Biaryl compound production method

Abstract

Provided is a biaryl compound production method including: producing a benzyne compound from a precursor of a benzyne compound; subjecting the benzyne compound and a furan compound to a Diels-Alder reaction to produce a condensed ring compound containing a 1,4-epoxy-1,4-dihydrobenzene ring; and subjecting the condensed ring compound and a halogenated aryl compound to a cross-coupling reaction to produce a biaryl compound.

Description

Method for producing biaryl compounds

[0001] The present invention relates to a method for producing a biaryl compound.

[0002] It is known that a cross-coupling reaction between an aryl halide compound and a naphthaleneboronic acid compound as reaction substrates is carried out to obtain a biaryl compound by introducing a naphthalene ring into an aryl halide compound. For example, Patent Document 1 describes a method in which an aromatic diazonium salt produced by diazotizing 5-bromoanthranilic acid is subjected to a Diels-Alder reaction with furan to obtain 6-bromo-1,4-epoxy-1,4-dihydronaphthalene. Furthermore, this 6-bromo-1,4-epoxy-1,4-dihydronaphthalene is used as a reaction substrate to obtain 2,8-dibromonaphthacene, which is then subjected to a cross-coupling reaction with 1-naphthylboronic acid to obtain the biaryl compound 2,8-dinaphthylnaphthacene. However, the 1-naphthylboronic acid and other fused polycyclic aromatic boronic acid compounds used in this coupling reaction are expensive, limiting the cost reduction potential of the production of biaryl compounds by this reaction.

[0003] In the Diels-Alder reaction, the aromatic diazonium salt generated from 5-bromoanthranilic acid functions as a precursor of an o-benzyne compound (a compound that generates an o-benzyne compound). That is, in Patent Document 1, the brominated o-benzyne generated by heating the aromatic diazonium salt to 70°C undergoes a Diels-Alder reaction with furan to generate the above-mentioned 6-bromo-1,4-epoxy-1,4-dihydronaphthalene.

[0004] Precursors of o-benzyne compounds themselves are widely known. In addition to aromatic diazonium salts generated from anthranilic acid compounds such as the above-mentioned 5-bromoanthranilic acid, for example, monohalogenobenzene compounds, o-dihalogenobenzene compounds, 2-(halogeno)phenyl trifluoromethanesulfonate compounds, and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate compounds are used as precursors of o-benzyne compounds in various Diels-Alder reactions.

[0005] International Publication No. 2021 / 078217

[0006] An object of the present invention is to provide a method for producing a biaryl compound, which comprises introducing a fused polycyclic aromatic structure into a halogenated aryl compound to obtain a target biaryl compound without using an expensive reagent such as a fused polycyclic aromatic boronic acid compound as a reaction substrate.

[0007] The present inventors have conducted extensive research in light of the above-mentioned problems. As a result, they have found that by performing a cross-coupling reaction between a fused ring compound containing a 1,4-epoxy-1,4-dihydrobenzene ring, obtained by the Diels-Alder reaction of an o-benzyne compound with a furan compound, and a halogenated aryl compound, the fused ring compound bonds to the halogen bond site of the halogenated aryl compound at a specific site, and then the epoxy group is cleaved to form a conjugated structure, thereby yielding the desired biaryl compound. The present invention was completed through further research based on these findings.

[0008] The above-mentioned problems of the present invention are solved by the following means. [1] A method for producing a biaryl compound, comprising: producing an o-benzyne compound from a precursor of the o-benzyne compound; subjecting the o-benzyne compound and a furan compound to a Diels-Alder reaction to produce a fused ring compound containing a 1,4-epoxy-1,4-dihydrobenzene ring; and subjecting the fused ring compound to a cross-coupling reaction with an aryl halide compound to produce a biaryl compound. [2] A method for producing a biaryl compound according to [1], wherein the precursor of the o-benzyne compound is an aromatic diazonium salt. [3] The method for producing a biaryl compound according to [1] or [2], comprises diazotizing an anthranilic acid compound under acidic conditions to obtain the aromatic diazonium salt, which is the precursor of the o-benzyne compound, and including a base in the reaction system for the Diels-Alder reaction. [4] A method for producing a biaryl compound according to [3], wherein the acidic conditions are established using an acid having a pKa of 0 or less. [5] A method for producing a biaryl compound according to [3] or [4], wherein the base is a hydroxide. [6] A method for producing a biaryl compound according to any one of [1] to [5], wherein the reaction temperature of the Diels-Alder reaction is 60°C or lower. [7] A method for producing a biaryl compound according to any one of [1] to [6], wherein the cross-coupling reaction is carried out in the presence of a catalyst, the catalyst comprising a palladium catalyst and / or a nickel catalyst. [8] A method for producing a biaryl compound according to any one of [1] to [7], wherein a reducing agent is used in the cross-coupling reaction, the reducing agent comprising zinc. [9] A method for producing a biaryl compound according to any one of [1] to [8], wherein the biaryl compound comprises an acene structure having 2 to 6 rings.

[10] A method for producing a biaryl compound according to [9], wherein the acene structure having 2 to 6 rings is a naphthalene structure or an anthracene structure.

[0009] In this specification, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the lower and upper limits.

[0010] In the present invention, the term "X compound" refers to not only the compound "X" itself but also a compound in which "X" has a substituent, provided that the effects of the present invention are not impaired. For example, "o-benzyne compound" refers to not only "o-benzyne" itself but also o-benzyne having a substituent, provided that the effects of the present invention are not impaired. Furthermore, the term "Y structure" refers to not only the chemical structure "Y" itself but also a structure in which "Y" has a substituent, provided that the effects of the present invention are not impaired. When there are multiple substituents as described above, the substituents may be bonded to each other to form a ring, provided that the effects of the present invention are not impaired. The ring formed may be an aromatic ring (preferably a benzene ring), an aliphatic ring, or a fused ring (preferably a naphthalene ring). Therefore, for example, "o-benzyne compound" includes a fused ring compound having two or more rings including an o-benzyne ring. Examples of the substituents (substituents that are not linked to each other to form a ring) include alkyl groups (preferably having 1 to 10 carbon atoms, more preferably having 1 to 6 carbon atoms, and even more preferably having 1 to 3 carbon atoms), alkoxy groups (preferably having 1 to 10 carbon atoms, more preferably having 1 to 6 carbon atoms, and even more preferably having 1 to 3 carbon atoms), halogen atoms (for example, fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms), acyl groups (preferably having 2 to 10 carbon atoms, more preferably having 2 to 6 carbon atoms, and even more preferably having 2 or 3 carbon atoms), and alkoxycarbonyl groups (preferably having 2 to 10 carbon atoms, more preferably having 2 to 6 carbon atoms, and even more preferably having 2 or 3 carbon atoms). These substituents may further have a substituent.

[0011] In the present invention, the term "fused ring compound" refers to a compound having a fused polycyclic structure formed by the fusion of two or more monocyclic rings. This "fused ring compound" is preferably a compound in which the fused polycyclic structure formed by the fusion of two or more monocyclic rings is linear (a compound in which the fusion direction is linear).

[0012] In the present invention, a "biaryl compound" refers to a compound having a structure in which aromatic hydrocarbon rings are linked together by a single bond. This aromatic hydrocarbon ring may be a monocyclic ring or a fused ring. In addition, a compound having a structure in which an aromatic hydrocarbon ring in a fused ring structure in which an aromatic hydrocarbon ring and an aliphatic ring are fused together is linked by a single bond to another aromatic hydrocarbon ring, or to another aromatic hydrocarbon ring in a fused ring structure in which an aromatic hydrocarbon ring and an aliphatic ring are fused together is also a "compound having a structure in which aromatic hydrocarbon rings are linked together by a single bond" (i.e., a biaryl compound). In the present invention, a "biaryl compound" is not limited to a compound having one "structure in which aromatic hydrocarbon rings are linked together by a single bond," and compounds having two or more "structures in which aromatic hydrocarbon rings are linked together by a single bond" are also included in the "biaryl compound."

[0013] According to the method for producing a biaryl compound of the present invention, when a fused polycyclic aromatic structure is introduced into a halogenated aryl compound to obtain a target biaryl compound, the target biaryl compound can be obtained without using an expensive reaction substrate such as a fused polycyclic aromatic boronic acid compound.

[0014] [Method for Producing Biaryl Compounds] In the method for producing biaryl compounds of the present invention (hereinafter also referred to as the "production method of the present invention"), first, an o-benzyne compound is produced from an o-benzyne compound precursor, and then this o-benzyne compound is subjected to a Diels-Alder reaction with a furan compound to produce a fused ring compound (cycloadduct) containing a 1,4-epoxy-1,4-dihydrobenzene ring. Furthermore, this fused ring compound is subjected to a cross-coupling reaction with an aryl halide compound to produce the target biaryl compound. Each reaction constituting the production method of the present invention will be described below.

[0015] Precursors of o-benzyne compounds are known, and those that produce o-benzyne compounds upon the action of external stimuli or reagents can be widely used as precursors of o-benzyne compounds in the present invention. For example, aromatic diazonium salts (diazonium salts having a structure in which a carboxy group is bonded to the 1-position of the benzene ring and a diazo group is bonded to the 2-position) obtained by reacting a nitrite compound, which is a diazotizing agent, with an anthranilic acid compound under acidic conditions can be suitably used as precursors of o-benzyne compounds. Nitrite ester compounds are suitable for use as such nitrite compounds. Examples of nitrite ester compounds that can be used include alkyl nitrites (the alkyl group preferably has 1 to 10 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms). For example, isoamyl nitrite is a well-known diazotizing agent. In addition to the above aromatic diazonium salts, it is known that monohalogenobenzene compounds, o-dihalogenobenzene compounds, trifluoromethanesulfonate-2-(halogeno)phenyl compounds, trifluoromethanesulfonate-2-(trimethylsilyl)phenyl compounds, and the like function as precursors of o-benzyne compounds.

[0016] When the aromatic diazonium salt is used as a precursor of an o-benzyne compound, the o-benzyne compound can be efficiently produced by treating the salt at a high temperature of about 70° C. or higher. Furthermore, the present inventors discovered during the course of their investigations into the present invention that when the aromatic diazonium salt is used as a precursor of an o-benzyne compound, the benzyne compound can be produced with high efficiency even at a lower temperature by adding a base, as described below.

[0017] When the monohalogenobenzene compound is used as a precursor of an o-benzyne compound, the o-benzyne compound can be produced by dehydrogenating the ortho-position relative to the carbon atom to which the halogen atom is bonded, for example, by the action of lithium diisopropylamide. The halogen atom contained in the monohalogenobenzene compound is preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and more preferably a chlorine atom or a bromine atom.

[0018] When the above-mentioned o-dihalogenobenzene compound is used as a precursor of an o-benzyne compound, the o-benzyne compound can be produced, for example, via a monolithiation product produced by the action of an alkyllithium (preferably butyllithium, more preferably n-butyllithium). The halogen atom contained in the o-dihalogenobenzene compound is preferably a chlorine atom, a bromine atom, or an iodine atom.

[0019] When the above-mentioned trifluoromethanesulfonate-2-(halogeno)phenyl compound is used as a precursor of the o-benzyne compound, the o-benzyne compound can be produced, for example, via a monolithiation product produced by the action of the above-mentioned alkyllithium. The halogen atom contained in the trifluoromethanesulfonate-2-(halogeno)phenyl compound is preferably a chlorine atom, a bromine atom, or an iodine atom.

[0020] When a trifluoromethanesulfonate-2-(trimethylsilyl)phenyl compound is used as a precursor of an o-benzyne compound, the o-benzyne compound can be produced, for example, through desilylation by the action of tetrabutylammonium fluoride.

[0021] Among these, aromatic diazonium salts obtained by diazotizing an anthranilic acid compound are preferred in that the starting anthranilic acid compound is inexpensive, an o-benzyne compound can be produced with high efficiency, and as a result, a fused ring compound containing a 1,4-epoxy-1,4-dihydrobenzene ring can be obtained in high yield by the subsequent Diels-Alder reaction.

[0022] Therefore, a preferred embodiment of the production method of the present invention includes, as a pre-step for producing an o-benzyne compound from a precursor of the o-benzyne compound, diazotizing an anthranilic acid compound under acidic conditions to obtain an aromatic diazonium salt. This diazotization reaction itself is known, and the reaction temperature and reaction time used in ordinary diazotization reactions can be adopted in the present invention as well.

[0023] Diazotizing an anthranilic acid compound under acidic conditions to produce an aromatic diazonium salt, followed by adding a furan compound and a base to carry out the Diels-Alder reaction, efficiently produces an o-benzyne compound without high temperatures, allowing the Diels-Alder reaction to proceed efficiently. This finding was previously unknown and was discovered through the studies of the present inventors. While the reason why the Diels-Alder reaction is made more efficient by adding a base is unclear, one possible reason is that decarboxylation occurs when the carboxy group contained in the aromatic diazonium salt is converted to a carboxy anion under basic conditions, facilitating subsequent denitrogenation. When combining a diazotization reaction under acidic conditions with a Diels-Alder reaction with the addition of a base, the reaction temperature of the Diels-Alder reaction can be set to, for example, 60°C or below, or alternatively, 55°C or below, or even 50°C or below. Even when the Diels-Alder reaction is carried out at a relatively low temperature, the desired fused ring compound containing a 1,4-epoxy-1,4-dihydrobenzene ring can be obtained in high yield. The reaction temperature is usually 30° C. or higher, preferably 35° C. or higher, and more preferably 40° C. or higher. Therefore, when a diazotization reaction under acidic conditions is combined with a Diels-Alder reaction in which a base is added, the reaction temperature for the Diels-Alder reaction is preferably 30 to 60° C., more preferably 35 to 55° C., and even more preferably 40 to 50° C. From the viewpoint of further suppressing side reactions in the Diels-Alder reaction, it is preferable to add a furan compound to the generated aromatic diazonium salt and then add a base.

[0024] In the diazotization reaction under acidic conditions, it is preferable to create acidic conditions using an acid (strong acid) with a pKa of 0 or less. In the present invention, the "pKa" can be a calculated value according to Advanced Chemistry Development (ACD / Labs) Software V11.02 (1994-2014 ACD / Labs) or a value described in literature (e.g., J. Phys. Chem. A 2011, 115, 6641-6645, etc.). Examples of acids with a pKa of 0 or less include hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, hydroiodic acid, hydrobromic acid, and nitric acid, and one or more of these can be used. Furthermore, it is preferable that the base added in the Diels-Alder reaction be a strong base. The strong base more reliably converts the carboxyl group of the aromatic diazonium salt into a salt state, enabling more efficient production of o-benzyne. Hydroxides are preferred as the base. For example, potassium hydroxide, sodium hydroxide, ammonium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, etc. can be preferably used.

[0025] Preferred specific examples of the anthranilic acid compound from which the above aromatic diazonium salt is derived are shown below: Me represents methyl.

[0026]

[0027] Preferred specific examples of the furan compound are shown below.

[0028]

[0029] In the Diels-Alder reaction, the molar ratio of the amount of the precursor of the o-benzyne compound to the amount of the furan compound used is preferably 0.1 / 10 to 10 / 10, more preferably 0.5 / 10 to 8 / 10, even more preferably 1 / 10 to 6 / 10, and even more preferably 1.2 / 10 to 4 / 10. The reaction time for the Diels-Alder reaction can be appropriately set depending on the reaction temperature and other factors. For example, in the case of a batch reaction, the reaction time can be approximately 10 minutes to 2 hours. Furthermore, when a flow reaction, as described below, is employed, the reaction can be carried out sufficiently even in a shorter time.

[0030] The above-mentioned processes from the production of the o-benzyne compound to the Diels-Alder reaction may be carried out in a batch system or a flow system. When the reaction solution can be kept in a solution state, a flow system is preferably used, since it allows the continuous production of a fused ring compound containing a 1,4-epoxy-1,4-dihydrobenzene ring.

[0031] For example, when 1-bromo-2-chlorobenzene is used as the precursor of the o-benzyne compound and furan is used as the furan compound, the following flow reaction system can be constructed. An o-bromochlorobenzene solution and an n-butyllithium solution flowing through separate flow paths are joined together. As this combined solution flows downstream, the bromine atoms are replaced with lithium atoms to produce a monolithiated product. This combined solution is then joined with a furan solution flowing through another flow path. As this combined solution flows downstream, a Diels-Alder reaction can occur between the o-benzyne compound produced from the monolithiated product and furan. If necessary, this combined solution can be joined with a quenching agent such as methanol to obtain the desired 1,4-epoxy-1,4-dihydronaphthalene. In this flow reaction system, the reaction temperature for monolithiation is controlled to a low temperature, for example, −40°C or lower. Furthermore, it is preferable to raise the temperature during the Diels-Alder reaction; for example, it is preferable to raise the temperature to about −30°C or higher to carry out the Diels-Alder reaction. In the above reaction, an organic solvent capable of dissolving the above starting materials or reagents can be used as the solvent, such as tetrahydrofuran or a hydrocarbon solvent.

[0032] Furthermore, when 2-(trimethylsilyl)phenyl trifluoromethanesulfonate is used as the precursor of the o-benzyne compound and furan is used as the furan compound, the following flow reaction system can be constructed, for example. A solution of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate and furan is circulated through a flow path, while a tetra-n-butylammonium fluoride solution is circulated through another flow path. These solutions are then combined. As the combined solution flows downstream, a Diels-Alder reaction can be carried out between the o-benzyne compound produced through desilylation of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate and furan, thereby obtaining the target 1,4-epoxy-1,4-dihydronaphthalene. In this flow reaction system, the reaction temperature of the Diels-Alder reaction is preferably controlled, for example, to about −40 to −10°C. In the above reaction, an organic solvent capable of dissolving the above-mentioned raw materials or reagents can be used as the solvent. For example, tetrahydrofuran, a hydrocarbon solvent, etc. can be used.

[0033] Next, the cross-coupling reaction between the fused ring compound containing a 1,4-epoxy-1,4-dihydrobenzene ring obtained by the Diels-Alder reaction (sometimes simply referred to as a "fused ring compound") and a halogenated aryl compound will be described.

[0034] The cross-coupling reaction is usually carried out in the presence of a catalyst. Examples of the catalyst include Pd (palladium) catalysts, Ni (nickel) catalysts, Cu (copper) catalysts, and Fe (iron) catalysts. Among these, Pd catalysts and / or Ni catalysts are preferred. Examples of Pd catalysts that can be used in various coupling reactions include bis(triphenylphosphine)palladium(II) dichloride, palladium(II) chloride, palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)palladium(0), and [1,2'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Similarly, the Ni catalyst may be a catalyst used in various coupling reactions, such as bis(triphenylphosphine)nickel(II) dichloride, nickel(II) chloride, [1,3-bis(diphenylphosphino)propane]dichloronickel(II), [1,2-bis(diphenylphosphino)ethane]dichloronickel(II), nickel(II) acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloronickel(II), etc. One type of catalyst may be used, or two or more types may be used in combination.

[0035] The cross-coupling reaction is usually carried out using a reducing agent. Examples of the reducing agent include zinc, magnesium, diisobutylaluminum hydride, n-butyllithium, and triphenylphosphine. Among these, zinc is preferred from the viewpoint of improving yield. One reducing agent may be used, or two or more reducing agents may be used in combination.

[0036] The cross-coupling reaction is preferably carried out in the presence of a base. A wide variety of bases that can be used in general cross-coupling reactions can be used as the base. From the viewpoint of reaction efficiency, organic amine compounds are preferred. For example, trialkylamines (the number of carbon atoms in the alkyl group is preferably 1 to 10, more preferably 1 to 8, even more preferably 2 to 6, and even more preferably 2 to 4), triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylbenzylamine, etc. are suitable bases, and triethylamine is particularly suitable.

[0037] In the cross-coupling reaction, the ratio of the amount of the fused ring compound to the amount of the aryl halide compound can be approximately determined based on stoichiometry. For example, when the number of halogen atoms in the aryl halide compound is 1, the molar ratio of the amount of the fused ring compound to the amount of the aryl halide compound is preferably 0.1 / 1 to 10 / 1, more preferably 0.5 / 1 to 5 / 1, and even more preferably 1 / 1 to 2 / 1.

[0038] The reaction temperature of the cross-coupling reaction is not particularly limited as long as the desired reaction proceeds. For example, it can be 60 to 150°C, preferably 80 to 130°C, and more preferably 100 to 120°C. The reaction time of the cross-coupling reaction is also not particularly limited as long as the desired reaction proceeds. For example, it can be 0.5 to 10 hours, or alternatively, 1 to 8 hours, and preferably 2 to 6 hours.

[0039] After the cross-coupling reaction is completed, the target biaryl compound can be obtained in the reaction mixture. This biaryl compound can be subjected to treatments such as washing, concentration, and purification as needed.

[0040] The biaryl compound obtained by the production method of the present invention contains a fused polycyclic aromatic structure derived from a fused ring compound containing a 1,4-epoxy-1,4-dihydrobenzene ring. This fused polycyclic aromatic structure is preferably an acene structure having 2 to 6 rings, and particularly preferably a naphthalene structure or an anthracene structure. Preferred specific examples of the biaryl compound obtained by the production method of the present invention are shown below, but the present invention is not limited to these unless otherwise specified in the present invention. Me represents methyl and Et represents ethyl.

[0041]

[0042] The present invention will be described in more detail based on examples, but the present invention should not be construed as being limited to these examples except as defined in the present invention.

[0043] Example 1 1,4-epoxy-1,4-dihydronaphthalene (referred to as "epoxydihydronaphthalene 1") was prepared according to the following reaction scheme.

[0044]

[0045] The preparation of epoxydihydronaphthalene 1 will be specifically described. A calcium chloride tube was attached to a 500 mL three-neck flask, and 200 mL of dehydrated tetrahydrofuran (dehydrated THF) and 5 g of anthranilic acid were added to the three-neck flask. After dissolving the anthranilic acid, 3.85 g of methanesulfonic acid (MsOH) was added dropwise to the three-neck flask while maintaining the solution at 0-10°C. Then, 6.41 g of isoamyl nitrite was added dropwise to the three-neck flask. The temperature was then raised to room temperature (25°C) and stirred for 30 minutes. Thus, an aromatic diazonium salt, a precursor to benzyne, was obtained in the solution. Disappearance of the anthranilic acid was confirmed by thin-layer chromatography (TLC). 12.4 g of furan was added to the three-neck flask, followed by 8.86 g of a 30% by weight potassium hydroxide solution (solvent: methanol). The mixture was heated to 45°C and stirred for 1 hour. This allowed a Diels-Alder reaction to proceed between the benzyne and furan generated from the aromatic diazonium salt, producing epoxydihydronaphthalene 1, a fused ring compound containing a 1,4-epoxy-1,4-dihydrobenzene ring, in the reaction mixture. The mixture was then cooled to 10-20°C, and 50 mL of a 20% by weight aqueous solution of sodium chloride was added dropwise to the three-neck flask. The reaction mixture was then transferred to a separatory funnel and the aqueous layer was removed. 500 μL of dimethylformamide (DMF) and 10 g of magnesium sulfate were added to the organic layer, and the organic layer was dried. The magnesium sulfate was then removed by filtration, and the resulting solution was concentrated to yield epoxydihydronaphthalene 1 (80% yield, 45% solids by weight). The presence of epoxydihydronaphthalene 1 was confirmed by high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and liquid chromatography / mass spectrometry (LC / MS).

[0046] According to the following reaction scheme, biaryl compound 1 having the following structure was prepared.

[0047]

[0048] The preparation of biaryl compound 1 will be specifically described. In a 50 mL three-neck flask, 0.22 g of 2-bromonaphthalene as an aryl halide compound, 0.41 g (1.2 equivalents relative to 2-bromonaphthalene) of the epoxydihydronaphthalene 1 (45% by mass solution) prepared above, 38.7 mg of zinc as a reducing agent, and bis(triphenylphosphine)palladium(II) dichloride (PdCl ) as a catalyst were added. ２ (PPh ３ ) ２ 20.8 mg of 2-(2-methyl-2-propanol) and 4 mL of DMF were added to the flask, and the atmosphere inside the flask was then replaced with nitrogen. 0.41 mL of triethylamine (TEA) was then added as a base to the flask, and the mixture was stirred at 110°C for 4 hours to carry out a cross-coupling reaction. The target biaryl compound 1 was thus obtained (HPLC yield: 80%). The "HPLC yield" was calculated using the following formula, using the following HPLC apparatus under the following operating conditions, and a calibration curve prepared using a standard sample of biaryl compound 1. Apparatus: Prominence Series (Shimadzu Corporation) Detector: UV / VIS absorption detector SPD-20A, 210 nm or 254 nm Column: Shiseido CAPCELL PAK C1, TYPE: UG120 5 μm, SIZE: 4.6φ×250 mm Column oven: 40°C Mobile phase A: water, 0.1% phosphoric acid, 0.1% triethylamine Mobile phase B: acetonitrile Mobile phase concentration gradient: 0.01 min (B 30%), 15.00 min (B 100%), 15.01 min (B 30%), 20.00 min (B 30%) HPLC production rate (%) = 100 × [yield of biaryl compound 1 determined from the calibration curve] / [theoretical yield of biaryl compound 1 calculated based on the amount charged]

[0049] [Example 2] Biaryl compound 2 having the following structure was obtained in the same manner as in Example 1, except that 4-bromoanisole was used instead of 2-bromonaphthalene as shown below in the preparation of biaryl compound 1 in Example 1 (HPLC yield: 50%).

[0050]

[0051] Example 3 Biaryl compound 3 having the following structure was obtained in the same manner as in Example 1, except that ethyl 4-bromobenzoate was used instead of 2-bromonaphthalene, as shown below (HPLC yield: 68%). Et represents ethyl.

[0052]

[0053] Example 4 Biaryl compound 4 having the following structure was obtained in the same manner as in Example 1, except that in the preparation of biaryl compound 1 in Example 1, 9,10-dibromoanthracene was used instead of 2-bromonaphthalene, as shown below, and epoxydihydronaphthalene 1 was used in an amount of 2.4 equivalents relative to 9,10-dibromoanthracene (HPLC yield: 40%).

[0054]

[0055] Example 5 Biaryl compound 5 having the following structure was obtained in the same manner as in Example 1, except that in the preparation of biaryl compound 1 in Example 1, 3,6-dibromofluorenone was used instead of 2-bromonaphthalene, and epoxydihydronaphthalene 1 was used in an amount of 2.4 equivalents relative to 3,6-dibromofluorenone (HPLC yield: 93%).

[0056]

[0057] [Example 6] As shown in the following reaction scheme, 6-methyl-1,4-epoxy-1,4-dihydronaphthalene (referred to as "epoxydihydronaphthalene 2") was obtained in the same manner as in the preparation of epoxydihydronaphthalene 1 of Example 1, except that 2-amino-5-methylbenzoic acid was used instead of anthranilic acid (yield 61%, solid content 49% by mass).

[0058]

[0059] As shown in the following reaction scheme, a methylated biaryl compound mainly composed of biaryl compound 6 having the following structure was obtained (HPLC production yield: 28%) in the same manner as in Example 5, except that in the preparation of biaryl compound 5 in Example 5, the epoxydihydronaphthalene 2 prepared above was used instead of epoxydihydronaphthalene 1.

[0060]

[0061] Example 7 As shown in the following reaction scheme, 1-methyl-1,4-epoxy-1,4-dihydronaphthalene (referred to as "epoxydihydronaphthalene 3") was obtained (yield 28%, solid content 18% by mass) in the same manner as in the preparation of epoxydihydronaphthalene 1 of Example 1, except that 2-methylfuran was used instead of furan.

[0062]

[0063] As shown in the following reaction scheme, a methylated biaryl compound mainly composed of biaryl compound 7 having the following structure was obtained (HPLC production yield: 76%) in the same manner as in Example 5, except that in the preparation of biaryl compound 5 in Example 5, the epoxydihydronaphthalene 3 prepared above was used instead of epoxydihydronaphthalene 1.

[0064]

[0065] Example 8 Biaryl compound 8 having the following structure was obtained in the same manner as in Example 5, except that in the preparation of biaryl compound 5 in Example 5, 2,7-dibromofluorenone was used instead of 3,6-dibromofluorenone, and epoxydihydronaphthalene 1 was used in an amount of 2.4 equivalents relative to 2,7-dibromofluorenone (HPLC yield: 80%).

[0066]

[0067] Example 9 Biaryl compound 9 having the following structure was obtained in the same manner as in Example 1, except that 4-bromobenzophenone was used instead of 2-bromonaphthalene as shown below in the preparation of biaryl compound 1 in Example 1 (HPLC yield: 91%).

[0068]

[0069] Example 10 In the preparation of biaryl compound 1 in Example 1, the catalyst was changed as follows to obtain biaryl compound 1. In a 50 mL three-neck flask, 122.5 mg of 2-bromonaphthalene as an aryl halide compound, 0.41 g of the epoxydihydronaphthalene 1 (45% by mass solution) prepared above, 100.6 mg of zinc, bis(triphenylphosphine)nickel(II) dichloride (NiCl ２ (PPh ３ ) ２ 38.7 mg of methyl 2-methylpropanol, 116.4 mg of triphenylphosphine, and 4 mL of DMF were added, and the atmosphere in the three-neck flask was then replaced with nitrogen. Subsequently, 0.41 mL of triethylamine (TEA) was added to the three-neck flask, and the mixture was stirred at 110°C for 4 hours to undergo a cross-coupling reaction. Ethyl acetate was added to the reaction solution, and the organic layer was washed with 1N hydrochloric acid and brine. The organic layer was dried over magnesium sulfate, concentrated, and purified using a column to obtain the desired biaryl compound 1 (HPLC yield: 80%).

[0070]

[0071] [Example 11] Biaryl compound 1 was obtained in the same manner as in Example 10, except that magnesium was used instead of zinc as the reducing agent and triphenylphosphine was not used (HPLC yield: 50%).

[0072]

[0073] Example 12 Biaryl compound 1 was obtained in the same manner as in Example 10, except that diisobutylaluminum hydride (DIBAH) was used instead of zinc as the reducing agent and triphenylphosphine was not used (HPLC yield: 30%).

[0074]

[0075] Example 13 Biaryl compound 1 was obtained in the same manner as in Example 10, except that n-butyllithium was used instead of zinc as the reducing agent and triphenylphosphine was not used (HPLC yield: 20%).

[0076]

[0077] Example 14 Biaryl compound 1 was obtained in the same manner as in Example 10, except that potassium phosphate was used as the base instead of triethylamine (HPLC yield: 20%).

[0078]

[0079] Example 15 Biaryl compound 1 was obtained in the same manner as in Example 10, except that sodium carbonate was used as the base instead of triethylamine (HPLC yield: 11%).

[0080]

[0081] Example 16 Biaryl compound 1 was obtained in the same manner as in Example 10, except that potassium hydroxide was used as the base instead of triethylamine (HPLC yield: 20%).

[0082]

[0083] Example 17 As shown in the following reaction scheme, 1,4-epoxy-1,4-dihydroanthracene (referred to as "epoxydihydroanthracene") was prepared in the same manner as in the preparation of epoxydihydronaphthalene 1 in Example 1, except that 3-amino-2-naphthoic acid was used instead of anthranilic acid (yield: 50%, solid content: 40% by mass).

[0084]

[0085] As shown in the following reaction scheme, biaryl compound 10 having the following structure was prepared in the same manner as in Example 1, except that the epoxydihydroanthracene prepared above was used instead of epoxydihydronaphthalene 1 in the preparation of biaryl compound 1 in Example 1 (HPLC yield: 50%).

[0086]

[0087] Example 18 Biaryl compound 11 having the following structure was obtained in the same manner as in Example 1, except that 5-bromo-1,10-phenanthroline was used instead of 2-bromonaphthalene in the preparation of biaryl compound 1 in Example 1 (HPLC yield: 17%).

[0088]

[0089] The above results demonstrate that the target biaryl compound can be obtained by the production method (novel synthesis route) of the present invention. Furthermore, a comparison of Examples 1 and 10 demonstrates that the target biaryl compound can be obtained in high yield regardless of whether a Pd catalyst or a Ni catalyst is used as the catalyst for the cross-coupling reaction. Furthermore, a comparison of Example 10 with Examples 11 to 13 demonstrates that the reducing agent used in the cross-coupling reaction affects the yield of the target biaryl compound, and that using zinc as the reducing agent in particular further increases the yield of the target biaryl compound. Furthermore, a comparison of Example 10 with Examples 14 to 16 demonstrates that the base used in the cross-coupling reaction affects the yield of the target biaryl compound.

[0090] While the present invention has been described in connection with embodiments thereof, we do not intend to limit our invention to any of the details of the description unless otherwise specified, and believe that the claims should be construed broadly without departing from the spirit and scope of the invention as set forth in the appended claims.

[0091] This application claims priority based on Japanese Patent Application No. 2023-202640, filed on November 30, 2023, the contents of which are incorporated herein by reference as part of the present specification.

Claims

1. A method for producing a biaryl compound, comprising: producing an o-benzyne compound from a precursor of the o-benzyne compound; subjecting the o-benzyne compound and a furan compound to a Diels-Alder reaction to produce a fused ring compound containing a 1,4-epoxy-1,4-dihydrobenzene ring; and subjecting the fused ring compound to a cross-coupling reaction with an aryl halide compound to produce a biaryl compound.

2. The method for producing a biaryl compound according to claim 1, wherein the precursor of the o-benzyne compound is an aromatic diazonium salt.

3. A method for producing a biaryl compound according to claim 1, comprising: diazotizing an anthranilic acid compound under acidic conditions to obtain an aromatic diazonium salt, which is a precursor of the o-benzyne compound; and including a base in the reaction system for the Diels-Alder reaction.

4. The method for producing a biaryl compound according to claim 3, wherein the acidic conditions are established using an acid having a pKa of 0 or less.

5. The method for producing a biaryl compound according to claim 4, wherein the base is a hydroxide.

6. The method for producing a biaryl compound according to claim 1, wherein the reaction temperature of the Diels-Alder reaction is 60° C. or lower.

7. The method for producing a biaryl compound according to claim 1, wherein the cross-coupling reaction is carried out in the presence of a catalyst, the catalyst comprising a palladium catalyst and / or a nickel catalyst.

8. The method for producing a biaryl compound according to claim 7, wherein a reducing agent is used in the cross-coupling reaction, and the reducing agent comprises zinc.

9. The method for producing a biaryl compound according to any one of claims 1 to 8, wherein the biaryl compound contains an acene structure having 2 to 6 rings.

10. The method for producing a biaryl compound according to claim 9, wherein the acene structure having 2 to 6 rings is a naphthalene structure or an anthracene structure.

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