Method for producing aromatic compounds containing an ethynyl group.

Abstract

The present invention addresses the problem of industrially and inexpensively providing an aromatic compound having an ethynyl group using Sonogashira coupling, with chloronitrobenzene, the raw materials of which are inexpensive, being used as a starting raw material.　The present invention is a method for reacting a nitrobenzene and an ethynyl compound through coupling to produce an aromatic compound having an ethynyl group, wherein: the nitrobenzene is represented by general formula (1); the ethynyl compound is represented by general formula (2); the aromatic compound having an ethynyl group is represented by general formula (3); and the coupling reaction is carried out in an organic solvent having a nitrogen atom in the chemical structure thereof, in the presence of an amine, palladium carbon, a phosphorus compound, and a copper compound. In formulas (1), (2), and (3), A represents hydrogen or fluorine, R represents a trialkylsilyl group or a hydrocarbon group having a hydroxyl group, and n represents an integer of 1-3.

Description

[Technical Field]

[0001] The present invention relates to a method for producing aromatic compounds having an ethynyl group. [Background technology]

[0002] Ethynylbenzene compounds containing a nitro group can be easily converted to ethynylaniline compounds containing an amino group by reducing the nitro group. Ethynylaniline compounds are used as raw materials for pharmaceuticals and for end encapsulation of electronic materials. They are very important compounds because they contain an amino group that can be converted to an amide group, an imide group, etc., and an ethynyl group that is polymerizable and is expected to interact with various metals (see, for example, Patent Documents 1 and 2).

[0003] These ethynylbenzene compounds containing a nitro group are generally known to be synthesized using a palladium-catalyzed Sonogashira coupling reaction between an aromatic halogen compound containing a nitro group and a compound containing an ethynyl group. Commonly used as starting materials are iodonitrobenzene containing iodine and bromonitrobenzene containing bromine (see, for example, Non-Patent Documents 1 and 2).

[0004] However, aromatic halogen compounds containing iodine or bromine are expensive, highly toxic to humans, and difficult and costly to treat after coupling reactions. For these reasons, there was a desire to use inexpensive and readily available aromatic compounds containing chlorine groups as raw materials.

[0005] In typical coupling reactions between 4-bromonitrobenzene and trimethylsilylacetylene, examples have been reported using triethylamine, copper iodide, and dichlorobis(triphenylphosphine)palladium as a palladium catalyst (see, for example, Patent Documents 3 and 4). However, dichlorobis(triphenylphosphine)palladium, used as a palladium catalyst, is an expensive metal coordination catalyst with a phosphorus compound coordinated to it, is easily decomposed in water, and is difficult to handle industrially. Furthermore, with this metal coordination catalyst, the coupling reaction does not proceed with the less expensive and less reactive chloronitrobenzene, resulting in the problem that aromatic compounds containing the desired ethynyl group cannot be synthesized.

[0006] On the other hand, there have been reports of synthesizing aromatic compounds having a desired ethynyl group by coupling 3-chloronitrobenzene and trimethylsilylacetylene (see, for example, Patent Document 5). However, this coupling reaction is a special case in which hexabis(tricyclo[3,3,1,13,7]deca-1-yl)phosphine, which has two special adamantane skeletons, is used as the phosphorus ligand for palladium acetate, a palladium catalyst. This makes it difficult to obtain or use in general, and its application to industrial production is challenging.

[0007] Therefore, there was a need for a method to produce aromatic compounds having an ethynyl group that could undergo a simple and inexpensive coupling reaction using inexpensive chloronitrobenzene. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Chinese Patent No. 103183722 Specification [Patent Document 2] Japanese Patent Publication No. 2014-178400 [Patent Document 3] Chinese Patent No. 103183722 Specification [Patent Document 4] U.S. Patent No. 7695912 Patent Document 5 Specification of China Patent No. 101195641 Non-Patent Document

[0009] Non-Patent Document 1 Chemistry-A European Journal, 2018, 24(15), 3893-3901 Non-Patent Document 2 Asian Journal of Organic Chemistry, 2021, 10(5), 1153-1160 Summary of the Invention Problem to be Solved by the Invention

[0010] An object of the present invention is to produce an aromatic compound having an ethynyl group at a high yield via a Sonogashira coupling reaction using an inexpensive aromatic compound having chlorine and a nitro group as a raw material. Means for Solving the Problem

[0011] The present invention relates to a method for producing an aromatic compound having an ethynyl group by subjecting chloronitrobenzene and an ethynyl compound to a coupling reaction, wherein the nitrobenzene is represented by the following general formula (1), the ethynyl compound is represented by the following general formula (2), and the aromatic compound having an ethynyl group is represented by the following general formula (3), and the coupling reaction is carried out in an organic solvent having a nitrogen atom in its chemical structure in the presence of an amine, palladium on carbon, a phosphorus compound, and a copper compound, this being the method for producing the aromatic compound having an ethynyl group.

[0012] [Chemical Formula]

[0013] [Chemical Formula]

[0014]

Chemical Formula

[0015] In the formula, A represents hydrogen or fluorine, R represents a hydrocarbon group having a hydroxyl group or a trialkylsilyl group, and n represents an integer of 1 to 3. [[ID=11】Effects of the Invention】

[0016] The method for producing an aromatic compound having an ethynyl group of the present invention uses inexpensive chloronitrobenzene as a starting material, and can industrially provide the aromatic compound having an ethynyl group at a lower cost. [[ID=18】Mode for Carrying Out the Invention】

[0017] Hereinafter, details of the production method of the present invention will be described.

[0018] In the method for producing an aromatic compound having an ethynyl group of the present invention, a coupling reaction is carried out between nitrobenzene and an ethynyl compound.

[0019] As the nitrobenzene, one represented by the following general formula (1) is used.

[0020]

Chemical Formula

[0021] In the formula, A represents hydrogen or fluorine, and n represents an integer of 1 to 3.

[0022] Examples of the nitrobenzene include 4-chloronitrobenzene, 3-chloronitrobenzene, 2-chloronitrobenzene, 1-chloro-2,4-dinitrobenzene, 3,4-dinitrochlorobenzene, 2,4,6-trinitrochlorobenzene (also known as 2-chloro-1,3,5-trinitrobenzene) and the like.

[0023] In particular, chloronitrobenzene represented by the following general formula (4), that is, chloronitrobenzene with one nitro group attached, is preferred because the raw materials can be obtained inexpensively.

[0024] [ka]

[0025] In the formula, A represents hydrogen or fluorine.

[0026] Preferred examples of chloronitrobenzene represented by the above general formula (4) include 4-chloronitrobenzene, 3-chloronitrobenzene, and 2-nitrochlorobenzene.

[0027] Furthermore, a coupling reaction can also be easily carried out with chlorofluoronitrobenzene, in which a fluorine group is bonded to the benzene ring. Preferably, the chlorofluoronitrobenzene has one nitro group bonded to the benzene ring, and examples include 1-chloro-2-fluoro-4-nitrobenzene, 1-chloro-4-fluoro-2-nitrobenzene, 3-chloro-4-fluoronitrobenzene, 4-chloro-2-fluoronitrobenzene, 5-chloro-2-fluoronitrobenzene, and 2-chloro-4-fluoronitrobenzene.

[0028] As the ethynyl compound, the compound represented by the following general formula (2) is used.

[0029] [ka]

[0030] In the formula, R represents a hydrocarbon group having a hydroxyl group, or a trialkylsilyl group.

[0031] When R is a hydrocarbon group having a hydroxyl group, the ethynyl compound is preferably one represented by the following general formula (5).

[0032]

Chemical Formula

[0033] In formula (5), R 1 and R 2 each represent a hydrogen atom or a hydrocarbon group. Further, R 1 and R 2 may be the same as or different from each other. R 1 and R 2 are preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and examples thereof include hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, n-pentyl group and the like.

[0034] Examples of the ethynyl compound represented by the general formula (5) include 2-propen-1-ol, 2-methyl-3-butyn-2-ol, 3-butyn-2-ol, 3-methyl-4-pentyn-3-ol, 4-pentyn-3-ol, 4-methyl-5-hexyn-4-ol, 5-hexyn-4-ol, and the like.

[0035] Further, when R in the general formula (2) is a trialkylsilyl group, the ethynyl compound is preferably a compound represented by the following general formula (6).

[0036]

Chemical Formula

[0037] In formula (6), R 1 , R 2 , and R 3 each represent a hydrocarbon group. Further, R 1 , R 2 , and R 3 may be the same as or different from each other. R 1 , R 2 , and R 3The group is preferably an alkyl group having 1 to 5 carbon atoms, such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, or n-pentyl group. Examples of ethynyl compounds represented by general formula (6) include trimethylsilylacetylene, triethylsilylacetylene, triisopropylsilylacetylene, and the like.

[0038] Furthermore, due to their ease of industrial availability, 2-methyl-3-butyne-2-ol, 3-butyne-2-ol, 2-propene-1-ol, and trimethylsilylacetylene are more preferred as the ethynyl compounds.

[0039] The amount of the ethynyl compound used is preferably 1.0 equivalent to 3.0 equivalents relative to the chlorine of the nitrobenzene. Using an amount of 1.0 equivalent or more allows for a more efficient coupling reaction. Furthermore, using an amount of 3.0 equivalents or less, more preferably 2.0 equivalents or less, prevents the reaction of excess ethynyl compounds with each other to produce an excess by-product of an ethynyl compound dimer represented by the following general formula (7).

[0040] [ka]

[0041] In formula (7), R represents a hydrocarbon group having a hydroxyl group or a trialkylsilyl group.

[0042] Examples of compounds represented by general formula (7) include 2,7-dimethyl-octa-3,5-diyne-2,7-diol and 2,4-hexadiyne-1,6-diol.

[0043] The aforementioned organic solvent having a nitrogen atom in its chemical structure can be used as the reaction solvent, and the palladium-carbon described later can be used as the catalyst to carry out the Sonogashira coupling reaction with chloronitrobenzenes.

[0044] The organic solvents are preferably N,N-dimethylacetamide, dimethylformamide, and N-methyl-2-pyrrolidone, with N,N-dimethylacetamide being particularly preferred due to its high reactivity.

[0045] The aforementioned organic solvent is preferably used in an amount of 3 to 10 times the mass of the nitrobenzene, and more preferably in an amount of 3 to 7 times the mass, because it is necessary to stir the chloroamine salt produced in the Sonogashira coupling reaction in a slurry form. By using the aforementioned organic solvent in an amount of 3 times the mass or more the nitrobenzene, the excessive by-production of the compound represented by the general formula (7) can be suppressed.

[0046] The aforementioned amine can trap halogens (chlorine) produced as by-products in the Sonogashira coupling reaction.

[0047] The amines are preferably alkylamines, and tertiary amines such as trimethylamine, triethylamine, tri-n-propylamine, and tri-n-butylamine, or secondary amines such as diisobutylamine, diisopropylamine, and diisobutylamine are preferred. Furthermore, triethylamine, diisopropylamine, and diisobutylamine are more preferred because they are inexpensive, readily available, have low boiling points, and can be removed by concentration.

[0048] The amount of amine added is preferably 1.0 to 3.0 equivalents, and more preferably 1.0 to 2.0 equivalents, relative to the chlorine of the nitrobenzene.

[0049] The aforementioned palladium-carbon can be used as a catalyst, and the aforementioned organic solvent can be used as the reaction solvent to carry out a Sonogashira coupling reaction with chloronitrobenzenes.

[0050] The aforementioned palladium-carbon is prepared by dispersing and supporting zero-valent palladium on activated carbon as a support, and is also called palladium carbon. Palladium-carbon can be used in both dry (without water) and wet (with water) forms. Since palladium-carbon easily ignites in air, it is industrially preferable to use the wet form. The type of palladium-carbon affects the reactivity of the Sonogashira coupling reaction, and commercially available palladium-carbon manufactured by N.E. Chemcat is particularly preferred due to its high reactivity. Among the palladium-carbons manufactured by N.E. Chemcat, Type NE, Type K, and Type E, which have particularly high reaction yields, are even more preferred. Type K and Type E are especially preferable because they allow for a smaller amount of palladium-carbon to be used.

[0051] Since palladium carbon is an expensive catalyst, its concentration is preferably 1.0 mol% or less relative to the number of moles of nitrobenzene, and even more preferably 0.5 mol% or less, which allows for lower usage and cheaper production.

[0052] As the phosphorus compound, organophosphorus compounds are preferred, and hydrocarbon phosphine compounds such as triphenylphosphine, trimethylphosphine, triethylphosphine, and tri-n-propylphosphine, which are readily available, are preferred. Triphenylphosphine is particularly preferred because it is generally inexpensive and readily available, and easy to handle as a granular powder.

[0053] The amount of the phosphorus compound used is preferably 4.0 equivalents or more relative to the palladium carbon, and more preferably 4.0 to 8.0 equivalents for effectively forming the palladium complex.

[0054] The copper compound functions as a reaction initiator.

[0055] As the copper compound, copper iodide, which is readily available, is preferred.

[0056] The amount of copper compound used is preferably 1.0 to 5.0 equivalents, and more preferably 1.0 to 3.0 equivalents, relative to the palladium carbon.

[0057] Furthermore, adding an alkali metal salt to the reaction system is also preferable because it improves the reaction yield.

[0058] As the alkali metal salt, lithium salts, sodium salts, and potassium salts are particularly preferred due to their significant effect in improving yield, and among these, lithium chloride, lithium bromide, lithium iodide, sodium bromide, and potassium bromide are more preferred, and it is even more preferable that at least one selected from lithium chloride, lithium bromide, lithium iodide, and sodium bromide is used, as this promotes the reaction more effectively.

[0059] The amount of alkali metal salt added is preferably 0.1 to 2.0 equivalents relative to the chlorine in the raw material chloronitrobenzene, and more preferably 0.3 to 1.0 equivalents, which allows the Sonogashira coupling reaction to proceed more effectively.

[0060] In a preferred embodiment of the coupling reaction, the reaction proceeds by adding the organic solvent, the nitrobenzene as a raw material, the palladium carbon as a catalyst, the phosphorus compound as an additive, the copper compound as a reaction initiator, the amine as a halogen trap, and the alkali metal salt as necessary, to a reaction apparatus, and then adding or dropping the ethynyl compound and heating.

[0061] The reaction temperature is preferably 50°C or higher, and more preferably 70°C or higher, as this allows the reaction to proceed easily.

[0062] The reaction time for the coupling reaction is preferably 1 hour or more, and more preferably 2 hours or more.

[0063] The aforementioned coupling reaction can be tracked while being analyzed using gas chromatography or high-performance liquid chromatography.

[0064] After the coupling reaction is complete, the mixture is cooled, water is added to dissolve the amine salt, and the mixture is extracted with an organic solvent such as toluene or ethyl acetate to obtain the aromatic compound having the ethynyl group of the target compound.

[0065] In this process, the palladium-carbon used in the reaction can be easily removed by filtration.

[0066] After the above extraction, the target compound can be further extracted with a non-aqueous organic solvent such as ethyl acetate, washed several times with water, concentrated with the organic solvent, and then recrystallized with a solvent such as toluene to obtain an aromatic compound having the ethynyl group of the target compound with higher purity.

[0067] The aforementioned aromatic compounds having an ethynyl group are represented by the following general formula (3).

[0068] [ka]

[0069] In the formula, R represents a hydrocarbon group having a hydroxyl group or a trialkylsilyl group, and A represents hydrogen or fluorine. n is an integer from 1 to 3.

[0070] The R in general formula (3) is the same as the R in general formula (1), and therefore no explanation is given.

[0071] Examples of aromatic compounds having an ethynyl group represented by the general formula (3) are: 2-methyl-4-(4-nitrophenyl)-3-butynic-2-ol, 2-methyl-4-(3-nitrophenyl)-3-butyne-2-ol, 2-methyl-4-(2-nitrophenyl)-3-butynic-2-ol, 2-methyl-4-(2-nitrophenyl)-3-butynic-2-ol, 2-methyl-4-(2,4-dinitrophenyl)-3-butyne-2-ol, 2-methyl-4-(3,4-dinitrophenyl)-3-butyne-2-ol, 2-methyl-4-(2,4,6-trinitrophenyl)-3-butyne-2-ol, 4-(4-nitrophenyl)-3-butyne-2-ol, 4-(3-nitrophenyl)-3-butyne-2-ol, 4-(2-nitrophenyl)-3-butyne-2-ol, 3-(4-nitrophenyl)-2-propen-1-ol, 3-(3-nitrophenyl)-2-propen-1-ol, 3-(2-nitrophenyl)-2-propen-1-ol, 1-Nitro-4-[2-(trimethylsilyl)ethynyl]benzene, 1-Nitro-3-[2-(trimethylsilyl)ethynyl]benzene, 1,3-Dinitro-4-[2-(trimethylsilyl)ethynyl]benzene, 1,3-Dinitro-5-[2-(trimethylsilyl)ethynyl]benzene, 2-methyl-4-(5-fluoro-3-nitrophenyl)-3-butyne-2-ol, 2-methyl-4-(2-fluoro-4-nitrophenyl)-3-butyne-2-ol, 2-methyl-4-(2-fluoro-5-nitrophenyl)-3-butyne-2-ol, 2-methyl-4-(3-fluoro-4-nitrophenyl)-3-butyne-2-ol, 4-(5-fluoro-3-nitrophenyl)-3-butyne-2-ol, 4-(2-fluoro-4-nitrophenyl)-3-butyne-2-ol, 4-(2-fluoro-5-nitrophenyl)-3-butyne-2-ol, 4-(3-fluoro-4-nitrophenyl)-3-butyne-2-ol, 4-Fluoro-3-[2-(trimethylsilyl)ethynyl]-nitrobenzene, 5-Fluoro-3-[2-(trimethylsilyl)ethynyl]-nitrobenzene, 3-Fluoro-4-[2-(trimethylsilyl)ethynyl]-nitrobenzene, 2-Fluoro-4-[2-(trimethylsilyl)ethynyl]-nitrobenzene These are some examples.

[0072] The resulting aromatic compounds containing an ethynyl group can be easily modified by removing the ethynyl-terminal R group under alkaline conditions, and by reducing the nitro group to an amino group, ethynylaniline compounds useful as pharmaceuticals and electronic materials can be obtained. In this way, by performing Sonogashira coupling using inexpensive chloronitrobenzene as a starting material in a simple manner, it becomes possible to synthesize aromatic compounds containing an ethynyl group in an inexpensive and useful manner. [Examples]

[0073] The present invention will be specifically described below with reference to examples.

[0074] [Measurement and Evaluation Methods] (1) Reaction yield, dimer content The reaction yield (%) of the aforementioned aromatic compound having an ethynyl group and the content (area %) of the dimer of the ethynyl compound represented by the general formula (7) were analyzed using gas chromatography (GC) under the following conditions, and the fraction of the peak area of ​​each compound was measured relative to the total peak area minus the peak area of ​​the nitrogen-containing organic solvent.

[0075] Furthermore, the reaction yield of the aromatic compound having an ethynyl group is a numerical value indicating how far the coupling reaction from the starting material, nitrobenzene (referred to as "starting material" in the following calculation formula) to the target compound having an ethynyl group (referred to as "coupling product" in the following calculation formula) proceeded, and was calculated as follows. Reaction yield (%) = Area fraction of coupling compound / (Area fraction of coupling compound + Area fraction of remaining raw materials) × 100.

[0076] For example, in Example 1, according to GC analysis, the content rate of residual 4-chloronitrobenzene was 61.5%, the content rate of the target compound 2-methyl-4-(4-nitrophenyl)-3-butyn-2-ol was 18.8%, and the dimer content rate was 4.2%, so the reaction yield was calculated to be 23.4%. 18.8 / (18.8+61.5)×100=23.4 (%).

[0077] <GC Analysis Conditions> Column: DB-5 (0.25mm × 30m × 0.25μm) (Agilent J&W) Carrier gas: Helium Inlet temperature: 300°C Detector temperature: 300°C Column temperature: After holding at 50°C for 2 minutes, the temperature is raised at 10°C / min, and then held at 300°C for 3 minutes. Column flow rate: 3.65 mL / min Purge flow rate: 5.0 mL / min Split ratio: 20 Sample volume: 1 μL Sample preparation: Weigh 0.5 g of the sample into a 10 mL volumetric flask, and make up to the mark with acetonitrile.

[0078] The retention times of the compounds under the above conditions are as follows. 4-Chloronitrobenzene (4-CNB): 12.6 minutes 3-Chloronitrobenzene (3-CNB): 12.9 minutes 3-BAN (3-Bromoaniline): 14.1 minutes 2-Chloro-4-fluoronitrobenzene (2CFNB): 11.9 minutes 2-Methyl-4-(4-nitrophenyl)-3-butyn-2-ol (coupled product of 4-CNB): 19.8 minutes (m / z=205 from GC-MS analysis, identified as the coupled product by similarity search.) 2-Methyl-4-(3-nitrophenyl)-3-butyn-2-ol (coupled product of 3-CNB): 19.5 minutes (m / z=205 from GC-MS analysis, identified as the coupled product by similarity search.) 2-methyl-4-(5-fluoro-3-nitrophenyl)-3-buty-2-ol (coupling compound of 2CFNB): 17.8 min (GC-MS analysis revealed m / z=223; identified as a coupling compound by similarity search.) Dimer of 2-methyl-3-butyne-2-ol (2,7-dimethyl-octa-3,5-diyne-2,7-diol): 13.8 min (GC-MS analysis showed m / z=166, identified as a coupling compound by similarity search).

[0079] Furthermore, commercially available reagents were used in the experiment. In addition, palladium-carbon from N.E.ChemCAT was purchased as a commercially available reagent from Fujifilm Wako Pure Chemical Industries.

[0080] (2) Industrial judgment The determination from the perspective of industrial implementation was made according to the following criteria. S: The yield of the target compound is high, the amount of expensive palladium catalyst used is small, and the content of dimers, which are impurities, is also low. A: The content is relatively high, and the amount of dimers, which are impurities, is low. B: The target compound has been obtained, although the yield is low. C: The target compound has hardly been obtained.

[0081] [Example 1] In a 200 mL flask equipped with a stirrer and condenser, add 25 g of N-methyl-2-pyrrolidone (NMP) (5 times by mass / 4-CNB) as the organic solvent, 5.0 g of 4-chloronitrobenzene (4-CNB) (31.7 mmol) as the nitrobenzene, and 0.639 g of 5% palladium carbon (Pd / C; Type K, manufactured by N.E. Chemcat, Pd content 4.7% by mass, 55% by mass water) as the palladium catalyst. 0.127 mmol, 0.40 mol / 4-CNB) of triphenylphosphine, 0.166 g (0.634 mmol) of copper(I) iodide, and 4.82 g (47.6 mmol, 1.5 equivalents / 4-CNB) of diisopropylamine were added, and 5.34 g (63.5 mmol, 2.0 equivalents / 4-CNB) of 2-methyl-3-butyne-2-ol was added dropwise at 20-30°C. After the dropwise addition was complete, the mixture was placed in an oil bath and reacted at a reaction temperature of 110-115°C for 6 hours.

[0082] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-butyne-2-ol, was 23.4%, and the by-product, which is dimerized 2-methyl-3-butyne-2-ol, amounted to 4.2% by area.

[0083] [Example 2] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to dimethylacetamide (DMAc) 25 g (5 times the mass / 4-CNB) and the reaction time was changed to 7 hours.

[0084] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-butyne-2-ol, was 42.9%, and the by-product, which is dimerized 2-methyl-3-butyne-2-ol, accounted for 27.2% of the area.

[0085] [Example 3] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of DMAc (5 times the mass / 4-CNB), an additional 0.83 g of lithium bromide (LiBr) (9.52 mmol, 0.3 equivalents / 4-CNB) was added before dropwise addition, and the reaction time was changed to 4 hours.

[0086] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-butyne-2-ol, was 85.1%, and the by-product, which is dimerized 2-methyl-3-butyne-2-ol, accounted for 13.2% of the area.

[0087] [Example 4] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of DMAc (5 times the mass / 4-CNB), an additional 1.65 g of LiBr (19.0 mmol, 0.6 equivalents / 4-CNB) was added before dropwise addition, and the reaction time was changed to 4 hours.

[0088] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-butyne-2-ol, was 95.9%, and the by-product, which is dimerized 2-methyl-3-butyne-2-ol, accounted for 15.3 area%.

[0089] [Example 5] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of DMAc (5 times the mass / 4-CNB), an additional 0.807 g of lithium chloride (LiCl) (19.0 mmol, 0.6 equivalents / 4-CNB) was added before dropwise addition, and the reaction time was changed to 4 hours.

[0090] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-buty-2-ol, was 81.7%, and the by-product, which is dimerized 2-methyl-3-buty-2-ol, accounted for 7.9 area%.

[0091] [Example 6] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of DMAc (5 times the mass / 4-CNB), an additional 1.96 g of sodium bromide (NaBr) (19.0 mmol, 0.6 equivalents / 4-CNB) was added before dropwise addition, and the reaction time was changed to 4 hours.

[0092] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-butyne-2-ol, was 77.8%, and the by-product, which is dimerized 2-methyl-3-butyne-2-ol, accounted for 21.2 area percent.

[0093] [Example 7] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of DMAc (5 times the mass / 4-CNB), an additional 2.55 g of lithium iodide (LiI) (19.0 mmol, 0.6 equivalents / 4-CNB) was added before dropwise addition, and the reaction time was changed to 4 hours.

[0094] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-butyne-2-ol, was 93.1%, and the by-product, which is dimerized 2-methyl-3-butyne-2-ol, accounted for 12.5% ​​of the area.

[0095] [Example 8] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of DMAc (5 times the mass / 4-CNB), an additional 2.27 g of potassium bromide (KBr) (19.0 mmol, 0.6 equivalents / 4-CNB) was added before dropwise addition, and the reaction time was changed to 4 hours.

[0096] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-butyne-2-ol, was 49.1%, and the by-product, which is dimerized 2-methyl-3-butyne-2-ol, accounted for 10.7 area%.

[0097] [Example 9] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 10 g of DMAc (2 times the mass / 4-CNB), an additional 1.95 g of LiBr (19.0 mmol, 0.6 equivalents / 4-CNB) was added before dropwise addition, and the reaction time was changed to 4 hours.

[0098] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-buty-2-ol, was 88.6%, and the by-product, which is dimerized 2-methyl-3-buty-2-ol, accounted for 26.4 area%.

[0099] [Example 10] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of DMAc (5 times the mass / 4-CNB), the palladium catalyst was changed to 0.265 g of 5% palladium carbon (Pd / C; Type E, manufactured by N.E. Chemcat, Pd content 5.1% by mass, 50% by mass water content) (0.0635 mmol, 0.20 mol / 4-CNB), an additional 1.65 g of LiBr (19.0 mmol, 0.6 equivalents / 4-CNB) was added before dropwise addition, and the reaction time was changed to 4 hours.

[0100] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-butyne-2-ol, was 96.8%, and the by-product, which is dimerized 2-methyl-3-butyne-2-ol, accounted for 11.2 area percent.

[0101] [Example 11] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of DMAc (5 times by mass / 3-CNB), the nitrobenzene to 5.0 g of 3-chloronitrobenzene (3-CNB) (31.7 mmol), the palladium catalyst to 0.265 g of 5% palladium carbon (Pd / C; Type E, manufactured by N.E. Chemcat, Pd content 5.1% by mass, 50% by mass water content) (0.0635 mmol, 0.20 mol / 3-CNB), an additional 1.65 g of LiBr (19.0 mmol, 0.6 equivalents / 4-CNB) was added before dropwise addition, and the reaction time was changed to 4 hours.

[0102] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(3-nitrophenyl)-3-butyne-2-ol, was 28.9%, and the by-product, which is dimerized 2-methyl-3-butyne-2-ol, accounted for 16.3% of the area.

[0103] [Example 12] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of DMAc (5 times the mass / 4-CNB), the palladium catalyst was changed to 0.265 g of 5% palladium carbon (Pd / C; Type E, manufactured by N.E. Chemcat, Pd content 5.1% by mass, 50% by mass water content) (0.0635 mmol, 0.20 mol% / 4-CNB), an additional 1.65 g of LiBr (19.0 mmol, 0.6 equivalents / 4-CNB) was added before dropwise addition, the reaction temperature was changed to 70-75°C and the reaction time to 19 hours.

[0104] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-buty-2-ol, was 96.4%, and the by-product, which is dimerized 2-methyl-3-buty-2-ol, accounted for 7.8 area%.

[0105] [Example 13] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to DMAc 25g (5 times by mass / 2CFNB), the nitrobenzene to 2-chloro-4-fluoronitrobenzene (2CFNB) 5.0g (28.5 mmol), the palladium catalyst to 5% palladium carbon (Pd / C; Type E, manufactured by N.E. Chemcat, Pd content 5.1% by mass, 50% by mass water content) 0.475g (0.114 mmol, 0.40 mol% / 2CFNB), an additional 1.48g of LiBr (17.1 mmol, 0.6 equivalents / 2CFNB) was added before dropwise addition, the amount of 2-methyl-3-buty-2-ol added was changed to 4.72g (57.0 mmol, 2.0 equivalents / 2CFNB), and the reaction time was changed to 4 hours.

[0106] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(5-fluoro-2-nitrophenyl)-3-butyne-2-ol, was 58.1%, and the by-product, which is dimerized 2-methyl-3-butyne-2-ol, amounted to 2.8 area%.

[0107] [Comparative Example 1] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to tetrahydrofuran (THF) 25 g (5 times by mass / 4-CNB), the palladium catalyst to palladium acetate (Pd(OAc)2) 0.285 g (0.127 mmol, 0.40 mol% / 4-CNB), the reaction temperature was changed to 80-85°C, and the reaction time was changed to 18 hours.

[0108] Analysis of the reaction solution by GC revealed that the formation of the target compound, 2-methyl-4-(4-nitrophenyl)-3-buty-2-ol, could not be confirmed. Furthermore, no by-products resulting from the dimerization of 2-methyl-3-buty-2-ol were detected.

[0109] [Comparative Example 2] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of 2-propanol (IPA) (5 times the mass / 4-CNB), the reaction temperature was changed to 85-90°C, and the reaction time was changed to 19 hours.

[0110] Analysis of the reaction solution by GC revealed that the reaction yield of the target compound, 2-methyl-4-(4-nitrophenyl)-3-buty-2-ol, was 5.2%. No dimerized by-products of 2-methyl-3-buty-2-ol were observed.

[0111] [Comparative Example 3] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of THF (5 times the mass / 3-CNB), the nitrobenzene to 5.0 g of 3-chloronitrobenzene (3-CNB) (31.7 mmol), the palladium catalyst to 20.285 g of Pd(OAc) (0.127 mmol, 0.40 mol% / 3-CNB), the reaction temperature was changed to 80-85°C, and the reaction time was changed to 18 hours.

[0112] Analysis of the reaction solution by GC revealed that the formation of the target compound, 2-methyl-4-(3-nitrophenyl)-3-buty-2-ol, could not be confirmed. Furthermore, no by-products resulting from the dimerization of 2-methyl-3-buty-2-ol were detected.

[0113] [Comparative Example 4] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of IPA (5 times the mass / 3-CNB), the nitrobenzene to 5.0 g of 3-chloronitrobenzene (3-CNB) (31.7 mmol), the reaction temperature was changed to 85-90°C, and the reaction time was changed to 19 hours.

[0114] Analysis of the reaction solution by GC revealed that the formation of the target compound, 2-methyl-4-(3-nitrophenyl)-3-buty-2-ol, could not be confirmed. Furthermore, no by-products resulting from the dimerization of 2-methyl-3-buty-2-ol were detected.

[0115] [Comparative Example 5] The reaction was carried out in the same manner as in Example 1, except that the organic solvent was changed to 25 g of THF (5 times by mass / 2CFNB), the nitrobenzene to 5.0 g of 2-chloro-4-fluoronitrobenzene (2CFNB) (28.5 mmol), the palladium catalyst to 20.0256 g of Pd(OAc) (0.114 mmol, 0.4 mol% / 2CFNB), the reaction temperature was changed to 85-90°C, and the reaction time was changed to 19 hours.

[0116] Analysis of the reaction solution by GC revealed that the formation of the target compound, 2-methyl-4-(4-nitrophenyl)-3-buty-2-ol, could not be confirmed. Furthermore, no by-products resulting from the dimerization of 2-methyl-3-buty-2-ol were detected.

[0117] The results of the examples and comparative examples are summarized in Table 1 below.

[0118] [Table 1]

[0119] As shown in the table above, the conditions in Example 10 are particularly preferable from an industrial standpoint, as they yield the target compound in high yield with minimal catalyst usage. [Industrial applicability]

[0120] The present invention provides a method for producing aromatic compounds having an ethynyl group, using chloronitrobenzene, an inexpensive chlorine compound, as a starting material and an inexpensive palladium-carbon material to produce aromatic compounds having an ethynyl group using the Sonogashira coupling reaction.

[0121] The Sonogashira coupling reaction of the present invention is an industrially superior production method because it allows for the acquisition of the desired aromatic compound having an ethynyl group in high yield simply by mixing and heating the respective starting materials, is easy to operate, and requires less palladium catalyst.

[0122] The aromatic compounds having an ethynyl group obtained in this invention have both a nitro group and an ethynyl group, and can be easily converted to anilines by reduction. These anilines can then be used as useful compounds for fine chemicals, pharmaceutical and agricultural chemical raw materials, resin and plastic raw materials, and electronic information materials and optical materials.

Claims

1. A method for producing an aromatic compound having an ethynyl group by coupling reaction of nitrobenzene and an ethynyl compound, wherein the nitrobenzene is represented by the following general formula (1), the ethynyl compound by the following general formula (2), and the aromatic compound having an ethynyl group by the following general formula (3), and the coupling reaction is carried out in an organic solvent having a nitrogen atom in its chemical structure in the presence of an amine, palladium carbon, a phosphorus compound, a copper compound, and an alkali metal salt, wherein the organic solvent is at least one selected from N,N-dimethylacetamide, dimethylformamide, and N-methyl-2-pyrrolidone, and the alkali metal salt is at least one selected from lithium chloride, lithium bromide, lithium iodide, and sodium bromide. 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 In the formula, A represents hydrogen or fluorine, R represents a hydrocarbon group having a hydroxyl group or a trialkylsilyl group, and n represents an integer from 1 to 3.

2. The method for producing an aromatic compound having an ethynyl group according to claim 1, wherein the organic solvent is N,N-dimethylacetamide or N-methyl-2-pyrrolidone.

3. A method for producing an aromatic compound having an ethynyl group according to claim 1 or 2, wherein the ethynyl compound is 2-methyl-3-butyne-2-ol, 3-butyne-2-ol, or 2-propene-1-ol.

4. A method for producing an aromatic compound having an ethynyl group according to claim 1 or 2, wherein the nitrobenzene is represented by the following general formula (4). 【Chemistry 4】 In the formula, A represents hydrogen or fluorine.

5. The method for producing an aromatic compound having an ethynyl group according to claim 4, wherein the nitrobenzene is 4-chloronitrobenzene, 3-chloronitrobenzene, or 2-chloronitrobenzene.

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