WO2019225742A1 - Procédé de couplage de composés organiques - Google Patents

Procédé de couplage de composés organiques Download PDF

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WO2019225742A1
WO2019225742A1 PCT/JP2019/020669 JP2019020669W WO2019225742A1 WO 2019225742 A1 WO2019225742 A1 WO 2019225742A1 JP 2019020669 W JP2019020669 W JP 2019020669W WO 2019225742 A1 WO2019225742 A1 WO 2019225742A1
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group
organic
sodium
reaction
coupling
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Japanese (ja)
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村上吉明
福島美幸
高井和彦
浅子壮美
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株式会社神鋼環境ソリューション
国立大学法人岡山大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/04—Substitution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/20—Polycyclic condensed hydrocarbons
    • C07C15/24—Polycyclic condensed hydrocarbons containing two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/45—Monoamines
    • C07C211/48—N-alkylated amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a method for coupling organic compounds.
  • the organic compound coupling method is a method of synthesizing a new organic compound by bonding two or more organic compounds to each other through a carbon atom-carbon atom bond (hereinafter abbreviated as “CC bond”). It has become a general-purpose technology in total synthesis and organic synthesis of functional materials such as medicines and agricultural chemicals, electronic materials, and intermediates thereof.
  • Non-patent Document 1 Non-patent Document 2, etc.
  • organic electrophile such as an organic halide
  • organoboron compound using palladium or nickel as a catalyst
  • Negishi coupling by reaction with an organic zinc compound see Non-Patent Document 3, Non-Patent Document 4, etc.
  • a Grignard reagent that is an organic magnesium compound.
  • the organoboric acid compound used for the Suzuki-Miyaura coupling is generally obtained by preparing a corresponding organolithium reagent or Grignard reagent from an organic halide and reacting these with a borate ester compound. It can be obtained (see Non-Patent Document 7 etc.), and an organozinc compound used for Negishi coupling can also be obtained by reacting an organolithium reagent or Grignard reagent with zinc halide (ZnX 2 ) such as zinc chloride. Yes (see Non-Patent Document 8 etc.).
  • n BuLi n-butyllithium
  • t BuLi organic halide
  • the organozinc compound is prepared by the following two-stage reaction (first stage: RI + n BuLi or t BuLi ⁇ R-Li, second stage: R-Li + ZnCl 2 ⁇ R-ZnCl). is there.
  • 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 goods by the Fire Service Law, and there is a problem that equipment and facilities suitable for handling are required.
  • the Grignard reagent is obtained by reacting an organic halide and metal magnesium in an anhydrous solvent such as tetrahydrofuran (hereinafter referred to as “THF”) or ether.
  • anhydrous solvent such as tetrahydrofuran (hereinafter referred to as “THF”) or ether.
  • THF tetrahydrofuran
  • the conventional method using the Grignard reagent has a long reaction time, which increases the cost.
  • the reactivity during synthesis of Grignard reagents is generally higher for organic bromides (R-Br) and organic iodides (RI) than for organic chlorides (R-Cl).
  • organic bromides or iodides have been widely used, but organic bromides and iodides are expensive.
  • organomagnesium bromide which is widely used as a Grignard reagent from the viewpoint of reactivity and the like, is a bromine-containing compound, but bromine is limited in the area where it is mined, and is highly toxic and has human residual properties. Use is decreasing. Therefore, there is also a problem that the circulation amount is reduced and it is difficult to obtain the target organic bromide. Therefore, there is a problem that the method using the Grignard reagent cannot sufficiently satisfy the market demand from an industrial and economical viewpoint.
  • boron and zinc which are constituent elements of organic boric acid compounds and organic zinc compounds, have a minable life of about 20 to 40 years and have a small amount of recognizable reserves, and lithium, which is a constituent element of organic lithium.
  • boron is an essential trace element of plants and animals, but overdose causes gastrointestinal tract disorders, central nervous system disorders, etc. to the human body. In particular, insects are known to exhibit strong toxicity and have a problem of high environmental burden.
  • the present inventors reacted an organic halide and a dispersion in which sodium was dispersed in a dispersion solvent in a reaction solvent to obtain an organic sodium compound, It was found that an organic compound can be efficiently coupled by reacting the obtained organic sodium compound with an organic chloride. Such a method for coupling organic compounds is difficult to handle and does not require toxic reagents, and the coupling reaction of organic compounds proceeds under mild conditions. Further, it is possible to couple an organic compound at a low cost with a small number of steps without requiring a complicated and expensive synthesis processing step or a disposal processing step. Based on these findings, the present inventors have completed the present invention.
  • the present invention relates to a coupling method, which is characterized by a general formula I (R 1 -X 1 ) [wherein R 1 is a substituent that does not react with sodium in a reaction solvent.
  • An aromatic hydrocarbon group which may have a group, or an aromatic heterocyclic group, and X 1 is a halogen atom] and a dispersion in which sodium is dispersed in a dispersion solvent; is reacted of general formula II (R 1 -Na) [wherein, in the formula, R 1 is the same as R 1 in formula I] to obtain an organic sodium compound shown,
  • the following general formula IV [Wherein, R a , R b , R
  • reaction catalyst comprising, in the general formula V (R 1 -R 2) [wherein, in the formula, R 1 is the same as R 1 of the general formula I and general formula II, R 2 is And the same as R 2 in the general formula III].
  • an organic sodium compound is synthesized from an organic halide, and then a palladium catalyst having a nitrogen-containing heterocyclic carbene (hereinafter abbreviated as “NHC”) ligand containing the sodium compound and the organic chloride.
  • NEC nitrogen-containing heterocyclic carbene
  • this configuration by using a dispersion in which sodium that is easy to handle is dispersed in a dispersion solvent, it is easy and quick in a small number of steps without requiring a complicated chemical method under mild conditions. Since an organic sodium compound can be synthesized at low cost from an organic halide and the subsequent coupling reaction can proceed smoothly, it is very advantageous economically and industrially.
  • reaction catalyst contains a metal chloride as a promoter.
  • the reaction catalyst contains a metal chloride as a co-catalyst, the coupling reaction can proceed more smoothly, which is very advantageous economically and industrially.
  • the palladium catalyst in the general formula IV is such that R a , R b , R c , and R d are all isopropyl groups.
  • a compound having a bulky NHC ligand 1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene group is used as a palladium catalyst. Since the palladium catalyst has high catalytic activity and is extremely stable, the coupling reaction can proceed more smoothly. Thereby, it becomes further economically and industrially advantageous.
  • the molar ratio of the organic halide: the dispersion in which the sodium is dispersed in the dispersion solvent is 1: 2 or more.
  • the organic sodium compound can be synthesized with higher efficiency and purity by optimizing the amount of the organic halide and the dispersion in which sodium is dispersed in the dispersion solvent, and the organic The coupling reaction with chloride can proceed more smoothly.
  • Example 1 BRIEF DESCRIPTION OF THE DRAWINGS It is a figure which summarizes the synthesis conditions and result of Example 1 which examined the synthesis
  • the organic compound coupling method comprises reacting an organic halide represented by the general formula I (R 1 -X 1 ) with a dispersion in which sodium is dispersed in a dispersion solvent in a reaction solvent.
  • a step of obtaining a coupling product represented by the general formula V (R 1 -R 2 ) step 2.
  • the coupling is a reaction of two or more types of molecules to synthesize one compound by CC bonding at a specific location. Coupling is classified into cross-coupling by molecules having different structures and homo-coupling by molecules having the same structure, but is preferably cross-coupling.
  • Step 1 in the method for coupling an organic compound according to the present embodiment comprises reacting 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 in a reaction solvent.
  • an organic sodium compound represented by the general formula II (R 1 -Na) is obtained.
  • 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 one of the objects to be coupled in the organic compound coupling method according to the present embodiment. .
  • R 1 is an aromatic hydrocarbon group or an aromatic heterocyclic group which may have a substituent that does not react with sodium. It is not preferable to have a substituent reactive with sodium because a dispersion in which the substituent and sodium are dispersed in a dispersion solvent reacts to induce a side reaction. Therefore, when using a compound having a substituent reactive with sodium as R 1 , it is necessary to protect the substituent with an appropriate protecting group or the like.
  • the aromatic hydrocarbon group is not particularly limited as long as it has an aromatic ring. Not only a single ring but also those having a ring assembly such as a condensed ring or 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.
  • aromatic hydrocarbon group examples include a monocyclic six-membered phenyl group, a bicyclic naphthyl group, a pentarenyl group, an indenyl group, an azulenyl group, a tricyclic biphenylenyl group, an indacenyl group, an acenaphthylenyl group, and a fluorenyl group.
  • Examples include, but are not limited to, a pentacenyl group of the formula, a heptacyclic rubicenyl group, a coronenyl group, a heptacenyl group, and the like. Particularly preferred is a phenyl group.
  • An aromatic heterocyclic group is an aromatic heterocyclic group having one or more heteroatoms as ring-constituting atoms. Not only a single ring but also those having a ring assembly such as a condensed ring or 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 atom.
  • the number of heteroatoms is not particularly limited, and the position of the heteroatoms is not limited.
  • the hetero atom is preferably exemplified by an oxygen atom, a nitrogen atom, a sulfur atom and the like.
  • an aromatic heterocyclic group having preferably 1 to 5 carbon atoms, particularly preferably 3 to 5 carbon atoms, and preferably 1 to 4 carbon atoms, particularly preferably 1 to 3 carbon atoms.
  • it may be the same kind of atom or a different kind of atom.
  • the monocyclic aromatic heterocyclic group may be a nitrogen-containing aromatic group such as a 5-membered pyrrolyl group, pyrazolyl group, pyridyl group, imidazolyl group, 6-membered cyclic pyrazinyl group, pyrimidinyl group, pyridazinyl group, etc.
  • An oxygen-containing aromatic heterocyclic group such as an aromatic group, a five-membered furyl group, an oxygen-containing aromatic heterocyclic group such as a five-membered thienyl group, a five-membered oxazolyl group, an isoxazolyl group
  • examples thereof include, but are not limited to, nitrogen-containing oxygen aromatic heterocyclic groups such as furazanyl groups, nitrogen-containing sulfur aromatic heterocyclic groups such as five-membered cyclic thiazolyl groups and isothiazolyl groups.
  • polycyclic aromatic heterocyclic group examples include bicyclic indolizinyl group, isoindolyl group, indolyl group, indazolyl group, purinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, and cinnolinyl.
  • the aromatic hydrocarbon group and the aromatic heterocyclic group may have a substituent.
  • One or a plurality of substituents may be present, and when a plurality of substituents are present, they may be the same or different from each other.
  • substituents include an optionally substituted aliphatic hydrocarbon group, alicyclic hydrocarbon group, alicyclic heterocyclic group, aromatic hydrocarbon group, aromatic heterocyclic group, alkoxy group, cycloalkoxy Group, aryloxy group, aralkyloxy group, alicyclic heterocyclic oxy group, aromatic heterocyclic oxy group, alkylthio group, cycloalkylthio group, arylthio group, aralkylthio group, alicyclic heterocyclic thio group, aromatic Examples include, but are not limited to, heterocyclic thio groups, alkylamino groups, cycloalkylamino groups, arylamino groups, aralkylamino groups, alicyclic heterocyclic amino groups, aromatic heterocyclic amino groups, and acyl groups. It is not a thing.
  • the aliphatic hydrocarbon group that may be present as a substituent is not limited to whether it is linear or branched, and may be saturated or unsaturated. Moreover, there is no restriction
  • Examples of the aliphatic hydrocarbon group include, but are not limited to, an alkyl group, an alkenyl group, and an alkynyl group, preferably having 1 to 20 carbon atoms, particularly preferably 3 to 20 carbon atoms. .
  • alkyl group methyl group, ethyl group, propyl group, butyl 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, 2-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-propylpropyl, n-heptyl, isoheptyl, s-heptyl, t-heptyl
  • alkenyl group examples include, but are not limited to, an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, and an octenyl group.
  • alkynyl group examples include, but are not limited to, ethynyl group, propynyl group, butynyl group, pentynyl group, heptynyl group, octynyl group and the like.
  • alicyclic hydrocarbon group which may be present as a substituent, there is no particular limitation on the number of ring members, regardless of whether the bond between ring constituent atoms is saturated or unsaturated. In addition, not only a single ring but also those having a ring assembly such as a condensed ring or a spiro ring are 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 carbon atoms. Examples thereof include several to 10 and particularly preferably 4 to 7 cycloalkenyl groups.
  • cycloalkyl group examples include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
  • cycloalkenyl group examples include, but are not limited to, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group.
  • the alicyclic heterocyclic group that may be present as a substituent is a non-aromatic heterocyclic group having one or more heteroatoms as ring-constituting atoms. Not only a single ring but also those having a ring assembly such as a condensed ring or a spiro ring are included. There is no particular limitation on the number of ring members, regardless of whether the bonds between ring atoms are saturated or unsaturated.
  • the hetero atom is not particularly limited as long as it does not react with sodium as a ring atom.
  • the number of heteroatoms is not particularly limited, and the position of the heteroatoms is not limited.
  • the hetero atom is preferably exemplified by an oxygen atom, a nitrogen atom, a sulfur atom and the like.
  • an alicyclic heterocyclic group having preferably 2 to 7 carbon atoms, particularly preferably 2 to 5 carbon atoms, and preferably 1 to 5 carbon atoms, particularly preferably 1 to 3 carbon atoms. Is mentioned.
  • it when it has a some hetero atom, it may be the same kind of atom or a different kind of atom.
  • alicyclic heterocyclic group examples include a monocyclic four-membered azetidinyl group, a five-membered pyrrolidinyl group, a six-membered piperidyl group, a nitrogen-containing alicyclic heterocyclic group such as a piperazinyl group, Oxygen-containing cycloaliphatic heterocyclic groups such as 3-membered oxiranyl group, 4-membered oxetanyl group, 5-membered tetrahydrofuryl group, 6-membered tetrahydropyranyl group, monocyclic ring Sulfur-containing alicyclic heterocyclic groups such as five-membered tetrahydrothiophenyl groups, nitrogen-containing oxygen alicyclic heterocyclic groups such as monocyclic six-membered morpholinyl groups, monocyclic six-membered cyclic groups Examples thereof include, but are not limited to, nitrogen-containing sulfur alicyclic heterocyclic group
  • aromatic hydrocarbon group and aromatic heterocyclic group that may be present as a substituent include the same as those described above.
  • the alkoxy group which may be substituted is preferably an alkoxy group having 1 to 10 carbon atoms, specifically, methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group, hexyl. Examples include, but are not limited to, oxy groups.
  • the cycloalkoxy group which may be substituted 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 which may be substituted as a substituent is preferably an aryloxy group having 6 to 20 carbon atoms, and specific examples include a phenyloxy group and a naphthyloxy group. It is not limited.
  • the aralkyloxy group that may be substituted is preferably an aralkyloxy group having 7 to 11 carbon atoms, and specific examples include a benzyloxy group and a phenethyloxy group.
  • the alicyclic heterocyclic oxy group and aromatic heterocyclic oxy group that may be present as a substituent are those having the alicyclic heterocyclic group and aromatic heterocyclic group shown above as the heterocyclic portion. Can be mentioned.
  • alkylthio group examples include an alkylthio group having 1 to 20 carbon atoms, and examples include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, and a hexylthio group.
  • the present invention is not limited to these.
  • Examples of the cycloalkylthio group that may be substituted include a cycloalkylthio group having 3 to 10 carbon atoms, and specifically include a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, and a cyclohexylthio group.
  • the arylthio group which may have a substituent is preferably an arylthio group having 6 to 20 carbon atoms, and specific examples thereof include a phenylthio group and a naphthylthio group, but are not limited thereto. Absent.
  • 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.
  • the alicyclic heterocyclic thio group and aromatic heterocyclic thio group which may have as a substituent are those having the alicyclic heterocyclic group and aromatic heterocyclic group shown above as the heterocyclic portion. Can be mentioned.
  • the various groups that may be present as the substituent may further have a substituent.
  • One or a plurality of substituents may be present, and when a plurality of substituents are present, they may be the same or different from each other.
  • 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 use of inexpensive organic chloride is economically more advantageous.
  • there is no problem such as uneven distribution and difficulty in obtaining bromine which is a problem in organic bromides widely used in the preparation of Grignard reagents, and the need for a high-load disposal facility for industrialization. There is no problem such as.
  • the organic halide represented by the general formula I (R 1 -X 1 ) to be coupled may be a commercially available product or a product produced by a method known in the art. You can do it.
  • a dispersion in which sodium is dispersed in a dispersion solvent is a dispersion in which sodium is dispersed in an insoluble solvent as fine particles, or sodium is a liquid. In this state, it is dispersed in an insoluble solvent.
  • examples of sodium include metal sodium and alloys containing metal sodium.
  • the average particle diameter of the fine particles is preferably less than 10 ⁇ m, and particularly preferably less than 5 ⁇ m. The average particle diameter was represented by the diameter of a sphere having a projected area equivalent to the projected area obtained by image analysis of micrographs.
  • the dispersion solvent a solvent known in the art should 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.
  • Examples thereof include aromatic solvents such as xylene and toluene, normal paraffin solvents such as normal decane, heterocyclic compound solvents such as tetrahydrothiophene, or mixed solvents thereof.
  • SD preferably has an activity such that the yield of phenyl sodium with respect to the added chlorobenzene is 99.0% or more when reacted in a reaction solvent at 2.1 molar equivalents or more with respect to chlorobenzene.
  • an organic sodium compound can be synthesized more efficiently from an organic halide at a low cost, and the subsequent coupling reaction can proceed smoothly.
  • it is preferable to store in a container having a high gas barrier property such as a glass vial.
  • a container having a low gas barrier property in which case it is used immediately after the production of SD, for example, within a few weeks, preferably within 3 weeks.
  • a solvent known in the technical field can be used as long as the reaction between the organic halide and SD is not inhibited.
  • 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.
  • a cyclic ether solvent is preferable, and tetrahydrofuran (hereinafter sometimes abbreviated as “THF”) and the like can be preferably used.
  • THF tetrahydrofuran
  • the paraffinic solvent cyclohexane, normal hexane, normal decane and the like are particularly preferable.
  • aromatic solvent xylene, toluene, benzene and the like are preferable, and halogenated aromatic solvents such as chlorobenzene and fluorobenzene can be used.
  • amine solvent ethylenediamine or the like can be preferably used. Tetrahydrothiophene or the like can be used as the heterocyclic compound solvent. These may be used alone or in combination of two or more as a mixed solvent.
  • the dispersion solvent and the reaction solvent described above may be the same type or different types.
  • the reaction temperature in step 1 is not particularly limited when a paraffin solvent is used as the solvent, and can be appropriately set depending on the type and amount of the organic halide, SD and 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. Since the boiling point under atmospheric pressure is higher than the boiling point, the reaction temperature can be set at a high temperature. 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. It is not necessary to provide a temperature control means for special heating or cooling, but a temperature control means may be provided if necessary.
  • the reaction time in step 1 is not particularly limited, and may be set as appropriate according to the type and amount of organic halide, SD, and reaction solvent, reaction pressure, reaction temperature, and the like.
  • the reaction is usually performed for 15 minutes to 24 hours, preferably 20 minutes to 6 hours.
  • Step 1 is suitable for carrying out under normal pressure conditions in the atmosphere because reagents such as SD and reaction solvent can be stably handled in the atmosphere.
  • phenyl sodium which is a preferred example of the organic sodium compound represented by the general formula II (R 1 -Na) obtained, is highly active and is protonated by moisture when air is mixed in, even if necessary.
  • it may be performed in an inert gas atmosphere filled with argon gas, nitrogen gas or the like.
  • the organic sodium compound represented by the general formula II (R 1 -Na) obtained by the step 1 is obtained by replacing the halogen atom of the organic halide represented by the general formula I (R 1 -X 1 ) with sodium. Accordingly, in the organic sodium compound represented by 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. Further, the organic halide remaining unreacted may be collected and used again for the reaction in Step 1. Moreover, you may carry out in inert gas atmosphere filled with argon gas, nitrogen gas, etc. similarly to the time of production
  • Step 2 in the organic compound coupling method according to the present embodiment includes an organic sodium compound represented by the general formula II (R 1 -Na) obtained by Step 1 and an organic chloride represented by the general formula III (R 2 -Cl).
  • an organic chloride represented by the general formula III (R 2 —Cl) is an organic compound containing a covalently bonded chlorine atom, and is another compound to be coupled in the organic compound coupling method according to the present embodiment. is there.
  • step 2 the organic sodium compound and organic chloride obtained in step 1 are coupled in the presence of a reaction catalyst containing a palladium catalyst, and the organic chloride is coupled as an object to be coupled to the organic sodium compound. By using it, the coupling reaction proceeds smoothly.
  • other organic halides such as organic bromides other than organic chlorides are used as coupling targets, a transmetal reaction occurs between the organic sodium compound and the organic bromide, and the coupling reaction is There is a problem that it does not proceed smoothly.
  • R 2 is an aliphatic hydrocarbon group, alicyclic hydrocarbon group, or alicyclic heterocyclic ring which may have a substituent that does not react with sodium.
  • the aliphatic hydrocarbon group may be linear or branched, and may be saturated or unsaturated. Moreover, there is no restriction
  • Examples of the aliphatic hydrocarbon group include, but are not limited to, an alkyl group, an alkenyl group, and an alkynyl group, preferably having 1 to 20 carbon atoms, particularly preferably 3 to 20 carbon atoms. .
  • alkyl group methyl group, ethyl group, propyl group, butyl 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, 2-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-propylpropyl, n-heptyl, isoheptyl, s-heptyl, t-heptyl
  • alkenyl group examples include, but are not limited to, an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, and an octenyl group.
  • alkynyl group examples include, but are not limited to, ethynyl group, propynyl group, butynyl group, pentynyl group, heptynyl group, octynyl group and the like.
  • alicyclic hydrocarbon group there is no particular limitation on the number of ring members, regardless of whether the bonds between ring constituent atoms are saturated or unsaturated. In addition, not only a single ring but also those having a ring assembly such as a condensed ring or a spiro ring are 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 carbon atoms. Examples thereof include several to 10 and particularly preferably 4 to 7 cycloalkenyl groups.
  • cycloalkyl group examples include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
  • cycloalkenyl group examples include, but are not limited to, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group.
  • An alicyclic heterocyclic group is a non-aromatic heterocyclic group having one or more heteroatoms as ring-constituting atoms. Not only a single ring but also those having a ring assembly such as a condensed ring or a spiro ring are included. There is no particular limitation on the number of ring members, regardless of whether the bonds between ring atoms are saturated or unsaturated.
  • the hetero atom is not particularly limited as long as it does not react with sodium as a ring atom.
  • the number of heteroatoms is not particularly limited, and the position of the heteroatoms is not limited.
  • the hetero atom is preferably exemplified by an oxygen atom, a nitrogen atom, a sulfur atom and the like.
  • an alicyclic heterocyclic group having preferably 2 to 7 carbon atoms, particularly preferably 2 to 5 carbon atoms, and preferably 1 to 5 carbon atoms, particularly preferably 1 to 3 carbon atoms. Is mentioned.
  • it when it has a some hetero atom, it may be the same kind of atom or a different kind of atom.
  • alicyclic heterocyclic group examples include a monocyclic four-membered azetidinyl group, a five-membered pyrrolidinyl group, a six-membered piperidyl group, a nitrogen-containing alicyclic heterocyclic group such as a piperazinyl group, Oxygen-containing cycloaliphatic heterocyclic groups such as 3-membered oxiranyl group, 4-membered oxetanyl group, 5-membered tetrahydrofuryl group, 6-membered tetrahydropyranyl group, monocyclic ring Sulfur-containing alicyclic heterocyclic groups such as five-membered tetrahydrothiophenyl groups, nitrogen-containing oxygen alicyclic heterocyclic groups such as monocyclic six-membered morpholinyl groups, monocyclic six-membered cyclic groups Examples thereof include, but are not limited to, nitrogen-containing sulfur alicyclic heterocyclic group
  • the aromatic hydrocarbon group is not particularly limited as long as it has an aromatic ring. Not only a single ring but also those having a ring assembly such as a condensed ring or 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.
  • aromatic hydrocarbon group examples include a monocyclic six-membered phenyl group, a bicyclic naphthyl group, a pentarenyl group, an indenyl group, an azulenyl group, a tricyclic biphenylenyl group, an indacenyl group, an acenaphthylenyl group, and a fluorenyl group.
  • phenalenyl group, phenanthryl group, anthryl group, etc. tetracyclic fluoranthenyl, aceantrirenyl group, triphenylenyl group, pyrenyl group, naphthacenyl group, etc., pentacyclic perylenyl group, tetraphenylenyl, etc., hexacyclic Examples include, but are not limited to, a pentacenyl group of the formula, a heptacyclic rubicenyl group, a coronenyl group, a heptacenyl group, and the like. Particularly preferred is a phenyl group.
  • An aromatic heterocyclic group is an aromatic heterocyclic group having one or more heteroatoms as ring-constituting atoms. Not only a single ring but also those having a ring assembly such as a condensed ring or 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 atom.
  • the number of heteroatoms is not particularly limited, and the position of the heteroatoms is not limited.
  • the hetero atom is preferably exemplified by an oxygen atom, a nitrogen atom, a sulfur atom and the like.
  • an aromatic heterocyclic group having 1 to 5 carbon atoms, particularly preferably 3 to 5 carbon atoms, and preferably 1 to 4 carbon atoms, particularly preferably 1 to 3 carbon atoms.
  • it may be the same kind of atom or a different kind of atom.
  • monocyclic aromatic heterocyclic groups include nitrogen-containing aromatics such as five-membered cyclic pyrrolyl, pyrazolyl, pyridyl, imidazolyl, six-membered cyclic pyrazinyl, pyrimidinyl, pyridazinyl, etc.
  • An oxygen-containing aromatic heterocyclic group such as an aromatic group, a five-membered furyl group, an oxygen-containing aromatic heterocyclic group such as a five-membered thienyl group, a five-membered oxazolyl group, an isoxazolyl group
  • examples thereof include, but are not limited to, nitrogen-containing oxygen aromatic heterocyclic groups such as furazanyl groups, nitrogen-containing sulfur aromatic heterocyclic groups such as five-membered cyclic thiazolyl groups and isothiazolyl groups.
  • polycyclic aromatic heterocyclic group examples include bicyclic indolizinyl group, isoindolyl group, indolyl group, indazolyl group, purinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, and cinnolinyl.
  • the aliphatic hydrocarbon group, alicyclic hydrocarbon group, alicyclic heterocyclic group, aromatic hydrocarbon group, and aromatic heterocyclic group may have a substituent.
  • One or a plurality of substituents may be present, and when a plurality of substituents are present, they may be the same or different from each other.
  • substituents include an optionally substituted aliphatic hydrocarbon group, alicyclic hydrocarbon group, alicyclic heterocyclic group, aromatic hydrocarbon group, aromatic heterocyclic group, alkoxy group, cycloalkoxy Group, aryloxy group, aralkyloxy group, alicyclic heterocyclic oxy group, aromatic heterocyclic oxy group, alkylthio group, cycloalkylthio group, arylthio group, aralkylthio group, alicyclic heterocyclic thio group, aromatic Examples include, but are not limited to, heterocyclic thio groups, alkylamino groups, cycloalkylamino groups, arylamino groups, aralkylamino groups, alicyclic heterocyclic amino groups, aromatic heterocyclic amino groups, and acyl groups.
  • substituents examples include the same ones as shown in the above R 1 section.
  • the various groups that may be present as the substituent may further have a substituent.
  • One or a plurality of substituents may be present, and when a plurality of substituents are present, they may be the same or different from each other.
  • substituent examples include the same as those described above.
  • the organic chloride represented by the general formula III (R 2 -Cl) to be coupled may be a commercially available product or a product produced by a method known in the art. It's okay.
  • the reaction of step 2 proceeds in the presence of a reaction catalyst.
  • the reaction catalyst includes a palladium catalyst, and includes those represented by the following general formula IV.
  • R a , R b , R c and R d are each independently hydrogen, methyl group, ethyl group, propyl group (2-propyl (isopropyl) group), pentyl group (3- A pentyl group), a heptyl group (4-heptyl group), a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, or a fluoro group.
  • R a , R b , R c , and R d may be all or part of the same, or all may be different from each other.
  • a broken line is a double bond or a single bond.
  • the palladium catalyst represented by the general formula IV is a nitrogen-containing heterocyclic carbene (NHC) palladium complex, and includes a catalyst called Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation (PEPPSI (trademark)).
  • the reaction catalyst can contain an auxiliary component having a function of increasing the catalytic activity of the palladium catalyst, for example, a cocatalyst.
  • a cocatalyst examples include boron halide, borate ester, and metal halide.
  • Specific examples of the boron halide include boron trichloride, boron trifluoride, boron tribromide, boron triiodide, and the like.
  • B (OR e 2 ) 3 As the borate ester, specifically, B (OR e 2 ) 3 [where R e is an aliphatic hydrocarbon group such as an alkyl group having 1 to 20 carbon atoms, an alicyclic hydrocarbon group, Compounds such as trimethyl borate, triethyl borate, tri-n-propyl borate, triisopropyl borate, tri-n-butyl borate, triisobutyl borate, and the like.
  • R e is an aliphatic hydrocarbon group such as an alkyl group having 1 to 20 carbon atoms, an alicyclic hydrocarbon group, Compounds such as trimethyl borate, triethyl borate, tri-n-propyl borate, triisopropyl borate, tri-n-butyl borate, triisobutyl borate, and the like.
  • metal halides include zinc chloride, zinc bromide, zinc iodide, zinc fluoride, magnesium chloride, magnesium bromide, magnesium iodide, magnesium fluoride, aluminum chloride, aluminum bromide, and indium chloride. Can be mentioned. However, it is not limited to these, and any known compound can be included as long as it has a function of increasing the catalytic activity of the palladium catalyst.
  • a ligand such as tetramethylethylenediamine (hereinafter abbreviated as “TMEDA”) can be used.
  • Step 2 may be performed by adding an organic chloride and a reaction catalyst to the reaction product obtained in Step 1, or after purifying the reaction product obtained in Step 1 by a purification means known in the art.
  • the reaction may be performed by adding an organic chloride and a reaction catalyst in the presence of a reaction solvent.
  • the reaction solvent the same solvent 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 the type and amount of the organic sodium compound obtained in the reaction in step 1, the organic chloride added in this step, SD, and the reaction solvent. Further, it can be set as appropriate 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. Since the boiling point under atmospheric pressure is higher than the boiling point, the reaction temperature can be set at a high temperature. 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.
  • a temperature control means for special heating or cooling, but a temperature control means may be provided if necessary.
  • a temperature control means may be provided if necessary.
  • the reaction is performed at a low temperature, preferably 0 to 20 ° C. It is good to do.
  • the reaction time in step 2 is not particularly limited, and the type and amount of the organic sodium compound obtained in the reaction in step 1, the organic chloride added in this step, SD, and the reaction solvent, the reaction pressure, the reaction temperature, etc. What is necessary is just to set suitably according to.
  • the reaction is performed for 5 minutes to 2 hours, preferably 10 minutes to 1 hour.
  • the step 2 is suitable to be performed under atmospheric pressure conditions. ing. However, you may carry out in inert gas atmosphere filled with argon gas, nitrogen gas, etc. as needed, such as the kind of organic sodium compound obtained by reaction of the process 1.
  • Step 2 a coupling reaction of R 1 -Na + R 2 -Cl ⁇ R 1 -R 2 + NaCl occurs, and the compound represented by the general formula V (R 1 -R 2 ) as a coupling product is obtained.
  • the compound represented by the general formula V (R 1 -R 2 ) which is a coupling product is represented by R 1 of the organic sodium compound represented by the general formula II (R 1 -Na) and the general formula III (R 2 -Cl).
  • the organic chloride R 2 shown is a CC-bonded compound.
  • R 1 is same as R 1 in general the above formula I (R 1 -X 1) and the general formula II (R 1 -Na) in and, R 2 is the same as R 2 of the general above formula III (R 2 -Cl).
  • the amount of SD used can be appropriately set according to the type and amount of the organic halogen compound to be reacted with SD in Step 1 and the reaction solvent.
  • the reaction is carried out in such an amount that the molar ratio of organic halide: SD is 1: 2 or more, particularly preferably 1: 2 or more and 3 or less.
  • the organozinc compound can be synthesized with high efficiency and high purity.
  • the amount of substance of SD means the amount of substance in terms of alkali metal contained in SD.
  • the coupling product represented by the general formula V (R 1 -R 2 ) finally synthesized in the coupling method according to this embodiment may be purified by a purification means known in the art such as recrystallization. Good. Moreover, you may comprise so that the organic halide, organic sodium compound, organic chloride, etc. which remain
  • the organic compound coupling method according to this embodiment can obtain an organic sodium compound stably and efficiently by using SD, and can smoothly proceed with the subsequent coupling reaction.
  • SD which is easy to handle, it is economical because it does not require complicated chemical methods under mild conditions, and the coupling reaction can be performed easily and in a short time with a small number of steps.
  • Sodium is a technology with excellent sustainability because it is very widely distributed on the earth.
  • solid metallic sodium when solid metallic sodium is used, the efficiency is low at a reaction temperature of room temperature, and it is necessary to perform the reaction at a high temperature such as a melting point (98 ° C.) or higher of metallic sodium.
  • the coupling method of the organic compound of the present embodiment can smoothly proceed with the coupling reaction of the organic compound having various molecular structures, various technical fields such as synthesis of functional materials such as medical and agricultural chemicals and electronic materials. Can be used.
  • Example 1 Examination of synthesis conditions of organic sodium compounds using SD-1
  • reaction conditions such as the addition amount of SD, were examined about the synthesis
  • the yield of phenyl sodium was determined by the Na-TMP (sodium 2,2,6,6-tetramethylpiperidine) obtained by reacting the synthesized phenyl sodium with TMP (2,2,6,6-tetramethylpiperidine). Perigide) yield was calculated. Specifically, synthesized phenyl sodium and 1.0 molar equivalent of TMP were reacted at room temperature for 30 minutes, the resulting Na-TMP was reacted with fluorene, quenched with heavy water, and the quenched product was subjected to 1 H NMR. Measured with Subsequently, the ratio (%) of actually obtained Na-TMP to Na-TMP theoretically generated from the halogenated benzene added to the reaction system was calculated.
  • Na-TMP sodium 2,2,6,6-tetramethylpiperidine
  • FIG. 1 summarizes the reaction scheme, reaction conditions, and yield.
  • Na-TMP can be synthesized in a high yield of 99% or more by reacting SD with 2.2 molar equivalents or more, and organic sodium compounds can be synthesized in high yield. it can.
  • chlorobenzene it is understood that Na-TMP can be synthesized at a high yield of 99% or more by reacting SD with 2.1 molar equivalents or more, and the organic sodium compound can be synthesized in a high yield.
  • the SD was less than 2.0 molar equivalents, it was found that the wurtz reaction, which is a side reaction, was induced and the yield of the organic sodium compound was lowered.
  • Example 2 Study on synthesis conditions of organic sodium compounds using SD-2
  • the synthesis of 4- n nonylphenyl sodium 2 as an organic sodium compound was examined under the synthesis conditions summarized in FIG. 2 and the obtained 4- n nonylphenyl sodium 2 was used to obtain an organic zinc compound.
  • Synthesis of 4-normal ( n ) nonylphenylzinc chloride 4 was investigated.
  • the synthesized 4- n nonylphenyl sodium 2 is evaluated by quenching 4- n nonylphenyl sodium 2 with heavy water and measuring the quenched product 3 by gas chromatography (hereinafter abbreviated as “GC”). It went by. This utilizes the fact that sodium of 4- n nonylphenyl sodium 2 is replaced by deuterium. As a yield, a ratio (%) of the actually obtained product 3 to the product 3 that can theoretically be produced 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 but also hydrogenated products.
  • the obtained product 3 was measured by 1 H NMR, and the deuterium ratio (D ratio (%)) relative to the product 3 was calculated. Moreover, 1-chloro-4- n nonylbenzene 1 remaining unreacted is measured by GC to calculate the unreacted rate (%), and 1-chloro-4- n nonylbenzene 1 is coupled to each other. In order to evaluate whether or not the reaction was induced, the production of the coupling product (Ar—Ar) was measured by 1 H NMR, and the Ar—Ar production rate (%) was calculated.
  • the synthesized 4- n nonylphenyl zinc chloride 4 was evaluated by quenching with heavy water and measuring the quenched product 5 by GC and 1HNMR, as described above.
  • organic sodium compounds such as aryl sodium can be synthesized in high yield and high purity, and the Wurtz reaction, which is a side reaction. It can be understood that the induction of can also be effectively suppressed.
  • Example 3 Synthesis of organic sodium compound using SD and examination of reaction conditions for coupling reaction with organic chloride
  • synthesis of organic sodium compound using SD and organic sodium compound synthesized using SD The reaction conditions were examined for the coupling reaction between chlorobenzene and organic chloride (see FIG. 3).
  • Experiment numbers 2-5) Experiment Nos. 2 to 5 examine the reaction conditions for the synthesis of an organic sodium compound using SD as in Experiment No. 1 and the coupling reaction between the organic sodium compound synthesized using SD and the organic chloride. In these experiments, however, the influence of the cocatalyst on the coupling reaction was also examined.
  • Example 4 Examination of reaction conditions for coupling reaction between organic sodium compound synthesized using SD and organic halide
  • coupling reaction between organic sodium compound synthesized using SD and organic bromide or organic chloride The reaction conditions were examined for (see FIG. 4).
  • 2,6-dimethoxyphenyl sodium which is an organic sodium compound synthesized according to the above example using SD, was 1.5 molar equivalent, 1 molar equivalent (0.25 mmol) of 1-bromonaphthalene, an organic bromide, and a palladium catalyst. 5 mol% of a certain Pd-PEPPSI (trademark) -IPent Cl was added and reacted at 30 ° C. for 1 hour. By this reaction, an organic sodium compound and an organic bromide were coupled to obtain 1- (2,6-dimethoxyphenyl) naphthalene as a coupling product (1a).
  • Example number 2 In Experiment number 2, a coupling reaction between an organic sodium compound and an organic bromide was examined in the same manner as in Example 1a except that 2-bromonaphthalene was used as the organic bromide (Experiment No. 2a). Further, a coupling reaction between an organic sodium compound and an organic chloride was examined in the same manner as in Example 1b except that 2-chloronaphthalene was used as the organic chloride (Experiment No. 2b). The results are shown in FIG. As shown in FIG. 4, in both Experiment No. 2a and Experiment No. 2b, 2- (2,6-dimethoxyphenyl) naphthalene was obtained as a coupling product, and Experiment No.
  • Experiment No. 3 examines the coupling reaction between an organic sodium compound and an organic chloride in the same manner as in Example 1b except that 2-methoxyphenyl sodium is used as the organic sodium compound and 2-chloronaphthalene is used as the organic chloride. went. The results are shown in FIG. As shown in FIG. 4, 2- (2-methoxyphenyl) naphthalene was obtained as a coupling product, and the yield was 81%. Accordingly, it can be understood that the coupling reaction can proceed smoothly as in the case of the experiment numbers 1-2.
  • Experiment No. 4 is similar to Example 1b except that 2-benzofuranyl sodium was used as the organic sodium compound and 1-chloro-4- (trifluoromethyl) benzene was used as the organic chloride. A chloride coupling reaction was examined. The results are shown in FIG. As shown in FIG. 4, 2- (4- (trifluoromethyl) phenyl) benzofuran was obtained as a coupling product, and the yield was 78%. Thus, it can be understood that the coupling reaction can proceed smoothly as in Experiment Nos. 1 to 3.
  • Example No. 5 In Experiment No. 5, a coupling reaction between an organic sodium compound and an organic chloride was examined in the same manner as in Example 1b except that 3-dimethylaminophenyl sodium was used as the organic sodium compound. The results are shown in FIG. As shown in FIG. 4, 1- (3-dimethylaminophenyl) naphthalene was obtained as a coupling product, and the yield was 73%. Thus, it can be understood that the coupling reaction can proceed smoothly as in Experiment Nos. 1 to 4.
  • Experiment No. 6 is the same as in Example 1b except that 3-dimethylaminophenyl sodium was used as the organic sodium compound and 1-chloroisoquinoline was used as the organic chloride. (6a).
  • the case where the coupling reaction of Experiment No. 6a was performed in the presence of the cocatalyst ZnCl 2 ⁇ TMEDA (10 mmol%) was also examined (6b). The results are shown in FIG.
  • 1- (3-dimethylaminophenyl) isoquinoline is obtained as a coupling product in both Experiment No. 6a and Experiment No. 6b, and is a coupling reaction in the absence of ZnCl 2 ⁇ TMEDA.
  • Example number 7 In Experiment number 7, a coupling reaction between an organic sodium compound and an organic chloride was examined in the same manner as in Example 1b except that 4-methylphenyl sodium was used as the organic sodium compound (7a). It was also examined having been subjected to the coupling reaction of Experiment No. 7a in the presence of a co-catalyst ZnCl 2 ⁇ TMEDA (10 mmol% ) (7b). Furthermore, what performed the coupling reaction of experiment number 7b on the 2.5 mmol scale was also examined (7c). The results are shown in FIG. As shown in FIG. 4, all of Experiment No. 7a, Experiment No. 7b, and Experiment No.
  • Experiment No. 8 is a coupling reaction between an organic sodium compound and an organic chloride in the same manner as in Example 1b except that 4-methylphenyl sodium was used as the organic sodium compound and 1-chloro-4-methoxybenzene was used as the organic chloride. (8a). It was also examined having been subjected to the coupling reaction of Experiment No. 8a in the presence of a co-catalyst ZnCl 2 ⁇ TMEDA (10 mmol% ) (8b). The results are shown in FIG. As shown in FIG.
  • the present invention is particularly useful in all technical fields using organic compound coupling methods and coupling products obtained by such coupling methods, particularly in the fields of medical and agricultural chemicals and electronic materials.

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Abstract

La présente invention concerne une technologie capable de coupler des composés organiques de manière efficace, peu coûteuse, simple, et en un court laps de temps par un petit nombre d'étapes. Le procédé de couplage de composés organiques comprend une étape consistant à : faire réagir, dans un solvant de réaction, un halogénure organique et une dispersion dans laquelle du sodium est dispersé dans un solvant de dispersion pour obtenir un composé organique de sodium ; et faire réagir un composé de sodium organique résultant et un chlorure organique en présence d'un catalyseur de réaction comprenant un catalyseur au palladium ayant un ligand carbène hétérocyclique contenant de l'azote (NHC) pour obtenir un produit de couplage.
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