阅读说明：本技术 一种芳基或杂芳基甲氧基化反应的方法 (Method for methoxylation of aryl or heteroaryl ) 是由 王东辉 王静茹 李辰 于 2021-07-30 设计创作，主要内容包括：本发明公开了一种芳基或杂芳基甲氧基化反应的方法。所述方法,包括如下步骤：将底物、偶联剂、配体、溶剂、催化剂和碱混合均匀在惰性气体中反应,得到所述芳基或杂芳基甲氧基化合物。本发明采用价格低廉的卤化亚铜为催化剂,实现了在卤化亚铜催化下,配体调控芳基卤化物或杂芳基卤化物的甲氧基化反应,与现有技术的甲氧基化反应的方法比较,本发明所述方法的反应体系条件温和,催化剂和配体的使用量分别低至底物物质的量的5％,提高了催化效率；且所述方法对不同底物拓展发现对不同官能团的芳基卤化物或杂芳基卤化物有较好的兼容性。采用本发明所述方法制备的芳基或杂芳基甲氧基化合物的产率为36％-89％。(The invention discloses a method for methoxylation of aryl or heteroaryl. The method comprises the following steps: and uniformly mixing a substrate, a coupling agent, a ligand, a solvent, a catalyst and alkali, and reacting in inert gas to obtain the aryl or heteroaryl methoxyl compound. The method adopts cheap cuprous halide as a catalyst, realizes the methoxylation reaction of the ligand-regulated aryl halide or heteroaryl halide under the catalysis of the cuprous halide, has mild reaction system conditions compared with the methoxylation reaction method in the prior art, and improves the catalytic efficiency, and the use amounts of the catalyst and the ligand are respectively as low as 5 percent of the amount of the substrate substance; and the method is developed for different substrates and has better compatibility for aryl halide or heteroaryl halide with different functional groups. The yield of the aryl or heteroaryl methoxy compound prepared by the method is 36-89%.)

1. A method for methoxylation of an aryl or heteroaryl group, comprising the steps of: uniformly mixing a substrate, a coupling agent, a ligand, a solvent, a catalyst and alkali, and reacting in an inert gas to obtain the aryl or heteroaryl methoxyl compound; the structural formula of the aryl or heteroaryl methoxyl compound is shown as a formula (1):

in the formula (1), m is the number of H on a benzene ring substituted by a substituent R, and m is a natural number of 0-5; when m is 2-5, a plurality of H on a benzene ring are substituted by a plurality of substituent groups R, and the substituent groups R on different substitution positions are the same group or different groups; r is benzene ring, substituted benzene ring, aromatic heterocycle, methylthio, ester group, carbonyl, alkoxy of C1-C6, alkyl of C1-C6, vinyl, cyano, naphthenic base, alcoholic hydroxyl of C1-C6, sulfonic group or nitro.

2. The method for methoxylating an aryl or heteroaryl according to claim 1, wherein the aryl or heteroaryl methoxylate compound has the structural formula of one of formulae (2) to (25):

3. the method of methoxylation of an aryl or heteroaryl group according to claim 1, wherein the coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate.

4. The method of methoxylation of an aryl or heteroaryl group according to claim 1, wherein the substrate has the formula (26):

in the formula (1), X is halogen, preferably one of-Cl and-Br.

5. The method of aryl or heteroaryl methoxylation of claim 1, wherein the molar ratio of the substrate, coupling agent, ligand, catalyst and base is substrate: coupling agent: ligand: catalyst: base ═ 0.2: 0.3: 0.01: 0.01: 0.02.

6. the method for methoxylating an aryl or heteroaryl according to claim 1, wherein the reaction is carried out at a temperature of 80 ℃ and for a period of 12 hours.

7. The method for methoxylating an aryl or heteroaryl group according to claim 1, wherein the ligand has the formula (la) according to one of formulae (27) to (32):

8. the method of methoxylating an aryl or heteroaryl group according to claim 7, wherein the ligand of one of the formulae (27) to (30) is prepared by a process comprising the steps of:

(1) sequentially adding the compound a, tetrahydrofuran and triethylamine into a container at 0-4 ℃, then adding oxalyl chloride, and stirring and reacting for 2 hours at room temperature to obtain a reaction liquid A;

(2) removing the solvent from the reaction solution A to obtain a residue, adding water, filtering, washing and drying to obtain a ligand with a structural formula of one of formulas (27) to (30);

the compound a is one of 2-phenyl-4-methylaniline, 2-phenoxyaniline, 3, 5-dimethyl-4-aminophenol and 2, 6-dimethylaniline; the mass ratio of the compound a to the triethylamine to the oxalyl chloride is that the compound a: triethylamine: oxalyl chloride ═ 1: 1.1: 0.5.

9. the method for methoxylating an aryl or heteroaryl group according to claim 7, wherein the ligand of formula (31) is prepared by a process comprising the steps of:

s1: sequentially adding the compound a, tetrahydrofuran and triethylamine into a container, then adding monomethyl oxalyl chloride, and stirring and reacting for 2 hours at room temperature to obtain a reaction solution B;

s2: removing the solvent from the reaction solution B to obtain a residue, adding water, extracting to obtain an upper organic phase, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain a solid C;

s3: dissolving solid C in tetrahydrofuran, adding BnNH₂Then stirring and reacting for 1h at 70 ℃, cooling and removing the solvent to obtain a residue, adding the residue into water, filtering, washing and drying to obtain the ligand with the structural formula (31);

in the S1, the structural formula of the compound a isThe mass concentration ratio of the compound a, triethylamine and monomethyl oxalyl chloride is that the compound a: triethylamine: monomethyloxalyl chloride ═ 0.5: 1.2: 1; in the S3, solid C and BnNH₂The mass ratio of (A) to (B) is solid: BnNH₂＝10：1.2。

10. The method for methoxylating an aryl or heteroaryl group according to claim 7, wherein the ligand of formula (32) is prepared by a process comprising the steps of:

a: dissolving 2-amino-3-methylbenzoic acid and N, N' -carbonyldiimidazole in tetrahydrofuran at 0-4 ℃, stirring overnight at room temperature, filtering, washing and drying to obtain a product a; the mass ratio of the 2-amino-3-methylbenzoic acid to the N, N' -carbonyldiimidazole is as follows: 1: 1.2;

b: dissolving the product a in ethanol, adding N₂H₄Then stirring and reacting for 4h at room temperature, removing the solvent, washing and drying to obtain a product b; the products a and N₂H₄The mass concentration ratio of the substances (1): 5;

c: dissolving the product b in ethanol, and sequentially adding NH₄Refluxing Cl and triethyl orthoacetate at 85 ℃ for 6h, removing the solvent, adding water for quenching, extracting, taking an upper organic phase, drying by using anhydrous sodium sulfate, filtering, spin-drying, and performing column chromatography separation to obtain a product c; the products b, NH₄The mass ratio of Cl to triethyl orthoacetate was product b: NH (NH)₄Cl: triethyl orthoacetate 1: 0.5: 1.2;

d: dissolving the product c in tetrahydrofuran at 0-4 ℃, sequentially adding triethylamine and monomethyl oxalyl chloride, stirring at room temperature for reaction for 2h, removing the solvent, adding water for quenching, extracting to obtain an upper organic phase, drying with anhydrous sodium sulfate, filtering, spin-drying, and separating by column chromatography to obtain a product d; the mass ratio of the product c, triethylamine and monomethyl oxalyl chloride is the product b: NH (NH)₄Cl: triethyl orthoacetate 1:1.2: 1.1;

e: dissolving the product d in tetrahydrofuran, adding 4-methoxybenzylamine, refluxing at 65 ℃ for 30min, removing the solvent, adding water for quenching, extracting an upper organic phase, drying with anhydrous sodium sulfate, filtering, spin-drying, and performing column chromatography separation to obtain a ligand with a structural formula (32); mass ratio of product d to 4-methoxybenzylamine 1: 1.5.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for methoxylation of aryl or heteroaryl.

Background

Methyl aryl ether and diaryl ether are very important structural fragments in chemistry, are ubiquitous in polypropylene polymers and many pesticides, are common general intermediates of active pharmaceutical compounds such as piperazinomycin (antifungal drug), vancomycin and K-13(ACE inhibitor), and are also important fragments in drug molecules such as papaverine, aniracetam, gefitinib, pantoprazole, naproxen and alpha-asarone and natural products. The synthesis of methyl (hetero) aryl ethers is therefore of great interest. The traditional synthesis of methyl aryl ether usually needs to use toxic reagents such as methyl iodide, diazomethane, dimethyl sulfate and the like, and brings much inconvenience to industrial production. Therefore, it is necessary to develop a synthesis method in which the reaction system is mild in conditions, the experimental operation is simple, the substrate applicability is good, and toxic or strongly corrosive chemical reagents are not required.

At present, the reported methoxylation reaction is mostly catalyzed by palladium, the required cost is too high, and a plurality of other problems exist. As shown in 2009, Clarke topic group reported methoxylation (Organic) using methoxylsilane as nucleophilic reagent&Biomolecular chemistry, 2009,7(12)), palladium acetate is used as a catalyst in the reaction, and 86% of methoxylated product can be obtained by the reaction at 120 ℃. In 2012, both Beller group (chemistry.2012,18(9),2498) and perunicellathan group (eur.j.org.chem.2012,6,4914) reported the coupling reaction of (hetero) aryl halides with methanol, and both electron deficient and charge neutral aryl halides in the reaction system gave methoxylated products with high efficiency, while the electron rich aryl halides gave very low yields. In 2013, Buchwald topic group reported the methoxylation of (hetero) aryl halides with high activity cyclic palladium species as catalysts (org. lett.2013,15(15), 3998). The reaction can efficiently construct methyl (hetero) aryl ether under mild conditions, and focuses on methoxylation of heterocyclic and polycyclic (five-membered ring and six-membered ring) aryl halides. In 2014, Novak group (adv. Synth. Catal.2014,356(1),125) reported KB (OMe)₄And NaB (OCD)₃)₄Aryl chlorides, which are methoxylating agents, are methoxylated in only 3 hours, but heteroaryl halides are not suitable for use in this system.

Relatively few reports are currently made about inexpensive transition metal-catalyzed methoxylation reactions. In 2015-2016, the major group of horses used cuprous iodide as a catalyst, and a series of novel carbon-heterobond coupling reactions (j.am. chem. soc.2015,137(37), 11942; org. lett.2015,17(23), 5934; angelw. chem., int. ed.2016,55(21), 6211; j.am. chem. soc.2016, 2016 (41),13493) were successively designed, which can be carried out under mild conditions, with both electron-rich and electron-deficient aryl and heteroaryl chlorides giving coupled products with high efficiency, and with low catalyst and ligand usage, and with relatively low temperature and reduced copper and ligand usage to 0.5 mol% when more active (hetero) aryl bromides and iodides are coupled with phenolic compounds. In 2019, the group also reported that two ligands together promoted the alkoxylation of copper-catalyzed (hetero) aryl halides, in the reaction system, aryl chlorides can also efficiently obtain corresponding ether products, and many carbohydrate derivatives are also suitable for the coupling reaction, with the yield of 29-98%.

The above prior art methods are not suitable for base sensitive groups and require water as a co-solvent. Based on the above current situation, there is a need to develop a new methoxy source, and the methoxy source can be used for the copper-catalyzed methoxylation of aryl halides.

Disclosure of Invention

In view of the above-mentioned disadvantages of the prior art, the present invention provides a method for methoxylation of aryl or heteroaryl groups.

In order to achieve the purpose, the invention adopts the technical scheme that:

a method of methoxylating an aryl or heteroaryl group comprising the steps of: uniformly mixing a substrate, a coupling agent, a ligand, a solvent, a catalyst and alkali, and reacting in an inert gas to obtain the aryl or heteroaryl methoxyl compound; the structural formula of the aryl or heteroaryl methoxyl compound is shown as a formula (1):

in the formula (1), m is the number of H on a benzene ring substituted by a substituent R, and m is a natural number of 0-5; when m is 2-5, a plurality of H on a benzene ring are substituted by a plurality of substituent groups R, and the substituent groups R on different substitution positions are the same group or different groups; r is benzene ring, substituted benzene ring, aromatic heterocycle, methylthio, ester group, carbonyl, alkoxy of C1-C6, alkyl of C1-C6, vinyl, cyano, naphthenic base, alcoholic hydroxyl of C1-C6, sulfonic group or nitro.

The reaction route of the aryl or heteroaryl methoxylation method of the invention is as follows:

the invention develops a methoxylation reaction of aryl halide or heteroaryl halide under the catalysis of copper by taking cuprous halide as a catalyst, can overcome the defects that the method in the prior art is not suitable for alkali-sensitive groups and needs water as a cosolvent, has mild reaction system conditions, simple experimental operation and relatively good substrate applicability, does not need to use toxic or strongly corrosive chemical reagents, and has the yield of 36-89% of aryl or heteroaryl methoxylated compounds prepared by the method.

M is the number of substituent groups R on a benzene ring, and m is a natural number of 0-5; when m is 0, H on the benzene ring is not substituted; when m is 1, represents a substituent R for one H on the benzene ring; when m is 2-5, the number of H substituted by substituent R on the benzene ring is 2-5, and the substituent R on different substituted positions is the same group or different groups; r is independently selected from a substituted benzene ring, an aromatic heterocycle, a methylthio group, an ester group, an alkoxy group of C1-C6, an alkyl group of C1-C6, an alcoholic hydroxyl group of C1-C6, a sulfonic group or a nitro group.

As a preferred embodiment of the present invention, the method for methoxylating an aryl or heteroaryl group comprises the following steps: sequentially adding a substrate and a ligand into a dry reaction tube at room temperature, then placing the reaction tube into a glove box, sequentially adding a catalyst, an alkali and a solvent, then taking out the reaction tube, replacing nitrogen for three times, adding a coupling agent, sealing, placing in an oil bath at 80 ℃ for reaction for 12 hours, after the reaction is finished, adding water for quenching, extracting with ethyl acetate, combining organic phases, concentrating under reduced pressure, and separating by column chromatography to obtain the aryl or heteroaryl methoxyl compound.

As a preferred embodiment of the present invention, the molar ratio of the substrate, the coupling agent, the ligand, the catalyst and the base is substrate: coupling agent: ligand: catalyst: base ═ 0.2: 0.3: 0.01: 0.01: 0.02.

in a preferred embodiment of the present invention, the aryl or heteroaryl methoxy compound has a structural formula of one of formulae (2) to (25):

as a preferred embodiment of the present invention, the coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate.

As a preferred embodiment of the invention, the substrate has the formula (26):

in the formula (1), X is halogen, preferably one of-Cl and-Br.

As a preferred embodiment of the present invention, the reaction temperature is 80 ℃ and the reaction time is 12 hours.

In a preferred embodiment of the present invention, the ligand has a structural formula of one of formulae (27) to (32):

the ligand of the invention mainly plays a role in stabilizing a catalyst in a reaction system, and the inventor of the application proves that the yield of the ligand to the methoxylation reaction sequentially from high to low: the structural formula is a ligand of a formula (29), the structural formula is a ligand of a formula (30), and the structural formulas are ligands of formulas (27) - (28) and (31) - (32).

As a preferred embodiment of the present invention, the method for preparing the ligand having one of the structural formulas (27) to (30) comprises the steps of:

(1) sequentially adding the compound a, tetrahydrofuran and triethylamine into a container at 0-4 ℃, then adding oxalyl chloride, and stirring and reacting for 2 hours at room temperature to obtain a reaction liquid A;

(2) removing the solvent from the reaction solution A to obtain a residue, adding water, filtering, washing and drying to obtain a ligand with a structural formula of one of formulas (27) to (30);

the compound a is one of 2-phenyl-4-methylaniline, 2-phenoxyaniline, 3, 5-dimethyl-4-aminophenol and 2, 6-dimethylaniline; the mass concentration ratio of the compound a, triethylamine and oxalyl chloride is that the compound a: triethylamine: oxalyl chloride ═ 1: 1.1: 0.5.

the structural formulas are synthetic routes to ligands of formulae (27) to (30):

more preferably, the step (2) is specifically: and (2) concentrating the reaction liquid A in vacuum to remove the solvent to obtain a residue, adding water into the residue, filtering, washing the filtered solid by using water and diethyl ether in sequence for more than three times, and then drying in vacuum to obtain the ligand with one of the structural formulas (27) to (30).

The water was added to the residue to dissolve Et in the system₃N & HCl, improving the purity of the product.

As a preferred embodiment of the present invention, the method for preparing the ligand of the formula (31) comprises the steps of:

s1: sequentially adding the compound a, tetrahydrofuran and triethylamine into a container, then adding monomethyl oxalyl chloride, and stirring and reacting for 2 hours at room temperature to obtain a reaction solution B;

s2: removing the solvent from the reaction solution B to obtain a residue, adding water, extracting to obtain an upper organic phase, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain a solid C;

s3: dissolving solid C in tetrahydrofuran, adding BnNH₂Then stirring and reacting for 1h at 70 ℃, cooling and removing the solvent to obtain a residue, adding the residue into water, filtering, washing and drying to obtain the ligand with the structural formula (31);

in the S1, the structural formula of the compound a isThe mass concentration ratio of the compound a, triethylamine and monomethyl oxalyl chloride is that the compound a: triethylamine: monomethyloxalyl chloride ═ 0.5: 1.2: 1; in the S3, solid C and BnNH₂The mass ratio of (A) to (B) is solid: BnNH₂＝10：1.2。

The structural formula is a synthetic route of the ligand of formula (31):

more preferably, the step S2 is specifically: and (3) concentrating the reaction liquid B in vacuum to remove the solvent to obtain a residue, adding water into the residue, extracting for more than three times by using ethyl acetate, taking an upper organic phase, introducing into a container, adding anhydrous sodium sulfate, drying, filtering, spin-drying, and performing column chromatography to obtain a solid C.

The step S3 specifically includes: and (2) concentrating the reaction solution after the stirring reaction in vacuum to remove the solvent to obtain a residue, adding water into the residue, filtering, washing the filtered solid by using water and diethyl ether in sequence for more than three times, and then drying in vacuum to obtain the ligand with the structural formula (31).

The water was added to the residue to dissolve Et in the system₃N & HCl, improving the purity of the product.

As a preferred embodiment of the present invention, the method for preparing the ligand of the formula (32) comprises the steps of:

a: mixing 2-amino-3-methylbenzoic acid, tetrahydrofuran and N, N' -carbonyldiimidazole at 0-4 ℃, stirring overnight at room temperature, filtering, washing and drying to obtain a product a; the mass ratio of the 2-amino-3-methylbenzoic acid to the N, N' -carbonyldiimidazole is as follows: 1: 1.2;

b: dissolving the product a in ethanol, adding N₂H₄Then stirring the mixture at room temperature for reaction for 4 hours, removing the solvent, washing and drying the mixture to obtain a productb; the products a and N₂H₄The mass ratio of (1): 5;

c: dissolving the product b in ethanol, and sequentially adding NH₄Refluxing Cl and triethyl orthoacetate at 85 ℃ for 6h, removing the solvent, adding water for quenching, extracting, taking an upper organic phase, drying by using anhydrous sodium sulfate, filtering, and spin-drying to obtain a product c; the products b, NH₄The mass ratio of Cl to triethyl orthoacetate was product b: NH (NH)₄Cl: triethyl orthoacetate 1: 0.5: 1.2;

d: dissolving the product c in tetrahydrofuran at 0-4 ℃, sequentially adding triethylamine and monomethyl oxalyl chloride, stirring at room temperature for reaction for 2h, removing the solvent, adding water for quenching, extracting to obtain an upper organic phase, drying with anhydrous sodium sulfate, filtering and spin-drying to obtain a product d; the mass ratio of the product c, triethylamine and monomethyl oxalyl chloride is the product c: triethylamine: oxalyl chloride monomethyl ester 1:1.2: 1.1;

e: dissolving the product d in tetrahydrofuran, adding 4-methoxybenzylamine, refluxing at 65 ℃ for 30min, removing the solvent, adding water for quenching, extracting to obtain an upper organic phase, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain a ligand with a structural formula (32); mass ratio of product d to 4-methoxybenzylamine 1: 1.5.

the structural formula is a synthetic route of the ligand of formula (32):

a：

b：

c：

d：

e：

compared with the prior art, the invention has the following beneficial effects: the method adopts cheap cuprous halide as a catalyst, realizes the methoxylation reaction of the ligand-regulated aryl halide or heteroaryl halide under the catalysis of the cuprous halide, has mild reaction system conditions compared with the methoxylation reaction method in the prior art, and improves the catalytic efficiency, and the use amounts of the catalyst and the ligand are respectively as low as 5 percent of the amount of the substrate substance; and the method is developed for different substrates and has better compatibility for aryl halide or heteroaryl halide with different functional groups. The yield of the aryl or heteroaryl methoxy compound prepared by the method is 36-89%.

Detailed Description

To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.

Example 1

The preparation method of the ligand with the structural formula of formula (27) comprises the following steps:

(1) taking a 50mL round-bottom flask, sequentially adding 20mL THF, 5mmol 2-phenyl-4-methylaniline and 5.5mmol triethylamine into the round-bottom flask, slowly adding 2.5mmol oxalyl chloride at 0-4 ℃, and stirring the reaction solution at room temperature for 2h to obtain reaction solution A;

(2) the reaction solution A was concentrated in vacuo to remove the solvent to give a residue, and water was added to the residue to dissolve Et₃N.HCl; filtering the slurry, washing the solid on the filter paper with water and ether in sequence for three times, and drying in vacuum to obtain 1.6g of ligand L1 white solid with the structural formula (27); the yield of the ligand L1 was 78%, and the structural formula of the ligand L1 was as follows:

the hydrogen spectrum and carbon spectrum data of the target product ligand L1 are as follows:¹H NMR(400MHz,CDCl3)δ9.48(s,2H),8.26(d,J＝8.0Hz,2H),7.54-7.50(m,4H),7.46-7.42(m,2H),7.39(d,J＝7.2Hz,4H),7.18(d,J＝8.4Hz,2H),7.12(s,2H),2.36(s,6H).¹³C NMR(100MHz,CDCl3)δ157.3,137.4,135.0,132.8,130.9,130.8,129.2,129.1,128.9.128.3,120.3,20.9.

example 2

The preparation method of the ligand with the structural formula of formula (28) comprises the following steps:

(1) taking a 50mL round-bottom flask, sequentially adding 20mL THF, 5mmol 2-phenoxyaniline and 5.5mmol triethylamine into the round-bottom flask, slowly adding 2.5mmol oxalyl chloride at 0-4 ℃, and stirring the reaction liquid at room temperature for 2h to obtain reaction liquid A;

(2) the reaction solution A was concentrated in vacuo to remove the solvent to give a residue, and water was added to the residue to dissolve Et₃N.HCl; filtering the slurry, washing the solid on the filter paper with water and ether sequentially for three times, and drying in vacuum to obtain 1.7g of ligand L2 white solid with the structural formula of (28); the yield of the ligand L2 was 81%, and the structural formula of the ligand L2 was as follows:

the hydrogen spectrum and carbon spectrum data of the target product ligand L2 are as follows:¹H NMR(400MHz,CDCl3)δ9.97(s,1H),8.48(d,J＝7.6Hz,2H),7.40-7.36(m,4H),7.54-7.50(m,4H),7.19-7.13(m,4H),7.11-7.07(m,6H),6.91(d,J＝7.6Hz,2H).¹³C NMR(100MHz,CDCl3)δ157.4,156.1,146.7,130.0,128.0,125.4,124.2,123.8,120.5,119.0,117.6.

example 3

The preparation method of the ligand with the structural formula of formula (29) comprises the following steps:

(1) taking a 50mL round-bottom flask, sequentially adding 20mL THF, 5mmol 3, 5-dimethyl-4-aminophenol and 5.5mmol triethylamine into the round-bottom flask, slowly adding 2.5mmol oxalyl chloride at 0-4 ℃, and stirring the reaction solution at room temperature for 2h to obtain reaction solution A;

(2) vacuum concentrating reaction solution A to remove solvent to obtain residue, addingWater to dissolve Et₃N.HCl; filtering the slurry, washing the solid on the filter paper with water and ether in sequence for three times, and drying in vacuum to obtain 1.38g of ligand L3 white solid with the structural formula of (29); the yield of the ligand L3 was 85%, and the structural formula of the ligand L3 was as follows:

the hydrogen spectrum and carbon spectrum data of the target product ligand L3 are as follows:¹H NMR(400MHz,DMSO)δ9.96(s,2H),6.50(s,4H),2.06(s,12H).¹³C NMR(100MHz,DMSO)δ159.3,155.9,136.1,125.5,114.3,18.1.

example 4

The preparation method of the ligand with the structural formula of formula (30) comprises the following steps:

(1) taking a 50mL round-bottom flask, sequentially adding 20mL THF, 5mmol 2, 6-dimethylaniline and 5.5mmol triethylamine into the round-bottom flask, slowly adding 2.5mmol oxalyl chloride at 0-4 ℃, and stirring the reaction solution at room temperature for 2h to obtain reaction solution A;

(2) the reaction solution A was concentrated in vacuo to remove the solvent to give a residue, and water was added to the residue to dissolve Et₃N.HCl; filtering the slurry, washing the solid on the filter paper with water and ether sequentially for three times, and drying in vacuum to obtain 1.15g of ligand L4 white solid with the structural formula of (30); the yield of the ligand L4 was 78%, and the structural formula of the ligand L4 was as follows:

the hydrogen spectrum and carbon spectrum data of the target product ligand L4 are as follows:¹H NMR(400MHz,DMSO)δ10.31(s,2H),7.13(s,6H),2.18(s,12H).¹³C NMR(100MHz,DMSO)δ159.3,135.5,134.5,128.2,127.4,18.4.

example 5

The preparation method of the ligand with the structural formula of formula (31) comprises the following steps:

s1: sequentially adding 0.5mmol of 4-methyl-2-phenylaniline, 20mL of tetrahydrofuran and 0.6mmol of triethylamine into a container, adding 0.5mmol of methyloxalyl chloride at 0-4 ℃, and stirring at room temperature for 2 hours to obtain a reaction solution B;

s2: the reaction solution B was concentrated in vacuo to remove the solvent to give a residue, and water was added to the residue to dissolve Et₃N.HCl; extracting with ethyl acetate for three times, taking the upper organic phase, pouring into a conical flask, drying with anhydrous sodium sulfate, filtering, spin-drying, and performing column chromatography to obtain solid C;

s3: dissolving the solid C obtained in the step S2 in 1.0M tetrahydrofuran, and adding BnNH₂Solid C and BnNH₂The mass ratio of (a) to (b) is solid C: BnNH₂1:1.2, stirring at 70 deg.C for 1h, cooling, vacuum concentrating to remove solvent to obtain residue, adding water to the residue to dissolve Et₃N.HCl; filtering the slurry, washing the solid on the filter paper with water and ether sequentially for three times, and drying in vacuum to obtain 1.26g of ligand L5 white solid with the structural formula (31); the yield of the ligand L5 was 73%, and the structural formula of the ligand L5 was as follows:

the hydrogen spectrum and carbon spectrum data of the target product ligand L5 are as follows:¹H NMR(400MHz,DMSO)δ9.83(s,1H),9.53(s,1H),7.90(d,J＝8.0Hz,1H),7.49-7.45(m,2H),7.42-7.40(m,3H),7.32-7.29(m,2H),7.25(d,J＝7.2Hz,4H),7.16(s,1H),4.32(d,J＝6.4Hz,2H),2.34(s,3H).¹³C NMR(100MHz,DMSO)δ159.8,157.9,138.5,137.9,135.1,134.5,131.1,130.8,128.8(4C),128.6,128.3(2C),127.7,127.4(2C),127.0,122.7,42.6,20.5.

example 6

The preparation method of the ligand with the structural formula of formula (32) comprises the following steps:

a: mixing 1mmol of 2-amino-3-methylbenzoic acid, 100mL of tetrahydrofuran and 1.2mmol of N, N' -carbonyldiimidazole at 0-4 ℃, stirring overnight at room temperature, filtering the reaction solution, washing the solid on the filter paper with diethyl ether, and drying in vacuum to obtain a product a;

b: 1mmol of product a are dissolved in 30mL of ethanol and 5mmol of N are added₂H₄Then stirring and reacting for 4h at room temperature, cooling, then carrying out vacuum concentration to remove the solvent, washing the solid with water and ether sequentially for three times, and carrying out vacuum drying to obtain a product b;

c: 1mmol of product b are dissolved in 30mL of ethanol and 0.5mmol of NH are added in succession₄Refluxing Cl and 1.2mmol triethyl orthoacetate at 85 ℃ for 6h, concentrating in vacuum to remove the solvent, then adding water for quenching, extracting with ethyl acetate for three times, taking the upper organic phase, pouring into an erlenmeyer flask, drying with anhydrous sodium sulfate, filtering, spin-drying, and performing column chromatography to obtain a product c;

d: dissolving 1mmol of product c in 20mL of tetrahydrofuran at 0-4 ℃, sequentially adding 1.2mmol of triethylamine and 1.1mmol of monomethyl oxalyl chloride, stirring and reacting for 2h at room temperature, vacuum concentrating to remove the solvent, adding water for quenching, extracting with ethyl acetate for three times, taking an upper organic phase, pouring the upper organic phase into a conical flask, drying with anhydrous sodium sulfate, filtering, spin-drying, and performing column chromatography to obtain a product d;

e: dissolving 1mmol of product d in 20mL of tetrahydrofuran, adding 1.5mmol of 4-methoxybenzylamine, refluxing at 65 ℃ for 30min, cooling to room temperature, concentrating under vacuum to remove the solvent, adding water for quenching, extracting with ethyl acetate for three times, taking the upper organic phase, pouring into a conical flask, drying with anhydrous sodium sulfate, filtering, spin-drying, and performing column chromatography to obtain 239mg of ligand L6 white solid with the structural formula of (32); the yield of the ligand L6 was 63%, and the structural formula of the ligand L6 was as follows:

the hydrogen spectrum and carbon spectrum data of the target product ligand L6 are as follows:¹H NMR(400MHz,DMSO)δ11.86(s,1H),9.59(t,J＝6.0Hz,1H),7.93(d,J＝8.0Hz,1H),7.73(d,J＝7.2Hz,1H),7.43(t,J＝7.6Hz,1H),7.26(d,J＝8.4Hz,2H),6.91(d,J＝8.4Hz,2H),4.32(m,1H),3.73(s,3H),2.53(s,3H),2.40(s,3H).¹³C NMR(100MHz,DMSO)δ159.2,158.3,158.1,154.3,144.8,135.5,135.3,130.3,129.0,126.5,124.1,120.4,113.8,55.1,41.9,21.3,17.1.

example 7

The invention relates to a method for methoxylation of aryl or heteroaryl, which specifically comprises the following steps:

uniformly mixing 0.2mmol of substrate, 0.3mmol of coupling agent, 0.01mmol of ligand, 1mL of solvent, 0.01mmol of catalyst and 0.4mmol of alkali, and reacting at 80 ℃ for 12h under the atmosphere of argon to obtain 28mg of methyl 4-methoxybenzoate as a white solid; the yield of methyl 4-methoxybenzoate was 83%;

the structural formula of the substrate isThe coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate; the ligand is L3;

the structural formula of the methyl 4-methoxybenzoate is as follows:

the hydrogen spectrum and carbon spectrum data of the target product 4-methoxy methyl benzoate are as follows:¹H NMR(400MHz,CDCl₃)δ7.99(d,J＝8.8Hz,2H),6.91(d,J＝8.8Hz,2H),3.87,(s,3H),3.84(s,3H).¹³C NMR(100MHz,CDCl₃)δ166.8,163.3,131.5,122.5,113.5,55.3,51.8.

example 8

The invention relates to a method for methoxylation of aryl or heteroaryl, which specifically comprises the following steps:

uniformly mixing 0.2mmol of substrate, 0.3mmol of coupling agent, 0.01mmol of ligand, 1mL of solvent, 0.01mmol of catalyst and 0.4mmol of alkali, and reacting at 80 ℃ for 12h under the argon atmosphere to obtain 29mg of (4-methoxyphenyl) cyclopropyl ketone white solid; the yield of (4-methoxyphenyl) cyclopropylmethanone was 82%;

the structural formula of the substrate isThe coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate; the ligand is L3;

the structural formula of the (4-methoxyphenyl) cyclopropyl ketone is as follows:

the hydrogen spectrum and carbon spectrum data of the target product (4-methoxyphenyl) cyclopropyl ketone are as follows:¹H NMR(400MHz,CDCl3)δ8.13-7.92(m,2H),7.02-6.90(m,2H),3.86(s,3H),2.66-2.60(m,1H),1.24-1.16(m,2H),0.99(dt,J＝7.2,3.5Hz,2H).¹³C NMR(100MHz,CDCl3)δ199.2,163.4,131.1,130.3,113.7,55.6,16.7,11.4.

example 9

The invention relates to a method for methoxylation of aryl or heteroaryl, which specifically comprises the following steps:

uniformly mixing 0.2mmol of substrate, 0.3mmol of coupling agent, 0.01mmol of ligand, 1mL of solvent, 0.01mmol of catalyst and 0.4mmol of alkali, and reacting at 80 ℃ for 12h under the atmosphere of argon to obtain 30mg of 4-methoxyphenyl ethyl acetate yellow liquid; the yield of ethyl 4-methoxyphenylacetate was 77%;

the structural formula of the substrate isThe coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate; the ligand is L3;

the structural formula of the 4-methoxy phenyl ethyl acetate is as follows:

the hydrogen spectrum and carbon spectrum data of the target product, namely 4-methoxy phenyl ethyl acetate, are as follows:¹H NMR(400MHz,CDCl3)δ7.20(d,J＝8.4Hz,2H),6.85(d,J＝8.8Hz,2H),7.36(q,J＝7.2Hz,2H),3.78(s,3H),3.53(s,2H),1.23(d,J＝7.2Hz,3H).¹³C NMR(100MHz,CDCl3)δ171.9,158.6,130.2,126.2,113.9,60.7,55.2,40.5,14.2.

example 10

The invention relates to a method for methoxylation of aryl or heteroaryl, which specifically comprises the following steps:

uniformly mixing 0.2mmol of substrate, 0.3mmol of coupling agent, 0.01mmol of ligand, 1mL of solvent, 0.01mmol of catalyst and 0.4mmol of alkali, and reacting at 80 ℃ for 12h under the argon atmosphere to obtain 26mg of 4-methoxythioanisole colorless oily substance; the yield of 4-methoxythioanisole is 84%;

the structural formula of the substrate isThe coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate; the ligand is L3;

the structural formula of the 4-methoxy thioanisole is as follows:

the hydrogen spectrum and carbon spectrum data of the target product 4-methoxy thioanisole are as follows:¹H NMR(400MHz,CDCl₃)δ7.28(d,J＝8.8Hz,2H),6.86(d,J＝8.8Hz,2H),3.79(s,3H),2.44(s,3H).¹³C NMR(100MHz,CDCl₃)δ158.2,130.2,128.8,114.7,55.4,18.2.

example 11

The invention relates to a method for methoxylation of aryl or heteroaryl, which specifically comprises the following steps:

uniformly mixing 0.2mmol of substrate, 0.3mmol of coupling agent, 0.01mmol of ligand, 1mL of solvent, 0.01mmol of catalyst and 0.4mmol of alkali, and reacting at 80 ℃ for 12h under the atmosphere of argon to obtain 34mg of 1-methoxy-4-cyclohexyl benzene white solid; the yield of 1-methoxy-4-cyclohexylbenzene was 89%;

the structural formula of the substrate isThe coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate; the ligand is L3;

the structural formula of the 1-methoxy-4-cyclohexylbenzene is as follows:

the hydrogen spectrum and carbon spectrum data of the target product 1-methoxy-4-cyclohexylbenzene are as follows:¹H NMR(400MHz,CDCl3)δ7.14(d,J＝8.4Hz,2H),6.85(d,J＝8.4Hz,2H),3.79(s,3H),2.45(br,1H),1.84(s,4H),1.75-1.72(m,1H),1.43-1.33(m,1H),1.25(br,1H).¹³C NMR(100MHz,CDCl3)δ157.6,140.3,127.6,113.6,55.2,43.7,34.7,26.9,26.1.

example 12

The invention relates to a method for methoxylation of aryl or heteroaryl, which specifically comprises the following steps:

uniformly mixing 0.2mmol of substrate, 0.3mmol of coupling agent, 0.01mmol of ligand, 1mL of solvent, 0.01mmol of catalyst and 0.4mmol of alkali, and reacting at 80 ℃ for 12h under the argon atmosphere to obtain 28mg of 5-methoxybenzothiophene white solid; the yield of the 5-methoxybenzothiophene is 85 percent;

the structural formula of the substrate isThe coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate; the ligand is L3;

the structural formula of the 5-methoxybenzothiophene is as follows:

the hydrogen spectrum and carbon spectrum data of the target product 5-methoxybenzothiophene are as follows:¹H NMR(400MHz,CDCl₃)δ7.75(d,J＝8.8Hz,1H),7.45(d,J＝5.6Hz,1H),7.29(d,J＝2.4Hz,1H),7.27(d,J＝5.6Hz,1H),7.02(dd,J＝8.8,2.4Hz,1H),3.88(s,3H).¹³C NMR(100MHz,CDCl₃)δ157.4,140.6,132.1,127.5,123.6,123.0,114.6,105.5,55.5.

example 13

The invention relates to a method for methoxylation of aryl or heteroaryl, which specifically comprises the following steps:

uniformly mixing 0.2mmol of substrate, 0.3mmol of coupling agent, 0.01mmol of ligand, 1mL of solvent, 0.01mmol of catalyst and 0.4mmol of alkali, and reacting at 80 ℃ for 12h under the atmosphere of argon to obtain 15mg of 7-methoxy-1-tetralone white solid; the yield of 7-methoxy-1-tetralone was 42%;

the structural formula of the substrate isThe coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate; the ligand is L3;

the structural formula of the 7-methoxy-1-tetralone is as follows:

the hydrogen spectrum and carbon spectrum data of the target product 7-methoxy-1-tetralone are as follows:¹H NMR(400MHz,CDCl₃)δ7.49(s,1H),7.14(d,J＝8.4Hz,1H),7.04-7.02(m,1H),3.81(s,3H),2.88(t,J＝5.9Hz,2H),2.61(t,J＝6.4Hz,2H),2.12-2.06(m,2H).¹³C NMR(100MHz,CDCl₃)δ198.4,158.3,137.2,133.4,130.1,121.8,109.1,55.5,39.1,28.9,23.6.

example 14

The invention relates to a method for methoxylation of aryl or heteroaryl, which specifically comprises the following steps:

uniformly mixing 0.2mmol of substrate, 0.3mmol of coupling agent, 0.01mmol of ligand, 1mL of solvent, 0.01mmol of catalyst and 0.4mmol of alkali, and reacting at 80 ℃ for 12H under the atmosphere of argon to obtain 14mg of 1-methoxy-9H-fluorene white solid; the yield of 1-methoxy-9H-fluorene was 36%;

the structural formula of the substrate isThe coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate; the ligand is L3;

the structural formula of the 1-methoxy-9H-fluorene is as follows:

the hydrogen spectrum and carbon spectrum data of the target product 1-methoxyl-9H-fluorene are as follows:¹H NMR(400MHz,CDCl3)δ7.69(dd,J＝7.9,4.8Hz,2H),7.51(d,J＝7.4Hz,1H),7.37-7.34(m,1H),7.26-7.22(m,1H),7.11-7.10(m,1H),6.94(dd,J＝8.4,2.3Hz,1H),3.88(s,5H).¹³CNMR(100MHz,CDCl3)δ159.4,145.2,142.8,141.8,134.9,126.9,125.7,125.0,120.6,119.2,113.1,110.7,55.7,37.1.

example 15

The invention relates to a method for methoxylation of aryl or heteroaryl, which specifically comprises the following steps:

uniformly mixing 0.2mmol of substrate, 0.3mmol of coupling agent, 0.01mmol of ligand, 1mL of solvent, 0.01mmol of catalyst and 0.4mmol of alkali, and reacting at 80 ℃ for 12h under the argon atmosphere to obtain 29mg of 4-pentylanisole colorless oily substance; the yield of 4-pentylanisole was 81%;

the structural formula of the substrate isThe coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate; the ligand is L4;

the structural formula of the methyl 4-methoxybenzoate is as follows:

the hydrogen spectrum and carbon spectrum data of the target product 4-methoxy methyl benzoate are as follows:¹H NMR(400MHz,CDCl3)δ7.12(d,J＝8.4Hz,2H),6.85(d,J＝8.4Hz,2H),3.80(s,3H),2.56(t,J＝8.0Hz,2H),1.61-1.58(m,2H),1.38-1.30(m,4H),0.91(t,J＝6.8Hz,3H).¹³CNMR(100MHz,CDCl3)δ157.6,135.0,129.2,113.6,55.2,35.0,31.5,22.6,14.0.

example 16

The invention relates to a method for methoxylation of aryl or heteroaryl, which specifically comprises the following steps:

uniformly mixing 0.2mmol of substrate, 0.3mmol of coupling agent, 0.01mmol of ligand, 1mL of solvent, 0.01mmol of catalyst and 0.4mmol of alkali, and reacting at 80 ℃ for 12h under the atmosphere of argon to obtain 11mg of methyl 4-methoxybenzoate as a white solid; the yield of methyl 4-methoxybenzoate was 34%;

the structural formula of the substrate isThe coupling agent is MeO-9-BBN; the solvent is N-methyl pyrrolidone; the catalyst is cuprous halide; the base is cesium carbonate; the ligand is L3;

the structural formula of the methyl 4-methoxybenzoate is as follows:

the hydrogen spectrum and carbon spectrum data of the target product 4-methoxy methyl benzoate are as follows:¹H NMR(400MHz,CDCl₃)δ7.99(d,J＝8.8Hz,2H),6.91(d,J＝8.8Hz,2H),3.87,(s,3H),3.84(s,3H).¹³C NMR(100MHz,CDCl₃)δ166.8,163.3,131.5,122.5,113.5,55.3,51.8.

finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.