A method for preparing biarylphenols with C1 symmetry

Abstract

This invention provides a method for preparing biarylphenols with C1 symmetry. The method includes: dissolving substituted arylphenol B in the reaction system under oxidizing conditions in a reaction solvent and in the presence of a catalyst; subsequently adding substituted arylphenol A in batches for a coupling reaction to obtain the biarylphenol with C1 symmetry; wherein the catalyst is a complex formed by the coordination of iron(III) with a naphthylphosphate ligand. This invention uses a catalyst formed by the coordination of a naphthylphosphate ligand with inexpensive metal Fe. Through the combination of functional groups on specific substituted arylphenol B and specific substituted arylphenol A, a highly efficient cross-coupling reaction can be achieved to obtain biarylphenols with C1 symmetry, avoiding the formation of self-coupling products. The overall preparation method is low-cost, safe and simple to operate, highly efficient, and can obtain high-purity biarylphenol products with C1 symmetry in high yield.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing biarylphenols with C1 symmetry. Background Technology

[0002] 2,2'-Biarylphenol derivatives, as an important subclass of axially chiral compounds, have irreplaceable application value in the field of high-end fine chemicals. They are mainly used as ligand skeletons for highly efficient asymmetric catalysts, precursors for phosphorus-containing chiral ligands, antioxidants in polymer materials, and intermediates for active pharmaceutical molecules. With the rapid development of homogeneous catalysis and the chiral pharmaceutical industry, the structural diversity and synthesis efficiency of these compounds have become key technological bottlenecks restricting industrial upgrading.

[0003] Current literature reports on the synthesis strategies of 2,2'-biarylphenols mainly focus on C2-symmetric structures, i.e., constructing a biaryl skeleton through the oxidative self-coupling reaction of the same phenolic compound. While these methods are technologically mature, the resulting products have limited structural diversity, making them insufficient for the current demands for precise catalyst design and diverse drug screening. Biarylphenols with C1 symmetry, constructed by cross-coupling two different phenolic compounds, exhibit unique performance advantages in asymmetric catalysis due to their structural asymmetry and tunable stereoelectronic effects, and have become a research hotspot in this field.

[0004] However, the synthesis of biarylphenols with C1 symmetry faces significant technical challenges. Traditional cross-coupling methods, lacking regioselectivity control, theoretically produce a mixture of C1-symmetric, C2-symmetric, and self-coupling products of the same phenol. This results in low target product selectivity, complex separation and purification routes, and high production costs, severely hindering their industrial application.

[0005] Existing technologies mainly propose three types of solutions to the above problems: (1) Noble metal catalytic cross-coupling method: Patents CN114181048A and CN113372201A use the Suzuki-Miyaura reaction. Although the yield is good, it requires the use of expensive palladium catalysts and the complex ligand structure, which results in the catalyst cost accounting for more than 40% of the total production cost.

[0006] (2) Organometallic reagent method: Although J. Am. Chem. Soc. 1992, 114, 8733 and J. Am. Chem. Soc. 1988, 110, 8153 have achieved the synthesis of C1 symmetrical biphenols catalyzed by inexpensive metals, they all require the use of high-risk organometallic reagents such as organolithium reagents or Grignard reagents, which have strict requirements for anhydrous and oxygen-free conditions in the reaction system, resulting in high risks for industrial-scale safe production.

[0007] (3) Peroxide oxidation method: Patent CN119874491A and others use hydrogen peroxide or tert-butyl hydrogen peroxide as oxidants. The active oxygen concentration is high and the reaction is exothermic, which poses a significant explosion safety hazard. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention discloses a method for preparing biarylphenols with C1 symmetry, thereby solving the technical problems of high cost, high safety risks, and high process difficulty in the existing preparation processes of biarylphenols with C1 symmetry.

[0009] To achieve the above technical objectives, this invention proposes a method for preparing biarylphenols with C1 symmetry. The method includes: under oxidizing conditions, dissolving substituted arylphenol B in the reaction system in a reaction solvent and in the presence of a catalyst, and then adding substituted arylphenol A in batches to carry out a coupling reaction to obtain the biarylphenol with C1 symmetry. The catalyst is a complex formed by the coordination of iron(III) with a naphthyl phosphate ligand; The substituted arylphenol A is a substituted phenol with substituents R1 to R5 on the benzene ring as shown in formula (1) or a substituted phenol with substituent R on the naphthalene ring as shown in formula (2). 11 -R 14 Substituted naphthols, and R1~R5 and R 11 -R 14 Each is independently selected from hydrogen, C1~C 10 Alkyl, C3~C 10 cycloalkyl, C1~C 10 Alkoxy, C6~C 14 Aryl, C2~C 10 alkenyl, C2~C 10 Alkyne, tri-C1-C6 alkylsilyl or halogen; Equation (1), Equation (2); The substituted arylphenol B is a benzene ring with substituents R6~R6 as shown in formula (3). 10 The substituted phenol or the naphthalene ring as shown in formula (4) has a substituent R. 15 ~R 18 Substituted naphthols, and R6~R 10 and R 15 ~R 18 Each group is independently selected from hydrogen, halogen, ester, acyl, aldehyde, cyano, or nitro groups; Equation (3), Equation (4).

[0010] In the above technical solution, a catalyst formed by the coordination of a naphthyl phosphate ligand with inexpensive metal Fe is used. A substituted aryl phenol A with a specific structure is added in multiple batches to a reaction system containing dissolved substituted aryl phenol B. Through the combination of functional groups on substituted aryl phenol B and substituted aryl phenol A, a highly efficient cross-coupling reaction can be achieved, and the formation of self-coupling products can be avoided. Simultaneously, the distance between the two reaction substrates is shortened by the regulation of the electron-rich ligand's electronegativity on the central metal Fe, and the steric hindrance of the reaction center site is restricted by the steric hindrance of the ligand, thereby improving the reaction activity and efficiency.

[0011] The research team hypothesizes that the cross-coupling reaction of C1-symmetric biarylphenols in this invention includes the following process: Fe(III) selectively oxidizes electron-rich substituted arylphenol A to generate a cationic free radical, which is then captured to form a Fe(II) complex; the concentration of substituted arylphenol B in the reaction system is much higher than that of substituted arylphenol A, prompting substituted arylphenol B to nucleophilically attack and couple with the coordinated substituted arylphenol A free radical, yielding a coupling intermediate; this intermediate is then oxidized and dehydrogenated by air to form a C1-symmetric biarylphenol product; Fe(II) is then oxidized by oxygen to regenerate Fe(III), completing the catalytic cycle. The overall reaction process effectively achieves high selectivity, requires no precious metal catalysts or peroxide oxidants, is inherently safe and low-cost, and is suitable for industrial production.

[0012] In a further example of the invention, the molar ratio of iron to the naphthyl phosphate ligand in the catalyst is 1:(3~6), based on iron element content. An appropriate excess of the naphthyl phosphate ligand promotes complete coordination of Fe(III) to avoid side reactions of uncoordinated iron salts. In an optional example of the invention, the molar ratio of iron to the naphthyl phosphate ligand in the catalyst is 1:3.

[0013] In a further example of the present invention, the naphthyl phosphate ligand is dinaphthol phosphate.

[0014] In a further example of the present invention, the preparation process of the catalyst was explored and optimized.

[0015] Optionally, the catalyst is prepared by reacting a trivalent iron salt with the naphthyl phosphate ligand in a mixed solvent containing trifluorotoluene and hexafluoroisopropanol in the presence of an inorganic base.

[0016] Further optionally, the trivalent iron salt is selected from at least one of ferric halides, ferric sulfate, ferric nitrate, ferric phosphate, ferric perchlorate, or their hydrates, and the raw materials are widely available and economical.

[0017] Further optionally, the inorganic base is selected from at least one of sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, and calcium oxide. The addition of the inorganic base can deprotonate to promote effective coordination, improve the catalyst preparation efficiency, and the formed alkali metal salt is easy to remove in the subsequent filtration step.

[0018] Further optionally, the molar ratio of the inorganic base to the ferric salt, calculated based on iron, is (1.5~10):1. An appropriate excess of the inorganic base can accelerate the deprotonation equilibrium shift, significantly shorten the coordination reaction time, and simultaneously buffer the pH of the system, inhibiting the oxidative decomposition of the ligand. In an optional example of the present invention, the molar ratio of the inorganic base to the ferric salt is (3~6):1.

[0019] Further optionally, the concentration of the ferric salt, calculated as elemental iron, is 1-10 mmol / L, which is the concentration of the ferric salt in the catalyst preparation reaction mixture. In an optional example of the present invention, the concentration of the ferric salt is 5-7 mmol / L.

[0020] Further optionally, the volume ratio of trifluorotoluene to hexafluoroisopropanol in the mixed solvent is (0.5~2):1. In this mixed solvent, the strongly polar solvent hexafluoroisopropanol can effectively dissolve iron salts, while the weakly polar trifluorotoluene can efficiently dissolve the naphthalenephosphate ligands. The good miscibility of trifluorotoluene and hexafluoroisopropanol provides a suitable reaction environment for the preparation of the catalyst used in this invention. Optimizing the volume ratio of trifluorotoluene to hexafluoroisopropanol in the mixed solvent can improve the dissolution efficiency of the raw materials, promote mass transfer, and improve coordination efficiency. In an optional example of this invention, the volume ratio of trifluorotoluene to hexafluoroisopropanol in the mixed solvent is 1:1.

[0021] Further optionally, the coordination reaction temperature is 20~80℃, preferably 40~60℃; the reaction time is 1~10h, preferably 3~5h.

[0022] Further optionally, the preparation of the catalyst further includes separating and purifying the reacted material; the separation and purification operation includes: (1) removing the mixed solvent from the reacted material to obtain a solid crude product; (2) dissolving and filtering the solid crude product with a haloalkane solvent to obtain a filtrate; (3) removing the haloalkane solvent from the filtrate to obtain the catalyst.

[0023] In step (2), the addition of a haloalkane solvent can dissolve the catalyst in the material after the removal of the mixed solvent, while the inorganic salts will not dissolve in the haloalkane solvent and can be removed by filtration; optionally, the haloalkane solvent is selected from at least one of dichloromethane and trichloromethane. In an optional example of the present invention, the haloalkane solvent is dichloromethane. Further optionally, the mass ratio of the haloalkane solvent to the crude solid product is (4~20):1, preferably (5~10):1, and even more preferably 10:1.

[0024] It should be noted that, according to the method of the present invention, after obtaining the filtrate containing the target catalyst, the solvent needs to be removed to obtain the solid catalyst product. The "removal of solvent" refers to the operation of separating the solvent phase from the solute (catalyst) using conventional solid-liquid separation methods in the art. The present invention does not limit the specific operation of removing the mixed solvent in step (1) or the specific operation of removing the haloalkane solvent in step (3). It can be selected by vacuum distillation (such as using a rotary evaporator), freeze drying (lyophilizer), atmospheric distillation, nitrogen blowing, etc. Those skilled in the art can choose the appropriate method as needed in actual work, which does not limit the scope of protection of the present invention.

[0025] In a further example of the invention, the alkyl, aryl, alkenyl and alkynyl groups may optionally be further substituted; alternatively, the alkyl, aryl, alkenyl and alkynyl groups may have further alkyl, alkoxy, or aryl substitutions.

[0026] In a further example of the invention, the types of substituted arylphenol A were explored and optimized. Optionally, R1~R5 and R 11 -R 14 Each of the following is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, trimethylsilyl, chlorine, or bromine. In an optional example of the invention, R1-R5 and R... 11 -R 14 Each is independently selected from hydrogen, phenyl, methoxy, 2-phenylethyl, methyl, bromine, tert-butyl, trimethylsilyl, and 2-phenylvinyl.

[0027] In a further example of the invention, the types of substituted arylphenol B were explored and optimized. Optionally, R6~R 10 and R 15 ~R 18 Each group is independently selected from hydrogen, fluorine, chlorine, bromine, C1-C6 alkyl ester, C1-C6 alkyl acyl, aldehyde, cyano, or nitro. In an optional example of the invention, R6-R... 10 and R 15 ~R18 Each group is independently selected from hydrogen, bromine, methyl formate (or methoxycarbonyl), acetyl, aldehyde, cyano, methyl, and nitro.

[0028] In a further example of the present invention, the molar ratio of the substituted arylphenol A to the substituted arylphenol B is 1:(1~5). An excess of substituted arylphenol B ensures that its concentration in the solution remains higher than that of substituted arylphenol A, driving the nucleophilic attack of substituted arylphenol B on the Fe(III)-substituted arylphenol A radical complex during the catalytic cycle, significantly improving the selectivity of the C1 symmetric product, while simultaneously suppressing the self-coupling side reaction of A. In an optional example of the present invention, the molar ratio of the substituted arylphenol A to the substituted arylphenol B is 1:(1~2).

[0029] In a further example of the present invention, the amount of catalyst, calculated based on iron, is 0.5% to 20% of the molar amount of the substituted arylphenol A. In an optional example of the present invention, the amount of catalyst is 1% to 5% of the molar amount of the substituted arylphenol A.

[0030] In a further example of the present invention, the reaction solvent is selected from at least one of toluene, xylene, diphenyl ether, dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, and 1,1,2-trichloroethane.

[0031] In a further example of the present invention, the concentration of the substituted arylphenol B is 0.05~2 mol / L. Controlling the substituted arylphenol B within a suitable concentration range is beneficial for regulating mass transfer and improving reaction efficiency. In an optional example of the present invention, the concentration of the substituted arylphenol B is 0.1~0.5 mol / L.

[0032] In a further example of the present invention, the reaction temperature of the coupling reaction is 0~100℃, preferably 20~80℃, more preferably 40~60℃; the reaction time is 30~74h, preferably 44~60h.

[0033] In a further example of the invention, the oxidation conditions are provided by an oxygen-containing atmosphere and / or an oxidizing agent. Optionally, the oxygen-containing atmosphere is selected from air, oxygen, or a mixture of oxygen and an inert gas. In an optional example of the invention, the oxygen-containing atmosphere is selected from air. Optionally, the oxidizing agent is at least one selected from hydrogen peroxide, tert-butanol peroxide, and peracetic acid; more preferably, the molar ratio of the oxidizing agent to the substituted arylphenol B is 1:(1~4), preferably 1:(2~4).

[0034] In a further example of the present invention, the method of adding the substituted arylphenol A to the reaction system was explored and optimized. Optionally, the substituted arylphenol A was added to the reaction system in three batches. More optionally, after adding the first batch of the substituted arylphenol A, the mixture was stirred for 5-12 hours, preferably 7-10 hours; after adding the second batch of the substituted arylphenol A, the mixture was stirred for 5-12 hours, preferably 7-10 hours; and after adding the third batch of the substituted arylphenol A, the mixture was stirred for 20-50 hours, preferably 30-40 hours. In an optional example of the present invention, the method of adding the substituted arylphenol A in batches was to add it in equal amounts in batches.

[0035] In a further example of the invention, the process further includes separating and purifying the reacted material to obtain a high-purity biarylphenol product with C1 symmetry. Optionally, the separation and purification includes column chromatography and / or recrystallization.

[0036] It should be noted that the column chromatography operation in this invention is used to separate the target product from the reaction product, and the specific operation of the column chromatography is not limited. Optionally, the column chromatography uses a silica gel column; further, the silica gel used in the silica gel column is 200-300 mesh; further, the mass ratio of the silica gel used in the silica gel column to the substituted arylphenol A is (10-100):1, preferably (20-80):1, more preferably (40-60):1; further, the eluent for the silica gel column is a mixed solution of dichloromethane, ethyl acetate, diethyl ether, acetone and n-hexane, with a volume ratio of 1:(1-10), preferably 1:(2-5).

[0037] It should be noted that the recrystallization operation in this invention is used for further purification of the target product; the specific recrystallization operation is not limited in this invention. Optionally, the solvent used in the recrystallization operation is selected from at least one of dichloromethane, n-hexane, acetonitrile, and acetone, or a mixture of dichloromethane and acetone, a mixture of dichloromethane and n-hexane, or a mixture of dichloromethane and acetonitrile; further optionally, when the solvent used in the recrystallization operation is a mixture of dichloromethane and acetonitrile, the mass ratio of dichloromethane to acetonitrile is 1:(1~20), preferably 1:(10~15).

[0038] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention uses a catalyst formed by the coordination of a naphthyl phosphate ligand and an inexpensive metal Fe. In a reaction system containing a substituted aryl phenol B with a specific structure, a substituted aryl phenol A with a specific structure is added in multiple batches. Through the combination of the functional groups on the substituted aryl phenol B and the substituted aryl phenol A, a highly efficient cross-coupling reaction can be achieved to obtain biaryl phenols with C1 symmetry, and the generation of self-coupling products can be avoided. The overall preparation method has low cost, is safe and simple to operate, has high reaction efficiency, and can obtain high-purity biaryl phenol products with C1 symmetry in high yield. Detailed Implementation

[0039] To facilitate understanding of the present invention, a more comprehensive description will be provided below, along with preferred embodiments. However, it should be understood that these embodiments are merely for more detailed explanation and should not be construed as limiting the invention in any way, i.e., not intended to limit the scope of protection of the invention.

[0040] Unless otherwise defined, the technical terms used in the following embodiments have the same meanings as commonly understood by those skilled in the art to which this invention pertains. Unless otherwise specified, the experimental reagents used in the following embodiments are conventional biochemical reagents; and the experimental methods described are conventional methods.

[0041] Furthermore, it should be noted that although the various steps of the preparation method of the present invention are described in a specific order in the description of the present invention, these orders are not restrictive. Without departing from the basic principles of the present invention, those skilled in the art can perform the steps in different orders.

[0042] Furthermore, the terms "first," "second," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined with "first," "second," etc., may explicitly or implicitly include one or more of that feature. In the description of this invention, unless otherwise stated, "multiple" or "at least one" means two or more.

[0043] All numerical designations, such as temperature, time, flow rate, and range, are approximate values. It should be understood that, while not always explicitly stated, all numerical designations are preceded by the term "approximately." It should also be understood that, while not always explicitly stated, the reagents described herein are merely examples, and their equivalents are known in the art.

[0044] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1–5” is disclosed, the described range should be interpreted as including ranges “1–4”, “1–3”, “1–2”, “1–2 and 4–5”, “1–3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0045] It should be noted that the naphthyl phosphate ligands involved in the preparation of the catalyst used in this invention are commercially available ligands, or they can be prepared in the laboratory, and this does not limit the scope of protection of this invention. For example, alternatively, dinaphthol phosphate can be prepared by the following method: (1) 75 mL of tetrahydrofuran and 35 mL of LDMF were added to a round-bottom flask. At 0 °C, 1.75 g of sodium hydride (60% kerosene mixture) was slowly added. 5 g of naphthol was added, and the mixture was stirred at room temperature for 2 h. Then, 3.3 mL of chloromethyl ether (MOM-Cl) was slowly added, and the mixture was stirred at room temperature for another 6 h. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The crude product was recrystallized to give 6.3 g of product M1, with a yield of 96%.

[0046] (2) 5g of tetrahydrofuran solution of M1 was cooled to -78℃, and 16mL of n-butyllithium n-hexane solution with a concentration of 2.5M was added. After reacting at 0℃ for 2h, 10.2g of iodine was added. After stirring at room temperature for 2h, saturated sodium thiosulfate solution was added to quench the reaction. The mixture was extracted with ethyl acetate and purified by column chromatography to obtain 6.6g of intermediate M2 with a yield of 79%.

[0047] (3) Dissolve 3g of intermediate M2 in 60mL of water / tetrahydrofuran solution (volume ratio 3:1), add 276mg of tetraphenylphosphine palladium, arylboronic acid (boric acid to M2 molar ratio of 2.2:1), and 1.15g of sodium hydroxide. After reacting at 80℃ for 6h, extract with ethyl acetate, and purify by column chromatography to obtain 2.53g of intermediate M3, yield 83%.

[0048] (4) 2.5g M3 was dissolved in 30mL of 1,4-dioxane, 6mL of 6N hydrochloric acid was added, and the mixture was reacted at 90℃ for 3h. The mixture was then neutralized with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and purified by column chromatography to obtain 1.96g intermediate M4, with a yield of 91%.

[0049] (5) 1.9 g of intermediate M4 was dissolved in 20 mL of pyridine, and 0.7 mL of phosphorus oxychloride POCl3 was slowly added. After stirring at room temperature for 10 min, the mixture was reacted at 90 °C for 2 h. After cooling, 20 mL of water was added, and the mixture was reacted at 90 °C for 2 h. After the reaction was completed, the mixture was extracted with dichloromethane, and the crude product was recrystallized from dichloromethane / n-hexane to give 1.98 g of ligand H-L, with a yield of 94%.

[0050] The reaction process is as follows: .

[0051] Example 1 A method for preparing a biarylphenol with C1 symmetry is as follows: 0.78 g of catalyst Fe(L)3 is dissolved in 500 mL of toluene; the mixture is stirred at 40 °C, and air is continuously bubbled into the system. 22.1 g of substituted arylphenol B1 is added to the system and stirred until dissolved; 3.7 g of substituted arylphenol A1 is added to the system, and the temperature is maintained while stirring for 7 h; another 3.7 g of substituted arylphenol A1 is added, and the mixture is stirred for 7 h; finally, another 3.7 g of substituted arylphenol A1 is added, and the mixture is stirred for 30 h; after the reaction is complete, the reaction solution is subjected to silica gel column chromatography using 440 g of silica gel. The silica gel column is washed with an eluent of ethyl acetate / n-hexane (volume ratio 1:2). The solvent in the filtrate is then removed to obtain a crude biarylphenol product P1 with C1 symmetry; after recrystallization using dichloromethane / acetonitrile (volume ratio 1:10) solvent, 18.7 g of the target product (pure) is obtained, with a yield of 85% and a purity of 99%. The reaction formula for this embodiment is as follows: .

[0052] The catalyst Fe(L)3 is prepared by dissolving FeCl3 and dinaphthol phosphate HL in a mixed solvent of trifluorotoluene / hexafluoroisopropanol (volume ratio 1:1), with a Fe ion concentration of 7 mmol / L. Inorganic base calcium carbonate is added in an amount of 3 molar equivalents of Fe salt, and the reaction is carried out at 50°C for 3 h to obtain the catalyst Fe(L)3.

[0053] Example 2

[0054] A method for preparing a biarylphenol with C1 symmetry, specifically: 0.78 g of catalyst Fe(L)3 is dissolved in 1000 mL of toluene; the mixture is stirred at 40 °C, and air is continuously bubbled into the system; 22.1 g of substituted arylphenol B2 is added to the system and stirred until dissolved; 2.9 g of substituted arylphenol A2 is added to the system, and the temperature is maintained while stirring for 7 h; another 2.9 g of substituted arylphenol A2 is added, and the mixture is stirred for 7 h; finally, 2.9 g of substituted arylphenol A is added. 2. Stir for 30 hours; then, pass the reaction solution through a short silica gel column chromatography using 348 g of silica gel. Wash the silica gel column with a dichloromethane / n-hexane (volume ratio 1:4) eluent. Remove the solvent from the filtrate to obtain the crude biarylphenol product P2 with C1 symmetry. Recrystallize using dichloromethane / acetonitrile (volume ratio 1:10) solvent to obtain 16.9 g of the target product in pure form, with a yield of 86% and a purity of 99%. The reaction formula for this example is as follows: .

[0055] The preparation process of the catalyst Fe(L)3 used in this embodiment is as follows: FeCl3 and dinaphthol phosphate HL are mixed and dissolved in a mixed solvent of trifluorotoluene / hexafluoroisopropanol (volume ratio 1:1), with a Fe ion concentration of 7 mmol / L. Inorganic base sodium carbonate is added in an amount of 3 molar equivalents of Fe salt, and the reaction is carried out at 40°C for 5 h to obtain the catalyst Fe(L)3.

[0056] Example 3

[0057] A method for preparing a biarylphenol with C1 symmetry is as follows: 1.55 g of catalyst Fe(L)3 is dissolved in 250 mL of toluene; the mixture is stirred at 60 °C, and air is continuously bubbled into the system. 20.2 g of substituted arylphenol B3 is added to the system and stirred until dissolved; then 4.1 g of substituted arylphenol A3 is added to the system, and the temperature is maintained while stirring for 7 h; another 4.1 g of substituted arylphenol A3 is added, and the mixture is stirred for 7 h; finally, 44.1 g of substituted arylphenol A3 is added, and the mixture is stirred for 30 h; the reaction solution is then subjected to silica gel column chromatography using 620 g of silica gel. The silica gel column is washed with an eluent of diethyl ether / n-hexane (volume ratio 1:5). The solvent in the filtrate is then removed to obtain a crude biarylphenol product P3 with C1 symmetry; recrystallization is performed using dichloromethane / acetonitrile (volume ratio 1:10) solvent to obtain 19.7 g of the target product in pure form, with a yield of 88% and a purity of 99%. The reaction formula for this embodiment is as follows: .

[0058] The preparation process of the catalyst Fe(L)3 used in this embodiment is as follows: FeCl3 and dinaphthol phosphate HL are mixed and dissolved in a mixed solvent of trifluorotoluene / hexafluoroisopropanol (volume ratio 1:1), with a Fe ion concentration of 7 mmol / L. Inorganic base potassium carbonate is added in an amount of 3 molar equivalents of Fe salt. The reaction is carried out at 60°C for 3 h to obtain the catalyst Fe(L)3.

[0059] Example 4

[0060] A method for preparing a C1-symmetric biarylphenol, specifically: 0.78 g of catalyst Fe(L)3 is dissolved in 200 mL of toluene; the mixture is stirred at 60 °C, and air is continuously bubbled into the system. 18.6 g of substituted arylphenol B4 is added to the system and stirred until dissolved. 3.7 g of substituted arylphenol A4 is added to the system, and the temperature is maintained while stirring for 7 h; another 3.7 g of substituted arylphenol A4 is added, and the mixture is stirred for 7 h; finally, another 3.7 g of substituted arylphenol A4 is added, and the mixture is stirred for 30 h; the reaction solution is then subjected to silica gel column chromatography using 440 g of silica gel. The silica gel column is washed with an eluent of ethyl acetate / n-hexane (volume ratio 1:2). The solvent in the filtrate is then removed to obtain a crude biarylphenol product P4 with C1 symmetry; recrystallization is then performed using dichloromethane / acetonitrile (volume ratio 1:10) solvent to obtain 17.4 g of the target product in pure form, with a yield of 86% and a purity of 99%. The reaction formula for this embodiment is as follows: .

[0061] The preparation process of the catalyst Fe(L)3 used in this embodiment is as follows: Fe2(SO4)3 and dinaphthol phosphate HL are mixed and dissolved in a mixed solvent of trifluorotoluene / hexafluoroisopropanol (volume ratio 1:1), with a Fe ion concentration of 7 mmol / L. Sodium hydroxide, an inorganic base, is added in an amount of 6 molar equivalents of Fe salt. The reaction is carried out at 40°C for 3 h to obtain the catalyst Fe(L)3.

[0062] Example 5

[0063] A method for preparing a C1-symmetric biarylphenol, specifically: 1.55 g of catalyst Fe(L)3 is dissolved in 500 mL of toluene; the mixture is stirred at 60 °C, and air is continuously bubbled into the system. 17.2 g of substituted arylphenol B5 is added to the system and stirred until dissolved. 2.6 g of substituted arylphenol A5 is added to the system, and the mixture is stirred for 7 h while maintaining the temperature. Another 2.6 g of substituted arylphenol A5 is added, and the mixture is stirred for 7 h. Finally, another 2.6 g of substituted arylphenol A5 is added, and the mixture is stirred for 30 h. The reaction solution is then subjected to silica gel column chromatography using 316 g of silica gel. The silica gel column is washed with an eluent of ethyl acetate / n-hexane (volume ratio 1:2). The solvent in the filtrate is then removed to obtain a crude biarylphenol product P5 with C1 symmetry. After recrystallization using dichloromethane / acetonitrile (volume ratio 1:10) solvent, 14.1 g of the target product (pure) is obtained, with a yield of 86% and a purity of 99%. The reaction formula for this embodiment is as follows: .

[0064] The preparation process of the catalyst Fe(L)3 used in this embodiment is as follows: FeCl3 and dinaphthol phosphate HL are mixed and dissolved in a mixed solvent of trifluorotoluene / hexafluoroisopropanol (volume ratio 1:1), with a Fe ion concentration of 7 mmol / L. Inorganic base calcium carbonate is added in an amount of 3 molar equivalents of Fe salt. The reaction is carried out at 50°C for 3 h to obtain the catalyst Fe(L)3.

[0065] Example 6

[0066] A method for preparing a biarylphenol with C1 symmetry, specifically: 6.22 g of catalyst Fe(L)3 is dissolved in 500 mL of toluene; the mixture is stirred at 60 °C, and air is continuously bubbled into the system; 16.9 g of substituted arylphenol B6 is added to the system and stirred until dissolved; 7.3 g of substituted arylphenol A6 is added to the system, and the temperature is maintained while stirring for 10 h; another 7.3 g of substituted arylphenol A6 is added, and the mixture is stirred for 10 h; finally, 7.3 g of substituted arylphenol B6 is added. Phenol A6 was stirred for 40 hours. The reaction mixture was then subjected to short-segment silica gel column chromatography using 880 g of silica gel. The column was washed with an eluent of acetone / n-hexane (volume ratio 1:5). The solvent in the filtrate was then removed to obtain the crude biarylphenol product P6 with C1 symmetry. Recrystallization was performed using dichloromethane / acetonitrile (volume ratio 1:10) to obtain 33.0 g of the pure target product, with a yield of 85% and a purity of 99%. The reaction formula for this example is as follows: .

[0067] The preparation process of the catalyst Fe(L)3 used in this embodiment is as follows: Fe(NO2)3 and dinaphthol phosphate HL are mixed and dissolved in a mixed solvent of trifluorotoluene / hexafluoroisopropanol (volume ratio 1:1), with a Fe ion concentration of 5 mmol / L. Inorganic base potassium hydroxide is added in an amount of 6 molar equivalents of Fe salt, and the reaction is carried out at 40°C for 3 h to obtain the catalyst Fe(L)3.

[0068] Example 7

[0069] A method for preparing a biarylphenol with C1 symmetry is as follows: 0.78 g of catalyst Fe(L)3 is dissolved in 500 mL of toluene; the mixture is stirred at 40 °C, and air is continuously bubbled into the system. 18.6 g of substituted arylphenol B7 is added to the system and stirred until dissolved; 3.0 g of substituted arylphenol A7 is added to the system, and the temperature is maintained while stirring for 7 h; another 3.0 g of substituted arylphenol A7 is added, and the mixture is stirred for 7 h; finally, another 3.0 g of substituted arylphenol A7 is added, and the mixture is stirred for 30 h; the reaction solution is then subjected to silica gel column chromatography using 540 g of silica gel. The silica gel column is washed with an eluent of ethyl acetate / n-hexane (volume ratio 1:2). The solvent in the filtrate is then removed to obtain a crude biarylphenol product P7 with C1 symmetry; recrystallization is performed using dichloromethane / acetonitrile (volume ratio 1:10) solvent to obtain 16.6 g of the target product in pure form, with a yield of 91% and a purity of 99%. The reaction formula for this embodiment is as follows: .

[0070] The preparation process of the catalyst Fe(L)3 used in this embodiment is as follows: Fe(ClO4)3 and dinaphthol phosphate HL are mixed and dissolved in a mixed solvent of trifluorotoluene / hexafluoroisopropanol (volume ratio 1:1), with a Fe ion concentration of 6 mmol / L. Inorganic base potassium carbonate is added in an amount of 3 molar equivalents of Fe salt. The reaction is carried out at 50°C for 4 h to obtain the catalyst Fe(L)3.

[0071] Example 8

[0072] A method for preparing biarylphenols with C1 symmetry, specifically: 7.77 g of catalyst Fe(L)3 is dissolved in 500 mL of toluene; the mixture is stirred at 60 °C, and air is continuously bubbled into the system. 13.9 g of substituted arylphenol B8 is added to the system and stirred until dissolved. 8.2 g of substituted arylphenol A8 was added to the system, and the mixture was stirred at the same temperature for 10 h. Then, another 8.2 g of substituted arylphenol A8 was added, and the mixture was stirred for 10 h. Finally, another 8.2 g of substituted arylphenol A8 was added, and the mixture was stirred for 40 h. The reaction solution was then subjected to silica gel column chromatography using 1476 g of silica gel. The silica gel column was washed with an eluent of ethyl acetate / n-hexane (volume ratio 1:2). The solvent in the filtrate was then removed, yielding a crude biarylphenol product P8 with C1 symmetry. Recrystallization was performed using dichloromethane / acetonitrile (volume ratio 1:10) to obtain 33.9 g of the target product in pure form, with a yield of 88% and a purity of 99%. The reaction formula for this example is as follows: .

[0073] The catalyst Fe(L)3 used in this embodiment is the same as the catalyst used in Example 1.

[0074] Example 9

[0075] A method for preparing a biarylphenol with C1 symmetry is as follows: 0.78 g of catalyst Fe(L)3 is dissolved in 500 mL of toluene; the mixture is stirred at 40 °C, and air is continuously bubbled into the system. 18.6 g of substituted arylphenol B7 is added to the system and stirred until dissolved; 3.6 g of substituted arylphenol A9 is added to the system, and the temperature is maintained while stirring for 7 h; another 3.6 g of substituted arylphenol A9 is added, and the mixture is stirred for 7 h; finally, another 3.6 g of substituted arylphenol A9 is added, and the mixture is stirred for 30 h; the reaction solution is then subjected to silica gel column chromatography using 648 g of silica gel. The silica gel column is washed with an eluent of ethyl acetate / n-hexane (volume ratio 1:2). The solvent in the filtrate is then removed to obtain a crude biarylphenol product with C1 symmetry; recrystallization is performed using dichloromethane / acetonitrile (volume ratio 1:10) solvent to obtain 18.0 g of the target product in pure form, with a yield of 90% and a purity of 99%. The reaction formula for this embodiment is as follows: .

[0076] The catalyst Fe(L)3 used in this embodiment is the same as the catalyst used in Example 1.

[0077] Example 10

[0078] A method for preparing a biarylphenol with C1 symmetry, specifically: 7.77 g of catalyst Fe(L)3 is dissolved in 500 mL of toluene; the mixture is stirred at 60 °C, and air is continuously bubbled into the system. 17.2 g of substituted arylphenol B5 is added to the system and stirred until dissolved; 7.0 g of substituted arylphenol A10 is added to the system, and the temperature is maintained while stirring for 7 h; another 7.0 g of substituted arylphenol A10 is added, and the mixture is stirred for 7 h; finally, 7.0 g of substituted arylphenol A1 is added. 0. Stir for 30 hours; then, pass the reaction solution through a short silica gel column chromatography using 1260 g of silica gel. Wash the silica gel column with ethyl acetate / n-hexane (volume ratio 1:2) as the eluent. Remove the solvent from the filtrate to obtain the crude biarylphenol product P10 with C1 symmetry. Recrystallize using dichloromethane / acetonitrile (volume ratio 1:10) to obtain 33.8 g of the target product in pure form, with a yield of 89% and a purity of 99%. The reaction formula for this example is as follows: .

[0079] The catalyst Fe(L)3 used in this embodiment is the same as the catalyst used in Example 1.

[0080] Example 11

[0081] A method for preparing a C1-symmetric biarylphenol, specifically: 1.5 g of catalyst Fe(L)3 is dissolved in 500 mL of toluene; the mixture is stirred at 60 °C, and air is continuously bubbled into the system. 18 g of substituted arylphenol A7 is added to the system and stirred until dissolved. Another 18 g of substituted arylphenol A7 is added to the system, and the mixture is stirred for 48 h while maintaining the temperature. The reaction solution is then subjected to silica gel column chromatography using 720 g of silica gel. The silica gel column is washed with an eluent of ethyl acetate / n-hexane (volume ratio 1:2). The solvent in the filtrate is then removed to obtain a crude biarylphenol product with C1 symmetry. After recrystallization using dichloromethane / acetonitrile (volume ratio 1:10) solvent, 32.6 g of the target product (pure) is obtained, with a yield of 91% and a purity of 98%. The reaction formula for this embodiment is as follows: .

[0082] The catalyst Fe(L)3 used in this embodiment is the same as the catalyst used in Example 1.

[0083] Example 12

[0084] A method for preparing a biarylphenol with C1 symmetry. The catalyst used in this embodiment is the same as that in Example 1. Specifically, 1.55 g of catalyst Fe(L)3 is dissolved in 500 mL of toluene. The amount of catalyst used is 2 mol% of the molar amount of the substituted arylphenol A1, calculated as iron. Similar to the operation in Example 1, air is continuously bubbled into the system under stirring at 40 °C. 22.1 g of substituted arylphenol B1 is added to the reaction system and stirred to dissolve. Then, 11.1 g of substituted arylphenol A1 is added in three equal batches. After separation and purification, 18.9 g of the target product is obtained, with a yield of 86% and a product purity of 99%.

[0085] Example 13

[0086] A method for preparing biarylphenols with C1 symmetry is described in this embodiment. The catalyst, operation process, and parameter control are the same as in Example 12, except that the atmosphere used is pure oxygen. This embodiment yielded 17.6 g of the target product after separation and purification, with a yield of 80% and a product purity of 99%.

[0087] Example 14

[0088] A method for preparing biarylphenols with C1 symmetry is described in this embodiment. The catalyst, operation process, and parameter control are the same as in Example 12, except that 50% hydrogen peroxide is added to the reaction system, making the molar equivalent ratio of hydrogen peroxide to the substituted arylphenol B1 1:4. This embodiment yielded 17.2 g of the target product after separation and purification, with a yield of 78% and a product purity of 99%.

[0089] Comparative Example 1 The preparation method of the C1-symmetric biarylphenol in this comparative example is the same as that in Example 12, except that the catalyst does not contain a naphthylphosphate ligand or uses other commercially available ligands. The ligand structure is as follows: .

[0090] The catalyst ligand types and preparation results of different embodiments are shown in Table 1.

[0091] Table 1

[0092] Combined with Example 12 and Comparative Example 1, it can be confirmed that the catalyst prepared with HL as the ligand has better catalytic performance compared with other commercial ligands.

[0093] Comparative Example 2 The preparation method of the biarylphenol with C1 symmetry in this comparative example is the same as that in Example 12, except that the substituted arylphenol B1 is replaced with the substituted arylphenol A5; the specific reaction formula is as follows: .

[0094] The yield of this comparative example was 59%, and the product purity was 99%.

[0095] Comparative Example 3 The preparation method of the biarylphenol with C1 symmetry in this comparative example is the same as that in Example 12, except that substituted arylphenol A is replaced with B6 and substituted arylphenol B is replaced with B5. The yield of this comparative example is 55%, and the purity of the product is 99%.

[0096] As can be seen from Example 12 and Comparative Examples 2 and 3, the preparation method of biarylphenols with C1 symmetry of the present invention can significantly improve the yield and selectivity of the target product and effectively suppress the occurrence of self-coupling side reactions compared with the reaction preparation process in which both substituted arylphenol A and substituted aryl B are electron-donating groups or electron-withdrawing groups.

[0097] Comparative Example 4 A method for preparing biarylphenols with C1 symmetry is disclosed in this embodiment. The catalyst, operation process, and parameter control are the same as in Example 12, except that the substituted arylphenol A1 is added to the reverse system in a single step, and the reaction is stirred for 44 hours. This embodiment yielded 15.2 g of the target product after separation and purification, with a yield of 69% and a product purity of 99%. Combined with Example 12 and Comparative Example 4, it can be verified that adding the substituted arylphenol A1 in batches can effectively promote a complete reaction and improve the yield.

[0098] It should be noted that the above description is a further detailed explanation of the present invention in conjunction with specific embodiments, and it should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, several simple improvements can be made without departing from the concept of the present invention, and all such improvements should be considered to fall within the scope of protection of the present invention.

Claims

1. A method for preparing biarylphenols with C1 symmetry, characterized in that, Under oxidizing conditions, substituted arylphenol B is dissolved in the reaction system in a reaction solvent and in the presence of a catalyst, and then substituted arylphenol A is added in batches to carry out a coupling reaction to obtain the biarylphenol with C1 symmetry. The catalyst is a complex formed by the coordination of iron(III) with a naphthyl phosphate ligand; The substituted arylphenol A is a substituted phenol with substituents R1 to R5 on the benzene ring as shown in formula (1) or a substituted phenol with substituent R on the naphthalene ring as shown in formula (2). 11 -R 14 Substituted naphthols, and R1~R5 and R 11 -R 14 Each is independently selected from hydrogen, C1~C 10 Alkyl, C3~C 10 cycloalkyl, C1~C 10 Alkoxy, C6~C 14 Aryl, C2~C 10 alkenyl, C2~C 10 Alkyne, tri-C1-C6 alkylsilyl or halogen; Equation (1), Equation (2); The substituted arylphenol B is a benzene ring with substituents R6~R6 as shown in formula (3). 10 The substituted phenol or the naphthalene ring as shown in formula (4) has a substituent R. 15 ~R 18 Substituted naphthols, and R6~R 10 and R 15 ~R 18 Each group is independently selected from hydrogen, halogen, ester, acyl, aldehyde, cyano, or nitro groups; Equation (3), Equation (4).

2. The method for preparing biarylphenols with C1 symmetry according to claim 1, characterized in that, Based on iron content, the molar ratio of iron to the naphthyl phosphate ligand in the catalyst is 1:(3~6), more preferably 1:3; And / or, the naphthyl phosphate ligand is dinaphthol phosphate.

3. The method for preparing biarylphenols with C1 symmetry according to claim 1 or 2, characterized in that, The catalyst is prepared by reacting a trivalent ferric salt with the binaphthyl phosphate ligand in a mixed solvent containing trifluorotoluene and hexafluoroisopropanol in the presence of an inorganic base. Preferably, the trivalent iron salt is selected from at least one of ferric halides, ferric sulfate, ferric nitrate, ferric phosphate, ferric perchlorate, or their hydrates; Preferably, the inorganic base is selected from at least one of sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, and calcium oxide; Preferably, the molar ratio of the inorganic base to the ferric salt, based on iron content, is (1.5~10):1, more preferably (3~6):1; Preferably, the concentration of the ferric salt, calculated as iron, is 1-10 mmol / L, more preferably 5-7 mmol / L; Preferably, the volume ratio of trifluorotoluene to hexafluoroisopropanol in the mixed solvent is (0.5~2):1; Preferably, the reaction temperature is 20~80℃, more preferably 40~60℃; the reaction time is 1~10h, more preferably 3~5h.

4. The method for preparing biarylphenols with C1 symmetry according to claim 3, characterized in that, The preparation of the catalyst also includes separating and purifying the reacted materials; The separation and purification operation includes: (1) Remove the mixed solvent from the reacted material to obtain a solid crude product; (2) The crude solid product is dissolved in a haloalkane solvent and filtered to obtain a filtrate; (3) Remove the haloalkane solvent from the filtrate to obtain the catalyst; Preferably, the haloalkane solvent is selected from at least one of dichloromethane and trichloromethane, with dichloromethane being more preferred; Preferably, the mass ratio of the haloalkane solvent to the crude solid product is (4~20):1, more preferably (5~10):

1.

5. The method for preparing biarylphenols with C1 symmetry according to claim 1, characterized in that, R1~R5 and R 11 -R 14 Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, phenyl, C2-C6 alkenyl, C2-C6 alkynyl, trimethylsilyl, chlorine or bromine; And / or, the R6~R 10 and R 15 ~R 18 Each group is independently selected from hydrogen, fluorine, chlorine, bromine, C1-C6 alkyl ester group, C1-C6 alkyl acyl group, aldehyde group, cyano group, or nitro group.

6. The method for preparing biarylphenols with C1 symmetry according to claim 1, characterized in that, The molar ratio of the substituted arylphenol A to the substituted arylphenol B is 1:(1~5), preferably 1:(1~2). And / or, based on iron, the amount of the catalyst is 0.5% to 20% of the molar amount of the substituted arylphenol A, preferably 1% to 5%.

7. The method for preparing biarylphenols with C1 symmetry according to claim 1, characterized in that, The reaction solvent is selected from at least one of toluene, xylene, diphenyl ether, dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, and 1,1,2-trichloroethane; And / or, the concentration of the substituted arylphenol B is 0.05~2 mol / L, preferably 0.1~0.5 mol / L.

8. The method for preparing biarylphenols with C1 symmetry according to claim 1, characterized in that, The reaction temperature of the coupling reaction is 0~100℃, preferably 20~80℃, more preferably 40~60℃; the reaction time is 30~74h, preferably 44~60h. And / or, the oxidation conditions are provided by an oxygen-containing atmosphere and / or an oxidizing agent; Preferably, the oxygen-containing atmosphere is selected from air, oxygen, or a mixture of oxygen and an inert gas; Preferably, the oxidant is at least one of hydrogen peroxide, tert-butanol peroxide, and peracetic acid; More preferably, the molar ratio of the oxidant to the substituted arylphenol B is 1:(1~4), more preferably 1:(2~4).

9. The method for preparing biarylphenols with C1 symmetry according to claim 1, characterized in that, The substituted arylphenol A was added to the reaction system in three batches; Preferably, the mixture is stirred for 5-12 hours, more preferably 7-10 hours, after adding the first batch of substituted arylphenol A; after adding the second batch of substituted arylphenol A, the mixture is stirred for 5-12 hours, more preferably 7-10 hours; and after adding the third batch of substituted arylphenol A, the mixture is stirred for 20-50 hours, more preferably 30-40 hours. Preferably, the method of adding the substituted arylphenol A in batches is to add it in equal batches.

10. The method for preparing biarylphenols with C1 symmetry according to claim 1, characterized in that, The preparation method further includes separating and purifying the reacted materials to obtain a high-purity biarylphenol product with C1 symmetry; Preferably, the separation and purification includes column chromatography and / or recrystallization.

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