WO2019004371A1 - Method for synthesizing organic zinc compound - Google Patents

Abstract

The purpose of the present invention is to realize a technique for efficiently synthesizing an organic zinc compound without using a toxic reagent and the like that are difficult to handle, and to do so with a small number of steps. This method for synthesizing an organic zinc compound includes a step in which, in a reaction solvent, an organic halide represented by general formula I (R1-X1) and a dispersion where sodium is dispersed in a dispersion solvent are reacted to obtain an organic sodium compound represented by general formula II (R1-Na), and the obtained organic sodium compound and zinc chloride are reacted to obtain an organic zinc compound represented by general formula III (R1-Zn-X2).

Description

Method of synthesizing organozinc compound

The present invention relates to a process for the synthesis of organozinc compounds.

Organic zinc compounds are used as important intermediates in organic synthesis reactions of functional materials such as pharmaceuticals and agricultural chemicals and electronic materials, and intermediates thereof. For example, in the coupling reaction for forming a carbon-carbon bond, Negishi coupling is known in which the organic zinc compound and the organic halide are coupled in the presence of a palladium catalyst or the like.

The synthesis of the organozinc compound is carried out by an oxidative addition method in which an organic halide (RX) is directly reacted with metallic zinc (Zn), an organolithium compound (R-Li) or a Grignard reagent (R-MgBr, etc.) R- metal exchange method of reacting a MgX) to zinc halides and zinc chloride (ZnX ₂₎ are known (e.g., see non-Patent Document 1).

In addition, as another synthetic method, a method is known in which an aryl halide is reacted with zinc and lithium chloride in the presence of a cobalt catalyst coordinated with xanthophos to obtain an arylzinc compound (for example, non-patent literature) 2).

The oxidative addition method is by the following reaction (RX + Zn → R-ZnX). However, when general zinc powder is used, there is a limitation on functional groups that can be used as organic halides, such as the inability to convert organic chlorides and the like to organic zinc compounds. Even when activated zinc is used, it is necessary to prepare activated zinc in advance by causing zinc chloride to act as a reducing agent such as lithium metal, potassium metal, etc. in THF under argon atmosphere. However, activated zinc is very expensive and has problems such as increased cost.

In the case of using an organolithium compound in the transmetallation method, organic halides such as organic iodide and the like, n-butyllithium (hereinafter, abbreviated as “ ⁿ BuLi”) and t-butyllithium (hereinafter, “ ^t BuLi” It is necessary to prepare the organolithium compound in advance by the lithium-halogen exchange reaction under the action of That is, it is due to the following two-step reaction (first step: RI + ⁿ BuLi or ^t BuLi → R-Li, second step: R-Li + ZnCl ₂ → R-ZnCl). However, since ⁿ BuLi and ^t BuLi are expensive reagents, there are problems such as an increase in cost. Furthermore, ⁿ BuLi and ^t BuLi are designated as Class 3 dangerous materials under the Fire Service Law, so there is a problem that equipment and facilities suitable for handling are required.

Moreover, although a Grignard reagent is obtained by reacting an organic halide and metal magnesium in an anhydrous solvent such as ether, the Grignard reagent is an active reagent which exhibits strong basicity, so oxygen, dioxide Reacts quickly with carbon and water. Therefore, it is necessary to strictly control the preparation and storage of the Grignard reagent so that air and moisture do not enter. Incidentally, ⁿ BuLi or ^t BuLi, also necessary to manage the same in the case of using the activated zinc. In the preparation of a Grignard reagent, an organic bromide is suitably used as an organic halide, in which case the following two-step reaction (first step: R-Br + Mg → R-MgBr, second step: R- Proceed with MgBr + ZnCl ₂ → R-ZnX). However, bromine is in limited use in areas where it is mined, has high toxicity, has human persistence, etc., and therefore its use is decreasing. For this reason, the amount of circulation decreases, and it tends to be difficult to obtain the desired organic bromide. There is also a problem that the organozinc compound obtained after the reaction with zinc chloride is mixed not only with the desired organozinc chloride (R-ZnCl) but also with the by-product organozinc bromide (R-ZnBr). On the other hand, when an organic chloride is used instead of the organic bromide in the preparation of the Grignard reagent, there is also a problem that the reaction with the first step magnesium metal does not proceed.

In the method of using a cobalt catalyst, there is a problem that the catalyst is essential and the separation operation becomes necessary and the number of processes increases because the catalyst is mixed in the synthesized aryl zinc compound.

Therefore, it has been desired to construct a technology capable of efficiently synthesizing an organozinc compound in a small number of steps without using reagents that are difficult to handle and have toxicity.

As a result of repeated researches to solve the above problems, the present inventors reacted a dispersion obtained by dispersing an organic halide and sodium in a dispersion solvent in a reaction solvent to obtain an organic sodium compound, and subsequently obtained It has been found that the organic zinc compound can be efficiently synthesized by reacting the selected organic sodium compound with zinc chloride. Such synthetic methods do not require difficult-to-handle and toxic reagents, and can synthesize organozinc compounds under mild conditions. In addition, the organic zinc compound can be inexpensively synthesized with a small number of steps without requiring complicated and expensive synthetic treatment steps, waste treatment steps and the like. The present inventors have completed the present invention based on these findings.

That is, the present invention relates to a method for synthesizing an organozinc compound, the characteristic feature of which is that, in a reaction solvent, a compound of the general formula I (R ¹ -X ¹ ) [wherein R ¹ is sodium and It is an aliphatic hydrocarbon group which may have a substituent which does not react, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, or an aromatic heterocyclic group, and X ¹ is And a dispersion in which sodium is dispersed in a dispersion solvent are reacted with a compound represented by the general formula II (R ¹ -Na) [wherein, R ¹ is a general formula An organosodium compound shown in R ^{1 of} I is obtained, and the obtained organosodium compound is reacted with zinc chloride to obtain a compound represented by the general formula III (R ¹ -Zn-X ² ) [wherein wherein, R ¹ is the same as R ¹ in formula I, X ² has Cl, or, to obtain an organic zinc compound shown in which R ¹ is], the There is a point.

According to this configuration, it is possible to provide a method for synthesizing an organozinc compound capable of stably and efficiently synthesizing an organozinc compound from an organohalide via an organosodium compound. According to this configuration, by using a dispersion in which sodium is easy to handle and dispersed in a dispersion solvent, a complicated chemical method is not required under mild conditions, and the number of steps is simple and short. The organic zinc compounds can be synthesized inexpensively, which is very advantageous economically and industrially. In addition, since the reaction proceeds under mild conditions, an organosodium compound can be efficiently obtained without inducing a side reaction such as a wurtz reaction in which organic halides are coupled to each other. Can be synthesized in high yield and high purity. In addition, sodium is a technology with excellent sustainability because it is widely distributed on the earth. Furthermore, the organozinc compound synthesized by the method for synthesizing the organozinc compound of the present configuration can be suitably used for Negishi coupling and the like. Therefore, the synthesis method of the organozinc compound of this configuration can be used in various technical fields such as synthesis of functional materials such as medicines and pesticides and electronic materials.

Another feature is that X ¹ is a chlorine atom.

According to this configuration, the use of inexpensive organic chloride as a starting compound is economically more advantageous. In addition, there are no problems such as the uneven distribution of the origin of the raw material of the raw material, which is a problem in the preparation of Grignard reagents, and the difficulty of obtaining the raw materials, and the need for a high load disposal facility at industrialization. There is no problem.

Another feature of the present invention is that the dispersion in which the sodium is dispersed in the dispersion solvent has a yield of phenyl sodium relative to the chlorobenzene added when the reaction is carried out with a reaction solvent at a concentration of at least 2.1 molar equivalents relative to chlorobenzene. It has an activity of 99.0% or more.

According to this configuration, the organic zinc compound can be synthesized more efficiently by using a dispersion in which highly active sodium is dispersed in a dispersion solvent.

Another feature is that the molar ratio of the organic halide: the dispersion of the sodium dispersed in the dispersion solvent: the zinc chloride is 1: 2 or more and 3 or less when X ^{2 in the} general formula III is Cl: 1. When X ^{2 in the} general formula III is R ¹ , it is in the range of 1: 2 to 3: 1.

According to this configuration, the organic zinc compound is synthesized with higher efficiency and high purity by optimizing the use amount of the organic halide, the dispersion in which sodium is dispersed in the dispersion solvent, and zinc chloride. Can.

It is a figure which summarizes the synthetic conditions and the result of Example 1 which examined the synthesis method of the organozinc compound concerning this embodiment. It is a figure which summarizes the synthetic | combination conditions and the result of Example 2 which examined the synthesis | combining method of the organozinc compound which concerns on this embodiment. It is a figure which summarizes the synthetic | combination conditions and the result of Example 3 which examined the synthesis | combining method of the organozinc compound which concerns on this embodiment. It is a figure which summarizes the synthetic | combination conditions and the result of Example 4 which examined the synthesis | combining method of the organozinc compound which concerns on this embodiment. It is a figure which summarizes the synthetic | combination conditions and result of Example 5 which examined the synthesis | combining method of the organozinc compound which concerns on this embodiment. It is a figure which summarizes the synthetic conditions and the result of Example 6 which examined the synthesis method of the organozinc compound concerning this embodiment. It is a figure which summarizes the synthetic conditions and the result of Example 6 which examined the synthesis method of the organozinc compound concerning this embodiment. It is a figure explaining a of FIG. 6A and FIG. 6B, and b.

Hereinafter, the synthesis method of the organozinc compound 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.

In the method of synthesizing the organozinc compound according to this embodiment, a dispersion obtained by dispersing sodium in an organic halide represented by the general formula I (R ¹ -X ¹ ) in a dispersion solvent is reacted in a reaction solvent, An organosodium compound of formula II (R ¹ -Na) is obtained (step 1). Subsequently, the obtained organosodium compound is reacted with zinc chloride to obtain an organozinc compound represented by the general formula III (R ¹ -Zn-X ² ) (Step 2).

(Step 1)
In step 1, a dispersion in which an organic halide represented by the general formula I (R ¹ -X ¹ ) and sodium are dispersed in a dispersion solvent is reacted in a reaction solvent to obtain a compound represented by general formula II (R ¹ -Na) It is a process of obtaining the organic sodium compound shown. The organic halide represented by the general formula I (R ¹ -X ¹ ) is an organic compound containing a covalently bonded halogen atom, and is a starting compound in the method of synthesizing the organozinc compound according to the embodiment of the present invention.

In the general formula I (R ¹ -X ¹ ), R ¹ is an aliphatic hydrocarbon group which may have a substituent which does not react with sodium, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic group A group hydrocarbon group or an aromatic heterocyclic group. When it has a substituent having reactivity with sodium, it is not preferable because a dispersion obtained by dispersing the substituent and sodium in a dispersion solvent reacts to induce a side reaction. Therefore, when a compound having a substituent having reactivity with sodium as R ¹ is used as a starting compound, it is necessary to protect the substituent with a suitable protecting group or the like.

The aliphatic hydrocarbon group may be linear or branched or saturated or unsaturated. Moreover, there is no restriction | limiting in particular also about 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 include, but are not limited to, 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, propyl group, butyl group, methyl group, ethyl group, propyl group, isopropyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group 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, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-propylpropyl, n-heptyl, isoheptyl, 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-ethyl pentyl 2-ethylpentyl 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 Group, 2-methyloctyl 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 , 3-methylnonyl group, 4-methylnonyl group, 5-methylnonyl group, 6-methylnonyl group, 7-methylnonyl but group, and the like, not limited thereto. Examples of the alkenyl group include ethenyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group and the like, but are not limited thereto. Examples of the alkynyl group include, but are not limited to, ethynyl group, propynyl group, butynyl group, pentynyl group, heptynyl group, octynyl group and the like.

The aliphatic hydrocarbon group may have a substituent. The substituents may have one or more, and when having a plurality of substituents, they may be the same or different from each other. As a 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, an alkoxy group, cycloalkoxy Group, aryloxy group, aralkyloxy group, alicyclic heterocyclic oxy group, aromatic heterocyclic oxy group, alkylthio group, cycloalkylthio group, arylthio group and aralkylthio group are alicyclic heterocyclic thio group, aromatic Examples thereof include, but are not limited to, heterocyclic thio group, alkylamino group, cycloalkylamino group, arylamino group, aralkylamino group, alicyclic heterocyclic amino group, aromatic heterocyclic amino group, acyl group and the like. It is not a thing. In addition, as an aliphatic hydrocarbon group, the thing similar to the thing shown above is shown below as an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, and an aromatic heterocyclic group. And the same as the

The alkoxy group is preferably an alkoxy group having 1 to 10 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group and the like. It is not limited to these. The cycloalkoxy group is preferably a cyclopropoxy group having a carbon number of 3 to 10, and examples thereof include a cyclobutoxy group, a cyclopentyloxy group and a cyclohexyloxy group. The aryloxy group is preferably an aryloxy group having a carbon number of 6 to 20. Specific examples thereof include, but are not limited to, a phenyloxy group, a naphthyloxy group and the like. 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. The alicyclic heterocyclic oxy group and the aromatic heterocyclic oxy group include an alicyclic heterocyclic group and an aromatic heterocyclic group which are shown below as a heterocyclic part.

The alkylthio group is preferably an alkylthio group having 1 to 20 carbon atoms, and examples thereof include, but not limited to, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like. . The cycloalkylthio group is exemplified by 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 a carbon number of 6 to 20. Specific examples thereof include, but are not limited to, a phenylthio group, a naphthylthio group and the like. The aralkylthio group is preferably, for example, an aralkylthio group having 7 to 11 carbon atoms, and specific examples thereof include, but are not limited to, a benzylthio group, a phenethylthio group and the like. The alicyclic heterocyclic thio group and the aromatic heterocyclic thio group include an alicyclic heterocyclic group and an aromatic heterocyclic group which are shown below as a heterocyclic part.

The alicyclic hydrocarbon group is not particularly limited in the number of ring members, regardless of whether the bond between the ring constituting atoms is saturated or unsaturated. In addition, those having a ring assembly such as a fused ring or a spiro ring as well as a single ring are included. The alicyclic hydrocarbon group is not limited thereto, 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 Several 4 to 10, particularly preferably 4 to 7 cycloalkenyl groups are exemplified. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, cyclooctenyl group and the like.

The alicyclic hydrocarbon group may have a substituent. The substituents may have one or more, and when having a plurality of substituents, they may be the same or different from each other. There is also no particular restriction on the position of the substituent. Examples of the substituent include the same as those exemplified as the substituent of the aliphatic hydrocarbon group.

The alicyclic heterocyclic group is a non-aromatic heterocyclic group having one or more hetero atoms as ring-constituting atoms. In addition to single rings, those having a ring assembly such as a fused ring or a spiro ring are also included. The bonds between the ring-constituting atoms are either 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 member atom. The number of heteroatoms is not particularly limited, and there is no limitation on the position of heteroatoms. As a hetero atom, Preferably, an oxygen atom, a nitrogen atom, a sulfur atom etc. are illustrated. For example, an alicyclic heterocyclic group having preferably 2 to 7 carbon atoms, particularly preferably 2 to 5 carbon atoms, and preferably 1 to 5 hetero atoms, particularly preferably 1 to 3 heteroatoms. Can be mentioned. In addition, when it has a plurality of hetero atoms, it may be the same type of atoms or different types of atoms. As the alicyclic heterocyclic group, a nitrogen-containing alicyclic heterocyclic group such as a monocyclic 4-membered azetidinyl group, a 5-membered cyclic pyrrolidinyl group, a 6-membered cyclic piperidyl group, a piperazinyl group, etc. Oxygen-containing alicyclic heterocyclic groups such as three-membered cyclic oxiranyl ring, four-membered oxetanyl group, five-membered tetrahydrofuryl group, six-membered tetrahydropyranyl group, etc., single ring Sulfur-containing alicyclic heterocyclic group such as 5-membered cyclic tetrahydrothiophenyl group, nitrogen-containing oxygen alicyclic heterocyclic group such as monocyclic 6-membered cyclic morpholinyl group, monocyclic 6-membered ring Although nitrogen-containing sulfur alicyclic heterocyclic group etc., such as a thiomorpholinyl group, etc. are mentioned, it does not limit to these.

The alicyclic heterocyclic ring may have a substituent. The substituents may have one or more, and when having a plurality of substituents, they may be the same or different from each other. There is also no particular restriction on the position of the substituent. Examples of the substituent include the same as those exemplified as the substituent of the aliphatic hydrocarbon group.

The aromatic hydrocarbon group is not particularly limited as long as it has an aromatic ring. In addition to single rings, those having a ring assembly such as a fused ring or a spiro ring are also included. The number of ring members is also not particularly limited. For example, aromatic hydrocarbon groups having preferably 6 to 22 and particularly preferably 6 to 14 carbon atoms can be mentioned. As the aromatic hydrocarbon group, monocyclic 6-membered ring phenyl group, etc., bicyclic naphthyl group, pentalenyl group, indenyl group, azulenyl group etc., tricyclic biphenylenyl group, indasenyl group, acenaphthyrenyl group, fluorenyl group Group, phenalenyl group, phenanthryl group, anthryl group etc., tetracyclic fluorantenyl, aceanthrenyl group, triphenylenyl group, pyrenyl group, naphthacenyl group etc., pentacyclic perylenyl group, tetraphenylenyl etc., hexacyclic Examples thereof include pentacenyl group of the formula, heptacyclic rubicenyl group, coronenyl group, heptacenyl group and the like, but not limited thereto. Particularly preferred is a phenyl group.

The aromatic hydrocarbon group may have a substituent. The substituents may have one or more, and when having a plurality of substituents, they may be the same or different from each other. There is also no particular restriction on the position of the substituent. Examples of the substituent include the same as those exemplified as the substituent of the aliphatic hydrocarbon group. Particularly preferred is an alkyl group such as a normal nonyl group.

The aromatic heterocyclic group is an aromatic heterocyclic group having one or more hetero atoms as ring-constituting atoms. In addition to single rings, those having a ring assembly such as a fused ring or a spiro ring are also included. The number of ring members is also not particularly limited. The hetero atom is not particularly limited as long as it does not react with sodium as a ring member atom. The number of heteroatoms is not particularly limited, and there is no limitation on the position of heteroatoms. As a hetero atom, Preferably, an oxygen atom, a nitrogen atom, a sulfur atom etc. are illustrated. For example, an aromatic heterocyclic group in which the number of carbon atoms is preferably 1 to 5, particularly preferably 3 to 5, and the number of hetero atoms is preferably 1 to 4, particularly preferably 1 to 3 is It can be mentioned. In addition, when it has a plurality of hetero atoms, it may be the same type of atoms or different types of atoms.

For example, as a monocyclic aromatic heterocyclic group, a nitrogen-containing aromatic ring such as a 5-membered cyclic pyrrolyl group, pyrazolyl group, pyridyl group, imidazolyl group, etc., a 6-membered cyclic pyrazinyl group, pyrimidinyl group, pyridazinyl group, etc. -Containing heterocyclic group, oxygen-containing aromatic heterocyclic group such as 5-membered cyclic furyl group, oxygen-containing aromatic heterocyclic group such as 5-membered cyclic thienyl group, 5-membered cyclic oxazolyl group, isoxazolyl group, Examples thereof include nitrogen-containing oxygen aromatic heterocyclic groups such as frazanyl groups, and nitrogen-containing sulfur aromatic heterocyclic groups such as 5-membered cyclic thiazolyl groups and isothiazolyl groups, but are not limited thereto.

As the polycyclic aromatic heterocyclic group, bicyclic indolizinyl group, isoindolyl group, indolyl group, indazolyl group, indazolyl group, purinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnorinyl And nitrogen-containing aromatic heterocyclic groups such as tricyclic carbazolyl group, carbazolyl group, carborinyl group, phenathridinyl group, acridinyl group, perimidinyl group, phenanthrolinyl group, phenazinyl group, etc., bicyclic benzofuranyl group, isobenzofuranyl group A sulfur-containing aromatic heterocyclic group such as an oxygen-containing aromatic heterocyclic group such as a nyl group and a benzopyranyl group, a bicyclic benzothienyl group and the like, a tricyclic thianthrenyl group and the like, and a bicyclic benzoxazolyl group Nitrogen-containing oxygen aromatic heterocyclic group such as benzoisoxazolyl group, bicyclic benzothiazolyl group Nitrogen-containing sulfur aromatic heterocyclic groups such as benzoisothiazolyl group and tricyclic phenothiazinyl group, and oxygen-containing sulfur aromatic heterocyclic groups such as tricyclic phenoxatyinyl group, etc. It is not limited to

The aromatic heterocyclic group may have a substituent. The substituents may have one or more, and when having a plurality of substituents, they may be the same or different from each other. There is also no particular restriction on the position of the substituent. Examples of the substituent include the same as those exemplified as the substituent of the aliphatic hydrocarbon group.

X ¹ is a halogen atom, specifically, a chlorine atom, a bromine atom, an iodine atom or a fluorine atom, preferably a chlorine atom. The economic advantage is further obtained by using cheap organic chlorides as starting compounds. In addition, there are no problems such as uneven distribution of the origin of the raw material of the raw material, which is a problem in the preparation of Grignard reagents, and difficulty in obtaining the raw material, which is a problem. There is no problem of

As the organic halides which are the starting compounds, those commercially available may be used, or those produced by methods known in the art may be used.

A dispersion in which sodium is dispersed in a dispersion solvent (hereinafter sometimes abbreviated as “SD” which is an abbreviation of Sodium Dispersion) is a dispersion of sodium as fine particles in an insoluble solvent, or sodium as a liquid It is dispersed in an insoluble solvent in the state. Examples of sodium include metallic sodium and alloys containing metallic sodium. The average particle size of the fine particles is preferably less than 10 μm, and particularly preferably less than 5 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 photomicrograph.

As a 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 a liquid state in an insoluble solvent and the reaction between the starting compound organic halide and SD is not inhibited. Can be used. Examples thereof include aromatic solvents such as xylene and toluene, normal paraffin solvents such as normal decane, heterocyclic compound solvents such as tetrahydrothiophene, and mixed solvents thereof.

As SD, it is preferable to use one having an activity such that the yield of phenyl sodium is 99.0% or more to chlorobenzene added when the reaction is carried out in a reaction solvent at 2.1 molar equivalents or more with respect to chlorobenzene (FIG. 2) See the reaction diagram of By using such highly active SD, organozinc compounds can be synthesized more efficiently. In order to maintain the activity of SD high, it is preferable to store in a container with high gas barrier properties such as a glass vial. However, storage in a container with low gas barrier properties is not excluded, and in that case, it is used immediately, for example, within several weeks, preferably within 3 weeks after production of SD.

As the reaction solvent in step 1, solvents known in the art can be used as long as they do not inhibit the reaction of the starting compound organic halide with SD. For example, ether solvents, paraffin solvents such as normal paraffin type and cyclo paraffin types, aromatic solvents, amine solvents, heterocyclic compound solvents can be used. As the ether solvent, a cyclic ether solvent is preferable, and tetrahydrofuran (hereinafter sometimes abbreviated as “THF”) can be preferably used. As the paraffin solvents, cyclohexane, normal hexane, normal decane and the like are particularly preferable. As the aromatic solvent, xylene, toluene, benzene and the like are preferable, and a halogenated aromatic solvent such as chlorobenzene and fluorobenzene can be used. Ethylenediamine etc. can be preferably used as an amine solvent. Tetrahydrothiophene etc. can be utilized as a heterocyclic compound solvent. Moreover, only 1 type may be used for these, and it can also be used as a mixed solvent combining 2 or more types. Here, the above-mentioned dispersion solvent and reaction solvent may be of the same type or different types.

The reaction temperature in step 1 is not particularly limited when a paraffinic solvent is used as the solvent, and can be appropriately set according to the type and amount of the starting compound organic halide, SD and the reaction solvent, the reaction pressure, etc. . Specifically, the reaction temperature is preferably set to a temperature that does not exceed the boiling point of the reaction solvent. The reaction temperature can be set at a high temperature because the pressure is higher than the boiling point under atmospheric pressure. The reaction can also be carried out at room temperature, preferably 0 to 100 ° C., particularly preferably 20 to 80 ° C., more preferably room temperature to 50 ° C. Although there is no need to provide temperature control means for special heating or cooling, etc., temperature control means may be provided if necessary. On the other hand, when a solvent other than paraffinic solvent is used, low temperature, preferably around 0 ° C., to prevent reaction of the solvent with phenyl sodium etc. which is a suitable example of R ¹ -Na produced in the reaction of Step 1. Good to do. Here, by adding the organic halide and equimolar equivalent of THF, it is possible to effectively suppress the formation of biphenyl and maintain a good reaction rate. Therefore, the target compound can be efficiently synthesized by appropriately controlling the type and addition amount of the reaction solvent.

The reaction time of step 1 is also not particularly limited, and may be appropriately set according to the type and amount of the starting compound organic halide, SD, and the reaction solvent, the reaction pressure, the reaction temperature, and the like. Usually, it is carried out for 15 minutes to 24 hours, preferably for 20 minutes to 6 hours.

The step 1 is suitable to be carried out under atmospheric pressure and normal pressure conditions since reagents such as SD and reaction solvents can be stably handled under the atmosphere. However, since phenyl sodium, which is a preferable example of R ¹ -Na to be produced, is highly active and is protonated by moisture when air is mixed in even a little, it is filled with argon gas, nitrogen gas, etc. as necessary. You may carry out under inert gas atmosphere.

The organosodium compound represented by the general formula II (R ¹ -Na) obtained by the step 1 is obtained by substituting the halogen atom of the organic halide represented by the general formula I (R ¹ -X ¹ ) which is a starting compound with sodium It is. Thus, in the general formula II (R ¹ -Na), R ¹ is the same as R ¹ of the general formula I as described above, Na is sodium atom. The obtained organic sodium compound may be purified by purification means known in the art such as column chromatography, distillation, recrystallization and the like. In addition, the organic halide which is the unreacted and remaining starting compound may be recovered, and may be configured to be subjected to the reaction of Step 1 again. The reaction may be performed in an inert gas atmosphere filled with argon gas, nitrogen gas or the like as in the production.

(Step 2)
In step 2, the organosodium compound represented by the general formula II (R ¹ -Na) obtained by step 1 is reacted with zinc chloride (ZnCl ₂ ) to obtain the final target compound of general formula III (R ¹ -Zn-X) ² ) a step of obtaining the organozinc compound shown in ² ).

Zinc chloride may be used alone or as a complex having N, N, N ', N'-tetramethylethylenediamine (hereinafter abbreviated as "TMEDA") coordinated. By forming a complex with TMEDA, zinc chloride is stable without being hygroscopically decomposed in air, and is advantageous for handling and storage.

Step 2 may be carried out by adding zinc chloride to the reaction product obtained by step 1, or after purifying the reaction product obtained by step 1 by a purification means known in the art, a reaction solvent It may be done by the addition of zinc chloride in the presence of As the reaction solvent, the same one as in Step 1 can be used.

The reaction temperature in step 2 is not particularly limited when a paraffinic solvent is used as the solvent, and can be appropriately set according to the type and amount of organic sodium compound, SD and reaction solvent, 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. The reaction temperature can be set at a high temperature because the pressure is higher than the boiling point under atmospheric pressure. The reaction can also be carried out at room temperature, preferably 0 to 100 ° C., particularly preferably 20 to 80 ° C., more preferably room temperature to 50 ° C. Although there is no need to provide temperature control means for special heating or cooling, etc., temperature control means may be provided if necessary. On the other hand, when a solvent other than paraffinic solvent is used, low temperature, preferably around 0 ° C., to prevent reaction of the solvent with phenyl sodium etc. which is a suitable example of R ¹ -Na produced in the reaction of Step 1. Good to do.

The reaction time of Step 2 is also not particularly limited, and may be appropriately set according to the type and amount of the organic sodium compound, SD, and the reaction solvent, the reaction pressure, the reaction temperature, and the like. Usually, it is carried out for 5 minutes to 2 hours, preferably 10 minutes to 1 hour.

In addition, since Step 2 can handle zinc chloride and reagents such as a reaction solvent stably in the atmosphere, it is suitable to be performed under atmospheric pressure. However, it may be carried out under an inert gas atmosphere filled with argon gas, nitrogen gas or the like, as necessary, such as the type of organic sodium compound.

By the reaction of step 2, an organozinc compound represented by the general formula III (R ¹ -Zn-X ² ) of the desired final target compound can be obtained. In step 2, a reaction of R ¹ -Na + ZnCl ₂ → R ¹ -Zn-Cl + NaCl or 2R ¹ -Na + ZnCl ₂ → R ¹ -Zn-R ¹ + 2NaCl occurs and R ¹ -Zn- Cl 2 or R ¹ -Zn-R ¹ can be obtained. In the organozinc compound represented by the general formula III (R ¹ -Zn-X ² ) synthesized here, sodium of the organosodium compound represented by the general formula II (R ¹ -Na) is substituted with zinc chloride or zinc It is done. Thus, in the general formula ^{III (R 1 -Zn-X 2} ), R 1 is the same as R ¹ of the general formula I (R ¹ -X ¹⁾ and the general formula II (R ¹ -Na). If the general formula ^{III (R 1 -Zn-X 2} ) in X ² is Cl, X ² is zinc chloride derived.

The amounts of SD and zinc chloride used in the method of synthesizing the organozinc compound according to the present embodiment can be appropriately set according to the types and amounts of the starting compound and the reaction solvent. Preferably, when X ² in the general formula III (R ¹ -ZnX ² ) is Cl, the molar ratio of the starting compound substance organic halide: SD: zinc chloride is 1: 2 to 3: 1. Preferably, the reaction is carried out. On the other hand, when X ² in the general formula III (R ¹ -ZnX ² ) is R ¹ , the molar ratio of the starting compound substance organic halide: SD: zinc chloride is 1: 2 or more and 3 or less: 1. It is preferable to make it react by quantity, It is more preferable to make it react by more than 1: 2: 3: 0.3 or more and less than 0.5. By reacting in this amount, the organozinc compound can be synthesized with high efficiency and high purity. Here, the amount of substance of SD means the amount of substance in terms of alkali metal contained in SD.

The organozinc compound finally synthesized in the method for synthesizing the organozinc compound according to the present embodiment may be purified by a purification means known in the art such as recrystallization. In addition, it may be configured to recover the organic halide and the organic sodium compound and the like remaining unreacted and to be used again for the synthesis of the organic zinc compound.

In the method of synthesizing the organozinc compound according to this embodiment, the organozinc compound can be stably and efficiently synthesized by using SD. By using SD which is easy to handle, the organozinc compound can be easily and inexpensively synthesized in a short time with a small number of steps, under mild conditions, without the need for complicated chemical methods, so that the economy is economical. And industrially very advantageous. Sodium is a technology with excellent sustainability because it is widely distributed on the earth. On the other hand, when solid metallic sodium is used, the reaction temperature is low at room temperature, and the reaction is required to be carried out at a high temperature such as the melting point (98 ° C.) of metallic sodium. By conducting the reaction at such a high temperature, the Wurtz reaction in which organic halides are coupled is induced, the organic sodium compound can not be synthesized efficiently, and the yield of the organic zinc compound is lowered. On the other hand, by using SD, the reaction can be allowed to proceed under mild conditions, so that the organosodium compound can be efficiently obtained without inducing a side reaction such as Wurtz reaction, As a result, the organozinc compound can be synthesized in high yield and high purity.

The organozinc compound synthesized by the method for synthesizing the organozinc compound of the present embodiment can be suitably used for Negishi coupling and the like. Therefore, the synthesis method of the organozinc compound of the present invention can be used in various technical fields such as synthesis of functional materials such as medicines and pesticides and electronic materials.

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

Example 1 Examination of Synthesis Conditions of Organosodium Compound (Aryl Sodium) and Synthesis Conditions of Organozinc Compound In this example, 4- ⁿ nonylphenyl sodium 2 as an organosodium compound under the synthesis conditions summarized in FIG. while considering the synthesis, by utilizing the obtained ^{4-n-nonylphenyl} sodium 2 was examined the synthesis of an organic zinc compound 4- normal ⁽ⁿ⁾ nonylphenyl zinc chloride 4.

Experiment No. 1
In cyclohexane 0.5 ml, was added to the SD ^{1-chloro-4-n-nonyl} benzene 1 and 2.5 molar equivalents of 0.25mmol the starting compound, allowed to react for 20 minutes at room temperature, was synthesized ^{4-n-nonylphenyl} sodium 2 . The molar equivalent is a molar equivalent to 4- ⁿ nonyl-chlorobenzene 1 which is a compound which is a starting material.

Experiment number 2
In 1 ml of hexane, 0.5 mmol of 4- ⁿ nonyl-chlorobenzene 1 as a starting compound and 2.5 molar equivalents of SD were added and reacted at 25 ° C. for 20 minutes to synthesize 4- ⁿ nonylphenyl sodium 2.

Experiment number 3
In 0.5 ml of hexane, 0.25 mmol of 4- ⁿ nonyl-chlorobenzene 1 as a starting compound and 2.5 molar equivalents of SD were added and reacted at 25 ° C. for 20 minutes to synthesize 4- ⁿ nonylphenyl sodium 2. A 1.0 molar equivalent of zinc chloride, TMEDA was added to 4- ⁿ nonylphenyl sodium 2 and reacted at 25 ° C. for 15 minutes to obtain 4- ⁿ nonylphenyl zinc chloride 4.

Evaluation of the synthesized ^{4-n-nonylphenyl} sodium 2 4- ^{n-nonylphenyl} sodium 2 quenched with deuterium oxide, be determined by the product 3 gas chromatography after quenching (hereinafter abbreviated as "GC") Went by. This utilizes the fact that sodium of 4- ⁿ nonylphenyl sodium 2 is substituted by deuterium. As the yield, the ratio (%) of the product 3 which could actually be obtained to the product 3 which can be theoretically generated from 1-chloro-4- ⁿ nonylbenzene 1 added to the reaction system was calculated. However, the product 3 measured by GC includes not only deuterated ones but also hydrogenated ones. Therefore, the obtained product 3 was measured by ¹ H NMR, and the deuterium ratio to the product 3 (D ratio (%)) was calculated. In addition, the unreacted 1-chloro-4- ⁿ nonylbenzene 1 is measured by GC to calculate the unreacted ratio (%), and the 1-chloro-4- ⁿ nonylbenzene 1 is coupled with Wurtz In order to evaluate whether or not the reaction was induced, the formation of coupling product (Ar-Ar) was measured by ¹ H NMR to calculate the Ar-Ar production rate (%).

The evaluation of the synthesized 4- ⁿ nonylphenyl zinc chloride 4 was carried out by quenching with heavy water and measuring the product 5 after quenching by GC and ¹ H NMR in the same manner as described above.

The results are shown in FIG. As shown in FIG. 1, in Experiment No. 1, the yield of the product 3 (organosodium compound) including the hydrogenated one was 98%, and the deuteration ratio was 93%. Thus, the actual yield of product 3 was 91%. On the other hand, the amount of unreacted 1-chloro-4- ⁿ nonylbenzene 1 remaining was extremely small, and the rate of formation of the coupling product associated with the Wurtz reaction was 1%. In Experiment No. 2, the yield of the product 3 including the hydrogenated one was 93%, and the deuteration ratio was 96%. Thus, the actual yield of product 3 was 89%. Thereby, it can be understood that by using SD, organosodium compounds such as aryl sodium can be synthesized in high yield and high purity, and induction of the Wurtz reaction which is a side reaction can be effectively suppressed.

In Experiment No. 3, the yield of the product 5 (organozinc compound) including the hydrogenated one was 90%, and the deuteration ratio was 94%. Thus, the actual yield of product 5 was 85%. Thus, ^4-n-nonyl - chlorobenzene 1 through ^{4-n-nonylphenyl} sodium 2, it was possible to carry out the synthesis of high yield ^{4-n-nonylphenyl} zinc chloride 4.

Example 2 Examination of Synthesis Conditions of Organosodium Compound (Aryl Sodium) -2
In this example, the synthesis of phenyl sodium 2 as an organosodium compound was examined under the synthesis conditions summarized in FIG. In 0.5 ml of hexane, 1.0 molar equivalent of the starting compound, benzene 1 and Y molar equivalent of SD were added and reacted at room temperature for 30 minutes to synthesize phenyl sodium 2.

The evaluation of the synthesized phenyl sodium 2 was carried out by reacting it with 1.0 molar equivalent of 2,2,6,6-tetramethylpiperidide 3 for 30 minutes at room temperature and obtaining sodium 2,2,6,6-tetramethyl obtained. Piperidide 4 was reacted with fluorene, quenched with heavy water, and the product after quenching was determined by ¹ H NMR. As the yield, sodium 2,2,6 actually obtained for sodium 2,2,6,6-tetramethylpiperidide 4 which can be theoretically generated from halogenated benzene 1 added to the reaction system The proportion (%) of 6, 6-tetramethylpiperidide 4 was calculated. In addition, in order to evaluate whether or not the Wurtz reaction in which halogenated benzenes 1 are coupled is induced, the formation of the coupling product (Ph-Ph) is measured by ¹ H NMR, and the Ph-Ph formation rate ( %) Was calculated.

The results are shown in FIG. As shown in FIG. 2, when bromobenzene 1 is used as the starting compound, it can be understood that phenyl sodium 2 can be synthesized with a high yield of 99% or more when SD is reacted at 2.2 molar equivalents or more. Further, when chlorobenzene 1 is used as a starting compound, it can be understood that phenyl sodium 2 can be synthesized with a high yield of 99% or more by reacting SD at 2.1 molar equivalents or more. On the other hand, it was also found that when the SD is less than 2.0 molar equivalents, it induces the Wurtz reaction which is a side reaction.

(Example 3) Investigation of synthesis conditions of organozinc compound and application to Negishi coupling-1
In this example, an organozinc compound was synthesized under the synthesis conditions summarized in FIG. 3, and it was examined whether the resulting organozinc compound could be used for Negishi coupling using a palladium catalyst. Here, bis (triphenylphosphine) palladium (II) dichloride (PdCl ₂ (PPh ₃ ) ₂ ) was used as a palladium catalyst.

Experiment No. 1
The synthesis of 4- ⁿ nonylphenyl zinc chloride 3 as an organozinc compound was studied. The starting compound, 1.2 molar equivalents of 4- ⁿ nonyl-chlorobenzene 1 and 2.8 molar equivalents of SD were added to 1 ml of hexane and reacted at room temperature for 15 minutes to synthesize 4- ⁿ nonylphenyl sodium 2. To the obtained 4- ⁿ nonylphenyl sodium 2 was added 1.2 molar equivalent of zinc chloride TMEDA, and reacted at room temperature for 15 minutes to obtain 4- ⁿ nonylphenyl zinc chloride 3.

Subsequently, it was examined whether the obtained 4- ⁿ nonylphenyl zinc chloride 3 could be used for Negishi coupling using a palladium catalyst. 4- ⁿ nonylphenyl zinc chloride 3 in the presence of palladium catalyst bis (triphenylphosphine) palladium (II) dichloride (PdCl ₂ (PPh ₃ ) ₂ 10 mol% (relative to 2-bromonaphthalene)) 1.0 The reaction was carried out with a molar equivalent of 2-bromonaphthalene 4 at 70 ° C. for 3 hours. As a result, as shown in FIG. 3, 2- (4- ⁿ nonylphenyl) naphthalene 5 was obtained.

The evaluation of the synthesized 2- (4- ⁿ nonylphenyl) naphthalene 5 was performed by measurement by ¹ H NMR. The yield can be theoretically generated from 2-bromonaphthalene 4 was added to the reaction system, for 2- ^{(4-n-nonylphenyl)} naphthalene 5, was actually obtained, 2- ^(4-n-nonyl It calculated by showing the ratio of phenyl) naphthalene 5 as a percentage. The yield was 96%. Thus, ^4-n-nonyl - through from chlorobenzene 1 ^{4-n-nonylphenyl} sodium 2, it was possible to carry out the synthesis of ^{4-n-nonylphenyl} zinc chloride 3 in high yield. Also, it can be understood that Negishi coupling with 4- ⁿ nonylphenylzinc chloride proceeds efficiently, and as a result, 2- (4- ⁿ nonylphenyl) naphthalene 5 is obtained in high yield.

Experiment number 2
The synthesis of 4-methylphenyl zinc chloride 3 as an organozinc compound was studied. The starting compounds, 1.2 molar equivalents of 4-methyl-chlorobenzene 1 and 2.6 molar equivalents of SD, were added to 1.2 ml of hexane and reacted at 25 ° C. for 1 hour to synthesize 4-methylphenyl sodium 2. 1.2 molar equivalents of zinc chloride TMEDA was added to the obtained 4-methylphenyl sodium 2 and reacted at 25 ° C. for 30 minutes to obtain 4-methylphenyl zinc chloride 3.

Subsequently, it was examined whether the obtained 4-methylphenyl zinc chloride 3 could be used for Negishi coupling using a palladium catalyst. 1.0 molar equivalent of 4-methylphenyl zinc chloride 3 in the presence of 5 mol% (relative to 2-bromonaphthalene) of palladium catalyst bis (triphenylphosphine) palladium (II) dichloride (PdCl ₂ (PPh ₃ ) ₂ The mixture was reacted with (0.5 mmol) of 2-bromonaphthalene 4 for 3 hours at 70 ° C. As a result, 2- (4-methylphenyl) naphthalene 5 was obtained as shown in FIG.

The evaluation of the synthesized 2- (4-methylphenyl) naphthalene 5 was performed by measurement by ¹ H NMR. The yield could actually be obtained for 2- (4-methylphenyl) naphthalene 5, which can theoretically be generated from 2-bromonaphthalene 4 added to the reaction system, 2- (4-methylphenyl) It calculated by showing the ratio of naphthalene 5 as a percentage. The yield was 94%. The isolated yield was 87%. Thus, 4-methylphenylzinc chloride 3 could be synthesized in high yield via 4-methyl-chlorobenzene 1 to 4-methylphenyl sodium 2. Also, it can be understood that Negishi coupling with 4-methylphenyl zinc chloride 3 proceeds efficiently, and as a result, 2- (4-methylphenyl) naphthalene 5 is obtained in high yield.

(Example 4) Examination of synthesis conditions of organozinc compound and application to Negishi coupling-2
In this example, an organozinc compound is synthesized under the synthesis conditions summarized in FIG. 4 following Example 3, and it is examined whether the resulting organozinc compound can be used for Negishi coupling using a palladium catalyst. did. Here, PEPPSI-IPr was used as a palladium catalyst.

Experiment No. 1
The synthesis of 4-methylphenyl zinc chloride 3 as an organozinc compound was studied. The starting compounds, 1.2 molar equivalents of 4-methyl-chlorobenzene 1 and 2.6 molar equivalents of SD, were added to 1.2 ml of hexane and reacted at 25 ° C. for 1 hour to synthesize 4-methylphenyl sodium 2. 1.2 molar equivalents of zinc chloride TMEDA was added to the obtained 4-methylphenyl sodium 2 and reacted at 25 ° C. for 30 minutes to obtain 4-methylphenyl zinc chloride 3.

Subsequently, it was examined whether the obtained 4-methylphenyl zinc chloride 3 could be used for Negishi coupling using a palladium catalyst. 4-Methylphenyl zinc chloride 3 is 1.0 molar equivalent (0.5 mmol) of THF / NMP (0.6 ml / 0.3 ml) in the presence of 1 mol% (relative to 2-chloronaphthalene) of palladium catalyst PEPPSI-IPr The reaction was carried out with 2-chloronaphthalene 4 at 70 ° C. for 3 hours. As a result, as shown in FIG. 4, 2- (4-methylphenyl) naphthalene 5 was obtained.

The evaluation of the synthesized 2- (4-methylphenyl) naphthalene 5 was performed by measurement by ¹ H NMR. The yield could actually be obtained for 2- (4-methylphenyl) naphthalene 5, which could theoretically be generated from 2-chloronaphthalene 4 added to the reaction system, 2- (4-methylphenyl) It calculated by showing the ratio of naphthalene 5 as a percentage. The yield was 99%. The isolated yield was 95%. Thus, 4-methylphenylzinc chloride 3 could be synthesized in high yield via 4-methyl-chlorobenzene 1 to 4-methylphenyl sodium 2. Also, it can be understood that Negishi coupling with 4-methylphenyl zinc chloride 3 proceeds efficiently, and as a result, 2- (4-methylphenyl) naphthalene 5 is obtained in high yield.

Experiment number 2
The synthesis of 2,6-dimethylphenyl zinc chloride 3 as an organozinc compound was studied. In 1.2 ml of hexane, 1.2 molar equivalents of 2,6-dimethyl-chlorobenzene 1 as a starting compound and 2.6 molar equivalents of SD are added and reacted at 25 ° C. for 1 hour to synthesize 2,6-dimethylphenyl sodium 2 did. To the obtained 2,6-dimethylphenyl sodium 2, 1.2 molar equivalent of zinc chloride TMEDA was added, and reacted at 25 ° C. for 30 minutes to obtain 2,6-dimethylphenyl zinc chloride 3.

Subsequently, it was examined whether the obtained 2,6-dimethylphenyl zinc chloride 3 could be used for Negishi coupling using a palladium catalyst. One molar equivalent (0.5 mmol) of 2,6-dimethylphenyl zinc chloride 3 in THF / NMP (0.6 ml / 0.3 ml) in the presence of 1.0 mol% (relative to 2-chloronaphthalene) of PEPPSI-IPr which is a palladium catalyst The reaction was carried out with 2-chloronaphthalene 4 at 70 ° C. for 3 hours. As a result, as shown in FIG. 4, 2- (2,6-dimethylphenyl) naphthalene 5 was obtained.

The evaluation of the synthesized 2- (2,6-dimethylphenyl) naphthalene 5 was performed by measurement by ¹ H NMR. The yield was actually obtained 2- (2, 6) for 2- (2, 6-dimethylphenyl) naphthalene 5, which can theoretically be generated from 2-chloronaphthalene 4 added to the reaction system It was calculated by showing the ratio of -dimethylphenyl) naphthalene 5 as a percentage. The yield was 96%. As a result, via 2,6-dimethyl-chlorobenzene 1 to 2,6-dimethylphenyl sodium 2, synthesis of 2,6-dimethylphenyl zinc chloride 3 could be performed in high yield. In addition, it can be understood that Negishi coupling with 2,6-dimethylphenyl zinc chloride 3 proceeds efficiently, and as a result, 2- (2,6-dimethylphenyl) naphthalene 5 is obtained in high yield.

(Example 5) Examination of synthesis conditions of organozinc compound and application to Negishi coupling-3
In this example, the synthesis conditions of phenyl zinc chloride 3 as an organozinc compound were examined under the examination conditions summarized in FIG. 5 following Examples 3 and 4. The starting compounds, 1.25 molar equivalents of chlorobenzene 1 and 2.9 molar equivalents of SD, were added to 1 ml of hexane and reacted at room temperature for 20 minutes to synthesize phenyl sodium 2. To the obtained phenyl sodium 2, 1.25 molar equivalent of zinc chloride TMEDA was added and reacted at room temperature for 15 minutes to obtain phenyl zinc chloride 3.

Subsequently, it was examined whether the obtained phenyl zinc chloride 3 could be used for Negishi coupling using a palladium catalyst. Phenyl zinc chloride 3 was reacted with 1.0 molar equivalent of 2-bromopyridine 4 at 70 ° C. for 3 hours in the presence of 10 mol% PdCl ₂ (PPh ₃ ) ₂ . As a result, as shown in FIG. 5, 2-phenylpyridine 5 was obtained.

Evaluation of the synthesized 2-phenylpyridine 5 was performed by measurement by ¹ H NMR. The yield is calculated by showing the ratio of 2-phenylpyridine 5 actually obtained to 2-phenylpyridine 5 which can be theoretically generated from 2-bromopyridine 4 added to the reaction system as a percentage. did. The yield was 68%. As a result, synthesis of phenylzinc chloride 3 could be carried out with high yield through chlorobenzene 1 to phenyl sodium 2. In addition, it can be understood that Negishi coupling using phenyl zinc chloride 3 proceeds efficiently, and as a result, 2-phenylpyridine 5 is obtained in high yield.

(Example 6) Investigation of synthesis conditions of organozinc compound and application to Negishi coupling-4
In this example, an organozinc compound is synthesized under the study conditions following Examples 3 to 5 and summarized in FIGS. 6A to 6C (Experiment Nos. 1 to 18), and the resulting organozinc compound uses a palladium catalyst. It was examined whether it could be used for Negishi coupling. Here, PEPPSI (registered trademark) -IPr ^CL was used as a palladium catalyst.

Experiment No. 1
Add 1.2 molar equivalents (0.6 mmol) of the starting compound, 4-chlorotoluene, which is organic chloride 1, and 2.5 molar equivalents of SD in 1.2 ml of hexane, and react at 30 ° C. for 30 minutes to obtain organic sodium compound 2 4-methylphenyl sodium was synthesized. To the obtained 4-methylphenyl sodium was added 1.2 molar equivalent of zinc chloride-TMEDA, and the mixture was reacted in hexane at 25 ° C. for 30 minutes to obtain organic zinc compound 3, 4-methylphenyl zinc chloride. Subsequently, it was examined whether the obtained 4-methylphenyl zinc chloride could be used for Negishi coupling using a palladium catalyst. In THF (0.6 ml) / NMP ( 0.3 ml), 4- methyl-phenyl zinc chloride, 1 mol% of a palladium catalyst PEPPSI 1 molar equivalent in the presence of (R) -iPr ^CL of (0.5 mmol) The reaction was carried out at 70 ° C. for 3 hours with 2-chloronaphthalene which is an organic chloride 4. As a result, as shown in FIG. 6A, coupling product 5, 2- (4-methylphenyl) naphthalene was obtained in 95% isolated yield.

Experiment number 2
Organosodium compound obtained by reaction with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 2-chlorotoluene as organic chloride 1 in 1.2 ml of hexane After 2), an organozinc compound 3 was synthesized. The reaction temperature was 30 ° C., and the reaction time was 1 hour. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . The mixture was reacted with 4-chloronaphthalene at 70 ° C. for 3 hours. As a result, as shown in FIG. 6A, 2- (2-methylphenyl) naphthalene as a coupling product 5 was obtained in 96% isolated yield.

Experiment number 3
Obtained by reacting with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 1-tert-butyl-2-chlorobenzene as organic chloride 1 in 1.2 ml of hexane. The organozinc compound 3 was synthesized via the prepared organosodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 5 hours. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.25 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . It was reacted with 4-chloronaphthalene at 70 ° C. for 24 hours. As a result, as shown in FIG. 6A, the coupling product 5, 2- (2-tert-butylphenyl) naphthalene was obtained in an isolated yield of 88%.

Experiment number 4
Obtained by reacting with 2.5 molar equivalents of SD in the same manner as in the above Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 2-chloro-m-xylene as organic chloride 1 in 1.2 ml of hexane An organozinc compound 3 was synthesized via the organosodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 3 hours. Subsequently, in THF (0.6 ml) / NMP ( 0.3 ml), the organic zinc compound 3, 1 mol% of PEPPSI (TM) 1 molar equivalent in the presence of -IPr ^CL (0.5 mmol) equivalents of the organic chloride The reaction was carried out at 70 ° C. for 3 hours with 2-chloronaphthalene which is the substance 4. As a result, as shown in FIG. 6A, coupling product 5, 2- (2,6-dimethylphenyl) naphthalene was obtained in 92% isolated yield.

Experiment number 5
Obtained by reacting with 2.5 molar equivalents of SD in the same manner as in the above Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 2-chloro-m-xylene as organic chloride 1 in 1.2 ml of hexane An organozinc compound 3 was synthesized via the organosodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 3 hours. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . It was reacted with 1-chloronaphthalene which is 4 at 70 ° C. for 3 hours. As a result, as shown in FIG. 6A, 1- (2,6-dimethylphenyl) naphthalene as a coupling product 5 was obtained in an isolated yield of 93%.

Experiment number 6
Organosodium compound obtained by reaction with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 4-chlorotoluene as organic chloride 1 in 1.2 ml of hexane After 2), an organozinc compound 3 was synthesized. The reaction temperature was 30 ° C., and the reaction time was 30 minutes. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . It was reacted with 1-chloro-4-methoxybenzene which is 4 at 70 ° C. for 3 hours. As a result, as shown in FIG. 6A, 4-methoxy-4′-methyl-1,1′-biphenyl as a coupling product 5 was obtained in 95% isolated yield.

Experiment number 7
Organosodium compound obtained by reaction with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 4-chlorotoluene as organic chloride 1 in 1.2 ml of hexane After 2), an organozinc compound 3 was synthesized. The reaction temperature was 30 ° C., and the reaction time was 30 minutes. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . It was reacted with methyl 4-chlorobenzoate which is 4 at 70 ° C. for 3 hours. As a result, as shown in FIG. 6A, 4-methoxycarbonyl-4′-methyl-1,1′-biphenyl as a coupling product 5 was obtained in 94% isolated yield.

Experiment No. 8
Organosodium compound obtained by reaction with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 4-chlorotoluene as organic chloride 1 in 1.2 ml of hexane After 2), an organozinc compound 3 was synthesized. The reaction temperature was 30 ° C., and the reaction time was 30 minutes. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . The mixture was reacted with 4-chloropyridine at 70 ° C. for 3 hours. As a result, as shown in FIG. 6A, 2- (4-methylphenyl) pyridine which is a coupling product 5 was obtained in 95% isolated yield.

Experiment number 9
Obtained by reacting with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 1,3-diisopropyl-2-chlorobenzene as organic chloride 1 in 1.2 ml of hexane. The organozinc compound 3 was synthesized via the prepared organosodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 3 hours. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . The mixture was reacted with 2-naphthalene, which is 4), at 70 ° C. for 5 hours. As a result, as shown in FIG. 6A, coupling product 5, 2- (2,6-diisopropylphenyl) naphthalene was obtained in 96% isolated yield.

Experiment number 10
Obtained by reacting with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 1,3-diisopropyl-2-chlorobenzene as organic chloride 1 in 1.2 ml of hexane. The organozinc compound 3 was synthesized via the prepared organosodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 3 hours. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . It was reacted with 1-naphthalene, which is 4 at 70 ° C. for 24 hours. As a result, as shown in FIG. 6A, coupling product 5, 1- (2,6-diisopropylphenyl) naphthalene was obtained in 92% isolated yield.

Experiment number 11
Obtained by reacting with 2.4 molar equivalents of SD in the same manner as in the above Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 2-chloro-m-xylene as organic chloride 1 in 1.2 ml of hexane An organozinc compound 3 was synthesized via the organosodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 3 hours. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . The mixture was reacted with 1, 2-dichlorobenzene which is 4 at 70 ° C. for 3 hours. As a result, as shown in FIG. 6B, coupling product 5, 1-chloro-2 ′, 6′-dimethyl-1,1′-biphenyl was obtained in 70% isolated yield.

Experiment number 12
Obtained by reacting with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 1-chloro-3-dimethylaminobenzene as organic chloride 1 in 1.2 ml of hexane. The organozinc compound 3 was synthesized via the prepared organosodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 1 hour. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . The mixture was reacted with 4-chloronaphthalene at 70 ° C. for 3 hours. As a result, as shown in FIG. 6B, coupling product 5, 2- [3- (dimethylamino) phenyl] naphthalene was obtained in 96% isolated yield.

Experiment number 13
Organic sodium obtained by reaction with 7.6 molar equivalents of SD in the same manner as in Experiment No. 1 above using 3.6 molar equivalents of 1-chloro-3-dimethylaminobenzene as organic chloride 1 in 1.2 ml of hexane The organic zinc compound 3 was synthesized via the compound 2. The reaction temperature was 30 ° C., and the reaction time was 1 hour. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.25 mmol) of organic chloride in the presence of 3 mol% of PEPPSI (registered trademark) -IPr ^CL . The reaction was carried out at 70 ° C. for 3 hours with 4, 1, 3, 5-trichlorobenzene. As a result, as shown in FIG. 6B, coupling product 5, 1,3,5-tri [3- (dimethylamino) phenyl] benzene was obtained in 90% isolated yield.

Experiment No. 14
Obtained by reacting with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 1-chloro-3-dimethylaminobenzene as organic chloride 1 in 1.2 ml of hexane. The organozinc compound 3 was synthesized via the prepared organosodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 1 hour. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . It was made to react with 2-thiophene which is 4 at 70 ° C. for 3 hours. As a result, as shown in FIG. 6B, coupling product 5, 2- [3- (dimethylamino) phenyl] thiophene was obtained in an isolated yield of 85%.

Experiment number 15
Obtained by reacting with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 1-chloro-3-dimethylaminobenzene as organic chloride 1 in 1.2 ml of hexane. The organozinc compound 3 was synthesized via the prepared organosodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 1 hour. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . It was reacted with N-tert-butoxycarbonyl-6-chloroindole which is 4 at 70 ° C. for 3 hours. As a result, as shown in FIG. 6B, 6- [3- (dimethylamino) phenyl] indole as a coupling product 5 was obtained in an isolated yield of 93%.

Experiment number 16
Obtained by reacting with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 1-chloro-2-methoxybenzene as organic chloride 1 in 1.2 ml of hexane. The organic zinc compound 3 was synthesized via the organic sodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 1 hour. Subsequently, organic zinc compound 3 is dissolved in THF (0.3 ml) / NMP (0.6 ml) in the presence of 2 mol% of PEPPSI (registered trademark) -IPr ^{CL in} an amount of 1 molar equivalent (0.5 mmol) of organic chloride It was reacted with 4-chloro-1- (trimethylsilyl) -1-pentyne at 70 ° C. for 24 hours. As a result, as shown in FIG. 6B, coupling product 5, 4- (2-methoxyphenyl) -1- (trimethylsilyl) -1-pentyne was obtained in 92% NMR yield and 87% isolated yield. The

Experiment number 17
Obtained by reacting with 2.5 molar equivalents of SD in the same manner as in Experiment No. 1 using 1.2 molar equivalents (0.6 mmol) of 1-chloro-2-methoxybenzene as organic chloride 1 in 1.2 ml of hexane. The organic zinc compound 3 was synthesized via the organic sodium compound 2. The reaction temperature was 30 ° C., and the reaction time was 1 hour. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . The mixture was reacted with 4-chloronaphthalene at 70 ° C. for 3 hours. As a result, as shown in FIG. 6B, coupling product 5, 2- (2-methoxyphenyl) naphthalene was obtained in 97% isolated yield.

Experiment number 18
The organosodium compound 2 is obtained by reaction with 2.5 molar equivalents of SD as in Example 1 above, using 0.6 mmol of 1-chloropentane as organic chloride 1 in 2.4 mL of hexane. The organozinc compound 3 was synthesized. The reaction temperature was 0 ° C., and the reaction time was 20 minutes. Subsequently, organozinc compound 3 is dissolved in THF (0.6 ml) / NMP (0.3 ml) in an amount of 1 molar equivalent (0.5 mmol) of organic chloride in the presence of 1 mol% of PEPPSI.RTM.-IPr ^CL . It was reacted with 1-chloroisoquinoline which is 4 at 70 ° C. for 3 hours. As a result, as shown in FIG. 6B, 1-pentylisoquinoline which is a coupling product 5 was obtained in 86% isolated yield.

The present invention can be suitably used as a synthesis method of an organozinc compound, and all technical fields utilizing the organozinc compound synthesized by such a synthesis method, in particular, as an intermediate of a coupling reaction, and a pharmaceutical, an agricultural chemical or an electron It is particularly useful in the field of material production.

Claims (4)

1. A method of synthesizing an organozinc compound, comprising
   In the reaction solvent, the general formula I (R ¹ -X ¹ )
   [Wherein, R ¹ represents an aliphatic hydrocarbon group which may have a substituent which does not react with sodium, an alicyclic hydrocarbon group, an alicyclic heterocyclic group, an aromatic hydrocarbon group, Or an aromatic heterocyclic group, wherein X ¹ is a halogen atom] and a reaction in which sodium is dispersed in a dispersion solvent is reacted with
   General Formula II (R ¹ -Na)
   [Here, in the formula, R ¹ is the same as R ¹ in formula I] to obtain an organic sodium compound shown,
   The obtained organic sodium compound is reacted with zinc chloride to obtain
   General formula III (R ¹ -Zn-X ² )
   [Wherein in the formula, R ¹ is the same as R ¹ in formula I, X ² is Cl, or, wherein R ¹ is] to obtain an organic zinc compound shown having, organic zinc compounds Synthetic method.
2. The method for synthesizing an organozinc compound according to claim 1, wherein the X ¹ is a chlorine atom.
3. The dispersion in which the sodium is dispersed in the dispersion solvent has an activity such that the yield of phenyl sodium is 99.0% or more with respect to the chlorobenzene added when the reaction is carried out in a reaction solvent at 2.1 molar equivalent or more relative to chlorobenzene. The synthesis | combining method of the organozinc compound of Claim 1 or 2 which has these.
4. The molar ratio of the organic halide: the dispersion of the sodium dispersed in the dispersion solvent: the zinc chloride in the general formula III when X ² is Cl is from 1: 2 to 3: 1, and the general formula III The method for synthesizing an organozinc compound according to any one of claims 1 to 3, wherein when X ² is R ¹ , it is 1: 2 or more and 3 or less: 1.

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