JP2020196689A - Methods for coupling organic sodium compound and an organic chloride - Google Patents

Abstract

To provide a technique capable of efficiently coupling an organic halogen compound with an organometallic compound by using only a metal species which is inexpensive and excellent in sustainability in a method for cross-coupling the organic halogen compound with organometallic compound in the presence of a metal catalyst.SOLUTION: There is provided a method for coupling an organic sodium compound with an organic chloride including a step of reacting an organic sodium compound with an organic chloride in a reaction solvent in the presence of a metal catalyst containing one or more first transition metals selected from atomic numbers 24 to 28 to obtain a coupling product by coupling the organic sodium compound with the organic chloride.SELECTED DRAWING: Figure 1

Description

The present invention relates to a method for coupling an organic sodium compound and an organic chloride.

The coupling method of organic compounds is a method of synthesizing a new organic compound by bonding two or more organic compounds by a carbon atom-carbon atom bond (hereinafter, abbreviated as "CC bond"), which is a natural product. It has become a general-purpose technique in total synthesis and organic synthesis of functional materials such as medical pesticides, electronic materials, and their intermediates.

In such an organic compound coupling method, a palladium-based catalyst is widely used as a metal catalyst for a coupling reaction, and an organic electromotive agent such as an organic halide having a halogen atom introduced and an arbitrary metal or semi-metal atom (for example). , Boron, zinc, magnesium, tin, silicon, lithium) are introduced and the organic metal (semi-metal) compound is reacted. By such a reaction, the carbon atom into which the halogen group is introduced and the carbon atom into which the metal (metalloid) atom is introduced form a new C-C bond, whereby the coupling reaction proceeds. Specifically, Suzuki-Miyaura couplings that form CC bonds by the reaction of organic halides with organoboron compounds, Negishi couplings by the reaction of organic halides with organozinc compounds, and organic halides and organomagnesium magnesium. Kumada / Tamao / Collue coupling by reaction with the compound Grignard reagent, Umeda / Kosugi / Still coupling by the reaction of the organic halide and the organic tin compound, Hiyama by the reaction of the organic halide and the organic silicon compound. Couplings, Murahashi couplings by the reaction of organic halides with organic lithium compounds, etc. have been reported.

Research on coupling methods using metal species other than palladium-based catalysts as catalysts is also underway. For example, in the above-mentioned Kumada-Tamao-Colly coupling, it is known that the coupling reaction proceeds even when a nickel-based catalyst or a cobalt-based catalyst is used.

Furthermore, in addition to the palladium-based catalyst, an iron-based catalyst, a cobalt-based catalyst, a nickel-based catalyst, a copper-based catalyst, a ruthenium-based catalyst, and a rhodium-based catalyst are used as metal catalysts for the coupling reaction, and 9,10-dihalogeno is used. A method for producing 9,10-diphenylanthracene by cross-coupling ananthracene with a metal or semi-metal phenyl compound has been reported (see, for example, Patent Document 1). At this time, as the metal or semi-metal phenyl compound, an organic boron compound such as phenylboronic acid, an organic zinc compound such as phenylzinc bromide and phenylzinc chloride, and an organic substance such as phenylmagnesium bromide, phenylmagnesium chloride and phenylmagnesium iodide are used. It has been reported that organic lithium compounds such as magnesium compounds and phenyllithium can be used.

In addition, a wide variety of methods using a nickel-based catalyst as a metal catalyst for a coupling reaction have been reported (see, for example, Non-Patent Document 1). Non-Patent Document 1 describes an alkyl or aryl compound having a halogen group or an alkoxy group selected from iodine, bromine, chlorine, and fluorine introduced therein, and a metal selected from magnesium, zinc, boron, and tin. It has been reported that a coupling method or the like is known in which an alkyl or aryl compound into which a metalloid) atom is introduced is reacted in the presence of a nickel-based catalyst to form a CC bond. In addition, in Non-Patent Document 1, a (hetero) aryl or alkyl compound having a halogen group or methoxy group selected from bromine, chlorine, and fluorine is used as a (hetero) aryl or alkyl compound having a lithium introduced therein. A coupling method has been reported in which a reaction is carried out in the presence of a nickel-based catalyst to form a CC bond. According to such a method, it has been reported that the reaction proceeds rapidly under mild conditions while suppressing the production of undesired homocoupling products.

Japanese Unexamined Patent Publication No. 2001-322952

Dorus Heijnen et al., “Nickel-Catalyzed Cross-Coupling of Organolithium Reagents with (Hetero) Aryl Electrophiles” Chemistry-A European Journal, 2016, 22 (12), 3991-3995

However, the palladium-based catalysts commonly used in conventional coupling methods are very expensive and costly. Moreover, since palladium is highly rare among precious metals, there is also a problem in terms of sustainability.

Furthermore, when an organolithium reagent is used to prepare an organoboric acid compound used in Suzuki-Miyaura coupling using a palladium-based catalyst or an organozinc compound used in Negishi coupling, an organohalide such as an organic iodide is used. To prepare an organolithium compound in advance by a lithium-halogen exchange reaction by allowing n-butyllithium (hereinafter abbreviated as " ⁿ BuLi") or t-butyllithium (hereinafter abbreviated as " ^t BuLi") to act on the compound. Is required. In other words, the preparation of the organozinc compound is carried out by the following two-step reaction (first step: RI + ⁿ BuLi or ^t BuLi → R-Li, second step: R-Li + ZnCl ₂ → R-ZnCl). is there. However, since ⁿ BuLi and ^t BuLi are expensive reagents, there are problems such as an increase in cost. Furthermore, since ⁿ BuLi and ^t BuLi are designated as Class 3 dangerous goods by the Fire Service Act, there is a problem that equipment and facilities suitable for handling are required.

In addition, zinc, which is a constituent element of organozinc compounds, has a small recoverable reserve of 20 to 40 years, and the remaining recoverable reserves are small. Lithium, which is a constituent element of organolithium, is not as good as zinc. There is a problem from the viewpoint of sustainability because the recoverable reserves are limited. Furthermore, boron is an essential trace element of plants and animals, but overdose causes gastrointestinal disorders, central nervous system disorders, and the like to the human body. In particular, it is known to be highly toxic to insects, and there is also a problem that it has a high environmental load. Furthermore, when an organozinc compound is used, zinc sludge is generated as a by-product of the coupling reaction, but the main component of zinc sludge is zinc halide, which is classified as a deleterious substance by the Poisonous and Deleterious Substances Control Law. There is. Therefore, it is necessary to dispose of it after making it non-deleterious, which causes a problem of increasing cost and environmental load. In addition, when zinc hydroxide is generated, since zinc hydroxide is poorly soluble in water, the viscosity of the reaction solution increases, the environmental load is large, and the waste treatment facility becomes economically high load during industrialization. There is a problem that such as is required.

As described above, in the Kumada-Tamao-Colly coupling, the coupling reaction proceeds by using a nickel-based catalyst, a cobalt-based catalyst, or the like in addition to the palladium-based catalyst, but it is used in such coupling. The Grignard reagent to be obtained is obtained by reacting an organic halide with metallic magnesium in an anhydrous solvent such as tetrahydrofuran (hereinafter referred to as "THF") or ether. However, the conventional method using a Grignard reagent has a long reaction time, which is a factor of increasing the cost. In addition, the reactivity of Grignard reagents in the synthesis is generally higher in organic bromide (R-Br) and organic iodide (RI) than in organic chloride (R-Cl). , Usually, organic bromides or organic iodides have been widely used, but organic bromides and organic iodides are expensive. On the other hand, although organic chlorides are cheaper than other organic halides, their reactivity during synthesis tends to be low, so that the yield of the target Grignard reagent tends to decrease. In particular, when synthesizing an aromatic Grignard reagent, an alkenyl Grignard reagent, etc., the target Grignard reagent cannot be synthesized in good yield, and the yield may be affected by substituents on the aromatic ring. Are known. In addition, when preparing a Grignard reagent that is easily homocoupled, such as an aromatic Grignard reagent, there is also the problem that strict temperature control or the like is required in order to suppress the induction of homocoupling, which causes a decrease in yield. is there. In addition, organic magnesium bromide, which is widely used as a Grignard reagent from the viewpoint of reactivity, is a bromine-containing compound, but bromine is highly toxic and persistent in the human body, so that the area where it is mined is limited. Use is decreasing. Therefore, there is also a problem that the distribution amount decreases and it tends to be difficult to obtain the target organic bromide. Therefore, there is a problem that the method using a Grignard reagent cannot sufficiently satisfy the market demand from an industrial and economic point of view.

Magnesium hydroxide is sparingly soluble in the disposal of magnesium residues (magnesium hydroxide (Mg (OH) ₂ ) and MgX ₂ (X = halogen atoms, etc.)) generated after coupling by Kumada / Tamao / Collew coupling. Therefore, there is a problem that the viscosity of the reaction solution becomes large, the environmental load is large, and a waste treatment facility or the like, which has an economically high load for industrialization, is required.

Since the Murahashi coupling uses an organic lithium compound, it includes problems such as preparation of the above-mentioned organic lithium reagent and recoverable reserves of lithium resources.

The methods described in Patent Document 1 and Non-Patent Document 1 also do not use an expensive palladium-based catalyst, but use organic boron compounds, organic zinc compounds, organic magnesium compounds, organic lithium compounds, and the like. It does not solve the above problems.

Therefore, in a method of cross-coupling an organohalogen compound and an organometallic compound in the presence of a metal catalyst, it is required to construct a technique capable of efficiently coupling using only a metal species that is inexpensive and excellent in terms of sustainability. Was there.

As a result of repeated studies to solve the above problems, the present inventors have made organic sodium compounds and organic chlorides in a reaction solvent into a chromium-based catalyst, a manganese-based catalyst, an iron-based catalyst, a cobalt-based catalyst, and a nickel-based catalyst. It has been found that the organic sodium compound and the organic chloride can be efficiently coupled by reacting in the presence of a catalyst. In such a coupling method, the coupling reaction can proceed smoothly by using only metal species that are inexpensive and excellent in terms of sustainability. Such a coupling method does not require a waste treatment process or the like, which has a high economic load, and has a small environmental load. The present inventors have completed the present invention based on these findings.

That is, the present invention relates to a method for coupling an organic sodium compound and an organic chloride, and the characteristic composition thereof is the general formula I (R ¹ -Na) in the reaction solvent [here, R in the formula, R. ¹ is an aliphatic hydrocarbon group which may have a substituent, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, or an aromatic heterocyclic group, and Na is The organic sodium compound shown in [Sodium atom] and the general formula II (R ^2- Cl) [where R ² is an aliphatic hydrocarbon group which may have a substituent and an alicyclic formula. A hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, or an aromatic heterocyclic group, Cl is a chlorine atom].
By reacting in the presence of a metal catalyst containing one or more first transition metals selected from atomic numbers 24-28, the organic sodium compound and the organic chloride are coupled.
Formula III (R ¹ -R ²⁾ [wherein, in the formula, R ¹ is the same as R ¹ of the general formula ^{I (R 1 -Na), R} 2 is Formula II of (R ² -Cl) Similar to R ² ], including the step of obtaining the organic compound shown in.

According to this configuration, organosodium compounds and organochlorides are stably and efficiently cupped in the presence of a metal catalyst containing one or more first transition metals selected from atomic numbers 24-28. Can be ringed. Therefore, according to this configuration, the coupling reaction can proceed smoothly by using only metal species that are inexpensive and excellent in terms of sustainability. Further, the organic sodium compound and the organic chloride can be coupled easily and in a short time with a small number of steps without requiring a waste treatment step having a high economic load or a complicated chemical method. Moreover, since the environmental load is small, it is very advantageous economically and industrially. In addition, since the reaction proceeds under mild conditions, the coupling reaction proceeds efficiently without inducing side reactions such as the Wurtz reaction in which organic sodium compounds and organic chlorides are coupled to each other, resulting in high yield. The coupling product, which is the target compound, can be obtained with high yield and high purity. The coupling method of this configuration can be suitably used in various technical fields such as the synthesis of functional materials such as medical pesticides and electronic materials, and their intermediates.

Another characteristic configuration is that the metal catalyst contains a metal chloride.

According to this configuration, it is economically more advantageous to use an inexpensive and easily available metal chloride as the metal catalyst. Further, the metal chloride can coordinate a wide variety of ligands, and by using such a metal complex catalyst, the stability and efficiency of the coupling reaction between the organic sodium compound and the organic chloride can be further improved. Can be improved.

Another characteristic configuration is that the organic sodium compound represented by the general formula I (R ¹ -Na) is a general formula IV (R ¹ -X) in a reaction solvent [where, R ¹ is the general formula. those are the same as R ¹ of formula I (R ¹ -Na), X is the organic halide shown in a halogen atom], and a sodium dispersion solvent dispersion dispersed in was obtained by reacting Is at the point.

According to this configuration, as an organic sodium compound which is one of the compounds to be coupled, a compound synthesized by using a dispersion in which sodium is dispersed in a dispersion solvent from an organic halide can be used, and 2 Hydrocarbons containing sodium bases such as sodium 2,2,6,6-tetramethylpiperidides obtained by reacting a dispersion obtained by dispersing 2,6,6-tetramethylpiperidines and sodium in a dispersion solvent. Aryl sodium obtained by reacting an alkyl sodium halide obtained by reacting an alkyl halide and a dispersion obtained by dispersing sodium in a dispersion solvent with an aryl halide, etc. , Can be used. The dispersion in which sodium used in this configuration is dispersed in a dispersion solvent is easy to handle, does not require complicated chemical methods under mild conditions, and can be easily and quickly made from an organic halogen compound with a small number of steps. Since an organic sodium compound can be synthesized at low cost, it is very advantageous economically and industrially. Further, since the reaction proceeds under mild conditions, an organic sodium compound can be efficiently obtained without inducing a side reaction such as the Wurtz reaction in which organic halides are coupled to each other. As a result, the stability and efficiency of the coupling reaction can be improved, and the coupling product can be synthesized with high yield and high purity.

Other features configurations, R ² R ¹ and Formula II (R ² -Cl) in the general formula I (R ¹ -Na) is at least one, or, both, an aromatic hydrocarbon group, or At the point, which is an aromatic heterocyclic group.

According to this configuration, one or both of the compounds to be coupled can be a compound containing an aromatic hydrocarbon group or an aromatic heterocyclic group, and the aromatic hydrocarbon group or the aromatic heterocyclic group and the aromatic can be used. A hydrocarbon group or an aromatic heterocyclic group can be coupled, or an aromatic hydrocarbon group or an aromatic heterocyclic group can be coupled with another group. Since many functional materials such as medical pesticides and electronic materials contain one or more aromatic hydrocarbon groups or aromatic heterocyclic groups in their molecules, the coupling method of this configuration is a medical pesticide and a coupling method. It can be suitably used in various technical fields such as functional materials such as electronic materials and synthesis of their intermediates.

It is a figure which summarizes the synthesis condition and result of Example 1, which examined the coupling method which concerns on this Embodiment. It is a chart which shows the result of Example 1 which examined the coupling method which concerns on this Embodiment, and is an example of the coupling method which concerns on this Embodiment, coupling generation when manganese chloride is used as a metal catalyst. It is a GC chart of a thing. It is a chart which shows the result of Example 1 which examined the coupling method which concerns on this Embodiment, and is an example of the coupling method which concerns on this Embodiment, coupling generation when cobalt chloride is used as a metal catalyst. It is a GC chart of a thing. It is a chart which shows the result of Example 1 which examined the coupling method which concerns on this Embodiment, and is an example of the coupling method which concerns on this Embodiment, bis (triphenylphosphine) cobalt (II) as a metal catalyst. It is a GC chart of the coupling product when dichloride is used.

Hereinafter, the coupling method according to the embodiment of the present invention will be described in detail. However, the present invention is not limited to the embodiments described later.

The coupling method according to the present embodiment is a coupling method of an organic sodium compound and an organic chloride, and in a reaction solvent, the organic sodium compound represented by the general formula I (R ¹ -Na) and the general formula II (R ^2). The organic chloride shown in -Cl) is reacted in the presence of a metal catalyst containing one or more first transition metals selected from atomic numbers 24-28 to obtain the organic sodium compound and the organic chloride. This includes a step of obtaining an organic compound represented by the general formula III (R ¹ -R ² ) by the coupling of.

In the coupling method according to the present embodiment, the organic sodium compound represented by the general formula I (R ¹ -Na) is one of the compounds to be coupled and is an organic compound containing a sodium atom in the molecule.

In the general formula I (R ¹ -Na), R ¹ is an aliphatic hydrocarbon group which may have a substituent, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, Alternatively, it is an aromatic heterocyclic group.

Aliphatic hydrocarbon groups may be linear or branched, saturated or unsaturated. In addition, there is no particular limitation on the chain length. When it has a substituent, the substituent is not particularly limited as long as it does not react with sodium. Further, the number of substituents and the introduction position are not particularly limited. Examples of the aliphatic hydrocarbon group are not limited to these, but preferably an alkyl group having 1 to 20 carbon atoms, particularly preferably an alkyl group having 3 to 20 carbon atoms, an alkenyl group, and an alkynyl group. .. Specifically, as the alkyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isopentyl group, Neopentyl group, t-pentyl group, s-pentyl group, 2-methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, isohexyl group, neohexyl group, t-hexyl group, 2,2- Dimethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1-propylpropyl group, n-heptyl group, isoheptyl group, s-heptyl group, t-heptyl group, 2,2-Dimethylpentyl group, 3,3-dimethylpentyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 1-ethylpentyl group, 2-ethylpentyl group Group, 3-ethylpentyl group, 1-propylbutyl group, 2-propylbutyl group, n-octyl group, isooctyl group, t-octyl group, neooctyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl Group, 4,4-dimethylhexyl group, 1-methylheptyl group, 2-methylheptyl group, 3-methylheptyl group, 4-methylheptyl group, 5-methylheptyl group, 1-ethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 1-propylpentyl group, 2-propylpentyl group, 3-propylpentyl group, n-nonyl group, isononyl group, t-nonyl group, 1-methyloctyl group, 2-methyl Octyl group, 3-methyloctyl group, 4-methyloctyl group, 5-methyloctyl group, 6-methyloctyl group, n-decyl group, isodecyl group, t-decyl group, 1-methylnonyl group, 2-methylnonyl group, Examples thereof include 3-methylnonyl group, 4-methylnonyl group, 5-methylnonyl group, 6-methylnonyl group, 7-methylnonyl group and the like, but the present invention is not limited thereto. Examples of the alkenyl group include, but are not limited to, an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group and the like. Examples of the alkynyl group include, but are not limited to, an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a heptynyl group, an octynyl group and the like.

The aliphatic hydrocarbon group may further have a substituent. The substituents may have one or more, and when they have a plurality of substituents, they may be the same or different from each other. As the substituent, an aliphatic hydrocarbon group which may have a substituent, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, an aromatic heterocyclic group, a halogen atom and an alkoxy group , Cycloalkoxy group, aryloxy group, aralkyloxy group, alicyclic heterocyclic oxy group, aromatic heterocyclic oxy group, alkylthio group, cycloalkylthio group, arylthio group, aralkylthio group are alicyclic heterocyclic thio group. , Aromatic heterocyclic thio group, alkylamino group, cycloalkylamino group, arylamino group, aralkylamino group, alicyclic heterocyclic amino group, aromatic heterocyclic amino group, silyl group and the like. It is not limited to. The aliphatic hydrocarbon group is the same as that shown above, and is an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, an aromatic heterocyclic group, a halogen atom and an alkoxy group. , Cycloalkoxy group, aryloxy group, aralkyloxy group, alicyclic heterocyclic oxy group, aromatic heterocyclic oxy group, alkylthio group, cycloalkylthio group, arylthio group, aralkylthio group are alicyclic heterocyclic thio group. , Aromatic heterocyclic thio group, alkylamino group, cycloalkylamino group, arylamino group, aralkylamino group, alicyclic heterocyclic amino group, aromatic heterocyclic amino group, silyl group are shown below. The same can be mentioned.

Examples of the halogen atom that may have as a substituent include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The alkoxy group that may have as a substituent is preferably an alkoxy group having 1 to 10 carbon atoms, and specifically, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, and the like. Examples thereof include, but are not limited to, hexyloxy groups. The cycloalkoxy group is preferably a cyclopropoxy group having 3 to 10 carbon atoms, and examples thereof include a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group. The aryloxy group is preferably an aryloxy group having 6 to 20 carbon atoms, and specific examples thereof include, but are not limited to, a phenyloxy group and a naphthyloxy group. The aralkyloxy group is preferably an aralkyloxy group having 7 to 11 carbon atoms, and specific examples thereof include a benzyloxy group and a phenethyloxy group. Examples of the alicyclic heterocyclic oxy group and the aromatic heterocyclic oxy group include the alicyclic heterocyclic group and the aromatic heterocyclic group shown below as the heterocyclic portion. In addition, these may further have a substituent. The substituents may have one or more, and when they have a plurality of substituents, they may be the same or different from each other. Further, the position of the substituent is not particularly limited. Examples of the substituent include those exemplified as the substituent of the aliphatic hydrocarbon group, and the same ones.

The alkylthio group which may have as a substituent is preferably an alkylthio group having 1 to 20 carbon atoms, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group and a hexylthio group. However, it is not limited to these. Examples of the cycloalkylthio group include a cycloalkylthio group having 3 to 10 carbon atoms, and specific examples thereof include a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, and a cyclohexylthio group. It is not limited. The arylthio group is preferably an arylthio group having 6 to 20 carbon atoms, and specific examples thereof include, but are not limited to, a phenylthio group and a naphthylthio group. The aralkylthio group is preferably an aralkylthio group having 7 to 11 carbon atoms, and specific examples thereof include, but are not limited to, a benzylthio group and a phenethylthio group. Examples of the alicyclic heterocyclic thio group and the aromatic heterocyclic thio group include the alicyclic heterocyclic group and the aromatic heterocyclic group shown below as the heterocyclic portion. In addition, these may further have a substituent. The substituents may have one or more, and when they have a plurality of substituents, they may be the same or different from each other. Further, the position of the substituent is not particularly limited. Examples of the substituent include those exemplified as the substituent of the aliphatic hydrocarbon group, and the same ones.

The silyl group that may have as a substituent is 1 to 3 aliphatic hydrocarbon groups, alicyclic hydrocarbon group, alicyclic heterocyclic group, aromatic hydrocarbon group, aromatic complex on silicon. It is a monovalent group having a substituent such as a ring group. Examples of the substituent of the aliphatic hydrocarbon group, the alicyclic hydrocarbon group, the alicyclic heterocyclic group, the aromatic hydrocarbon group, the aromatic heterocyclic group and the like include the same as those described above. Specific examples thereof include, but are not limited to, a dimethylsilyl group, a diphenylsilyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethyl-t-butylsilyl group, a diphenyl-t-butylsilyl group and the like. Absent. In addition, these may further have a substituent. The substituents may have one or more, and when they have a plurality of substituents, they may be the same or different from each other. Further, the position of the substituent is not particularly limited. Examples of the substituent include those exemplified as the substituent of the aliphatic hydrocarbon group, and the same ones.

The alicyclic hydrocarbon group has no particular limitation on the number of ring members, regardless of whether the bonds between the ring-constituting atoms are saturated or unsaturated. Further, not only a single ring but also one having a ring set such as a fused ring or a spiro ring is included. The alicyclic hydrocarbon group is not limited to these, but is preferably a cycloalkyl group having 3 to 10 carbon atoms, particularly preferably 3 to 7 carbon atoms, and a cycloalkenyl group, preferably a carbon atom. Examples thereof include a number of 4 to 10, particularly preferably 4 to 7, cycloalkenyl groups and the like. Specific examples of the cycloalkyl group include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like. Examples of the cycloalkenyl group include, but are not limited to, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group and the like.

The alicyclic hydrocarbon group may have a substituent. The substituents may have one or more, and when they have a plurality of substituents, they may be the same or different from each other. Further, the position of the substituent is not particularly limited. Examples of the substituent include those exemplified as the substituent of the aliphatic hydrocarbon group, and the same ones.

The alicyclic heterocyclic group is a non-aromatic heterocyclic group having one or more heteroatoms as ring-constituting atoms. Not only monocyclic rings but also those having a ring set such as a fused ring and a spiro ring are included. The bonds between the ring-constituting atoms are not limited to saturated or unsaturated, and the number of ring members is not particularly limited. The hetero atom is not particularly limited as long as it does not react with sodium as a ring-constituting atom. The number of heteroatoms is not particularly limited, and the positions of heteroatoms are also not limited. As the hetero atom, preferably, an oxygen atom, a nitrogen atom, a sulfur atom and the like are exemplified. For example, an alicyclic heterocyclic group having a carbon atom number of preferably 2 to 7, particularly preferably 2 to 5, and a heteroatom number of preferably 1 to 5, particularly preferably 1 to 3. Can be mentioned. When it has a plurality of heteroatoms, it may be an atom of the same type or an atom of a different type. Examples of the alicyclic heterocyclic group include a nitrogen-containing alicyclic heterocyclic group such as a monocyclic 4-membered ring-type azetidinyl group, a 5-membered ring-type pyrrolidinyl group, a 6-membered ring-type piperidyl group, and a piperazinyl group. Oxygen-containing alicyclic heterocyclic groups such as three-membered ring-type oxylanyl groups, four-membered ring-type oxetanyl groups, five-membered ring-type tetrahydrofuryl groups, and six-membered ring-type tetrahydropyranyl groups, monocyclic Sulfur-containing alicyclic heterocyclic groups such as five-membered tetrahydrothiophenyl groups, nitrogen-containing oxygen-containing alicyclic heterocyclic groups such as monocyclic six-membered ring morpholinyl groups, and monocyclic six-membered ring-type Examples thereof include nitrogen-containing sulfur alicyclic heterocyclic groups such as thiomorpholinyl groups, but the present invention is not limited thereto.

The alicyclic heterocyclic group may have a substituent. The substituents may have one or more, and when they have a plurality of substituents, they may be the same or different from each other. Further, the position of the substituent is not particularly limited. Examples of the substituent include those exemplified as the substituent of the aliphatic hydrocarbon group, and the same ones.

The aromatic hydrocarbon group is not particularly limited as long as it has an aromatic ring. Not only monocyclic rings but also those having a ring set such as a fused ring and a spiro ring are included. There is no particular limitation on the number of members. For example, an aromatic hydrocarbon group having preferably 6 to 22 carbon atoms, particularly preferably 6 to 14 carbon atoms can be mentioned. Examples of the aromatic hydrocarbon group include a monocyclic six-membered ring phenyl group, a bicyclic naphthyl group, a pentarenyl group, an indenyl group, an azulenyl group, and the like, a tricyclic biphenylenyl group, an indacenyl group, an acenaphthylenyl group, and a fluorenyl group. Group, phenalenyl group, phenanthryl group, anthryl group, etc., tetracyclic fluoranthenyl, acetylenyl group, triphenylenyl group, pyrenyl group, naphthacenyl group, etc., pentacyclic perylenel group, tetraphenylenyl group, etc. Examples thereof include, but are not limited to, a pentasenyl group of the formula, a rubicenyl group of the seven-ring type, a coronenyl group, and a heptasenyl group. Particularly preferred are phenyl groups and tolyl groups.

The aromatic hydrocarbon group may have a substituent. The substituents may have one or more, and when they have a plurality of substituents, they may be the same or different from each other. Further, the position of the substituent is not particularly limited. Examples of the substituent include those exemplified as the substituent of the aliphatic hydrocarbon group, and the same ones.

An aromatic heterocyclic group is an aromatic heterocyclic group having one or more heteroatoms as ring-constituting atoms. Not only monocyclic rings but also those having a ring set such as a fused ring and a spiro ring are included. There is no particular limitation on the number of members. The hetero atom is not particularly limited as long as it does not react with sodium as a ring-constituting atom. The number of heteroatoms is not particularly limited, and the positions of heteroatoms are also not limited. As the hetero atom, preferably, an oxygen atom, a nitrogen atom, a sulfur atom and the like are exemplified. For example, an aromatic heterocyclic group having a carbon atom number of preferably 1 to 5, particularly preferably 3 to 5, and a heteroatom number of preferably 1 to 4, particularly preferably 1 to 3. Can be mentioned. When it has a plurality of heteroatoms, it may be an atom of the same type or an atom of a different type.

For example, as the monocyclic aromatic heterocyclic group, a nitrogen-containing fragrance such as a five-membered cyclic pyrrolyl group, pyrazolyl group, pyridyl group, imidazolyl group, etc., and a six-membered ring pyrazinyl group, pyrimidinyl group, pyridadinyl group, etc. Group heterocyclic groups, oxygen-containing aromatic heterocyclic groups such as 5-membered frill groups, oxygen-containing aromatic heterocyclic groups such as 5-membered thienyl groups, 5-membered oxazolyl groups, isooxazolyl groups, Examples thereof include, but are not limited to, a nitrogen-containing oxygen-containing aromatic heterocyclic group such as a flazanyl group, a five-membered ring-type thiazolyl group, and a nitrogen-containing sulfur-containing sulfur-containing aromatic heterocyclic group such as an isothiazolyl group.

The polycyclic aromatic heterocyclic groups include bicyclic indridinyl groups, isoindryl groups, indolyl groups, indazolyl groups, prynyl groups, isoquinolyl groups, quinolyl groups, phthalazinyl groups, naphthyldinyl groups, quinoxalinyl groups, quinazolinyl groups, and cinnolinyl groups. Group, etc., tricyclic carbazolyl group, carbolinyl group, phenatridinyl group, acridinyl group, perimidinyl group, phenanthrolinyl group, phenazinyl group and other nitrogen-containing aromatic heterocyclic groups, bicyclic benzofranyl group, isobenzofla Oxygen-containing aromatic heterocyclic groups such as nyl group and benzopyranyl group, sulfur-containing aromatic heterocyclic groups such as bicyclic benzothienyl group and tricyclic thiantranyl group, bicyclic benzoxazolyl group and benzo Nitrogen-containing oxygen aromatic heterocyclic groups such as isooxazolyl groups, bicyclic benzothiazolyl groups, benzoisothiazolyl groups, tricyclic phenothiazinyl groups and other nitrogen-containing sulfur-containing aromatic heterocyclic groups, tricyclic Examples include, but are not limited to, oxygen-containing sulfur aromatic heterocyclic groups such as the phenoxatinyl group of.

The aromatic heterocyclic group may have a substituent. The substituents may have one or more, and when they have a plurality of substituents, they may be the same or different from each other. Further, the position of the substituent is not particularly limited. Examples of the substituent include those similar to those exemplified as the substituent of the aliphatic hydrocarbon group.

In general formula II (R ¹ -Na), Na is a sodium atom.

As the organic sodium compound which is one of the compounds to be coupled, a commercially available compound may be used, or a compound produced by a method known in the art may be used.

In the coupling method according to the present embodiment, the organic chloride represented by the general formula II (R ^2- Cl) is another coupling target compound, and is an organic containing a chlorine atom covalently bonded to a carbon atom in the molecule. It is a compound.

In the general formula II (R ^2- Cl), R ² is an aliphatic hydrocarbon group which may have a substituent, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, Alternatively, it is an aromatic heterocyclic group. Here, an aliphatic hydrocarbon group, alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, or an aromatic heterocyclic group, R ¹ of the general formula I (R ¹ -Na) Examples thereof include the same as those exemplified as the aliphatic hydrocarbon group, the alicyclic hydrocarbon group, the alicyclic heterocyclic group, the aromatic hydrocarbon group, or the aromatic heterocyclic group. Particularly preferred is a naphthyl group.

R ² of general formula II (R ² -Cl) may be the same group as R ¹ in the general formula I (R ¹ -Na), may be a different group. R ² of the general formula I (R ¹ -Na) of R ¹ and the general formula II (R ² -Cl) are preferably referred aromatic and aryl hydrocarbon group or referred aromatic heteroaryl group It can be a group heterocyclic group, in which an aromatic hydrocarbon group or an aromatic heterocyclic group is coupled with an aromatic hydrocarbon group or an aromatic heterocyclic group, or an aromatic hydrocarbon group or an aromatic heterocyclic group. And other groups can be coupled. Since many functional materials such as medical pesticides and electronic materials contain one or more aromatic hydrocarbon groups or aromatic heterocyclic groups in their molecules, the coupling method of this configuration is a medical pesticide and a coupling method. It can be suitably used in various technical fields such as functional materials such as electronic materials and synthesis of their intermediates.

In the general formula I (R ^2- Cl), Cl is a chlorine atom.

As the organic chloride which is one of the compounds to be coupled, a commercially available compound may be used, or a compound produced by a method known in the art may be used.

The metal catalyst used in the coupling method according to the present embodiment is chromium (Cr) having an atomic number of 24, manganese (Mn) having an atomic number of 25, iron (Fe) having an atomic number of 26, and cobalt (Co) having an atomic number of 27. , Contains one or more first transition metals selected from the group consisting of nickel (Ni) with atomic number 28. As the metal catalyst, one type of metal catalyst may be used alone, or a plurality of types of metal catalysts may be combined. When combining a plurality of types of metal catalysts, a plurality of types of metal catalysts containing the same type of metal having different types of salts and ligands may be combined, or a metal catalyst containing different types of metals may be combined. Good. Further, a metal catalyst containing another metal species may be combined.

Metal catalysts include halides of chromium, manganese, iron, cobalt, nickel, carbonates, sulfates, acetates, nitrates, oxides, hydroxides, sulfides, acetylacetonate salts, trifluoromethanesulfonates, etc. It may be in the form of, particularly preferably chloride. It is economically more advantageous to use an inexpensive and easily available metal chloride as the metal catalyst. Further, the metal catalyst may have a ligand. The ligand is preferably an electron-donating ligand. Specific examples of the ligand include a diketone ligand such as acetylacetonato (acac) and hexafluoroacetylacetonato (hfacac), triphenylphosphine (PPh ₃ ), tricyclohexylphosphine (PCy ₃ ), and dicyclohexylphenylphosphine. (PCy ₂ Ph) Tributylphosphine (P (Bu) ₃ ), 1,3-bis (diphenylphosphine) propane (dppp), 1,2-bis (diphenylphosphine) ethane (dppp), [1,1' -Phosphine ligands such as bis (diphenylphosphine) ferrocene (dbpf), pyridine ligands such as bipyridine, amine ligands such as N, N, N', N'-tetramethylethylenediamine, 1,3- Bis (2,6-diisopropylphenyl) imidazol-2-iriden, 1,3-bis (2,6-diisopropylphenyl) imidazolidine-2-iriden, 1,3-bis (2,6-bis (1-ethyl)) Propyl) phenyl) imidazol-2-idene, 1,3-bis (2,6-bis (1-ethylpropyl) phenyl) imidazolidine-2-idene, 1,3-dimesityl imidazol-2-idene, 1 Examples thereof include, but are not limited to, N-heterocyclic carben (NHC) ligands such as 3-bis (2,4,6-trimethylphenyl) imidazolidine-2-ylidene. In addition, metal chloride, which is a suitable metal catalyst, can coordinate a wide variety of ligands, and by using such a metal complex catalyst, the coupling reaction between the organic sodium compound and the organic chloride can be carried out. Stability and efficiency can be further improved.

Chromium-based catalysts that are metal catalysts containing chromium include chromium chloride, chromium bromide, chromium iodide (II), chromium iodide (III), chromium fluoride, chromium acetate (II) (Chromium (II) acetate: Cr (OAc) ₂ ), chromium acetate (III) (chromium (III) acetate: Cr (OAc) ₃ ), tris (2,4-pentanedionato) chromium (III) (tris (2,4-pentanedionato) chromium (III): Cr (acac) ₃ ), etc., but are not limited to these.

Manganese-based catalysts that are metal catalysts containing manganese include manganese chloride, manganese bromide, manganese iodide (II), manganese fluoride, manganese acetate (II) (manganese (II) acetate: Mn (OAc) ₂ ), Manganese acetate (III) (manganese (III) acetate: Mn (OAc) ₃ ), Tris (2,4-pentanedionato) Manganese (III) (tris (2,4-pentanedionato) manganese (III): Mn (acac) ) ₃ ), bis (2,4-pentanedionato) manganese (II) dihydrate (bis (2,4-pentanedionato) manganese (II) dihydrate: Mn (acac) ₂ ), bis (hexafluoroacetylacetate) Examples include, but are not limited to, manganese (II) hydrate (bis (hexafluoroacetylacetonato) manganese (II) hydrate: Mn (hfacac) ₂ ).

Iron-based catalysts that are metal catalysts containing iron include iron chloride, iron bromide, iron iodide (II), iron iodide (III), iron fluoride, and iron trifluoromethanesulfonate (II) (Fe (OTf). ) ₂ ), Iron trifluoromethanesulfonate (III) (Fe (OTf) ₃ ), Iron (II) (iron (II) acetate: Fe (OAc) ₂ ), Iron (III) acetate (iron (III) acetate : Fe (OAc) ₃ ), Tris (2,4-pentanedionato) Iron (III) (tris (2,4-pentanedionato) iron (III): [Fe (acac) ₃ ]), Tris (hexafluoroacetyl) Acetonato iron (III) (tris (hexafluoroacetylacetonato) iron (III): Fe (hfacac) ₂ ), tris (dibenzoylmethanato) iron: [Fe (dppd) ₃ ]), bis (tri) Phenylphosphine iron (II) dichloride (bis (triphenylphosphine) iron (II) dichloride: [FeCl ₂ (PPh ₃ ) ₂ ]), [1,2-bis (diphenylphosphino) ethane] iron (II) dichloride ([ 1,2-bis (diphenylphosphino) ethane] iron (II) dichloride: [FeCl ₂ (dppe)]), [1,3-bis (diphenylphosphino) propane] iron (II) dichloride ([1,3-bis) (diphenylphosphino) propane] iron (II) dichloride: [FeCl ₂ (dppp)]), [1,3-bis (2,6-diisopropylphenyl) imidazol-2-iriden] iron (II) dichloride ([1,3) -bis (2,6-diisopropylphenyl) imidazole-2-ylidene] iron (II) dichloride: [FeCl _2- IPr]), [1,3-bis (2,6-diisopropylphenyl) imidazolidine-2-ylidene] Iron (II) dichloride ([1,3-bis (2,6-diisopropylphenyl) imidazolidin-2-ylidene] iron (II) dichloride: [FeCl _2- SIPr]), [1,3-bis (2,6-diisopropylphenyl) imidazol-2-idene] iron (III) trichloride ([1,3-bis (2,6-diisopropylphenyl) imidazole-2-ylidene] iron (III) trichloride: [FeCl _3- IPr ]), [1,3-bis (2,6-diisopropylphenyl) imidazolidine-2-ylidene] iron (III) trichloride ([1,3-bis (2,6-diisopropylphenyl) imidazolidin-2-ylidene] iron (III) trichloride: [FeCl _3- SIPr]), etc., but is not limited to these.

Cobalt-based catalysts that are metal catalysts containing cobalt include cobalt chloride, cobalt bromide, cobalt iodide (II), cobalt iodide (III), cobalt fluoride, and cobalt trifluoromethanesulfonate (II) (Co (OTf). ) ₂ ), Cobalt Trifluoromethanesulfonate (III) (Co (OTf) ₃ ), Cobalt (II) Acetate (cobalt (II) acetate: Co (OAc) ₂ ), Cobalt Cobalt (III) (cobalt (III) acetate) : Co (OAc) ₃ ), Tris (2,4-pentanedionato) cobalt (III): [Co (acac) ₃ ]), Bis (2,4) -Pentandionato cobalt (II) dihydrate (bis (2,4-pentanedionato) cobalt (II) dihydrate: [Co (acac) ₂ ]), bis (hexafluoroacetylacetonato) cobalt (II) water Japanese (bis (hexafluoroacetylacetonato) cobalt (II) hydrate: Co (hfacac) ₂ ), bis (triphenylphosphine) cobalt (II) dichloride: [CoCl ₂ (PPh ₃ ) ₂ ]), [1,2-bis (diphenylphosphino) ethane] cobalt (II) dichloride ([1,2-bis (diphenylphosphino) ethane] cobalt (II) dichloride: [CoCl ₂ (dppe)], [1, 3-bis (diphenylphosphino) propane] cobalt (II) dichloride ([1,3-bis (diphenylphosphino) propane] cobalt (II) dichloride: [CoCl ₂ (dppp)]), bis (tricyclohexylphosphin) cobalt ( II) Dichloride (bis (tricyclohexylphosphine) cobalt (II) dichloride: [CoCl ₂ (PCy ₃ ) ₂ ]), [1,1'-bis (diphenylphosphino) ferrocene] cobalt (II) dichloride ([1,1' -bis (diphenylphosphino) ferrocone] coba lt (II) dichloride: CoCl ₂ (dbpf)), tris (2,2'-bipyridine) cobalt (II) bis (hexafluorophosphate) (tris (2,2'-bipyridine) cobalt (II) bis (hexafluorophosphate) )), Tris (2,2'-bipyridine) cobalt (III) tris (hexafluorophosphate) (tris (2,2'-bipyridine) cobalt (III) tris (hexafluorophosphate)), [1,3-bis (bipyridine) 2,6-diisopropylphenyl) imidazol-2-iriden] cobalt (II) dichloride ([1,3-bis (2,6-diisopropylphenyl) imidazole-2-ylidene] cobalt (II) dichloride: [CoCl _2- IPr] ), [1,3-bis (2,6-diisopropylphenyl) imidazolidine-2-ylidene] cobalt (II) dichloride ([1,3-bis (2,6-diisopropylphenyl) imidazolidin-2-ylidene] cobalt ( II) dichloride: [CoCl _2- SIPr]), [1,3-bis (2,6-diisopropylphenyl) imidazol-2-iriden] cobalt (III) trichloride ([1,3-bis (2,6-diisopropylphenyl)) ) imidazole-2-ylidene] cobalt (III) trichloride: [CoCl _3- IPr]), [1,3-bis (2,6-diisopropylphenyl) imidazolidine-2-iriden] cobalt (III) trichloride ([1) , 3-bis (2,6-diisopropylphenyl) imidazolidin-2-ylidene] Co (III) trichloride: [CoCl _3- SIPr]), etc., but is not limited to these.

Nickel-based catalysts that are metal catalysts containing nickel include nickel chloride, nickel bromide, nickel iodide (II), nickel fluoride, nickel trifluoromethanesulfonate (II) (Ni (OTf) ₂ ), and nickel acetate (II). II) (nickel (II) acetate: Ni (OAc) ₂ ), bis (2,4-pentanedionato) nickel (II) hydrate (bis (2,4-pentanedionato) nickel (II) Hydrate: [Ni (acac) ₂ ]), bis (hexafluoroacetylacetonato) nickel (II) hydrate: Ni (hfacac) ₂ ) bis (1,5-cyclooctadiene) nickel (0) (Bis (1,5-cyclooctadiene) nickel (0): [Ni (COD) ₂ ]), bis (triphenylphosphine) nickel (II) dichloride (bis (triphenylphosphine) nickel (II) dichloride: [NiCl ₂ (PPh ₃ ) ₂ ]), [1,2-bis (diphenylphosphino) ethane] nickel (II) dichloride ([1,2-bis (diphenylphosphino) ethane] nickel (II) dichloride: [NiCl ₂ (dppe) )]), [1,3-bis (diphenylphosphino) propane] nickel (II) dichloride ([1,3-bis (diphenylphosphino) propane] nickel (II) dichloride: [NiCl ₂ (dppp)]), bis (Tricyclohexylphosphine) nickel (II) dichloride (bis (tricyclohexylphosphine) nickel (II) dichloride: [NiCl ₂ (PCy ₃ ) ₂ ]), bis (dicyclohexylphenylphosphino) nickel (II) dichloride (bis (dicyclohexylphenylphosphino) nickel (II) dichloride: [NiCl ₂ (PCy ₂ Ph) ₂ ]), [1,3-bis (2,6-diisopropylphenyl) imidazole-2-idene] triphenylphosphine nickel (II) dichloride ([1,3) -bis (2, 6-diisopropylphenyl) imidazol-2-ylidene] triphenylphosphine nickel (II) dichloride: [NiCl ₂ (PPh ₃ ) IPr)]), [1,1'-bis (diphenylphosphine) ferrocene] nickel (II) dichloride ([ 1,1'-bis (diphenylphosphino) ferrocone] nickel (II) dichloride: NiCl ₂ (dbpf)), etc., but are not limited to these.

As the reaction solvent, a solvent known in the art can be used as long as the coupling reaction between the organic sodium compound and the organic chloride is not inhibited. For example, an ether solvent, a paraffin solvent such as normal paraffin or cycloparaffin, an aromatic solvent, an amine solvent, or a heterocyclic compound solvent can be used. As the ether solvent, a cyclic ether solvent is preferable, and tetrahydrofuran (hereinafter, may be abbreviated as "THF") or the like can be preferably used. As the paraffin solvent, cyclohexane, normal hexane, normal decane and the like are particularly preferable. As the aromatic solvent, xylene, toluene, benzene and the like can be preferably used. Ethylenediamine or the like can be preferably used as the amine solvent. As the heterocyclic compound solvent, tetrahydrothiophene or the like can be used. In addition, only one of these may be used, or two or more of these may be used in combination as a mixed solvent.

The reaction temperature is not particularly limited when a paraffin-based solvent is used as the solvent, and the type and amount of the organic sodium compound and the organic chloride which are the coupling target compounds, the type and amount of the metal catalyst, the type and amount of the reaction solvent, and the like. In addition, it can be appropriately set depending on the reaction pressure and the like. Specifically, the reaction temperature is preferably set to a temperature that does not exceed the boiling point of the reaction solvent. Under pressure, the reaction temperature can be set at a high temperature because it is higher than the boiling point under atmospheric pressure. The reaction can also be carried out at room temperature, preferably from 0 to 100 ° C, particularly preferably from 20 to 80 ° C, and even more preferably from room temperature to 50 ° C. It is not necessary to provide a special temperature control means for heating, cooling, or the like, but a temperature control means may be provided if necessary. On the other hand, when a solvent other than paraffin is used, the temperature is low, preferably 0, in order to prevent the reaction between phenyl sodium and the like, which are preferably exemplified as the organic sodium compound represented by the general formula I (R ¹ -Na), with the solvent. It is recommended to carry out at around ° C. By appropriately controlling the type and amount of the reaction solvent added in this way, the coupling reaction can proceed more efficiently.

The reaction time is also not particularly limited, and depends on the type and amount of the organic sodium compound and the organic chloride of the compound to be coupled, the type and amount of the metal catalyst, the type and amount of the reaction solvent, the reaction pressure, the reaction temperature, and the like. It may be set appropriately. It is usually carried out for 15 minutes to 24 hours, preferably 20 minutes to 6 hours.

The coupling reaction may be appropriately set according to the type and amount of the organic sodium compound and organic chloride of the compound to be coupled, the type and amount of the metal catalyst, the type and amount of the reaction solvent, and the reaction pressure and reaction temperature. However, as a general rule, it is preferable to carry out the reaction in an inert gas atmosphere filled with argon gas, nitrogen gas or the like.

In the method for synthesizing an organozinc compound according to the present embodiment, the amount of the metal catalyst used is the type of the metal catalyst, the type and amount of the organic sodium compound and the organic chloride which are the compounds to be coupled, and the type of the reaction solvent. It can be set as appropriate according to the amount and the like. Preferably, the reaction is carried out in an amount such that the molar ratio of the organic sodium compound: organic chloride: metal catalyst is 0.8 to 2.0: 1: 0.01 to 0.25. Further, preferably, the reaction is carried out in an amount such that the molar ratio of the organic sodium compound: organic chloride: metal catalyst is 1.0 to 1.5: 1: 0.05 to 0.20. By reacting at such a ratio, the coupling reaction proceeds stably and efficiently, and the coupling product which is the target compound can be synthesized with high efficiency and high purity.

By the coupling method according to the present embodiment, the organic compound represented by the general formula III (R ¹ -R ² ) of the desired final target compound can be obtained as a coupling product. The organic compounds represented by the general formula III (R ¹ -R ² ), which are coupling products, are the organic group (R ¹ ) of the organic sodium compound represented by the general formula I (R ¹ -Na) and the general formula II (R). The organic group (R ² ) of the organic chloride shown in ^2- Cl) is linked by a CC bond. Accordingly, in the organic compound represented by the general formula III (R ¹ -R ^2), R ¹ is the same as R ¹ of the organic sodium compound represented by the general formula ^{I (R 1 -Na), R} 2 is Formula II ( is the same as R ² of the organic chloride shown in R ² -Cl).

The obtained coupling product may be purified by purification means known in the art such as column chromatography, distillation, recrystallization and the like. Further, the organic sodium compound and the organic chloride remaining unreacted may be recovered and subjected to the reaction of the coupling method of the present embodiment again. Further, it may be carried out in an inert gas atmosphere filled with argon gas, nitrogen gas or the like as in the case of the coupling reaction.

According to the coupling method according to the present embodiment, the organosodium compound and the organochloride are stable in the presence of a metal catalyst containing one or more first transition metals selected from atomic numbers 24 to 28. It can be coupled efficiently and efficiently. Therefore, the cross-coupling reaction can proceed smoothly by using only metal species that are inexpensive and excellent in terms of sustainability. Further, the organic sodium compound and the organic chloride can be coupled easily and in a short time with a small number of steps without requiring a waste treatment step having a high economic load or a complicated chemical method. Moreover, since the environmental load is small, it is very advantageous economically and industrially. In addition, since the reaction proceeds under mild conditions, the coupling reaction proceeds efficiently without inducing side reactions such as the Wurtz reaction in which organic sodium compounds and organic chlorides are coupled to each other, resulting in high yield. The coupling product, which is the target compound, can be obtained with high yield and high purity. Therefore, the coupling method according to the present embodiment can be suitably used in various technical fields such as the synthesis of functional materials such as medical pesticides and electronic materials, and their intermediates.

[Another Embodiment]
In addition to the above-described embodiment, the configuration may be as follows.

In the coupling method according to the present embodiment described above, the organic sodium compound represented by the general formula I (R ¹ -Na), which is one of the compounds to be coupled, is contained in the reaction solvent under the general formula IV (R ¹ -X). ) Can be obtained by reacting a dispersion in which the organic halide shown in) and sodium are dispersed in a dispersion solvent.

The organic halide represented by the general formula IV (R ¹ -X) is an organic compound containing a covalently bonded halogen atom. R ¹ of the general formula IV (R ¹ -X) is optionally substituted aliphatic hydrocarbon group, alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, or , Aromatic heterocyclic group. Wherein, R ¹ of the general formula IV (R ¹ -X) is identical to the R ¹ of the general formula I (R ¹ -Na). However, if R ¹ has a substituent that is reactive with sodium, the substituent and the dispersion in which sodium is dispersed in a dispersion solvent react with each other and induce a side reaction, which is not preferable. Therefore, the substituent is appropriate. It is necessary to protect with a protective group.

In the general formula IV (R ¹ -X), X is a halogen atom, specifically, a chlorine atom, a bromine atom, an iodine atom, or a fluorine atom, preferably a chlorine atom. It is economically more advantageous to use inexpensive organic chlorides. For example, there is no problem such as uneven distribution of production areas of bromine, which is a raw material, and difficulty in obtaining it, which is a problem in organic bromides that are widely used in the preparation of Grignard reagents, and there is a need for a high-load disposal facility for industrialization. There is no problem such as.

As the organic halide represented by the general formula IV (R ¹ -X), a commercially available one may be used, or one manufactured by a method known in the art may be used.

A dispersion in which sodium is dispersed in a dispersion solvent (hereinafter, may be abbreviated as "SD", which is an abbreviation for Sodium Dispersion) is one in which sodium is dispersed as fine particles in an insoluble solvent, or sodium is a liquid. It is dispersed in an insoluble solvent in a state. Examples of sodium include metallic sodium and alloys containing metallic sodium. The average particle size of the fine particles is preferably less than 100 μm, particularly preferably less than 50 μm, further preferably less than 30 μm, and even more preferably less than 10 μm. The average particle size was represented by the diameter of a sphere having a projected area equivalent to the projected area obtained by image analysis of a micrograph.

As the dispersion solvent, a solvent known in the art can be used as long as sodium can be dispersed as fine particles or sodium can be dispersed in an insoluble solvent in a liquid state and the reaction between the organic halide and SD is not inhibited. it can. For example, aromatic solvents such as xylene and toluene, normal paraffin solvents such as normal decane, heterocyclic solvent such as tetrahydrothiophene, and mixed solvents thereof can be mentioned.

It is preferable to use SD having an activity of 99.0% or more of phenylsodium with respect to the added chlorobenzene when reacted with chlorobenzene in a reaction solvent at 2.1 molar equivalents or more. By using such a highly active SD, an organic sodium compound can be synthesized more efficiently from an organic halide at low cost, and the subsequent coupling reaction can proceed smoothly. Here, in order to maintain high SD activity, it is preferable to store it in a container having a high gas barrier property such as a glass vial. However, it does not exclude storage in a container having a low gas barrier property, and in that case, it is used immediately after the production of SD, for example, within several weeks, preferably within 3 weeks.

As the reaction solvent, a solvent known in the art can be used as long as the reaction between the organic halide and SD is not inhibited. For example, an ether solvent, a paraffin solvent such as normal paraffin or cycloparaffin, an aromatic solvent, an amine solvent, or a heterocyclic compound solvent can be used. As the ether solvent, a cyclic ether solvent is preferable, and tetrahydrofuran (hereinafter, may be abbreviated as "THF") or the like can be preferably used. As the paraffin solvent, cyclohexane, normal hexane, normal decane and the like are particularly preferable. As the aromatic solvent, xylene, toluene, benzene and the like can be preferably used. Ethylenediamine or the like can be preferably used as the amine solvent. As the heterocyclic compound solvent, tetrahydrothiophene or the like can be used. In addition, only one of these may be used, or two or more of these may be used in combination as a mixed solvent. Here, the same type of dispersion solvent and reaction solvent may be used, or different types may be used.

The reaction temperature is not particularly limited when a paraffin-based solvent is used as the solvent, and can be appropriately set depending on the type and amount of the organic halide, SD and the reaction solvent, the reaction pressure and the like. Specifically, the reaction temperature is preferably set to a temperature that does not exceed the boiling point of the reaction solvent. Under pressure, the reaction temperature can be set at a high temperature because it is higher than the boiling point under atmospheric pressure. The reaction can also be carried out at room temperature, preferably from 0 to 100 ° C, particularly preferably from 20 to 80 ° C, and even more preferably from room temperature to 50 ° C. It is not necessary to provide a special temperature control means for heating, cooling, or the like, but a temperature control means may be provided if necessary. On the other hand, when a solvent other than paraffin is used, it is necessary to prevent the reaction between the solvent and phenyl sodium, which is a preferable example of the organic sodium compound represented by the general formula I (R ¹ -Na), which is the compound to be coupled. It is preferable to carry out at a low temperature, preferably around 0 ° C. Here, by adding an equimolar equivalent of THF with the organic halide, the formation of biphenyl can be effectively suppressed and a good reaction rate can be maintained. Therefore, by appropriately controlling the type and amount of the reaction solvent added, the organic sodium compound which is the target compound can be synthesized more efficiently.

The reaction time is also not particularly limited, and may be appropriately set according to the type and amount of the organic halide, SD, and the reaction solvent, the reaction pressure, the reaction temperature, and the like. It is usually carried out for 15 minutes to 24 hours, preferably 20 minutes to 6 hours.

Since SD and reagents such as reaction solvents can be handled stably in the atmosphere, they are suitable for use under normal pressure conditions in the atmosphere. However, phenylsodium, which is a preferable example of the organic sodium compound represented by the general formula I (R ¹ -Na), which is the target compound, has high activity and is protonated by water when even a small amount of air is mixed in, so it is necessary. Depending on the situation, it may be carried out in an inert gas atmosphere filled with argon gas, nitrogen gas or the like.

The amount of SD used can be appropriately set according to the type and amount of the organic halide, the type and amount of the reaction solvent, and the like. Preferably, the reaction is carried out in an amount such that the molar ratio of organic halide: SD is 1: 2.0 to 3.0. Further, preferably, the reaction is carried out in an amount such that the molar ratio of organic halide: SD is 1: 2.0 to 2.3. By reacting at such a ratio, the organic sodium compound can be synthesized with high efficiency and high purity. Here, the amount of substance of SD means the amount of substance in alkali metal equivalent contained in SD.

The obtained organic sodium compound may be purified by a purification means known in the art such as column chromatography, distillation, recrystallization and the like. Further, the organic halide remaining unreacted may be recovered and subjected to the synthesis reaction of the organic sodium compound again. Further, it may be carried out in an inert gas atmosphere filled with argon gas, nitrogen gas or the like as in the case of production.

According to the coupling method according to the present embodiment, as an organic sodium compound which is one of the compounds to be coupled, a compound synthesized from an organic halide using SD can be used. SD is easy to handle, does not require complicated chemical methods under mild conditions, and can easily and inexpensively synthesize an organic sodium compound from an organic halogen compound with a small number of steps. It is very advantageous both economically and industrially. In addition, sodium is a technology with excellent sustainability because it is extremely widely distributed on the earth. On the other hand, when solid metallic sodium is used, the reaction temperature is inefficient at room temperature, and it is necessary to carry out the reaction at a high temperature such as the melting point of metallic sodium (98 ° C.) or higher. By carrying out the reaction at such a high temperature, the Wurtz reaction in which organic halides are coupled to each other is induced. On the other hand, since the reaction proceeds under mild conditions, the organic sodium compound can be efficiently obtained without inducing a side reaction such as the Wurtz reaction in which organic halides are coupled to each other. As a result, the stability and efficiency of the coupling reaction can be improved, and the coupling product can be synthesized with high yield and high purity.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples. As the SD in the following examples, a dispersion in which metallic sodium is dispersed as fine particles in normal paraffin oil is used, and the amount of substance of SD is a numerical value in terms of metallic sodium contained in SD.

(Example 1) Synthesis reaction of organic sodium compound and examination of coupling reaction conditions of organic sodium compound and organic chloride In this example, metal catalysts using various metal species are used according to the reaction conditions summarized in FIG. The cross-coupling reaction between the organic sodium compound and the organic chloride was investigated.

(Experiment number 1)
Under a nitrogen atmosphere, hexane (1.50 ml), SD (140 mg, 1.58 mmol, 3.15 mol equivalents) and 4-chlorotoluene (95 mg, 0.75 mmol, 1.50 mol equivalents) were added in this order to a closed Schlenk tube at 30 ° C. 4-Methylphenyl sodium was obtained by stirring with. After confirming that the solution turned black, [1,3-bis (2,6-diisopropylphenyl) imidazol-2-iriden] triphenylphosphine nickel (II) dichloride: NiCl ₂ (PPh ₃ ) IPr ( 10 mol%) and 1-chloronaphthalene (81 mg, 0.5 mmol, 1.00 mol equivalent) were added, and 4-methylphenylsodium and 1-chloronaphthalene were subjected to a coupling reaction by stirring at 70 ° C. for 3 hours. .. Subsequently, water (3.0 ml) was added to stop the reaction. Then, a liquid separation and a short column were carried out to purify the product, and then the product was subjected to NMR analysis. The results are shown in FIG.

FIG. 1 summarizes the product yields calculated based on the data obtained by NMR along with the reaction conditions. The product yield was calculated by indicating the ratio of the amount of substance of the product produced by the reaction system to the amount of substance of 1-chloronaphthalene added to the reaction system as a percentage.

From the results shown in FIG. 1, naphthalene-1- (4-methylphenyl), which is the target product of the cross-coupling reaction, was obtained in a yield of 74.0%. It was found that the cross-coupling reaction between the organic sodium compound and the organic chloride proceeded efficiently in the presence of the nickel-based catalyst. Reactions using nickel as a metal catalyst are known in the art, and it can be expected that the coupling reaction can proceed efficiently by appropriately changing the type of ligand and the like.

(Experiment number 2)
Dichloro (N, N, N', N'-tetramethylethylenediamine) zinc (II): ZnCl _2- TMEDA (20 mol%) is used as a metal catalyst in addition to NiCl ₂ (PPh ₃ ) IPr (10 mol%). The coupling reaction was carried out in the same manner as in Experiment No. 1, and the product was subjected to NMR analysis to calculate the yield of the product. The results are shown in FIG.

FIG. 1 summarizes the yield of the product calculated based on the data obtained by NMR together with the reaction conditions, and is the target product of the cross-coupling reaction, naphthalene-1- (4-methylphenyl). ) Was obtained in a yield of 81.0%. It was found that the cross-coupling reaction between the organic sodium compound and the organic chloride proceeded more efficiently in the presence of the nickel-based catalyst to which the zinc-based catalyst was added. It was also found that the cross-coupling reaction between the organic sodium compound and the organic chloride proceeded efficiently even when the nickel-based catalyst was coexisted with a metal catalyst using another metal species.

(Experiment number 3)
The coupling reaction was carried out in the same manner as in Experiment No. 1 except that FeCl _3- IPr (10 mol%) was used as the metal catalyst, and the product was subjected to NMR analysis to calculate the yield of the product. The results are shown in FIG.

FIG. 1 summarizes the yield of the product calculated based on the data obtained by NMR together with the reaction conditions, and is the target product of the cross-coupling reaction, naphthalene-1- (4-methylphenyl). ) Was obtained in a yield of 30.0%. Although the coupling efficiency is lower than that of the nickel-based catalysts of Experiment Nos. 1 and 2, it was confirmed that the cross-coupling reaction between the organic sodium compound and the organic chloride proceeds more efficiently in the presence of the iron-based catalyst. .. Reactions using iron as a metal catalyst are known in the art, and it can be expected that the coupling reaction can proceed efficiently by appropriately changing the type of ligand and the like.

(Experiment number 4)
Under a nitrogen atmosphere, hexane (3.00 ml), SD (0.57 g, 6.34 mmol) and 4-chlorotoluene (0.38 g, 2.93 mmol) were added in this order to a closed Schlenk tube, and the mixture was stirred at 30 ° C. for 1 hour and 4-. Methylphenyl sodium was obtained. After confirming that the solution turned black, add manganese chloride: MnCl ₂ (0.1 mmol) and 1-chloronaphthalene (0.17 g, 1.05 mmol), and stir at 70 ° C. for 3 hours to 4-methyl. Phenylsodium and 1-chloronaphthalene were subjected to a coupling reaction. Subsequently, water (3.0 ml) was added to stop the reaction. Then, the product was purified by liquid separation and short column, and then NMR and GC / MS analysis of the product were performed. The results are shown in FIGS. 1 and 2.

FIG. 1 summarizes the product yields calculated based on the data obtained by NMR along with the reaction conditions. The product yield was calculated by indicating the ratio of the amount of substance of the product produced by the reaction system to the amount of substance of 1-chloronaphthalene added to the reaction system as a percentage. FIG. 2 shows a GC chart of the product, which is not shown in detail here, but is around 12.769 min from the GC chart of the product obtained by a coupling reaction using a conventionally known palladium catalyst. It is estimated that the peak of naphthalene-1- (4-methylphenyl), which is the target product of the cross-coupling reaction, is the peak of naphthalene-2- (4-methylphenyl), which is a by-product, around 13.416 min. Will be done.

From the results of FIGS. 1 and 2, the target product of the cross-coupling reaction, naphthalene-1- (4-methylphenyl), was obtained in a yield of 8.0%, whereas the by-product, naphthalene- 2- (4-Methylphenyl) was obtained in a yield of 16.0% and a cross-coupling yield was 24.0%. In this experiment, manganese chloride was used as a metal catalyst. Although not shown in detail here, when the coupling reaction was carried out without a metal catalyst, only a very small amount of coupling product was obtained, whereas in the presence of manganese chloride, an organic sodium compound was obtained. It was confirmed that the cross-coupling reaction of organic chloride proceeded. Reactions using manganese as a metal catalyst are known in the art, and it can be expected that the coupling efficiency can be improved by appropriately changing the type of ligand and the like.

(Experiment number 5)
The coupling reaction was carried out in the same manner as in Experiment No. 4 except that cobalt chloride: CoCl ₂ was used as the metal catalyst, and the product was subjected to NMR and GC / MS analysis to calculate the yield of the product. The results are shown in FIGS. 1 and 3.

FIG. 1 summarizes the yield of the product calculated based on the data obtained by NMR together with the reaction conditions. However, since a good NMR spectrum was not obtained by this experiment, the yield was calculated. Couldn't. FIG. 3 shows a GC chart of the product. From FIG. 3, it was not observed that the cross-coupling reaction between the organic sodium compound and the organic chloride proceeded in the presence of cobalt chloride.

(Experiment number 6)
Coupling reaction was carried out in the same manner as in Experiment No. 4 except that bis (triphenylphosphine) cobalt (II) dichloride: CoCl ₂ (PPh ₃ ) ₂ was used as the metal catalyst, and the product was subjected to NMR and GC / MS analysis. The yield of the product was calculated. The results are shown in FIGS. 1 and 4.

FIG. 1 summarizes the product yields calculated based on the data obtained by NMR along with the reaction conditions. FIG. 4 shows a GC chart of the product.

From the results of FIGS. 1 and 4, naphthalene-1- (4-methylphenyl), which is the target product of the cross-coupling reaction, was obtained in a yield of 27.0%, whereas naphthalene-, a by-product, was obtained. 2- (4-Methylphenyl) was obtained in a yield of 10.4% and a cross-coupling yield was 37.4%. In this experiment, cobalt chloride coordinated with triphenylphosphine (PPh ₃ ) as a ligand was used as a metal catalyst. As a result, naphthalene-1- (4-methylphenyl), which is the target product of the cross-coupling reaction, was obtained as the main product. In the GC chart of FIG. 4, the peak of naphthalene-1- (4-methylphenyl), which is the target product of the cross-coupling reaction, is located near 12.769 min, which is the by-product naphthalene-2- (4-methylphenyl). It can be confirmed larger than the peak of. Therefore, from the experiment of Experiment No. 5 in addition to this Experiment No. 6, it was confirmed that the cross-coupling reaction between the organic sodium compound and the organic chloride proceeded in the presence of the cobalt catalyst by using the cobalt catalyst, and PPh ₃ It was also found that the coupling efficiency was improved by coordinating as a ligand. Reactions using cobalt as a metal catalyst are known in the art, and it can be expected that the coupling efficiency can be further improved by appropriately changing the type of ligand and the like.

The present invention is particularly useful in all technical fields utilizing organic compound coupling methods and coupling products obtained by such coupling methods, particularly in the fields of manufacturing agricultural chemicals and electronic materials.

Claims (4)

It is a coupling method between an organic sodium compound and an organic chloride.
In the reaction solvent, the general formula I (R ¹ -Na)
[Here, in the formula, R ¹ is an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, or an aromatic group which may have a substituent. It is a heterocyclic group, and Na is a sodium atom.]
General formula II (R ^2- Cl)
[Here, in the formula, R ² is an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, or an aromatic group which may have a substituent. It is a heterocyclic group and Cl is a chlorine atom.]
With the organic chloride shown in
By reacting in the presence of a metal catalyst containing one or more first transition metals selected from atomic numbers 24-28, the organic sodium compound and the organic chloride are coupled.
General formula III (R ¹ -R ² )
[Here, in the formula, R ¹ is the same as R ¹ in the general formula I (R ¹ -Na), R ² is the same as R ² in the general formula II (R ² -Cl)]
A coupling method comprising the step of obtaining the organic compound shown in. The coupling method according to claim 1, wherein the metal catalyst contains a metal chloride. The organic sodium compound represented by the general formula I (R ¹ -Na) is contained in a reaction solvent under the general formula IV (R ¹ -X).
[Here, in the formula, R ¹ is the same as R ¹ in the general formula I (R ¹ -Na), X is a halogen atom] and an organic halide shown,
The coupling method according to claim 1 or 2, which is obtained by reacting a dispersion in which sodium is dispersed in a dispersion solvent. R ² in the general formula I (R ¹ -Na) of R ¹ and Formula II (R ² -Cl) is at least one, or, both, aromatic hydrocarbon group or aromatic heterocyclic group The coupling method according to any one of claims 1 to 3.

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