Method for producing diarylether compound and apparatus used for the method

Abstract

To provide a method for producing a diarylether compound which can reduce environmental load and to provide an apparatus used for the method.SOLUTION: There is provided a method for producing a diarylether compound in which a diarylether compound is obtained by oxidative aromatization of the cyclohexene ring of an aryl enol ether with an oxidant or an oxidation catalyst. In addition, the method may comprise: a step of using phenols and cyclohexanone dialkyl ketal as raw material compounds to obtain an aryl enol ether by the elimination reaction of an alkyl alcohol derived from ketal in the presence of an acid catalyst; and a step of obtaining a diarylether compound by the oxidative aromatization of the cyclohexene ring of the resulting aryl enol ether using an oxidant or an oxidation catalyst. Then, the apparatus used in this method should be equipped with an adsorbent for the alcohol eliminated by the elimination reaction of an alkyl alcohol.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a method for producing a diaryl ether compound, specifically, a method for producing a diaryl ether compound by oxidative aromatization of an aryl enol ether compound, particularly, a method for producing a diaryl ether compound by a stepwise synthesis method comprising a first-stage reaction for producing an aryl enol ether compound in the presence of a catalyst using a phenol and a cyclohexanone dialkyl ketal as raw materials, and a second-stage reaction for oxidative aromatization of the obtained aryl enol ether compound in the presence of an oxidizing agent or an oxidation catalyst. [Background technology]

[0002] Diaryl ether compounds have important structures that are included in the basic skeletons of pharmaceuticals, agricultural chemicals, and functional materials, so it is important to develop efficient methods for their synthesis. The synthesis methods include methods that use aromatic halogen compounds as raw materials, such as aromatic nucleophilic substitution reactions, Buchwald-Hartwig alkoxylation, and Ullmann coupling (Non-Patent Documents 1-2).

[0003] This aromatic nucleophilic substitution reaction is carried out by heating in the presence of a strong base such as sodium hydride or cesium fluoride, while the Buchwald-Hartwig alkoxylation and Ullmann coupling require homogeneous transition metal catalysts such as palladium or copper catalysts. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] J. Scott Sawyer, Tetrahedron, 2000, 56, pp.5045-5065. [Non-Patent Document 2] F. Theil, Angew. Chem. Int. Ed., 1999, 38, pp.2345-2347. Summary of the Invention [Problem to be solved by the invention]

[0005] The methods described in Non-Patent Documents 1-2 have problems in that they use aromatic halogen compounds, which have a large environmental load, as raw materials, and that the aromatic nucleophilic substitution reaction requires heating in the presence of a strong base such as sodium hydride or cesium fluoride, making it impossible to apply compounds that are sensitive to bases. Furthermore, these methods require the use of homogeneous transition metal catalysts such as palladium catalysts and copper catalysts, which leads to problems in the treatment of residual metals in the products and environmental load.

[0006] The present invention has been made to solve such problems, and an object of the present invention is to provide a method for producing a diaryl ether compound that can reduce the burden on the environment, and an object of the present invention is to provide an apparatus for use in the method that can easily carry out the method. [Means for solving the problem]

[0007] The present inventors have found that diaryl ether compounds can be produced by oxidative aromatization of aryl enol ether compounds, and in particular that diaryl ether compounds can be produced with reduced environmental impact by a two-step reaction consisting of a first-step reaction in which an aryl enol ether compound is synthesized from a phenol and a cyclohexanone dialkyl ketal, and a second-step reaction in which the obtained aryl enol ether compound is oxidatively aromatized. As a method for synthesizing alkylaryl ethers, in which one of the aryl groups of diaryl ethers is an alkyl group, there is a method that uses aliphatic alcohols and cyclohexanone as raw materials (Reference 1: IY El-Deeb, M. Tian, ​​T. Funakoshi, R. Matsubara and M. Hayashi, Eur. J. Org. Chem., 2017, 2017, pp.409-413.). In this method, in the presence of a palladium carbon catalyst, aliphatic alcohols and cyclohexanone are reacted with alkylcyclohexenyl ethers (alkyl enol ethers) as intermediates, accompanied by the elimination of water molecules, and the cyclohexene ring is oxidatively aromatized using palladium carbon as a catalyst, with the only co-products being water and hydrogen.

[0008] In this reference, an alkyl enol ether is obtained as an intermediate, and this is oxidatively aromatized to obtain an alkyl aryl ether. The present inventors therefore believed that a diaryl ether compound could be synthesized by oxidatively aromatizing an aryl enol ether compound in which the alkyl group is an aryl group, and thus completed the present invention. Furthermore, they found that an aryl enol ether compound could be synthesized by reacting phenols and cyclohexanone dialkyl ketal as raw materials in the presence of a catalyst. Specifically, the method is as follows.

[0009] (1) A method for producing a diaryl ether compound, comprising a diaryl ether synthesis step of oxidatively aromatizing a cyclohexene ring of an aryl enol ether compound represented by the following formula (3) using an oxidizing agent or an oxidation catalyst to obtain a diaryl ether compound represented by the following formula (4). [ka] (In the formula, Ar represents an aryl group having 6 to 20 carbon atoms, which may have a substituent on the aromatic ring. R is selected from an alkyl group having 1 to 10 carbon atoms, an ester group having 1 to 10 carbon atoms, and an aryl group having 6 to 20 carbon atoms. [ka] (In the formula, Ar is an aryl group in formula (3), and R is R in formula (3).) (2) A method for producing a diaryl ether compound, comprising: an aryl enol ether synthesis step of obtaining an aryl enol ether compound represented by the following formula (3) by an elimination reaction of an alkyl alcohol derived from the cyclohexanone dialkyl ketal in the presence of an acid catalyst using a phenol represented by the following formula (1) and a cyclohexanone dialkyl ketal represented by the following formula (2) as raw materials; and a diaryl ether synthesis step of obtaining a diaryl ether compound represented by the following formula (4) by oxidative aromatization of a cyclohexene ring of the obtained aryl enol ether compound in the presence of an oxidizing agent or an oxidation catalyst. [ka] (In the formula, Ar represents an aryl group having 6 to 20 carbon atoms, which may have a substituent on the aromatic ring.) [ka] (In the formula, R 1 and R 2 is an alkyl group having 1 to 4 carbon atoms, and R 3 is selected from an alkyl group having 1 to 10 carbon atoms, a carboalkoxy group having 1 to 10 carbon atoms, and an aryl group having 6 to 20 carbon atoms. 1 and R 2 and R 3 may be the same or different.) [ka] (wherein Ar is an aryl group in formula (1), and R is an R 3 It is.) [ka] (wherein Ar is an aryl group in formula (1), and R is an aryl group in formula (2) 3 It is.) (3) The acid catalyst is represented by MX3, where M is selected from the representative metals of Groups 12-15 of the periodic table, and X is chlorine, a methyl group, an alkoxy group (OR 4 ) is selected from the group consisting of R 4 is selected from alkyl groups having 1 to 4 carbon atoms. (4) The method for producing a diaryl ether compound according to (2) or (3) above, wherein the aryl enol ether synthesis step is carried out under heating in the presence of an organic solvent. (5) The method for producing a diaryl ether compound according to any one of (1) to (3), wherein the diaryl ether synthesis step is a step of using the oxidizing agent and obtaining a diaryl ether compound using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone as the oxidizing agent. (6) The method for producing a diaryl ether compound according to (4) above, wherein the diaryl ether synthesis step is a step using the oxidizing agent, and is a step of obtaining a diaryl ether compound using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone as the oxidizing agent. (7) The method for producing a diaryl ether compound according to any one of (1) to (3), wherein the diaryl ether synthesis step is a step using the oxidation catalyst and obtaining a diaryl ether compound using a transition metal catalyst containing at least palladium as the oxidation catalyst. (8) The method for producing a diaryl ether compound according to (4) above, wherein the diaryl ether synthesis step is a step using the oxidation catalyst, and is a step of obtaining a diaryl ether compound using a transition metal catalyst containing at least palladium as the oxidation catalyst. (9) The method for producing a diaryl ether compound according to (7) above, wherein the diaryl ether synthesis step further comprises obtaining a diaryl ether compound by using a hydrogen scavenger. (10) The method for producing a diaryl ether compound according to (8) above, wherein the diaryl ether synthesis step further comprises obtaining a diaryl ether compound by using a hydrogen scavenger.

[0010] (11) The method for producing a diaryl ether compound according to (4) above, wherein the aryl enol ether synthesis step and the diaryl ether synthesis step are carried out continuously in one reaction vessel. (12) The method for producing a diaryl ether compound according to (6) above, wherein the aryl enol ether synthesis step and the diaryl ether synthesis step are carried out continuously in one reaction vessel. (13) The method for producing a diaryl ether compound according to (8) above, wherein the aryl enol ether synthesis step and the diaryl ether synthesis step are carried out continuously in one reaction vessel. (14) The method for producing a diaryl ether compound according to (10) above, wherein the aryl enol ether synthesis step and the diaryl ether synthesis step are carried out continuously in one reaction vessel. (15) The method for producing a diaryl ether compound according to (4) above, wherein in the aryl enol ether synthesis step, the aryl enol ether is obtained while removing the eliminated alkyl alcohol.

[0011] (16) An apparatus used in the method for producing a diaryl ether compound according to (15) above, comprising: a reactor for accommodating the phenol, the cyclohexanone dialkyl ketal, the organic solvent, and the acid catalyst; an incubator for maintaining the reactor at a predetermined temperature; a cooler connected to the reactor for refluxing the organic solvent evaporated by heating to the predetermined temperature; and a liquid reservoir connected to the cooler and equipped therein with an adsorbent for removing the desorbed alkyl alcohol. Effect of the Invention

[0012] According to the present invention, it is possible to provide a method for producing a diaryl ether compound, which can reduce the burden on the environment, and an apparatus for use in the method, which can easily carry out the method, can be provided. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 is a configuration diagram of an apparatus used for producing a diaryl ether compound. [Diagram 2] 1 is a 1H NMR spectrum of the aryl enol ether of Example 1. [Diagram 3] 1 is a C NMR spectrum of the aryl enol ether of Example 1. [Figure 4] 1H NMR spectrum of the diaryl ether of Example 14. [Diagram 5] 13C NMR spectrum of the diaryl ether of Example 14. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Hereinafter, the embodiments of the present invention will be described in detail. In the embodiments of the present invention, when a temperature range, a concentration range, etc. are indicated, the upper limit and the lower limit are included unless otherwise specified. In addition, the percentage concentration indicates mass %.

[0015] The method for producing a diaryl ether compound according to the present embodiment is a method for producing a diaryl ether compound by oxidative aromatization of an aryl enol ether compound, and is particularly achieved by a two-step reaction consisting of a first step reaction (reaction 1) for synthesizing an aryl enol ether compound from a phenol and a cyclohexanone dialkyl ketal, and a second step reaction (reaction 2) for oxidative aromatization of the resulting aryl enol ether compound. These reactions will be specifically described below.

[0016] In reaction 1, phenols (compound (1)) and cyclohexanone dialkyl ketals (compound (2)) are reacted in the presence of an acid catalyst to synthesize aryl enol ethers (compound (3)) while eliminating two molecules of alkyl alcohol. In reaction 2, compound (3) is used as the raw material to obtain the desired diaryl ether (compound (4)) by oxidative aromatization using an oxidizing agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or an oxidation catalyst such as a palladium catalyst. [ka]

[0017] In the first stage reaction, a phenol, a cyclohexanone dialkyl ketal, an acid catalyst and a solvent are added to a reaction vessel and heated to synthesize an aryl enol ether compound. (Phenols) Phenols are compounds represented by Ar-OH, and are not limited as long as they do not affect the reaction. Examples of the aryl group (Ar) include aromatic rings having 6 to 20 carbon atoms, such as phenyl, naphthyl, indenyl, phenanthryl, and pyrenyl groups. The aromatic ring may have a substituent. Examples of the substituent on the aromatic ring include alkyl groups having 1 to 10 carbon atoms, oxygen-containing groups, nitrogen-containing groups, sulfur-containing groups, and halogen atoms. Specific examples of the alkyl group include linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, neopentyl, and n-hexyl groups. Specific examples of the oxygen-containing group include a hydroxy group, an alkoxy group, an aryloxy group, an ester group, an acyl group, a carboxy group, a carbonyl group, and an epoxy group. Specific examples of the nitrogen-containing group include an amino group, an imino group, an amido group, an imido group, a hydrazino group, a hydrazono group, a nitro group, a nitroso group, a cyano group, an isocyano group, a cyanate ester group, an amidino group, and a diazo group. Specific examples of the sulfur-containing group include a thiol group and a sulfo group. Examples of the halogen atom include fluorine, chlorine, bromine, and iodine. As the substituent, from the viewpoint of the reactivity of phenols in the ketal exchange reaction, a versatile alkyl group having 1 to 10 carbon atoms is preferably used, and those not having an electron-withdrawing group such as a nitro group or a carboxy group, for example, an ether group, an ester group, an amino group, an amide group, a halogen atom, etc. are preferred.

[0018] For example, phenols include various o-, m-, and p-isomers of alkylphenols, ether-substituted phenols such as methoxyphenol, and halogen-substituted phenols such as bromophenol. Examples of phenols include phenol, o-cresol, m-cresol, p-cresol, p-methoxyphenol, p-dimethylaminophenol, p-acetamidophenol, p-bromophenol, methyl p-hydroxybenzoate, and 2-naphthol. In particular, from the viewpoint of the reactivity of phenols in the ketal exchange reaction, 2-naphthol, o-, m-, and p-cresol, p-methoxyphenol, and p-bromophenol are preferred, and 2-naphthol, p-cresol, and p-methoxyphenol are more preferred. The concentration of phenols as raw materials (concentration of phenols in the solution) is not particularly specified, but is preferably 0.1-50%, and from the viewpoint of reaction efficiency, is preferably 0.1-20%.

[0019] (Cyclohexanone dialkyl ketal) Cyclohexanone dialkyl ketals include those represented by the following formula (2). This is a cyclohexanone dialkyl ketal formed by the reaction of a cyclohexanone derivative with two molecules of alcohol (OR 1 and OR 2 ) is formed. [ka] The two molecules of alcohol are alcohols consisting of 1-4 carbon atoms, specifically R 1 and R2 are each independently selected from linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, and butyl. 1 and R 2 may be the same or different. Furthermore, the cyclohexanone derivatives may have a substituent (R 3 ) may be present. Specific examples of the substituent include an alkyl group having 1 to 10 carbon atoms, a carboalkoxy group (ester group) having 1 to 10 carbon atoms, and an aryl group having 6 to 20 carbon atoms (such as a phenyl group or a naphthyl group). R 3 is R 1 Or R 2 may be the same as or different from.

[0020] In addition, the cyclohexanone dialkyl ketal is preferably an unsubstituted ketal or an ester-substituted ketal. Examples include cyclohexanone dimethyl ketal, cyclohexanone diethyl ketal, cyclohexanone methyl ethyl ketal, and methyl 4,4-dimethylcyclohexane-1-carboxylate. In particular, from the viewpoint of ease of removal of the eliminated alcohol, cyclohexanone dimethyl ketal and methyl 4,4-dimethylcyclohexane-1-carboxylate are preferred. In addition, for example, the equivalent of cyclohexanone dimethyl ketal is preferably 1 to 10 equivalents relative to the phenol, and more preferably 2 to 3 equivalents.

[0021] (acid catalyst) The acid catalyst may be a Lewis acid catalyst containing a typical metal, represented by MX3, where M is selected from typical metals in Groups 12-15 of the periodic table, preferably from metals in Group 13, more preferably from aluminum (Al) and gallium (Ga). X is chlorine, a methyl group, an alkoxy group (OR 4 The alkoxy group R 4 is selected from alkyl groups having 1 to 4 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, etc. These may be linear or branched. Examples of the catalyst include aluminum ethoxide, aluminum isopropoxide, gallium isopropoxide, and indium isopropoxide. Examples of the catalyst include chlorides of typical metals such as aluminum chloride, gallium chloride, and indium chloride, and organometallic compounds such as trimethylaluminum, trimethylgallium, and trimethylindium. Among these, from the viewpoint of reactivity, alkoxides and chlorides derived from aluminum and gallium, such as aluminum ethoxide, aluminum isopropoxide, aluminum chloride, trimethylaluminum, and gallium isopropoxide, are more preferred. Also, a plurality of these catalysts may be used. From the viewpoint of controlling side reactions, the equivalent amount of the acid catalyst is preferably 1-20 mol % relative to the phenols, and more preferably 1-10 mol %. For example, a side reaction is the formation of metal triphenoxide from phenols and the acid catalyst, and if the amount of catalyst is large, the phenols are consumed in the formation of the metal triphenoxide, so it is preferable to use a small amount of catalyst.

[0022] (solvent) The solvent may be any common organic solvent that dissolves phenols well and does not inhibit the progress of the reaction, and is not particularly limited. Examples of the solvent include aromatic hydrocarbon solvents such as toluene and xylene, and ether solvents such as 1,4-dioxane and cyclopentyl methyl ether. From the viewpoint of reactivity, toluene and xylene are preferable.

[0023] The heating temperature of the first-stage reaction is a temperature equal to or higher than the boiling point of the co-product (e.g., methanol when the ketal is dimethyl ketal) and capable of removing the co-product such as methanol from the reaction system, for example, 70°C to 160°C, preferably 100°C to 140°C, more preferably 120°C to 140°C.

[0024] In the latter reaction, the cyclohexene ring of the aryl enol ether compound is oxidatively aromatized using an oxidizing agent or an oxidation catalyst to synthesize a diaryl ether compound. The aryl enol ether compound used as the raw material in the latter reaction can be synthesized by a conventional method, for example, the method described in Reference 2 (Z. Wan, CD Jones, TM Koenig, YJ Pu and D. Mitchell, Tetrahedron Lett., 2003, 44, pp8257-8259. Table 2) or Reference 3 (David J. Winternheimer, Ryan E. Shade and Craig A. Merlic, Synthesis, 2010, pp.2497-2511. Scheme 56).

[0025] (Aryl enol ether) Aryl enol ether is represented by the following formula (3), and has a structure in which an aryl group (Ar) and a cyclohexenyl group are ether-bonded via an oxygen atom. In the formula, R is selected from an alkyl group having 1-10 carbon atoms, an ester group having 1-10 carbon atoms, and an aryl group having 6-20 carbon atoms (such as a phenyl group or a naphthyl group). In addition, Ar in the formula can be the same as the phenols mentioned above. Here, when the aryl enol ether synthesized in the first-stage reaction is used as the raw material, R in the formula is the R of the cyclohexanone dialkyl ketal, which is the raw material of the first-stage reaction. 3 Similarly, Ar is also common to the phenols used in the previous reaction. [ka] First, the oxidative aromatization reaction using an oxidizing agent will be described.

[0026] (Oxidizing agent) The oxidizing agent used is an oxidizing agent that aromatizes the cyclohexene ring of the aryl enol ether by dehydrogenating it, and DDQ is preferred from the viewpoint of reactivity. DDQ is involved in the oxidative aromatization of the cyclohexene ring of the aryl enol ether, acts as an oxidizing agent and a hydrogen scavenger, and is converted to 2,3-dichloro-5,6-dicyanohydroquinone after the reaction. For example, in the case of DDQ, its equivalent is preferably 2-4 molar equivalents relative to the aryl enol ether, and more preferably 2-3 equivalents.

[0027] The solvent used in this aromatization reaction with an oxidizing agent may be the same as that used in the above-mentioned previous catalytic reaction, and the heating temperature in this reaction is preferably from the viewpoint of reaction efficiency 120° C. to 160° C., more preferably from 140° C. to 160° C. Next, the oxidative aromatization reaction using an oxidation catalyst will be described.

[0028] (Oxidation catalyst) The oxidation catalyst used is a catalyst that dehydrogenates the cyclohexene ring of the aryl enol ether to aromatize it, and examples of the catalyst include transition metal catalysts. In particular, from the viewpoint of dehydrogenation efficiency, transition metal catalysts containing at least palladium (Pd) are preferred. Other examples of transition metals include first transition elements such as vanadium (V), manganese (Mn), iron (Fe), cobalt (Co), and nickel (Ni), second transition elements such as ruthenium (Ru) and rhodium (Rh), and third transition elements such as osmium (Os), iridium (Ir), and platinum (Pt), and a plurality of transition metals may be used. Among these, in particular, Pd, Ru, Rh, Ir, Pt, and the like are preferred from the viewpoint of dehydrogenation efficiency. In addition, the catalyst may be a catalyst of only an active metal (for example, palladium alone) or a metal catalyst supported on a carrier, in which case the carrier used is activated carbon, alumina, silica gel, or the like, and preferably activated carbon from the viewpoint of catalytic activity. The loading amount is applicable to 1-20% based on the carrier, preferably 10-20%, more preferably 15-20%. In the case of a palladium catalyst, the equivalent amount is preferably 1-20 mol %, particularly preferably 5-10 mol %, based on the aryl enol ether in terms of reactivity as the amount of palladium metal.

[0029] In the oxidative aromatization reaction using an oxidation catalyst, the use of a hydrogen trapping agent is preferable because the reaction is accelerated. In this reaction, the cyclohexene ring is oxidized to an aromatic ring while being dehydrogenated by a Pd catalyst, and hydrogen gas is generated during the reaction. Here, if hydrogen gas and a Pd catalyst coexist, hydrogenation of the alkene part of the cyclohexene ring is promoted, and there is a risk of partial conversion to cyclohexane. However, by using a hydrogen trapping agent, the hydrogen trapping agent is preferentially hydrogenated, so that hydrogenation of the cyclohexene ring can be avoided. There is no particular restriction on the hydrogen trapping agent as long as it does not inhibit the reaction, but it is preferable to use one having a reducing functional group (alkene, alkyne, nitro group, etc.), such as styrene or its derivative. In addition, the aromatic ring of styrene may have a substituent (an alkyl group having 1-10 carbon atoms or an aryl group having 6-20 carbon atoms). The alkene of the cyclohexene ring is a tri-substituted alkene, and has a structure that is relatively difficult to hydrogenate. On the other hand, styrene is a mono-substituted alkene, and is easily hydrogenated. By using a hydrogen trapping agent, the cyclohexene ring can be efficiently aromatized. Other examples of the hydrogen trapping agent include acrylic acid and aliphatic alkenes having 6 to 20 carbon atoms (hexene, heptene, octene, nonene, decene, etc.). The equivalent of the hydrogen trapping agent is preferably 1 to 5 molar equivalents, more preferably 2 to 3 molar equivalents, from the viewpoint of hydrogen trapping efficiency.

[0030] The solvent used in this catalytic reaction is not particularly limited as long as it dissolves the aryl enol ether well and does not inhibit the progress of the reaction, but examples of the solvent include aromatic hydrocarbon solvents such as toluene, xylene, and benzene, and ether solvents such as 1,4-dioxane and cyclopentyl methyl ether, and from the viewpoint of reactivity, toluene and xylene are preferable. From the viewpoint of reaction efficiency, the heating temperature of the catalytic reaction is preferably 120° C. or higher and 160° C. or lower, and more preferably 140° C. or higher and 160° C. or lower.

[0031] Here, according to this embodiment, the present invention can be applied to a one-pot reaction in which the oxidizing agent or oxidation catalyst is added directly to a vessel such as a flask used in the first-stage reaction, and the oxidative aromatization reaction in the second stage is carried out in one flask. FIG. 1 shows the configuration of an apparatus used for producing such diaryl ether compounds. This apparatus is composed of a thermostatic bath 1, a reaction vessel 2, a Dean-Stark apparatus fractional distillation tube (glass tube) 3, a Dean-Stark apparatus liquid reservoir 4 with a stopcock, a Dimroth condenser 5, a glass stopper 6 for the condenser 5, and the like. Specifically, the Dean-Stark apparatus fractional distillation tube 3 and the Dimroth condenser 5 are connected to the reaction vessel 2 placed on the thermostatic bath 1, and the Dean-Stark apparatus liquid reservoir 4 is filled with dry molecular sieves 7. The reaction vessel 2 contains a solution containing phenols, cyclohexanone dialkyl ketal, an acid catalyst, and the like, and is heated and reacted to synthesize an aryl enol ether. In this case, the co-product of alcohol derived from cyclohexanone dialkyl ketal, which is generated during the first-stage reaction, can be removed by using an adsorbent such as molecular sieve 7. Note that molecular sieves have holes of molecular size, and whether or not they can be adsorbed depends on the molecular size. Since methanol molecules are small and toluene molecules are large, only methanol can be adsorbed by selecting a molecular sieve with an appropriate hole size. In this way, aryl enol ether can be efficiently synthesized while removing the desorbed alcohol. Note that the adsorbent is not limited to molecular sieve 7, and porous adsorbents such as activated carbon and silica gel may be used. In addition, the Dimroth cooler 5 cools the solvent boiled during the reaction and returns it to the reaction vessel 2 for circulation, i.e., by refluxing, a part of the boiled cyclohexanone dimethyl ketal is returned to the reaction vessel 2, thereby preventing the reaction from stopping due to the disappearance of cyclohexanone dimethyl ketal. Then, an oxidizing agent or an oxidation catalyst is added to the reaction vessel 2 as it is, and the reaction vessel 2 is heated again to obtain a diaryl ether compound. In this manner, the synthesis of aryl enol ethers and diaryl ether compounds can be easily performed by this apparatus.

[0032] This apparatus may be used only for the first-stage reaction or the second-stage reaction, but as described above, by adding an oxidizing agent or an oxidation catalyst following the first-stage reaction, it can also be used for the second-stage reaction as it is. As described above, in this embodiment, in the first-stage reaction, no halogen compound is used as a raw material compound, and no transition metal catalyst is used. In the second-stage reaction, a transition metal catalyst is used as an oxidation catalyst, and DDQ (a chlorine compound) is used as an oxidizing agent, but the transition metal catalyst and the halogen compound are used alone, not both, and neither the first-stage nor the second-stage reaction is carried out in the presence of a strong base, so that the method can be applied to compounds that are sensitive to bases (e.g., compounds having an ester group, aromatic bromine compounds, etc.) and can reduce the burden on the environment. In addition, DDQ is used as an oxidizing agent in the latter reaction, but the chlorine in DDQ is not eliminated and remains in the organic compound. On the other hand, in the conventional methods using halides such as Buchwald-Hartwig alkoxylation and Ullmann coupling, the eliminated halogen migrates to the wastewater, which is a concern for the environmental load. However, the present embodiment reduces the load on the environment compared to these methods.

[0033] In addition, in reaction 1, when cyclohexanone dialkyl ketal, for example, cyclohexanone dimethyl ketal or cyclohexanone diethyl ketal, is used as a raw material, an alkyl alcohol such as methanol or ethanol is used as a leaving group, and since the compound that is eliminated is only an alcohol such as methanol or ethanol, it can be said that this is a method with low environmental impact. Similarly, in reaction 2, only hydrogen is eliminated, so it can be said that this is a method with low environmental impact. And, since the aryl enol ether obtained in this embodiment can be used as a polymer raw material, the aryl enol ether itself has high synthetic value. Therefore, the aryl enol ether can be used as a target compound instead of a mere intermediate. And, as described above, reaction 1 and reaction 2 can be said to be methods that can reduce the burden on the environment. Next, a more detailed explanation will be given with examples, but the scope of the invention is not limited to the following examples. EXAMPLES

[0034] In the following Examples 1-5, the acid catalyst in the first step reaction was replaced with 2-(1-cyclohexenyl)oxynaphthalene (aryl enol ether), as shown in reaction formula (5) below. [ka] (Example 1) Synthesis of 2-(1-cyclohexenyl)oxynaphthalene (Compound 3a) (first step reaction) Using the apparatus in FIG. 1, 2-(1-cyclohexenyl)oxynaphthalene was synthesized. A glass tube 3 filled with molecular sieves 4 Å (7.0 g, Fujifilm Wako Pure Chemical Industries, Ltd.) and a Dimroth condenser 5 were attached to a 100 mL round-bottom flask, which was a reaction vessel 2, and 2-naphthol (1.4 g, 10 mmol, Tokyo Chemical Industry Co., Ltd.), a stirrer bar and toluene (40 mL, Kanto Chemical Co., Ltd.) were added to the flask. The temperature of the thermostatic chamber 1 was set to 140°C, and the mixture was heated and stirred for 30 minutes, then cooled to room temperature, and a toluene solution (60 μL, Tokyo Chemical Industry Co., Ltd.) containing trimethylaluminum (1 mol%, 1.8 mol / L) was added, and the thermostatic chamber 1 was heated again to 140°C. Cyclohexanone dimethyl ketal (2.3 g, 20 mmol, Fujifilm Wako Pure Chemical Industries, Ltd.) was then added with a syringe, and the mixture was heated and stirred at 140°C for 19 hours, and the reaction was carried out under reflux conditions. After cooling to room temperature, an aqueous solution of sodium bicarbonate and ethyl acetate were added to the flask to extract the reaction mixture, which was then concentrated using an evaporator. The concentrated reaction mixture was purified using silica gel column chromatography (mobile phase: hexane / ethyl acetate).

[0035] Also, in Figure 2, 1 HNMR spectrum (400 MHz, CDCl3) is shown in FIG. 13 The CNMR spectrum (100 MHz, CDCl3) is shown. 1 HNMR and 13For CNMR spectrum measurement, a sample was prepared by the following method, and a nuclear magnetic resonance apparatus (Avance NEO 400 MHz NMR manufactured by Bruker) was used under the following measurement conditions. In the following examples, spectrum measurement was performed using the same apparatus and under the same operation and conditions. Preparation method: 50 mg of the product was added to a flask and dissolved in 0.5 mL of deuterated chloroform (Kanto Chemical Co., Ltd.), and the solution was introduced into an NMR tube. Measurement conditions: Measurement nuclide ( 1 H and 13 C), measurement frequency (400 MHz and 100 MHz), 13 C decoupling (on), number of integrations (16), temperature control (none)

[0036] 1 HNMR (400 MHz, CDCl3): δ 7.79&-7.76 (m, 2H), 7.73 (d, J = 8.2 Hz, 1H), 7.44 (ddd, J = 7.5, 7.5, 1.3 Hz, 1H), 7.36 (ddd, J = 7.5, 7.5, 1.3 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.21 (dd, J = 8.9, 2.4 Hz, 1H),5.11 (t, J = 3.9 Hz, 1H),2.26&-2.22(m, 2H), 2.14&-2.08 (m, 2H), 1.82&-1.76 (m, 2H), 1.67&-1.61 (m, 2H); 13 CNMR (100 MHz, CDCl3): δ 154.1, 153.2, 134.4, 129.9, 12.94, 127.7, 127.0, 126.3, 124.3, 120.3, 113.6, 107.5, 26.6, 23.7, 22.9, 22.3. Analysis by gas chromatography confirmed that the conversion rate was 92%, and that 2-(1-cyclohexenyl)oxynaphthalene was produced in a yield of 86%. Furthermore, when the weight yield was calculated from the weight after purification (1.9 g), the yield was also 86%. In the catalyst examination of Examples 2-5, the conversion rate and yield were calculated from the results of analysis by gas chromatography. In these Examples, the product is the same as that in Example 1, so the weight yield of the product is not shown. On the other hand, in Examples 6 and onwards, 1 The weight yield after purification was calculated except for the yields obtained from HNMR spectrum. The weight yield was not calculated for products that are easily decomposed by purification by silica gel column chromatography. 1 The yield was determined from the 1 H NMR spectrum. The analytical conditions by gas chromatography are as follows, which are also used in the following examples. GC device: GC-2014 (manufactured by Shimadzu Corporation) Column: SH-Rtx-5 Amine, length 30 m, inner diameter 0.25 mm (Shimadzu Corporation) Carrier gas: Nitrogen, constant linear velocity (33.2 cm / sec) Vaporization chamber temperature: 250℃ Detector temperature: 280℃ Column oven temperature: 50°C 2 min → (20°C / min) → 250°C 10 min (total 22 min) Detector: Flame ionization detector

[0037] The conversion rate and yield were calculated by the following formulas (1) and (2). Conversion rate (%) = {1-(number of moles of remaining raw material) / (number of moles of raw material used)} x 100 (1) Yield (%) = (number of moles of target compound) / (number of moles of raw material used) × 100 (2) In the following examples, unless otherwise noted, aryl enol ethers were synthesized in the same manner and under the same conditions as in Example 1. In addition, the same reagents were used for common compounds.

[0038] Example 2 The same conditions and methods were used as in Example 1, except that aluminum ethoxide (1 mol%, 16 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of trimethylaluminum as a catalyst. The same applies to the following Examples. Analysis by gas chromatography confirmed that the conversion rate was 83% and the yield of 2-(1-cyclohexenyl)oxynaphthalene was 72%.

[0039] Example 3 Except for using gallium isopropoxide (1 mol%, 25 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) instead of trimethylaluminum as a catalyst, the same conditions and method as in Example 1 were used. Analysis by gas chromatography confirmed that the conversion rate was 88% and the yield of 2-(1-cyclohexenyl)oxynaphthalene was 58%. Example 4 Except for using aluminum isopropoxide (1 mol%, 20 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) instead of trimethylaluminum as a catalyst, the same conditions and method as in Example 1 were used. Analysis by gas chromatography confirmed that the conversion rate was 66% and the yield of 2-(1-cyclohexenyl)oxynaphthalene was 51%.

[0040] Example 5 Except for using aluminum chloride (1 mol%, 13 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) instead of trimethylaluminum as a catalyst, the same conditions and method as in Example 1 were used. Analysis by gas chromatography confirmed that the conversion rate was 69% and the yield of 2-(1-cyclohexenyl)oxynaphthalene was 51%.

[0041] From the above, it was found that typical metals, such as aluminum catalysts (alkoxide, chloride, trimethyl) and gallium alkoxide, showed good results.

[0042] In the following Example 6-13, aryl enol ethers were synthesized by replacing the phenols in the first step of the reaction. The reaction formula (6) is shown below. [ka] (Example 6) Synthesis of 1-(1-cyclohexenyl)oxy-4-methylbenzene (Compound 3b) (first step reaction) The same conditions and method as in Example 1 were used except that p-cresol (1.1 g, 10 mmol, manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of 2-naphthol as the raw material, to obtain 1-(1-cyclohexenyl)oxy-4-methylbenzene (1.4 g, 75% yield). The yield was confirmed from the weight after purification. 1 HNMR (400 MHz, CDCl3): δ 7.09 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 4.95 (t, J = 3.9 Hz, 1H), 2.30 (s, 3H), 2.20&-2.15(m, 2H), 2.08&-2.03 (m, 2H), 1.77&-1.71 (m, 2H), 1.61&-1.56 (m, 2H); 13 CNMR (100 MHz, CDCl3): δ 153.9, 153.6, 132.1, 129.9, 119.0, 105.6, 26.7, 23.6, 22.9, 22.3, 20.6.

[0043] (Example 7) Synthesis of 1-(1-cyclohexenyl)oxy-3-methylbenzene (Compound 3c) (first step reaction) The same conditions and method as in Example 1 were used except that p-cresol (1.1 g, 10 mmol, manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of 2-naphthol as the raw material, to obtain 1-(1-cyclohexenyl)oxy-3-methylbenzene (1.2 g, 64% yield). The yield was confirmed from the weight after purification. 1HNMR (400 MHz, CDCl3): δ 7.16 (dd, J = 7.5, 7.5 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 6.79&-6.77 (m, 2H), 5.03 (t, J = 3.9 Hz, 1H), 2.32 (s, 3H), 2.19&-2.14 (m, 2H), 2.10&-2.05 (m, 2H), 1.78&-1.72 (m, 2H), 1.63&-1.57 (m, 2H); 13 CNMR (100 MHz, CDCl3): δ 156.3, 153.1, 139.5, 129.1, 123.3, 119.4, 115.6, 106.8, 26.6, 23.6, 22.9, 22.2, 21.4.

[0044] (Example 8) Synthesis of 1-(1-cyclohexenyl)oxy-2-methylbenzene (Compound 3d) (first step reaction) The same conditions and method as in Example 1 were used except that o-cresol (1.1 g, 10 mmol, manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of 2-naphthol as the raw material, to obtain 1-(1-cyclohexenyl)oxy-2-methylbenzene (822.6 mg, 44% yield). The yield was confirmed from the weight after purification. 1 HNMR (400 MHz, CDCl3): δ 7.18&-7.11 (m, 2H), 6.98 (ddd, J = 7.7, 7.7, 1.1 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 4.71 (t, J = 3.9 Hz, 1H), 2.23&-2.20 (m, 5H), 2.05&-1.99 (m, 2H), 1.78&-1.72 (m, 2H), 1.61&-1.55 (m, 2H); 13 CNMR (100 MHz, CDCl3): δ 153.8, 153.5, 131.0, 129.7, 126.7, 123.2, 119.5, 103.1, 26.8, 23.5, 22.9, 22.4, 16.0.

[0045] (Example 9) Synthesis of 1-(1-cyclohexenyl)oxy-4-methoxybenzene (Compound 3e) (first step reaction) A glass tube 3 filled with molecular sieves 4 Å (7.0 g) and a Dimroth condenser 5 were attached to a 100 mL round-bottom flask, which was a reaction vessel 2, and 2-naphthol (1.4 g, 10 mmol), a stir bar and toluene (40 mL) were added to the flask. The temperature of the thermostatic bath 1 was set to 140°C, and after heating and stirring for 30 minutes, it was cooled to room temperature, a toluene solution (60 μL) containing trimethylaluminum (1 mol%, 1.8 mol / L) was added, and the thermostatic bath 1 was heated to 140°C again. Cyclohexanone dimethyl ketal (2.3 g, 20 mmol) was then added using a syringe, and the mixture was heated and stirred at 140°C for 19 hours to carry out a reaction under reflux conditions. After cooling to room temperature, an aqueous solution of sodium bicarbonate and ethyl acetate were added to the flask to extract the reaction mixture, which was then concentrated using an evaporator. Ethylene carbonate was added to the concentrated reaction mixture as an internal standard substance, and deuterated chloroform was used as a deuterated solvent. 1 HNMR spectrum was measured. 1 HNMR spectrum confirmed that 1-(1-cyclohexenyl)oxy-4-methoxybenzene was produced in 68% yield. 1 HNMR (400 MHz, CDCl3): δ 6.92 (d, J = 9.1 Hz, 2H), 6.83 (d, J = 9.1 Hz, 2H), 4.82 (t, J = 4.0 Hz, 1H), 3.78 (s, 3H), 2.21&-2.16 (m, 2H), 2.05&-2.00 (m, 2H), 1.76&-1.70 (m, 2H), 1.60&-1.54 (m, 2H); 13 CNMR (100 MHz, CDCl3): δ 155.4, 154.5, 149.4, 120.8, 114.5, 103.7, 55.6, 26.9, 23.5, 22.9, 22.3.

[0046] (Example 10) Synthesis of 1-(1-cyclohexenyl)oxy-N,N-dimethylaniline (Compound 3f) (first step reaction) The same conditions and method as in Example 9 were used, except that p-dimethylaminophenol (1.4 g, 10 mmol, manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of p-methoxyphenol as the raw material. 1 It was confirmed from the HNMR spectrum that 1-(1-cyclohexenyl)oxy-N,N-dimethylaniline was produced in 43% yield. 1 HNMR (400 MHz, CDCl3): δ 6.90 (d, J = 9.0 Hz, 2H), 6.70 (d, J = 9.0 Hz, 2H), 4.77 (t, J = 3.9 Hz, 1H), 2.90 (s, 6H), 2.21&-2.17 (m, 2H), 2.04&-1.99 (m, 2H), 1.76&-1.70 (m, 2H), 1.60&-1.54 (m, 2H); 13 CNMR (100 MHz, CDCl3): δ 154.9, 147.2, 146.9, 120.8, 113.9, 102.5, 41.3, 27.0, 23.5, 22.9, 22.4.

[0047] (Example 11) Synthesis of 1-bromo-4-(1-cyclohexenyl)oxybenzene (Compound 3g) (first step reaction) The same conditions and method as in Example 9 were used, except that p-bromophenol (1.7 g, 10 mmol, manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of p-methoxyphenol as the raw material. 1 It was confirmed from the HNMR spectrum that 1-bromo-4-(1-cyclohexenyl)oxybenzene was produced in 48% yield. 1 HNMR (400 MHz, CDCl3): δ 7.38 (d, J = 8.9 HZ, 2H), 6.86 (d, J = 8.9 Hz, 2H), 5.06 (t, J = 3.9 Hz, 1H), 2.16&-2.13 (m, 2H), 2.10&-2.05 (m, 2H), 1.77&-1.71 (m, 2H), 1.62&-1.57 (m, 2H); 13CNMR (100 MHz, CDCl3): δ 155.6, 152.8, 132.3, 120.4, 114.9, 107.8, 26.5, 23.6, 22.8, 21.1.

[0048] (Example 12) Synthesis of methyl 4-(1-cyclohexenyl)oxybenzoate (Compound 3h) (first step reaction) The same conditions and method as in Example 9 were used, except that methyl p-hydroxybenzoate (1.5 g, 10 mmol, manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of p-methoxyphenol as the raw material. 1 HNMR spectrum confirmed that methyl 4-(1-cyclohexenyl)oxybenzoate was produced in 49% yield. 1 HNMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.9 Hz, 2H), 6.98 (J = 8.9 Hz, 2H), 5.27 (t, J = 3.9 Hz, 1H), 3.89 (s, 3H), 2.16&-2.11 (m, 4H), 1.80&-1.74 (m, 2H), 1.66&-1.60 (m, 2H); 13 CNMR (100 MHz, CDCl3): δ 166.7, 160.9, 151.6, 131.5, 123.8, 117.0, 110.9, 61.9, 26.3, 23.7, 22.8, 22.0.

[0049] (Example 13) Synthesis of methyl 4-(naphthalene-2-yloxy)cyclohexene-3-ene-1-carboxylate (compound 3i) (first step reaction) The same conditions and method as in Example 9 were used, except that 2-naphthol (1.4 g, 10 mmol) was used instead of p-methoxyphenol and methyl 4,4-dimethylcyclohexane-1-carboxylate (4.0 g, 20 mmol, Sigma-Aldrich) was used instead of cyclohexanone dimethyl ketal as the raw material. 1It was confirmed from the HNMR spectrum that methyl 4-(naphthalene-2-yloxy)cyclohexene-3-ene-1-carboxylate was produced in 80% yield. 1 HNMR (400 MHz, CDCl3): δ 7.80&-7.77 (m, 2H), 7.73 (d, J = 8.2 Hz, 1H), 7.45 (ddd, J = 7.5, 7.5, 1.3 Hz, 1H), 7.38 (ddd, J = 7.5, 7.5, 1.3 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.19 (dd, J = 8.9, 2.4 Hz, 1H), 5.04 (t, J = 3.8 Hz, 1H), 3.72 (s, 3H), 2.67&-2.60 (m, 1H), 2.39&-2.33 (m, 4H), 2.17&-2.11 (m, 1H), 1.98&-1.88 (m, 1H); 13 CNMR (100 MHz, CDCl3): δ 175.7, 153.7, 152.9, 134.3, 130.1, 129.5, 127.7, 127.0, 126.4, 124.5, 120.3, 114.2, 104.8, 51.7, 39.0, 26.1, 25.8, 25.3.

[0050] The chemical structural formulas of the aryl enol ethers synthesized in each Example are shown below. Compound 3a was synthesized in Examples 1-5, compound 3b in Example 6, compound 3c in Example 7, compound 3d in Example 8, compound 3e in Example 9, compound 3f in Example 10, compound 3g in Example 11, compound 3h in Example 12, and compound 3i in Example 13. These were obtained in relatively good yields. In the first stage reaction, the yield was high when phenols derived from 2-naphthol, p-cresol, and p-methoxyphenol, such as compounds 3a, 3b, 3e, and 3i, were used. In addition, the results when phenols such as compounds 3c, 3d, and 3h were used indicate that the reaction is susceptible to the steric hindrance and electron density of the substituents on the aromatic ring. By synthesizing a compound having a halogen, such as compound 3g, a diaryl ether compound having a halogen can be synthesized by oxidative aromatization in the second stage reaction. Here, in the method using a conventional transition metal catalyst as described in Non-Patent Documents 1-2, the halogen itself in the raw material is reacted as a leaving group, so that a diaryl ether having a halogen cannot be synthesized. However, according to this embodiment, since a compound having a halogen can be synthesized, it can be said to be a very useful method. [ka]

[0051] In the following Examples 14-20, diaryl ether compounds were synthesized in the second reaction by oxidative aromatization using an oxidizing agent or an oxidation catalyst, using the aryl enol ether synthesized in the first reaction as a raw material. Note that the apparatus in FIG. 1 was not used in these Examples 14-20. In the following Examples 14-18, diaryl ether compounds were synthesized in the second reaction by using an oxidizing agent (DDQ). Reaction formula (7) is shown below. Hereinafter, this second reaction is referred to as second reaction A. In the formula, R is H or CO2Me. [ka]

[0052] (Example 14) Synthesis of 2-phenoxynaphthalene (Compound 4a) (Later Reaction A) First, 2-(1-cyclohexenyl)oxynaphthalene (compound 3a) (44.8 mg, 0.2 mmol) synthesized by the above-mentioned first-stage reaction, DDQ (2 equivalents, 90.8 mg, manufactured by Tokyo Chemical Industry Co., Ltd.), toluene (5 mL), and a stirrer bar were added to a screw-cap test tube, and after sealing, the reaction was carried out by heating and stirring at 120°C in a thermostatic bath for 17 hours. Thereafter, the reaction was cooled to room temperature, and filtered through Celite (registered trademark) while washing with ethyl acetate, and the reaction mixture was concentrated in an evaporator. The concentrated reaction mixture was purified by silica gel column chromatography (mobile phase: hexane / ethyl acetate) to obtain 2-phenoxynaphthalene (39.2 mg, 89% yield). The yield was confirmed from the weight after purification. In addition, FIG. 4 shows 1 HNMR spectrum (400 MHz, CDCl3) is shown in FIG. 13 CNMR spectrum (100 MHz, CDCl3) is shown. 1 HNMR (400 MHz, CDCl3): δ 7.84&-7.80 (m, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.46&-7.36 (m, 4H), 7.31 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 8.9, 2.4 Hz, 1H), 7.13 (dd, J = 7.4, 7.4 Hz, 1H), 7.07 (dd, J = 8.6, 1.0 Hz, 2H); 13 CNMR (100 MHz, CDCl3): δ 157.2, 155.1, 134.3, 130.2, 129.8, 129.8, 127.7, 127.1, 126.5, 124.7, 123.4, 120.0, 119.1, 114.1.

[0053] (Example 15) Synthesis of 1-methyl-4-phenoxybenzene (Compound 4b) (Later Reaction A) The same conditions and method as in Example 14 were used except that 1-(1-cyclohexenyl)oxy-4-methylbenzene (compound 3b) (37.5 mg, 0.2 mmol) synthesized in Example 6 was used instead of 2-(1-cyclohexenyl)oxynaphthalene as the raw material, to obtain 1-methyl-4-phenoxybenzene (25.1 mg, 68% yield). The yield was confirmed from the weight after purification. 1 HNMR (400 MHz, CDCl3): δ 7.32&-7.24 (m, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.06 (dd, J = 7.4, 7.4 Hz, 2H), 6.97 (dd, J = 8.6, 1.0 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 2.33 (s, 3H); 13 CNMR (100 MHz, CDCl3): δ 157.8, 154.8, 132.9, 130.2, 129.6, 122.8, 119.1, 118.4, 20.7.

[0054] (Example 16) Synthesis of 1-methoxy-4-phenoxybenzene (Compound 4e) (Second step reaction A) The procedure was carried out under the same conditions and by the same method as in Example 14, except that 1-(1-cyclohexenyl)oxy-4-methoxybenzene (compound 3e) (40.9 mg, 0.2 mmol) synthesized in Example 9 was used instead of 2-(1-cyclohexenyl)oxynaphthalene as the raw material, to obtain 1-methoxy-4-phenoxybenzene (34.2 mg, 85% yield). The yield was confirmed from the weight after purification. 1 HNMR (400 MHz, CDCl3): δ 7.29 (dd, J = 7.6, 7.6 Hz, 2H), 7.04 (ddd, J = 7.6, 7.6, 0.9 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.94 (dd, J = 7.6, 0.9 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 3.80 (s, 3H); 13CNMR (100 MHz, CDCl3): δ 158.5, 155.9, 150.1, 129.6, 122.4, 120.8, 117.6, 114.9, 55.6.

[0055] (Example 17) Synthesis of methyl 4-phenoxybenzoate (compound 4h) (second step reaction A) Methyl 4-phenoxybenzoate (40.8 mg, 90% yield) was obtained under the same conditions and by the same method as in Example 14, except that methyl 4-(1-cyclohexenyl)oxybenzoate (compound 3h) (46.4 mg, 0.2 mmol) synthesized in Example 12 was used instead of 2-(1-cyclohexenyl)oxynaphthalene as the raw material. The yield was confirmed from the weight after purification. 1 HNMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.9 Hz, 2H), 7.41&-7.37 (m, 2H), 7.19 (dd, J = 7.4, 7.4 Hz, 1H), 7.06 (dd, J = 8.6, 1.0 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 3.90 (s, 3H); 13 CNMR (100 MHz, CDCl3): δ 166.6, 161.8, 155.6, 131.7, 130.0, 124.5(2C), 120.1, 117.3, 52.0.

[0056] (Example 18) Synthesis of methyl 4-(naphthalene-2-yloxy)benzoate (compound 4i) (second step reaction A) Methyl 4-(naphthalen-2-yloxy)benzoate (44.4 mg, 80% yield) was obtained under the same conditions and by the same method as in Example 14, except that methyl 4-(naphthalen-2-yloxy)cyclohexen-3-ene-1-carboxylate (compound 3i) (56.6 mg, 0.2 mmol) synthesized in Example 13 was used instead of 2-(1-cyclohexenyl)oxynaphthalene as the raw material. The yield was confirmed from the weight after purification. 1HNMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.9 Hz, 2H), 7.89&-7.84 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.51&-7.43 (m, 3H), 7.25 (dd, J = 8.8, 2.4 Hz, 1H), 7.04 (d, J = 8.9 Hz, 2H), 3.91 (s, 3H); 13 CNMR (100 MHz, CDCl3): δ 166.6, 161.8, 153.4, 134.3, 131.7, 130.7, 130.2, 127.8, 127.3, 126.7, 125.3, 124.7, 120.3, 117.5, 116.1, 52.0.

[0057] Next, in the following Examples 19-20, a diaryl ether compound was synthesized in the second step reaction using an oxidation catalyst (palladium catalyst). Reaction formula (8) is shown below. Hereinafter, this second step reaction is referred to as second step reaction B. In the formula, R is H. [ka]

[0058] (Example 19) Synthesis of 2-phenoxynaphthalene (compound 4a) (second reaction B) 20% palladium carbon (UR type, 106.4 mg, 10 mol%, N.E. Chemcat Corporation) was added to the screw-top test tube and dried with a vacuum pump. After drying, 2-(1-cyclohexenyl)oxynaphthalene (224.2 mg, 1.0 mmol) synthesized by the above-mentioned first stage reaction, xylene (5 mL, Kanto Corporation), styrene (2 equivalents, 230 μL, Fujifilm Wako Pure Chemical Industries, Ltd.), and a stir bar were added, sealed, and the reaction was carried out by heating and stirring in thermostatic chamber 1 at 160 ° C for 19 hours. After that, it was cooled to room temperature, filtered through Celite (registered trademark) while washing with ethyl acetate, and the reaction mixture was concentrated with an evaporator. The concentrated reaction mixture was purified by silica gel ethyl acetate chromatography (mobile phase: hexane / ethyl acetate) to obtain 2-phenoxynaphthalene (143.8 mg, 64% yield). The yield was confirmed from the weight after purification.

[0059] (Example 20) Synthesis of 1-methoxy-4-phenoxybenzene (Compound 4e) (Later Reaction B) The same conditions and method as in Example 19 were used except that 1-(1-cyclohexenyl)oxy-4-methoxybenzene (204.1 mg, 1.0 mmol) synthesized in Example 9 was used instead of 2-(1-cyclohexenyl)oxynaphthalene as the raw material, to obtain 1-methoxy-4-phenoxybenzene (109.0 mg, 54% yield). The yield was confirmed from the weight after purification.

[0060] The chemical structural formulas of the diaryl ether compounds synthesized in each Example and the chemical structural formulas of the aryl enol ethers used as raw materials (five patterns) are shown in Table 1. Compound 4a was synthesized in Examples 14 and 19, compound 4b in Example 15, compound 4e in Examples 16 and 20, compound 4h in Example 17, and compound 4i in Example 18. From the above, it can be said that in the latter reaction A, oxidative aromatization proceeded without any influence of the substituent effect of the aryl enol ether. In the latter reaction, reaction B, it is thought that the effect of substituents is easily affected, and an unsubstituted aromatic ring such as 2-naphthol is more suitable. [Table 1]

[0061] In addition, an example in which the first-stage reaction and the second-stage reaction A are applied to a one-pot reaction using the apparatus shown in FIG. 1 is shown. (Example 21) One-pot synthesis of 2-phenoxynaphthalene 1 [ka]

[0062] A glass tube 3 filled with molecular sieves 4 Å (7.0 g) and a Dimroth condenser 5 were attached to a 100 mL round-bottom flask, which was a reaction vessel 2, and 2-naphthol (1.4 g, 10 mmol), a stir bar and toluene (40 mL) were added to the flask. The temperature of the thermostatic bath 1 was set to 140°C, and the mixture was heated and stirred for 30 minutes, then cooled to room temperature, and a toluene solution (60 μL) containing trimethylaluminum (1 mol%, 1.8 mol / L) was added, and the thermostatic bath 1 was heated to 140°C again. Cyclohexanone dimethyl ketal (2.3 g, 20 mmol) was then added with a syringe, and the mixture was heated and stirred at 140°C for 19 hours, and the reaction was carried out under reflux conditions. Then, after cooling to room temperature, DDQ (4 equivalents, 9.1 g) was added, and the thermostatic bath 1 was heated and stirred at 120°C for 19 hours, and the reaction was carried out under reflux conditions. The reaction mixture was extracted with an aqueous solution of sodium bicarbonate and ethyl acetate, and then concentrated with an evaporator. Ethylene carbonate was added to the concentrated reaction mixture as an internal standard substance, and deuterated chloroform was used as a deuterated solvent. 1 HNMR spectrum was measured. 1 HNMR spectrum confirmed that 2-phenoxynaphthalene was produced in 32% yield.

[0063] Furthermore, an example of applying the first-stage reaction and the second-stage reaction B to a one-pot reaction using the apparatus shown in Figure 1 will be shown. (Example 22) One-pot synthesis of 2-phenoxynaphthalene 2 [ka]

[0064] A glass tube 3 filled with molecular sieves 4 Å (7.0 g) and a Dimroth condenser 5 were attached to a 100 mL round-bottom flask, and 2-naphthol (1.4 g, 10 mmol), a stir bar and xylene (40 mL) were added to the flask. The temperature of the thermostatic bath 1 was set to 160 ° C., and after heating and stirring for 30 minutes, the mixture was cooled to room temperature, and then a toluene solution (60 μL) containing trimethylaluminum (1 mol%, 1.8 mol / L) was added, and the thermostatic bath 1 was heated to 160 ° C. again. Cyclohexanone dimethyl ketal (2.3 g, 20 mmol) was then added by syringe, and the mixture was heated and stirred for 19 hours, and the reaction was carried out under reflux conditions. After cooling to room temperature, 20% palladium carbon and 4-tert-butylstyrene (2 equivalents, 4.1 mL, manufactured by Tokyo Chemical Industry Co., Ltd.) were added, and the thermostatic bath 1 was heated and stirred at 160 ° C., and the reaction was carried out under reflux conditions. After cooling to room temperature, sodium bicarbonate aqueous solution and ethyl acetate were added to the flask to extract the reaction mixture, which was then concentrated using an evaporator. The concentrated reaction mixture was purified using silica gel column chromatography (mobile phase: hexane / ethyl acetate) to obtain 2-phenoxynaphthalene (1.7 g, 51% yield). The yield was confirmed from the weight after purification. According to this example, by adding an oxidizing agent or an oxidation catalyst to a container such as a flask used in the first-stage reaction, the second-stage oxidative aromatization reaction can be carried out in a single flask, and a diaryl ether compound can be synthesized simply and easily. In addition, in the one-pot reaction, reaction B using an oxidation catalyst has a higher yield than reaction A using DDQ, and is therefore more suitable. [Industrial Applicability]

[0065] INDUSTRIAL APPLICABILITY The present invention is applicable as a method for producing diaryl ether compounds for various applications, such as pharmaceuticals, agricultural chemicals, functional materials, and the like, as well as their synthetic intermediates. [Explanation of symbols]

[0066] 1 Temperature bath 2 Reaction vessel 3. Dean-Stark apparatus fractionating column 4. Dean-Stark Apparatus Reservoir 5 Dimroth Cooler 6 Glass stoppers 7 Molecular Sieves

Claims

1. A method for producing a diaryl ether compound, comprising a diaryl ether synthesis step of oxidatively aromatizing a cyclohexene ring of an aryl enol ether compound represented by the following formula (3) using an oxidizing agent or an oxidation catalyst to obtain a diaryl ether compound represented by the following formula (4). 【Chemistry 1】 (In the formula, Ar represents an aryl group having 6 to 20 carbon atoms, which may have a substituent on the aromatic ring. R is selected from an alkyl group having 1 to 10 carbon atoms, an ester group having 1 to 10 carbon atoms, and an aryl group having 6 to 20 carbon atoms. 【Chemistry 2】 (In the formula, Ar is an aryl group in formula (3), and R is R in formula (3).)

2. an aryl enol ether synthesis step of using a phenol represented by the following formula (1) and a cyclohexanone dialkyl ketal represented by the following formula (2) as raw materials in the presence of an acid catalyst to obtain an aryl enol ether compound represented by the following formula (3) by an elimination reaction of an alkyl alcohol derived from the cyclohexanone dialkyl ketal; a diaryl ether synthesis step in which the cyclohexene ring of the obtained aryl enol ether compound is oxidatively aromatized in the presence of an oxidizing agent or an oxidation catalyst to obtain a diaryl ether compound represented by the following formula (4); The present invention relates to a method for producing a diaryl ether compound. 【Chemistry 3】 (In the formula, Ar represents an aryl group having 6 to 20 carbon atoms, which may have a substituent on the aromatic ring.) 【Chemistry 4】 (In the formula, R １ and R ２ is an alkyl group having 1 to 4 carbon atoms; R ３ is selected from an alkyl group having 1 to 10 carbon atoms, a carboalkoxy group having 1 to 10 carbon atoms, and an aryl group having 6 to 20 carbon atoms. １ and R ２ and R ３ may be the same or different.) 【Chemistry 5】 (wherein Ar is an aryl group in formula (1), and R is an R ３ It is.) 【Chemistry 6】 (wherein Ar is an aryl group in formula (1), and R is an R ３ It is.)

3. The acid catalyst is MX ３ (wherein M is selected from the group consisting of typical metals of Groups 12-15 of the Periodic Table, and X is chlorine, a methyl group, an alkoxy group (OR ４ In addition, R of an alkoxy group is selected from the group consisting of ４ is selected from an alkyl group having 1 to 4 carbon atoms.

4. The method for producing a diaryl ether compound according to claim 2 or 3, wherein the aryl enol ether synthesis step is carried out under heating in the presence of an organic solvent.

5. The method for producing a diaryl ether compound according to any one of claims 1 to 3, wherein the diaryl ether synthesis step is a step of using the oxidizing agent, and is a step of obtaining a diaryl ether compound by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone as the oxidizing agent.

6. The method for producing a diaryl ether compound according to claim 4, wherein the diaryl ether synthesis step is a step of using the oxidizing agent, and is a step of obtaining a diaryl ether compound by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone as the oxidizing agent.

7. The method for producing a diaryl ether compound according to any one of claims 1 to 3, wherein the diaryl ether synthesis step is a step using the oxidation catalyst, and is a step of obtaining a diaryl ether compound using a transition metal catalyst containing at least palladium as the oxidation catalyst.

8. The method for producing a diaryl ether compound according to claim 4, wherein the diaryl ether synthesis step is a step using the oxidation catalyst, and is a step of obtaining a diaryl ether compound using a transition metal catalyst containing at least palladium as the oxidation catalyst.

9. The method for producing a diaryl ether compound according to claim 7 , wherein the diaryl ether synthesis step further comprises using a hydrogen scavenger to obtain a diaryl ether compound.

10. The method for producing a diaryl ether compound according to claim 8 , wherein the diaryl ether synthesis step is a step of obtaining a diaryl ether compound by further using a hydrogen scavenger.

11. The method for producing a diaryl ether compound according to claim 4, wherein the aryl enol ether synthesis step and the diaryl ether synthesis step are carried out continuously in one reactor.

12. The method for producing a diaryl ether compound according to claim 6, wherein the aryl enol ether synthesis step and the diaryl ether synthesis step are carried out continuously in one reactor.

13. The method for producing a diaryl ether compound according to claim 8, wherein the aryl enol ether synthesis step and the diaryl ether synthesis step are carried out continuously in one reactor.

14. The method for producing a diaryl ether compound according to claim 10, wherein the aryl enol ether synthesis step and the diaryl ether synthesis step are carried out continuously in one reactor.

15. The method for producing a diaryl ether compound according to claim 4, wherein in the aryl enol ether synthesis step, the aryl enol ether is obtained while removing the eliminated alkyl alcohol.

16. An apparatus for use in the method for producing a diaryl ether compound according to claim 15, comprising: a reactor containing the phenol, the cyclohexanone dialkyl ketal, the organic solvent, and the acid catalyst; an incubator for maintaining the reactor at a predetermined temperature; a cooler connected to the reactor for refluxing the organic solvent evaporated by heating to the predetermined temperature; A liquid reservoir connected to a cooler and equipped with an adsorbent for removing the desorbed alkyl alcohol. An apparatus comprising:

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