A method for preparing deuterated methyl ether compounds based on visible light / nickel synergistic catalysis

Abstract

This invention discloses a method for preparing deuterated methyl ether compounds based on visible light / nickel synergistic catalysis. A mixed solution comprising a trideuterium-containing methylating agent (Formula 1), an aryl halide (Formula 2), a photocatalyst and a nickel catalyst, a base additive, and a solvent is reacted in a reaction apparatus irradiated with visible light to produce an aryl deuterated methyl ether compound (Formula 3). This method utilizes inexpensive metal catalysts and low-toxic solvents, uses visible light as an energy source, and is carried out at room temperature. The reaction conditions are clean, green, and environmentally friendly, while achieving a product yield of up to 85%. This method effectively overcomes the problems of traditional synthetic pathways, such as complex operations, long reaction times, the need for expensive catalysts, and low atom economy. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and particularly relates to a method for preparing deuterated methyl ether compounds based on visible light / nickel synergistic catalysis. Background Art

[0002] Methyl groups are one of the most common groups in pharmaceuticals, significantly influencing the biological activity and physical properties of drug molecules. Introducing methyl groups into target compounds has become one of the most commonly used strategies for optimizing lead compounds. Furthermore, deuterium, as the most readily available, stable, and non-radioactive hydrogen isotope, and deuterated methyl groups are widely used in the development of new drugs, making the deuterated methylation of target molecules through appropriate means a research hotspot in recent years.

[0003] For decades, chemists have often used deuterated reducing agents, such as deuterated DMSO, as deuterated methylation sources to achieve deuterated methylation reactions. For example, in 2014, Jinghan Gui et al. prepared a deuterated reducing agent that could convert methylated intermediates into deuterated methylated products under open-air conditions at room temperature. This method boasts advantages such as readily available and inexpensive substrates, ease of operation, room temperature operation, and the absence of a protective atmosphere (Journal of the American Chemical Society, 2014, 136, 4853–4856). In the same year, Xiao et al. used deuterated DMSO to generate methylated products from aryl nitro compounds under iron catalysis. This method also offers advantages such as simplicity and high efficiency (Chemistry-a European Journal, 2014, 20, 58–63). However, these methods still suffer from the use of volatile, corrosive, and highly toxic reagents, harsh reaction conditions, and limited scale to microgram quantities.

[0004] Compared with traditional catalytic reaction methods, visible light catalytic reaction technology uses green and clean visible light as the light source and electrons as redox reagents. It can achieve redox reactions without adding additional oxidants. It has the advantages of milder reaction conditions and can effectively avoid strong exothermic processes. It greatly improves the safety of the reaction and makes the reaction more green and environmentally friendly. Summary of the Invention

[0005] Purpose of the invention: The technical problem to be solved by the present invention is to address the deficiencies of the existing technology and provide a method for preparing deuterated methyl ether compounds based on visible light / nickel synergistic catalysis, so as to solve the problems existing in the existing technology such as cumbersome reaction operation, low product yield, low atom economy efficiency, and difficulty in large-scale expansion.

[0006] In order to solve the above technical problems, the present invention discloses a method for preparing deuterated methyl ether compounds based on visible light / nickel synergistic catalysis, wherein a mixed solution comprising a trideuterium-containing methylating agent shown in Formula 1, an aryl halide shown in Formula 2, a photocatalyst and a nickel catalyst, an alkaline additive and a solvent is reacted in a reaction device irradiated with visible light to obtain an aryl deuterated methyl ether compound shown in Formula 3;

[0007]

[0008] in,

[0009] Dashed lines indicate absence, a single bond, or —R1—;

[0010] R1 is selected from S, or O;

[0011] R2 is selected from cyano, formyl, acetyl, benzoyl, methyl formate, ethyl formate, or methylsulfone.

[0012] In some embodiments, the deuterated methylation agent represented by Formula 1 is any one of the following structures:

[0013]

[0014] In some embodiments, the aryl halide represented by Formula 2 is an aryl bromide, which is any one of the following structures:

[0015]

[0016] In some embodiments, the nickel catalyst is any one or a combination of nickel chloride, nickel fluoride, nickel bromide, nickel iodide, nickel trifluoromethanesulfonate, nickel acetylacetonate, nickel acetate, nickel sulfate, ethylene glycol dimethyl ether nickel bromide, bis(triphenylphosphine) nickel dichloride and 1,2-bis(diphenylphosphine)ethane nickel chloride; preferably ethylene glycol dimethyl ether nickel bromide.

[0017] In some embodiments, the photocatalyst is any one or a combination of tris(2,2'-bipyridine)ruthenium di(hexafluorophosphate), Fac-Ir(2-phenylpyridyl)3, eosin Y, acridinium salt, 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, tris(2-(3-tert-butylphenyl)-4-tert-butylpyridine)iridium, fac-Ir[df(pt-Bu)ppy]3 and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III)hexafluorophosphate; preferably (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III)hexafluorophosphate.

[0018] In some embodiments, the base additive is any one or a combination of potassium carbonate, triethylamine, diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine, 4-dimethylaminopyridine, triethylenediamine, ethylenediamine, diethylamine, pyridine, 2,6-lutidine, 2,6-di-tert-butylpyridine and 2,4,6-trimethylpyridine; preferably 4,4'-dimethoxy-2,2'-bipyridine and potassium carbonate.

[0019] In some embodiments, it is a combination of an organic solvent and water; preferably, the organic solvent includes any one or a combination of acetonitrile, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, ethyl acetate, tetrahydrofuran, acetone, 1,2-dichloroethane, 1,4-dioxane and toluene, preferably N,N-dimethylacetamide; preferably, the molar ratio of the organic solvent to water is 0.3-0.5:1.

[0020] In some embodiments, in the mixed solution, the concentration of the trideuterium-containing methylation reagent represented by Formula 1 is 0.01 to 0.2 mmol / mL, preferably 0.05 to 0.15 mmol / mL, and more preferably 0.05 to 0.1 mmol / mL.

[0021] In some embodiments, in the mixed solution, the concentration of the aryl halide represented by Formula 2 is 0.02 to 0.4 mmol / mL, preferably 0.1 to 0.2 mmol / mL, and more preferably 0.1 to 0.14 mmol / mL.

[0022] In some embodiments, the photocatalyst is 1% to 3% by mole of the aryl halide represented by Formula 2, preferably 2%.

[0023] In some embodiments, the nickel catalyst is 5% to 25% of the molar ratio of the aryl halide represented by Formula 2, preferably 5% to 15%, and more preferably 10%.

[0024] In some embodiments, the base additive is 0.5 to 2.5 times the molar ratio of the aryl halide represented by Formula 2.

[0025] In some embodiments, the visible light wavelength range is 400 to 800 nm, preferably 400 to 600 nm; more preferably 450 to 470 nm.

[0026] In some embodiments, the reaction temperature is 20-30°C, preferably room temperature.

[0027] In some embodiments, the reaction residence time of the reaction is 14-22 hours, preferably 18 hours.

[0028] The deuterated methyl ether products shown in Formula 3 provided by the present invention can be used for the specific site modification of aryl bromides in synthetic design. At the same time, the present invention also provides new ideas for deuterated methylated drug molecules.

[0029] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0030] (1) The deuterated methylation reagent used in the present invention is low in toxicity and corrosiveness, non-volatile, simple in structure, and stable in properties. It can be synthesized from commercial raw materials through simple steps, which reduces the difficulty of synthesis and the cost of raw materials, and effectively overcomes the problems of complex steps, long reaction time, expensive catalysts, and low atom economy efficiency in traditional synthesis routes.

[0031] (2) The present invention does not require the use of expensive photocatalysts, but uses cheap and readily available catalysts to achieve the deuterated methylation of aromatic halides through photo / nickel synergistic catalysis.

[0032] (3) The product yield of the reaction involved in the present invention can reach 45% to 85%. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more apparent.

[0034] Figure 1 A diagram of the reaction apparatus.

[0035] Figure 2 This is the H NMR spectrum of product 3aa.

[0036] Figure 3 This is the carbon NMR spectrum of product 3aa.

[0037] Figure 4 This is the H NMR spectrum of product 3ab.

[0038] Figure 5 This is the carbon NMR spectrum of product 3ab.

[0039] Figure 6 This is the H NMR spectrum of the product 3ac.

[0040] Figure 7 This is the carbon NMR spectrum of product 3ac.

[0041] Figure 8 This is the H NMR spectrum of the product 3ad.

[0042] Figure 9 This is the carbon NMR spectrum of the product 3ad.

[0043] Figure 10This is the H NMR spectrum of the product 3ae.

[0044] Figure 11 This is the carbon NMR spectrum of product 3ae.

[0045] Figure 12 This is the H NMR spectrum of the product 3af.

[0046] Figure 13 This is the carbon NMR spectrum of product 3af.

[0047] Figure 14 This is the H NMR spectrum of the product 3ag.

[0048] Figure 15 This is the carbon NMR spectrum of product 3ag. DETAILED DESCRIPTION

[0049] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0050] The reactions described in the following examples, unless otherwise specified, were carried out at room temperature, and the visible light was blue light with a wavelength of 450 to 455 nm.

[0051] Example 1

[0052]

[0053] 153.2 mg (0.4 mmol, 2.0 equiv.) of 5-trideuteriomethyl 5H-dithioanthracene 5-ium trifluoromethanesulfonate, 36.4 mg (0.2 mmol, 1 equiv.) of p-bromobenzonitrile, 3.65 mg (0.004 mmol, 2 mol%) of (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 6.17 mg (0.02 mmol, 10 mol%) of nickel(II) chloride ethylene glycol dimethyl ether complex, 6.48 mg (0.03 mmol, 15 mol%) of 4,4'-dimethoxy-2,2'-bipyridyl, 18 uL (1 mmol, 5.0 equiv.) of water, and 55.28 mg (0.4 mmol, 2.0 equiv.) of potassium carbonate were weighed in sequence, DMA was added, and the mixture was stirred thoroughly to dissolve to prepare a 10 mL solution. The reaction solution was placed in a reaction apparatus illuminated by a blue LED for 18 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched and extracted with ethyl acetate and saturated brine (3×25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The product 3aa was obtained by silica gel column chromatography (petroleum ether:ethyl acetate) with a yield of 85%. The characterization data of 3aa are as follows ( Figure 2 、 Figure 3 ): 1 H NMR (400MHz, CDCl3) δ7.54–7.48(m,2H),6.90–6.84(m,2H). 13 C NMR(100MHz, CDCl3)δ162.9,134.0,119.3,114.8,103.9.HRMS(ESI)m / z:calcd for C8H4D3OSNa[M+Na] + :159.0608,found:159.0608.

[0054] Example 2

[0055]

[0056] 153.2 mg (0.4 mmol, 2.0 equiv.) 5-trideuterated 5H-dithioanthracene 5-ium trifluoromethanesulfonate, 39.81 mg (0.2 mmol, 1 equiv.) 4-bromoacetophenone, 3.65 mg (0.004 mmol, 2 mol%) (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 6.17 100 mg (0.02 mmol, 10 mol%) nickel (II) chloride ethylene glycol dimethyl ether complex, 6.48 mg (0.03 mmol, 15 mol%) 4,4'-dimethoxy-2,2'-bipyridine, 18 uL (1 mmol, 5.0 equiv.) water, 55.28 mg (0.4 mmol, 2.0 equiv.) potassium carbonate, DMA was added and stirred thoroughly to dissolve, and a 10 mL solution was prepared. The reaction solution was placed in a reaction apparatus illuminated by blue LED light for 18 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction was quenched and extracted with ethyl acetate and saturated brine (3×25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After that, the product 3ab 13.70 mg was obtained by silica gel column chromatography (petroleum ether:ethyl acetate) with a yield of 45%. The characterization data of 3ab are as follows ( Figure 4 、 Figure 5 ): 1H NMR (400MHz, CDCl3) δ7.96–7.92(m,2H),6.95–6.91(m,2H),2.56(s,3H). 13 C NMR(100MHz, CDCl3)δ196.8,163.5,130.6,130.3,113.7,26.4.HRMS(ESI)m / z:calcd for C9H7D3O2Na[M+Na] + :176.0761,found:176.0774.

[0057] Example 3

[0058]

[0059] 153.2 mg (0.4 mmol, 2.0 equiv.) 5-trideuterated 5H-dithioanthracene 5-ium trifluoromethanesulfonate, 42.61 mg (0.2 mmol, 1 equiv.) 4-bromopropiophenone, 3.65 mg (0.004 mmol, 2 mol%) (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 6.17 100 mg (0.02 mmol, 10 mol%) nickel(II) chloride ethylene glycol dimethyl ether complex, 6.48 mg (0.03 mmol, 15 mol%) 4,4'-dimethoxy-2,2'-bipyridine, 18 uL (1 mmol, 5.0 equiv.) water, and 55.28 mg (0.4 mmol, 2.0 equiv.) potassium carbonate were added to DMA and stirred thoroughly to dissolve to prepare a 10 mL solution. The reaction solution was placed in a reaction apparatus illuminated by blue LED light for 18 hours and monitored by TLC. After the reaction was completed, the reaction was quenched and extracted with ethyl acetate and saturated brine (3×25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After purification, the product 3ac (14.95 mg) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate) with a product yield of 45%. The characterization data of 3ac are as follows ( Figure 6 、 Figure 7 ): 1 H NMR (400MHz, CDCl3) δ7.90–7.85(m,2H),6.88–6.83(m,2H),2.88(q,J=7.3Hz,2H),1.14(t,J=7.3Hz,3H). 13 C NMR(100MHz, CDCl3)δ199.5,163.3,130.2,130.0,113.7,31.4,8.5.HRMS(ESI)m / z:calcd forC 10 H9D3O2Na[M+Na] + :190.0918,found:190.0957.

[0060] Example 4

[0061]

[0062] 153.2 mg (0.4 mmol, 2.0 equiv.) of 5-trideuterated 5H-dithioanthracene 5-ium trifluoromethanesulfonate, 52.22 mg (0.2 mmol, 1 equiv.) of 4-bromobenzophenone, 3.65 mg (0.004 mmol, 2 mol%) of (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 6.17 10 mg (0.02 mmol, 10 mol%) nickel(II) chloride ethylene glycol dimethyl ether complex, 6.48 mg (0.03 mmol, 15 mol%) 4,4'-dimethoxy-2,2'-bipyridine, 18 uL (1 mmol, 5.0 equiv.) water, and 55.28 mg (0.4 mmol, 2.0 equiv.) potassium carbonate were added to DMA and stirred thoroughly to dissolve to prepare a 10 mL solution. The reaction solution was placed in a reaction apparatus illuminated by blue LED light for 18 hours and monitored by TLC. After completion of the reaction, the reaction was quenched and extracted with ethyl acetate and saturated brine (3×25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. 22.71 mg of the product 3ad was obtained by silica gel column chromatography (petroleum ether:ethyl acetate) with a product yield of 53%. The characterization data of 3ad are as follows ( Figure 8 、 Figure 9 ): 1 H NMR (400MHz, CDCl3) δ7.78–7.72(m,2H),7.70–7.64(m,2H),7.51–7.46(m,1H),7.42–7.35(m,2H),6.91–6.85(m,2H). 13 CNMR(100MHz, CDCl3)δ195.6,163.2,138.3,132.6,131.9,130.1,129.8,128.2,113.6.HRMS(ESI)m / z:calcd for C 14 H9D3O2Na[M+Na] + :238.0938,found:238.0938.

[0063] Example 5

[0064]

[0065] 153.2 mg (0.4 mmol, 2.0 equiv.) of 5-trideuterated 5H-dithioanthracene 5-ium trifluoromethanesulfonate, 43.01 mg (0.2 mmol, 1 equiv.) of methyl p-bromobenzoate, 3.65 mg (0.004 mmol, 2 mol%) of (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 6.17 10 mg (0.02 mmol, 10 mol%) nickel (II) chloride ethylene glycol dimethyl ether complex, 6.48 mg (0.03 mmol, 15 mol%) 4,4'-dimethoxy-2,2'-bipyridine, 18 uL (1 mmol, 5.0 equiv.) water, 55.28 mg (0.4 mmol, 2.0 equiv.) potassium carbonate, DMA was added and stirred thoroughly to dissolve, and a 10 mL solution was prepared. The reaction solution was placed in a reaction apparatus illuminated by blue LED light for 18 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction was quenched and extracted with ethyl acetate and saturated brine (3×25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After that, the product 3ae 16.82 mg was obtained by silica gel column chromatography (petroleum ether:ethyl acetate) with a yield of 50%. The characterization data of 3ae are as follows ( Figure 10 、 Figure 11 ): 1 H NMR (400MHz, CDCl3) δ7.95–7.90(m,2H),6.87–6.82(m,2H),3.82(s,3H). 13 C NMR(100MHz, CDCl3)δ166.9,163.3,131.6,122.6,113.6,51.9.HRMS(ESI)m / z:calcd for C9H7D3O3Na[M+Na] + :192.0710,found:192.0750.

[0066] Example 6

[0067]

[0068] 153.2 mg (0.4 mmol, 2.0 equiv.) of 5-trideuterated methyl 5H-dithioanthracene 5-ium trifluoromethanesulfonate, 45.81 mg (0.2 mmol, 1 equiv.) of ethyl 4-bromobenzoate, 3.65 mg (0.004 mmol, 2 mol%) of (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 6.1 7 mg (0.02 mmol, 10 mol%) nickel(II) chloride ethylene glycol dimethyl ether complex, 6.48 mg (0.03 mmol, 15 mol%) 4,4'-dimethoxy-2,2'-bipyridine, 18 uL (1 mmol, 5.0 equiv.) water, and 55.28 mg (0.4 mmol, 2.0 equiv.) potassium carbonate were added to DMA and stirred thoroughly to dissolve to prepare a 10 mL solution. The reaction solution was placed in a reaction apparatus illuminated by blue LED light for 18 hours and monitored by TLC. After the reaction was completed, the reaction was quenched and extracted with ethyl acetate and saturated brine (3×25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The product 3af (17.49 mg) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate) with a yield of 48%. The characterization data of 3af are as follows ( Figure 12 、 Figure 13 ): 1 H NMR (400MHz, CDCl3) δ7.95–7.90(m,2H),6.87–6.81(m,2H),4.27(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H). 13 C NMR(100MHz, CDCl3)δ166.4,163.3,131.6,122.9,113.5,60.6,14.4.HRMS(ESI)m / z:calcd for C 10 H9D3O3Na[M+Na] + :206.0867,found:206.0877.

[0069] Example 7

[0070]

[0071] 153.2 mg (0.4 mmol, 2.0 equiv.) of 5-trideuterated 5H-dithioanthracene 5-ium trifluoromethanesulfonate, 47.02 mg (0.2 mmol, 1 equiv.) of 4-bromobenzylsulfone, 3.65 mg (0.004 mmol, 2 mol%) of (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 6.17 100 mg (0.02 mmol, 10 mol%) nickel (II) chloride ethylene glycol dimethyl ether complex, 6.48 mg (0.03 mmol, 15 mol%) 4,4'-dimethoxy-2,2'-bipyridine, 18 uL (1 mmol, 5.0 equiv.) water, 55.28 mg (0.4 mmol, 2.0 equiv.) potassium carbonate, DMA was added and stirred thoroughly to dissolve, and a 10 mL solution was prepared. The reaction solution was placed in a reaction apparatus illuminated by blue LED light for 18 hours, and the reaction was monitored by TLC. After the reaction was completed, the reaction was quenched and extracted with ethyl acetate and saturated brine (3×25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After that, the product 3ag 23.34 mg was obtained by silica gel column chromatography (petroleum ether:ethyl acetate) with a recovery rate of 62%. The characterization data of 3ag are as follows ( Figure 14 、 Figure 15 ): 1 H NMR (400MHz, CDCl3) δ7.87 (dt, J = 9.9, 2.0Hz, 2H), 7.06–7.00 (m, 2H), 3.05–3.02 (m, 3H). 13 C NMR(100MHz, CDCl3)δ163.7,132.1,129.5,114.5,44.9.HRMS(ESI)m / z:calcd for C8H7D3O3SNa[M+Na] + :212.0431,found:212.0434.

[0072] Example 8

[0073]

[0074] 145.74 mg (0.4 mmol, 2.0 equiv.) 10-trideuteriomethyl 10H-phenoxathiol trifluoromethanesulfonate, 36.4 mg (0.2 mmol, 1 equiv.) p-bromobenzonitrile, 3.65 mg (0.004 mmol, 2 mol%) (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 6.17 mg (0.02 mmol, 10 mol%) nickel(II) chloride ethylene glycol dimethyl ether complex, 6.48 mg (0.03 mmol, 15 mol%) 4,4'-dimethoxy-2,2'-bipyridyl, 18 uL (1 mmol, 5.0 equiv.) water, and 55.28 mg (0.4 mmol, 2.0 equiv.) potassium carbonate were weighed in sequence, DMA was added, and the mixture was stirred thoroughly to dissolve to prepare a 10 mL solution. The reaction solution was placed in a reaction apparatus illuminated by a blue LED for 18 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction was quenched and extracted with ethyl acetate and saturated brine (3×25 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and then purified by silica gel column chromatography (petroleum ether:ethyl acetate) to obtain 7.03 mg of the product 3aa in a product yield of 26%.

[0075] Example 9

[0076]

[0077] 140.54 mg (0.4 mmol, 2.0 equiv.) 5-trideuterated methyl 5H-dibenzothiophene 5-trifluoromethanesulfonate, 36.4 mg (0.2 mmol, 1 equiv.) p-bromobenzonitrile, 3.65 mg (0.004 mmol, 2 mol%) (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 6.17 mg ( DMA (0.02 mmol, 10 mol%) nickel(II) chloride-ethylene glycol dimethyl ether complex, 6.48 mg (0.03 mmol, 15 mol%) 4,4'-dimethoxy-2,2'-bipyridine, 18 uL (1 mmol, 5.0 equiv.) of deionized water, and 55.28 mg (0.4 mmol, 2.0 equiv.) of potassium carbonate were added and thoroughly stirred to dissolve to make a 10 mL solution. The reaction solution was placed in a reaction vessel illuminated by blue LED light for 18 hours and monitored by TLC. After completion, the reaction was quenched and extracted with ethyl acetate and saturated brine (3 x 25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The product 3aa (6.54 mg) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate) in a 24% yield.

[0078] Example 10

[0079]

[0080] 141.35 mg (0.4 mmol, 2.0 equiv.) trideuterated methyldiphenylsulfonium trifluoromethanesulfonate, 36.4 mg (0.2 mmol, 1 equiv.) p-bromobenzonitrile, 3.65 mg (0.004 mmol, 2 mol%) (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 6.17 mg (0.02 mmol, 10 mol%) nickel(II) chloride ethylene glycol dimethyl ether complex, 6.48 mg (0.03 mmol, 15 mol%) 4,4'-dimethoxy-2,2'-bipyridyl, 18 uL (1 mmol, 5.0 equiv.) water, and 55.28 mg (0.4 mmol, 2.0 equiv.) potassium carbonate were weighed in sequence, DMA was added, and the mixture was stirred thoroughly to dissolve to prepare a 10 mL solution. The reaction solution was placed in a reaction apparatus illuminated by a blue LED for 18 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction was quenched and extracted with ethyl acetate and saturated brine (3×25 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and then purified by silica gel column chromatography (petroleum ether:ethyl acetate) to obtain 7.35 mg of the product 3aa in a yield of 27%.

[0081] Example 1-11 is a method for preparing deuterated aromatic phenol compounds based on visible light / nickel synergistic catalysis. The main parameters and the obtained yields are shown in Table 1. 1a in the raw materials is 5-trideuteriomethyl 5H-dithioanthracene 5-onium trifluoromethanesulfonate, 2a is 4-bromobenzonitrile, 2b is 4-bromoacetophenone, 2c is 4-bromopropiophenone, 2d is 4-bromobenzophenone, 2e is methyl 4-bromobenzoate, 2f is ethyl 4-bromobenzoate, 2g is 4-bromobenzylsulfone, 1b is 10-trideuteriomethyl 10H-phenoxathiol trifluoromethanesulfonate, 1c is 5-trideuteriomethyl 5H-dibenzothiophene 5-trifluoromethanesulfonate, and 1d is trideuteriomethyl diphenylsulfonium trifluoromethanesulfonate.

[0082] Table 1

[0083]

[0084] The present invention provides a method for preparing deuterated arylphenol compounds based on visible light / nickel synergistic catalysis. There are many methods and approaches for implementing this technical solution. The above is only a preferred embodiment of the present invention. It should be noted that those skilled in the art may make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications are also considered to be within the scope of protection of the present invention. Any components not specified in this embodiment may be implemented using existing technologies.

Claims

1. A method for preparing deuterated methyl ether compounds based on visible light / nickel synergistic catalysis, characterized in that: A mixed solution comprising a trideuterium-containing methylating agent represented by Formula 1, an aryl halide represented by Formula 2, a photocatalyst and a nickel catalyst, a base additive, and a solvent is reacted in a reaction device irradiated with visible light to obtain an aryl deuterated methyl ether compound represented by Formula 3; in, Dashed lines indicate absence, a single bond, or —R1—; R1 is selected from S, or O; R2 is selected from cyano, formyl, acetyl, benzoyl, methyl formate, ethyl formate, or methyl sulfone; the photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate; the nickel catalyst is nickel(II) chloride ethylene glycol dimethyl ether complex; the base is potassium carbonate, and the light is a blue LED.

2. The method according to claim 1, characterized in that The trideuterium-containing methylation reagent shown in Formula 1 is any one of the following compounds; 3. The method according to claim 1, characterized in that The aryl halide represented by formula 2 is any one of the following compounds; 4. The method according to claim 1, characterized in that The solvent is a combination of an organic solvent and water.

5. The method according to claim 4, characterized in that: The organic solvent includes any one or a combination of acetonitrile, dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, ethyl acetate, tetrahydrofuran, acetone, 1,2-dichloroethane, 1,4-dioxane and toluene.

6. The method according to claim 4, characterized in that: The molar ratio of the organic solvent to water is 0.3-0.5:

1.

7. The method according to claim 1, characterized in that In the mixed solution, the concentration of the trideuterium-containing methylation reagent represented by Formula 1 is 0.01 to 0.2 mmol / mL.

8. The method according to claim 1, characterized in that: In the mixed solution, the concentration of the aryl halide represented by Formula 2 is 0.02 to 0.4 mmol / mL.

9. The method according to claim 1, characterized in that: The photocatalyst is 1% to 3% of the molar ratio of the aryl halide shown in Formula 2; the nickel catalyst is 5% to 25% of the molar ratio of the aryl halide shown in Formula 2; and the base additive is 0.5 to 2.5 times the molar ratio of the aryl halide shown in Formula 2.

10. The method according to claim 1, characterized in that: The visible light wavelength range is 400-800 nm.

11. The method according to claim 1, characterized in that: The reaction temperature is 20-30° C.; the reaction time is 14-22 hours.

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