3>, wherein in the general formula (1), X is bromine.
<5> The method for producing an aromatic nitrile according to any one of <1> to <3>, wherein in the general formula (1), X is triflate.
<6> A fragrance according to any one of <1> to <5>, wherein a bidentate ligand having at least one neutral nitrogen atom as a coordination atom is used as a further additive. For producing a group nitrile.
<7> The method for producing an aromatic nitrile according to <6>, wherein a 2,2′-bipyridyl derivative or a 1,10-phenanthroline derivative is used as the bidentate ligand.
<8> The method for producing an aromatic nitrile according to any one of <1> to <7>, wherein a metal chloride is used as a further additive.
<9> The method for producing an aromatic nitrile according to <8>, wherein zinc chloride or manganese chloride is used as the additive.

  The method for producing an aromatic nitrile provided by the present invention can be efficiently produced with a small amount of a reducing agent using acetonitrile which is easily available and low in toxicity as a cyanide source, using an inexpensive nickel compound as a catalyst. In addition, the aromatic nitrile compound synthesized by the method of the present invention is industrially important as fine chemicals such as starting materials for intermediates of medical and agrochemical products. Therefore, the method of the present invention can be said to be an invention that has a great industrial effect.

  The method for producing an aromatic nitrile according to the method of the present invention comprises reacting an aromatic halide or pseudohalide at an appropriate reaction temperature in an acetonitrile solution as a cyanide source in the presence of a nickel compound and an organosilicon compound. Features.

  The aromatic halide or pseudohalide used in the production method of the present invention is represented by the formula (1). In the formula, Ar represents an aromatic group or a heteroaromatic group. The hydrogen atom which these rings have may be substituted with other substituents. X represents a halogen atom or a pseudohalogen group.

  In the general formula (1), examples of the aromatic when Ar is an aromatic group include an aromatic ring having 6 to 20 carbon atoms. Specific examples thereof include a phenyl group, a naphthyl group, and an anthranyl group. Is mentioned.

  In the general formula (1), examples of the aromatic when Ar is a heteroaromatic group include heteroaromatic rings having 4 to 20 carbon atoms. Specific examples thereof include a pyridyl group, a furyl group, A thienyl group, a quinolyl group, a quinoxalyl group, an indolyl group, a benzofuranyl group, and the like can be given.

  In the general formula (1), when Ar is an optionally substituted aromatic group or heteroaromatic group, the substituent may be a linear or branched alkyl group having 1 to 12 carbon atoms, Examples include chain or branched alkoxy groups having 1 to 12 carbon atoms, halogen atoms, aromatic groups, heteroaromatic groups, carboxyl groups, nitro groups, and cyano groups.

  In the general formula (1), when X is a pseudohalogen group, examples of the pseudohalogen group include triflate, mesylate, and tosylate.

  In the present invention, various aromatic halides or aromatic pseudohalides represented by the general formula (1) can be used. Preferably, bromobenzene, 4-bromoanisole, 4 -Bromotoluene, 1-bromo-4-chlorobenzene, methyl 4-bromobenzoate, 3-bromotoluene, 2-bromonaphthalene, 2-bromothiophene, 2-bromo-6-methylpyridine, phenyl triflate, 4-methoxyphenyl It is desirable to use triflate.

  The nickel compound used in the present invention includes, for example, nickel (II) acetylacetonate, nickel (II) hexaacetonitrile tetrafluoroborate, nickel (II) bromide, nickel (II) chloride, nickel (II) acetate, bis (Cyclooctadiene) nickel (0) and the like can be mentioned, and nickel (II) acetylacetonate or nickel (II) hexaacetonitrile tetrafluoroborate is preferable. These may be used alone or in combination of two or more. The amount used is selected from the range of 0.001 to 0.4 molar equivalents, preferably 0.01 to 0.2 molar equivalents, relative to the substrate.

The reducing agent used in the production method of the present invention is an organosilicon compound represented by the general formula (2). In the general formula (2), X represents CH or N, and R ^{1 to} R ⁴ represent H or a methyl group. Among these, an organosilicon compound (Me ₄ BTDP) in which X = N and R ¹ = R ² = R ³ = R ⁴ = Me is preferable. These may be used alone or in combination of two or more. The amount used is selected from the range of 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to the substrate.

  The amount of acetonitrile used in the production method of the present invention is selected from a range of 10 to 10,000 times, preferably 100 to 1000 times the weight ratio of the substrate.

  In the production method of the present invention, the reaction proceeds only with a nickel compound, an organosilicon compound, and acetonitrile, but a bidentate ligand may be used as an additive. Examples of the bidentate ligand used in this production method include 2,2′-biviridine, 4,4′-dimethyl-2,2′-biviridine, 4,4′-ditert-butyl-2,2′- Biviridine, 1,10-phenanthroline and the like can be mentioned, and 2,2′-biviridine and 1,10-phenanthroline are particularly preferable. These may be used alone or in combination of two or more. The amount used is selected from the range of 0.001 to 0.4 molar equivalents, preferably 0.01 to 0.2 molar equivalents, relative to the substrate.

  In the production method of the present invention, the reaction proceeds with only a nickel compound, an organosilicon compound, and acetonitrile, but a metal chloride such as zinc chloride or manganese chloride may be used as an additive. These may be used alone or in combination of two or more. The amount used is selected from the range of 0.01 to 0.5 molar equivalents, preferably 0.1 to 0.3 molar equivalents relative to the substrate.

  The reaction conditions for the method of the present invention are not particularly limited, but the reaction is usually carried out in the range of 0 to 150 ° C, preferably 50 to 130 ° C.

  The reaction time in the production method of the present invention depends on the amount of the catalyst used, the reaction temperature, etc., and cannot be generally defined, but is usually in the range of 10 to 100 hours, preferably in the range of 10 to 40 hours. Is called.

  The aromatic nitrile obtained by the method of the present invention includes, for example, benzonitrile, 4-methoxybenzonitrile, 4-methylbenzonitrile, 4-chlorobenzonitrile, methyl 4-cyanobenzoate, 3-methylbenzonitrile, 2-cyano. Examples include naphthalene, 2-cyanothiophene, 2-cyano-6-methylpyridine and the like.

  In a general embodiment of the present invention, a catalyst and a substrate are mixed in a reactor, and the reaction is carried out at a predetermined temperature by replacing the inside with an inert gas. After completion of the reaction, the obtained aromatic nitrile can be taken out by ordinary methods such as distillation, chromatographic separation, recrystallization and sublimation.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, this invention is not restrict | limited to a following example.

Reference Example 1: Synthesis of organosilicon compound The organosilicon compound used in this production method was synthesized based on the method described in JP-A-2016-124824.

Example 1
3 mL Collection Bayal (manufactured by Sekiya Rika Co., Ltd.), 2.6 mg (10 mmol) of nickel (II) acetylacetonate (manufactured by Sigma-Aldrich), 12.5 μL (100 mmol) of 4-bromoanisole (manufactured by Tokyo Chemical Industry Co., Ltd.) And dissolved in 3.0 mL of acetonitrile (manufactured by Kanto Chemical Co., Inc.). 70.6 mg (250 mmol) of Me4BTDP was added, and the mixture was stirred at 80 ° C. for 24 hours under an Ar atmosphere. Then, 3.7 mg (20 mmol) of ferrocene (manufactured by Tokyo Chemical Industry Co., Ltd.) was added as an internal standard, the reaction solution was concentrated, and ¹ H NMR (400 MHz, CDCl ₃ ) measurement was performed. The yield was 60%.

Example 2
To 3 mL collection vial (manufactured by Sekiya Rika Co., Ltd.), 2.6 mg (10 mmol) of nickel (II) acetylacetonate (manufactured by Sigma-Aldrich), 1.6 mg of 2,2′-bipyridine (manufactured by Tokyo Chemical Industry Co., Ltd.) 10 mmol), 4-bromoanisole (Tokyo Chemical Industry Co., Ltd.) 12.5 μL (100 mmol) was added, and dissolved in 3.0 mL of acetonitrile (Kanto Chemical Co., Ltd.). 70.6 mg (250 mmol) of Me4BTDP was added, and the mixture was stirred at 80 ° C. for 24 hours under an Ar atmosphere. Thereafter, 3.7 mg (20 mmol) of ferrocene (manufactured by Tokyo Chemical Industry Co., Ltd.) was added as an internal standard, a part of the reaction solution was concentrated, and ¹ H NMR (400 MHz, CDCl ₃ ) measurement was performed. The yield of benzonitrile was 72%.

Example 3
To 3 mL collection vial (manufactured by Sekiya Rika Co., Ltd.), nickel (II) acetylacetonate (manufactured by Sigma-Aldrich) 2.6 mg (10 mmol), 1,10-phenanthroline (manufactured by Sigma-Aldrich) 1.8 mg (10 mmol), 4-Bromoanisole (Tokyo Chemical Industry Co., Ltd.) 12.5 μL (100 mmol) was added and dissolved in 3.0 mL of acetonitrile (Kanto Chemical Co., Ltd.). 42.3 mg (150 mmol) of Me4BTDP was added, and the mixture was stirred at 80 ° C. for 24 hours under an Ar atmosphere. Thereafter, 3.7 mg (20 mmol) of ferrocene (manufactured by Tokyo Chemical Industry Co., Ltd.) was added as an internal standard, a part of the reaction solution was concentrated, and ¹ H NMR (400 MHz, CDCl ₃ ) measurement was performed. The yield of benzonitrile was 58%.

Example 4
Under the conditions of Example 2, in addition to 2,2′-bipyridine as an additive, 2.7 mg (20 mmol) of zinc chloride (manufactured by Nacalai Tesque) was further added to carry out the reaction. As a result, the yield of 4-methoxybenzonitrile was 93%.

Example 5
Under the conditions of Example 2, in addition to 2,2′-bipyridine as an additive, 2.5 mg (20 mmol) of manganese chloride (Merck) was further added to carry out the reaction. As a result, the yield of 4-methoxybenzonitrile was 94%.

Example 6
To 3 mL collection vial (manufactured by Sekiya Rika Co., Ltd.), 2.6 mg (10 mmol) of nickel (II) acetylacetonate (manufactured by Sigma-Aldrich), 1.6 mg of 2,2′-bipyridine (manufactured by Tokyo Chemical Industry Co., Ltd.) 10 mmol), 4-methoxyphenyl triflate (Tokyo Chemical Industry Co., Ltd.) 18.0 μL (100 mmol) was added and dissolved in 3.0 mL of acetonitrile (Kanto Chemical Co., Ltd.). 70.6 mg (250 mmol) of Me4BTDP was added, and the mixture was stirred at 80 ° C. for 24 hours under an Ar atmosphere. Then, 3.7 mg (20 mmol) of ferrocene (manufactured by Tokyo Chemical Industry Co., Ltd.) was added as an internal standard, the reaction solution was concentrated, and ¹ H NMR (400 MHz, CDCl ₃ ) measurement was performed. The yield was 64%.

Example 7
To 3 mL collection vial (manufactured by Sekiya Rika Co., Ltd.), nickel (II) hexaacetonitrile tetrafluoroborate (4.8 mg, 10 mmol), 1,10-phenanthroline (manufactured by Sigma-Aldrich), 1.8 mg (10 mmol), 4-bromo Anisole (Tokyo Kasei Kogyo Co., Ltd.) 12.5 μL (100 mmol) was added and dissolved in 2.0 mL of acetonitrile (Kanto Chemical Co., Ltd.). 42.3 mg (150 mmol) of Me4BTDP was added, and the mixture was stirred at 80 ° C. for 24 hours under an Ar atmosphere. Thereafter, 3.7 mg (20 mmol) of ferrocene (manufactured by Tokyo Chemical Industry Co., Ltd.) was added as an internal standard, a part of the reaction solution was concentrated, and ¹ H NMR (400 MHz, CDCl ₃ ) measurement was performed. The yield of benzonitrile was 84%.

Example 8
To 3 mL collection vial (manufactured by Sekiya Rika Co., Ltd.), 2.4 mg (5 mmol) of nickel (II) hexaacetonitrile tetrafluoroborate, 0.9 mg (5 mmol) of 1,10-phenanthroline (manufactured by Sigma-Aldrich), 4-bromo Anisole (Tokyo Kasei Kogyo Co., Ltd.) 12.5 μL (100 mmol) was added and dissolved in 4.0 mL of acetonitrile (Kanto Chemical Co., Ltd.). 70.6 mg (250 mmol) of Me4BTDP was added, and the mixture was stirred at 80 ° C. for 24 hours under an Ar atmosphere. Thereafter, 11.2 mg (67 mmol) of 1,3,5-trimethoxybenzene (Sigma-Aldrich) was added as an internal standard, a part of the reaction solution was concentrated, and ¹ H NMR (400 MHz, CDCl ₃ ) measurement was performed. As a result, the yield of 4-methoxybenzonitrile was 88%.

Claims (9)

Production of an aromatic nitrile characterized by reacting an aromatic halide or aromatic pseudohalide represented by the following general formula with acetonitrile as a cyanide source, a nickel compound as a catalyst, and an organosilicon compound as a reducing agent Method.

(In the general formula (1), Ar represents an optionally substituted aromatic or heteroaromatic group, and X represents chlorine, bromine, iodine, triflate, mesylate or tosylate.)   The method for producing an aromatic nitrile according to claim 1, wherein nickel (II) acetylacetonate is used as the nickel compound. The method for producing an aromatic nitrile according to claim 1 or 2, wherein a compound having a structure represented by the following general formula (2) is used as the organosilicon compound.

(In general formula (2), X represents CH or N, and R ^{1 to} R ⁴ represent H or a methyl group.)   The method for producing an aromatic nitrile according to any one of claims 1 to 3, wherein in the general formula (1), X is bromine.   In the said General formula (1), X is a triflate, The manufacturing method of the aromatic nitrile in any one of Claims 1-3 characterized by the above-mentioned.   The method for producing an aromatic nitrile according to any one of claims 1 to 5, wherein a bidentate ligand having at least one neutral nitrogen atom as a coordination atom is used as a further additive. .   The method for producing an aromatic nitrile according to claim 6, wherein a 2,2'-bipyridyl derivative or a 1,10-phenanthroline derivative is used as the bidentate ligand.   The method for producing an aromatic nitrile according to any one of claims 1 to 7, wherein a metal chloride is used as a further additive.   The method for producing an aromatic nitrile according to claim 8, wherein zinc chloride or manganese chloride is used as the additive.