A method for preparing axially chiral biaryl diphenol derivatives

Abstract

The present invention relates to the field of organic and pharmaceutical synthesis technology, and discloses a method for preparing an axially chiral biaryl diphenol derivative, which specifically comprises the following steps: under direct current conditions, using chiral phosphoric acid (CPA) as a catalyst, promoting the reaction of a hydroquinone derivative as shown in formula (II) and a naphthol derivative as shown in formula (III) in electrolyte A and solvent B, and obtaining an axially chiral biaryl diphenol derivative as shown in formula (I) through separation and purification after the reaction. The traditional method uses p-benzoquinone and naphthol as raw materials and obtains the product through nucleophilic addition reaction, which has many disadvantages. The present invention obtains the axially chiral compound through an electrochemical method, and the reaction only produces hydrogen, which has little pollution to the environment and high atom utilization rate, and is consistent with the requirements of current green chemistry.

Description

Technical Field

[0001] The present invention relates to the technical field of organic and pharmaceutical synthesis, and in particular to a method for preparing an axially chiral biaryl diphenol derivative. Background Art

[0002] Biaryl diphenols are widely found in a variety of bioactive natural products, pharmaceuticals, and polymeric materials, and are widely used in the development of chiral ligands and organocatalysts for asymmetric transformations. Among them, axially chiral biaryl phosphine compounds have attracted considerable attention due to their superior skeletal structures. Therefore, the construction of axially chiral biaryl diphenol derivatives has become an important research direction in synthetic organic chemistry.

[0003] The main method for synthesizing axially chiral biaryl diphenol derivatives traditionally uses benzodiquinone and naphthol derivatives as substrates, but this method suffers from low atom utilization and the unstable quinone structure, which is easily degraded. In 2016, Mauro's group developed a quinine-catalyzed asymmetric coupling reaction of 2-naphthol with quinone derivatives (Angew. Chem. Int. Ed. 2016, 55, 6525–6529.), with yields of 60–99% and an er value of 92:8. In 2020, Gavin's group discovered that a small modular tetrameric peptide containing a Lewis basic residue, β-dimethylaminoalanine (DMAA), can selectively couple with naphthol and ester quinone compounds to generate non-C2-symmetric BINOL-type scaffolds with good yields and enantioselectivity, with an enantiomeric ratio (er) as high as 93:7 (Angew. Chem. Int. Ed. 2020, 59, 2875–2880.). However, in these reactions, quinones are prepared by oxidizing phenols with stoichiometric amounts of oxidants, which is not only costly but also requires high energy consumption when the reaction is performed at low temperatures. Currently, there are relatively few reports on the preparation of axially chiral biaryl diphenol derivatives.

[0004] Organic electrochemical catalysis shows great promise in this field, with its advantages primarily reflected in the high efficiency, environmental friendliness, and sustainability of the catalytic process. In particular, the use of phenolic compounds as substrates, rather than traditional quinone compounds, not only effectively shortens synthesis time and avoids waste generation, but also significantly reduces reliance on hazardous and harmful reagents. This approach aligns with the principles of green chemistry and meets the requirements of environmentally friendly synthesis. Furthermore, phenolic substrates have lower redox potentials, making it easier to stimulate reactions in electrochemical catalysis and contributing to improved catalytic efficiency. Summary of the Invention

[0005] In view of the above technical problems existing in the prior art, the object of the present invention is to provide a method for efficiently preparing axially chiral biaryl diphenol derivatives by synergistically catalyzing the asymmetric free radical coupling reaction of hydroquinone derivatives and naphthol derivatives with electro / chiral phosphoric acid.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A method for preparing an axially chiral biaryl diphenol derivative comprises the following steps:

[0008] Step 1: chiral phosphoric acid (CPA), a hydroquinone derivative represented by formula (II), a naphthol derivative represented by formula (III), electrolyte A, and solvent B are sequentially added to a Shrek tube equipped with a magnet, electrodes are inserted, and the mixture is stirred at room temperature (25°C) and the current reaction is started;

[0009] Step 2: After the reaction is completed, water is added to quench the reaction, and the product is extracted with dichloromethane. The separated organic layer is concentrated under reduced pressure, and the resulting residue is separated by column chromatography to obtain a chiral biaryl diphenol derivative represented by formula (I);

[0010] The specific reaction route is as follows:

[0011]

[0012] In formula (II), R 1 CO2R 3 OR PO(OR 3 )2,R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl or substituted benzyl; in formula (III), R 2 is hydrogen, halogen, methoxy, cyano or substituted aryl.

[0013] Preferably, in step 1, the electrolyte A is n-Bu4NBF4; and the solvent B is at least one of dichloromethane and 1,2-dichloroethane.

[0014] Preferably, in step 1, the structural formula of the chiral phosphoric acid is as follows:

[0015]

[0016] Preferably, in the step 1, the molar ratio of the hydroquinone derivative, the naphthol derivative, the electrolyte A and the chiral phosphoric acid is 1:(1.0-1.2):2:(0.15-0.2).

[0017] Preferably, in step 1, the reaction voltage for the current reaction is set to 1.8-2.0V.

[0018] Preferably, in step 1, the reaction time of the current reaction is 12 to 24 hours.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] Compared with traditional reactions, the present invention:

[0021] 1. A novel method for the efficient preparation of axially chiral biaryl diphenol derivatives by the asymmetric radical addition reaction of hydroquinone derivatives with naphthol derivatives catalyzed by electrophilic / chiral phosphoric acid is provided, with a yield of up to 95% and an ee value of up to 97%;

[0022] 2. It has the characteristics of low energy consumption, high atomic economy and low green pollution;

[0023] 3. It has important application prospects in the preparation of new catalysts and drug modification. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The cyclic voltammetry curves of 7-methoxy-2-naphthol (IIIa) and methyl 2,5-dihydroxybenzoate (IIa) in the preparation method of an axially chiral biaryl diphenol derivative proposed in the present invention are shown. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0026] Example 1: Preparation of methyl 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Iaa)

[0027]

[0028] To a Shrek tube equipped with a magnet, methyl 2,5-dihydroxybenzoate (16.8 mg, 0.1 mmol), 7-methoxy-2-naphthol (20.9 mg, 0.12 mmol), chiral phosphoric acid CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 29.95 mg of methyl 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Iaa) as a white solid with a melting point of 179-180° C., a yield of 88%, and an ee value of 93%.

[0029] Example 2: Preparation of ethyl 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Iba)

[0030]

[0031] To a Shrek tube equipped with a magnet, ethyl 2,5-dihydroxybenzoate (18.2 mg, 0.1 mmol), 7-methoxy-2-naphthol (20.9 mg, 0.12 mmol), chiral phosphoric acid CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 33.62 mg of ethyl 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Iba) as a white solid with a melting point of 202-203° C., a yield of 95%, and an ee value of 92%.

[0032] Example 3: Preparation of 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)propyl benzoate (Ica)

[0033]

[0034] To a Shrek tube equipped with a magnet, propyl 2,5-dihydroxybenzoate (19.6 mg, 0.1 mmol), 7-methoxy-2-naphthol (20.9 mg, 0.12 mmol), chiral phosphate CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 31.9 mg of propyl 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Ica) as a white solid with a melting point of 223-224° C., a yield of 89%, and an ee value of 92%.

[0035] Example 4: Preparation of 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoic acid isopropyl ester (Ida)

[0036]

[0037] To a Shrek tube equipped with a magnet, isopropyl 2,5-dihydroxybenzoate (19.6 mg, 0.1 mmol), 7-methoxy-2-naphthol (20.9 mg, 0.12 mmol), CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 31.6 mg of isopropyl 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Ida) as a light yellow solid with a melting point of 195-196° C., a yield of 88%, and an ee value of 92%.

[0038] Example 5: Preparation of 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoic acid n-butyl ester (Iea)

[0039]

[0040] To a Shrek tube equipped with a magnet, n-butyl 2,5-dihydroxybenzoate (21.0 mg, 0.1 mmol), 7-methoxy-2-naphthol (20.9 mg, 0.12 mmol), chiral phosphoric acid CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 32.5 mg of n-butyl 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Iea) as a light yellow solid with a melting point of 207-208° C., a yield of 85%, and an ee value of 90%.

[0041] Example 6: Preparation of 4-bromobenzyl-3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Ifa)

[0042]

[0043] To a Shrek tube equipped with a magnet, 4-bromobenzyl-2,5-dihydroxybenzoate (32.3 mg, 0.1 mmol), 7-methoxy-2-naphthol (20.9 mg, 0.12 mmol), CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 41.5 mg of 4-bromobenzyl 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Ifa) as a light yellow solid with a melting point of 201-202° C., a yield of 84%, and an ee value of 92%.

[0044] Example 7: Preparation of 3-bromobenzyl-3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Iga)

[0045]

[0046] To a Shrek tube equipped with a magnet, 3-bromobenzyl-2,5-dihydroxybenzoate (32.3 mg, 0.1 mmol), 7-methoxy-2-naphthol (20.9 mg, 0.12 mmol), CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 34.1 mg of 3-bromobenzyl 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Iga) as a light yellow solid with a melting point of 189-190° C., a yield of 69%, and an ee value of 95%.

[0047] Example 8: Preparation of 2-bromobenzyl-3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Iha)

[0048]

[0049] To a Shrek tube equipped with a magnet, 2-bromobenzyl-2,5-dihydroxybenzoate (32.3 mg, 0.1 mmol), 7-methoxy-2-naphthol (20.9 mg, 0.12 mmol), CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 36.5 mg of 2-bromobenzyl 3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)benzoate (Iha) as a light yellow solid with a melting point of 197-198° C., a yield of 74%, and an ee value of 97%.

[0050] Example 9: Preparation of ethyl 2-(7-(4-chlorophenyl)-2-hydroxynaphthalen-1-yl)-3,6-dihydroxybenzoate (Ibb)

[0051]

[0052] To a Shrek tube equipped with a magnet, ethyl 2,5-dihydroxybenzoate (18.2 mg, 0.1 mmol), 7-(4-chlorophenyl)-2-hydroxynaphthalene (30.6 mg, 0.12 mmol), CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 38.6 mg of ethyl 2-(7-(4-chlorophenyl)-2-hydroxynaphthalen-1-yl)-3,6-dihydroxybenzoate (Ibb) as a light yellow solid with a melting point of 212-213° C., a yield of 89%, and an ee value of 90%.

[0053] Structural characterization of (Ibb): 1 H NMR (600MHz, DMSO-d6, ppm) δ9.29(s,1H),9.27(s,1H),8.54(s,1H),7.86(d,J=8.4Hz,1H),7.76(d,J=9.0Hz,1H),7.55–7.49(m, 5H),7.38(s,1H),7.20(d,J=9.0Hz,1H),6.92(d,J=9.0Hz,1H),6.83(d,J=8.4Hz,1H),3.65–3.59(m,2H),0.37(t,J=6.6Hz,3H). 13 C NMR (150MHz, DMSO-d6, ppm) δ167.8,153.4,148.5,148.3,140.3,136.2,134.5,132.6,129.4,128.9 ,128.8,128.5,127.5,123.1,123.0,122.2,121.5,119.0,118.6,117.2,116.6,59.9,13.3.Chiral HPLC: The ee was determined by DaicelChiralcel IA, Hexanes / IPA=85 / 15, 1.0mL / min, λ=254nm, T=25℃, t(major)=42.869min, t(minor)=18.116min.HRMS(ESI):calcd for C 25 H 20 ClO5[M+H] + 435.0994, found 435.1007.

[0054] Example 10: Preparation of ethyl 2-(6-cyano-2-hydroxynaphthalen-1-yl)-3,6-dihydroxybenzoate (Ibc)

[0055]

[0056] To a Shrek tube equipped with a magnet, ethyl 2,5-dihydroxybenzoate (18.2 mg, 0.1 mmol), 6-hydroxy-2-naphthocarbonitrile (20.3 mg, 0.12 mmol), CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 30.1 mg of ethyl 2-(6-cyano-2-hydroxynaphthalen-1-yl)-3,6-dihydroxybenzoate (Ibc) as a light yellow solid with a melting point of 167-168° C., a yield of 63%, and an ee value of 96%.

[0057] Example 11: Preparation of ethyl 2-(7-bromo-2-hydroxynaphthalen-1-yl)-3,6-dihydroxybenzoate (Ibd)

[0058]

[0059] To a Shrek tube equipped with a magnet, ethyl 2,5-dihydroxybenzoate (18.2 mg, 0.1 mmol), 7-bromo-2-naphthol (26.5 mg, 0.12 mmol), CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 37.3 mg of ethyl 2-(7-bromo-2-hydroxynaphthalen-1-yl)-3,6-dihydroxybenzoate (Ibd) as a red solid with a melting point of 185-186° C., a yield of 93%, and an ee value of 91%.

[0060] Example 12: Preparation of ethyl 3,6-dihydroxy-2-(2-hydroxy-8-iodonaphthalen-1-yl)benzoate (Ibe)

[0061]

[0062] To a Shrek tube equipped with a magnet, ethyl 2,5-dihydroxybenzoate (18.2 mg, 0.1 mmol), 8-iodo-2-naphthol (32.4 mg, 0.12 mmol), CPA1 (11.3 mg, 15 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and dichloromethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 1.8 V for 12 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 40.5 mg of ethyl 3,6-dihydroxy-2-(2-hydroxy-8-iodonaphthalen-1-yl)benzoate (Ibe) as a brown solid with a melting point of 171-172° C., a yield of 90%, and an ee value of 95%.

[0063] Structural characterization of (Ibe): 1 H NMR (400MHz, Acetone-d6, ppm) δ10.79(s,1H),8.16(d,J=7.2Hz,1H),8.04(s,1H),7.91(d,J=8.0Hz,1H),7.83(d,J=8 .8Hz,1H),7.33–7.30(m,2H),7.12(d,J=8.8Hz,1H),7.00–6.94(m,2H),3.76(q,J=7.2Hz,2H),0.32(t,J=7.2Hz,3H). 13 C NMR (100MHz, Acetone-d6, ppm) δ171.0,156.4,153.4,150.1,142.3,132.8,130.2,130.2,1 30.1,123.5,122.9,121.9,118.6,118.6,118.5,115.7,89.0,60.3,12.1.ChiralHPLC:The ee was determined by Daicel Chiralcel AD-H, Hexanes / IPA=80 / 20, 1.0mL / min, λ=254nm, T=25℃, t(major)=16.203min, t(minor)=29.347min.HRMS(ESI):calcdfor C 19 H 16 IO5[M+H] + 451.0037,found 451.0025.

[0064] Example 13: Preparation of dimethyl (3,6-dihydroxy-2-(2-hydroxynaphthalen-1-yl)phenyl)phosphate (Vaf)

[0065]

[0066] To a Shrek tube equipped with a magnet, dimethyl (2,5-dihydroxyphenyl) phosphate (21.8 mg, 0.1 mmol), β-naphthol (14.4 mg, 0.1 mmol), CPA2 (13.3 mg, 20 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and 1,2-dichloroethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 2.0 V for 24 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 28.4 mg of dimethyl (3,6-dihydroxy-2-(2-hydroxynaphthalen-1-yl)phenyl)phosphate (Vaf) as a reddish-brown solid with a melting point of 232-233° C., a yield of 79%, and an ee value of 91%.

[0067] Example 14: Preparation of diethyl (3,6-dihydroxy-2-(2-hydroxynaphthalen-1-yl)phenyl)phosphate (Vbf)

[0068]

[0069] To a Shrek tube equipped with a magnet, diethyl (2,5-dihydroxyphenyl) phosphate (24.6 mg, 0.1 mmol), β-naphthol (14.4 mg, 0.1 mmol), CPA2 (13.3 mg, 20 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and 1,2-dichloroethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 2.0 V for 24 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 31.4 mg of diethyl (3,6-dihydroxy-2-(2-hydroxynaphthalen-1-yl)phenyl)phosphate (Vbf) as a reddish-brown solid with a melting point of 214-215° C., a yield of 81%, and an ee value of 87%.

[0070] Example 15: Preparation of diisopropyl (3,6-dihydroxy-2-(2-hydroxynaphthalen-1-yl)phenyl) phosphate (Vcf)

[0071]

[0072] To a Shrek tube equipped with a magnet, diisopropyl (2,5-dihydroxyphenyl) phosphate (24.6 mg, 0.1 mmol), β-naphthol (14.4 mg, 0.1 mmol), CPA2 (13.3 mg, 20 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and 1,2-dichloroethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 2.0 V for 24 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 32.8 mg of diisopropyl (3,6-dihydroxy-2-(2-hydroxynaphthalen-1-yl)phenyl) phosphate (Vcf) as a brown solid with a melting point of 187-188° C., a yield of 79%, and an ee value of 89%.

[0073] Example 16: Preparation of dibutyl (3,6-dihydroxy-2-(2-hydroxynaphthalen-1-yl)phenyl) phosphate (Vdf)

[0074]

[0075] To a Shrek tube equipped with a magnet, dibutyl (2,5-dihydroxyphenyl) phosphate (30.2 mg, 0.1 mmol), β-naphthol (14.4 mg, 0.1 mmol), CPA2 (13.3 mg, 20 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and 1,2-dichloroethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 2.0 V for 24 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 32.8 mg of dibutyl (3,6-dihydroxy-2-(2-hydroxynaphthalen-1-yl)phenyl) phosphate (Vdf) as a brown solid with a melting point of 236-237° C., a yield of 79%, and an ee value of 89%.

[0076] Example 17: Preparation of diethyl (3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)phenyl)phosphate (Vba)

[0077]

[0078] To a Shrek tube equipped with a magnet, diethyl (2,5-dihydroxyphenyl) phosphate (24.6 mg, 0.1 mmol), 7-methoxy-2-naphthol (17.4 mg, 0.1 mmol), CPA2 (13.3 mg, 20 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and 1,2-dichloroethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 2.0 V for 24 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 35.4 mg of diethyl (3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)phenyl)phosphonate (Vba) as a reddish-brown solid with a melting point of 168-169° C., a yield of 85%, and an ee value of 93%.

[0079] Example 18: Preparation of dibutyl-(3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)) phosphate (Vda)

[0080]

[0081] To a Shrek tube equipped with a magnet, dibutyl (2,5-dihydroxyphenyl) phosphate (30.2 mg, 0.1 mmol), 7-methoxy-2-naphthol (17.4 mg, 0.1 mmol), CPA2 (13.3 mg, 20 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and 1,2-dichloroethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 2.0 V for 24 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 41.2 mg of dibutyl-(3,6-dihydroxy-2-(2-hydroxy-7-methoxynaphthalen-1-yl)) phosphate (Vda) as a light yellow solid with a melting point of 163-164° C., a yield of 87%, and an ee value of 92%.

[0082] Structural characterization of (Vda): 1 H NMR (400 MHz, Acetone-d 6,ppm)δ11.13(s,1H),7.85(s,1H),7.73(d,J=8.8Hz,2H),7.19(d,J=8.8Hz,1H ),7.07(d,J=8.8Hz,1H),6.96–6.89(m,3H),6.53(s,1H),3.99–3.84(m,2H), 3.68(s,3H),3.43–4.40(m,1H),3.24–3.20(m,1H),1.63–1.55(m,2H),1.34– 1.28(m,3H),0.90(d,J=7.2Hz,3H),0.85–0.71(m,3H),0.66(t,J=7.2Hz,3H). 13 C NMR (100MHz, Acetone-d6, ppm) δ158.0,157.4,157.4,154.1,148.4,148.2,136.3,129.3,129.2,124.0,123.9,123.8,123.3,123.3,1 18.6,118.5,115.8,114.3,113.9,110.7,108.9,104.2,66.1,66.1,65.5,65.4,54.4,32.1,32.0,31.2,31.2,18.4,18.1,13.0,12.8. 31 P NMR (162MHz, Acetone-d6, ppm) δ21.9. Chiral HPLC: The ee was determined by Daicel Chiralcel AD-H, Hexanes / IPA=80 / 20, 1.0mL / min, λ=254nm, T=25℃, t(major)=8.418min, t(minor)=17.038min.HRMS-ESI(m / z):calcd for C 25 H 32 O7P[M+H] + 475.1880, found 475.1892.

[0083] Example 19: Preparation of diethyl (3,6-dihydroxy-2-(2-hydroxy-6-methoxynaphthalen-1-ylphenyl) phosphate (Vbg)

[0084]

[0085] To a Shrek tube equipped with a magnet, diethyl (2,5-dihydroxyphenyl) phosphate (24.6 mg, 0.1 mmol), 6-methoxy-2-naphthol (17.4 mg, 0.1 mmol), CPA2 (13.3 mg, 20 mol%), n-Bu4NBF4 (65.8 mg, 0.2 mmol), and 1,2-dichloroethane (5.0 mL) were added sequentially. An electrode was inserted and the mixture was stirred at room temperature (25°C) with a direct current of 2.0 V for 24 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 28.3 mg of diethyl (3,6-dihydroxy-2-(2-hydroxy-6-methoxynaphthalen-1-ylphenyl) phosphate (Vbg) as a reddish-brown solid with a melting point of 155-156° C., a yield of 68%, and an ee value of 90%.

[0086] In the above embodiments, the structural formula of CPA1 is:

[0087]

[0088] The structural formula of CPA2 is:

[0089]

[0090] Example 20: Cyclic voltammetry curve of Iaa

[0091]

[0092] Voltammograms were recorded on a CHI 600E instrument using a 3 mm diameter glassy carbon working electrode, a platinum wire auxiliary electrode, and an Ag / AgCl reference electrode. The electrolyte solution consisted of n-Bu4NBF4 (65.8 mg, 0.2 mmol) dissolved in 5 mL of dichloromethane. Experiments were performed at room temperature (25°C) with a scan rate of 100 mV / s.

[0093] The cyclic voltammetric behavior of 7-methoxy-2-naphthol (Ⅲa) and methyl 2,5-dihydroxybenzoate (Ⅱa) showed that the oxidation onset potential of Ⅱa was about 1.23V ( Figure 1 , dark blue wave), which is consistent with the starting potential of Ⅲa of 1.42 V ( Figure 1 , purple wave) is not much different. It is worth noting that the mixture of IIa and CPA1 shows a slightly reduced signal with an onset potential of 1.31 V ( Figure 1 , green wave), while the mixture of IIIa and CPA1 showed an early signal with an onset potential of 1.27 V ( Figure 1, orange wave). Furthermore, the onset potential of the mixture of IIIa, IIa, and CPA1 is approximately 1.20 V. These results demonstrate that IIIa and IIa can be oxidized simultaneously, a property that is crucial for the overall design of the present invention, improving reaction efficiency and enhancing catalytic effectiveness.

[0094] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing an axially chiral biaryl diphenol derivative, characterized in that: The following steps are involved: Step 1: chiral phosphoric acid (CPA), a hydroquinone derivative represented by formula (II), a naphthol derivative represented by formula (III), electrolyte A, and solvent B are sequentially added to a Shrek tube equipped with a magnet, electrodes are inserted, and the mixture is stirred at room temperature (25°C) and the current reaction is started; Step 2: After the reaction is completed, water is added to quench the reaction, and the product is extracted with dichloromethane. The separated organic layer is concentrated under reduced pressure, and the resulting residue is separated by column chromatography to obtain a chiral biaryl diphenol derivative represented by formula (I); The specific reaction route is as follows: In formula (II), R 1 CO2R 3 OR PO(OR 3 )2,R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl or substituted benzyl; in formula (III), R 2 is hydrogen, halogen, methoxy, cyano or substituted aryl.

2. The method for preparing an axially chiral biaryl diphenol derivative according to claim 1, characterized in that: In the step 1, the electrolyte A is n-Bu4NBF4; the solvent B is at least one of dichloromethane and 1,2-dichloroethane.

3. The method for preparing an axially chiral biaryl diphenol derivative according to claim 1, wherein: In the step 1, the structural formula of the chiral phosphoric acid is as follows:

4. The method for preparing an axially chiral biaryl diphenol derivative according to claim 2, wherein: In the step 1, the structural formula of the chiral phosphoric acid is as follows:

5. The method for preparing an axially chiral biaryl diphenol derivative according to claim 1, wherein: In the step 1, the molar ratio of the hydroquinone derivative, the naphthol derivative, the electrolyte A and the chiral phosphoric acid is 1:(1.0-1.2):2:(0.15-0.2).

6. The method for preparing an axially chiral biaryl diphenol derivative according to claim 1, wherein: In the step 1, the reaction voltage for the current reaction is set to 1.8-2.0V.

7. The method for preparing an axially chiral biaryl diphenol derivative according to claim 1, wherein: In the step 1, the reaction time of the current reaction is 12 to 24 hours.

Images