阅读说明：本技术 一种二芳基甲烷结构化合物的制备方法 (Preparation method of diarylmethane structure compound ) 是由 舒兴中 郭鹏 于 2020-04-29 设计创作，主要内容包括：本发明公开一种二芳基甲烷结构化合物的制备方法。本发明的制备方法如式I：<Image he="174" wi="700" file="DDA0002472588810000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>示,利用廉价金属镍催化剂,以1,1’-双(二苯基膦)二茂铁和1,10-菲罗啉为配体,草酸二甲酯为添加剂,锰粉为还原剂,通过苄醇和芳基亲电试剂反应制备目标化合物。本发明具有原料易得、反应条件温和、反应底物宽广、反应官能团兼容性好以及化学选择性独特等优点。该方法不仅能够制备简单的二芳基甲烷化合物,而且能够适用于对具有原料类似结构生物活性分子的修饰。(The invention discloses a preparation method of a diaryl methane structure compound. The preparation method of the invention is shown as formula I:)

1. A preparation method of a diaryl methane structure compound is characterized in that the compound is shown as a formula I

Under the catalysis of nickel, 1,1' -bis (diphenylphosphino) ferrocene and 1, 10-phenanthroline are used as ligands, dimethyl oxalate is used as an additive, manganese powder is used as a reducing agent, N, N-Dimethylformamide (DMF) is used as a solvent, benzyl alcohol and an aryl electrophilic reagent react to prepare a target compound, wherein a ring is any one of a benzene ring, a furan ring, a thiophene ring, a pyridine ring, an indole ring or ferrocene, and a ring B is a benzene ring or a pyridine ring; r¹，R²Each independently is alkyl or substituted alkyl or aryl or substituted aryl at different positions, and X is any one of chlorine, bromine, iodine or triflate.

2. The method for producing a diarylmethane structural compound according to claim 1, wherein the target compound is methyl 4- (furan-2-ylmethyl) benzoate, 0.02mmol of nickel (II) bromide-diethylene glycol dimethyl ether complex, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.02mmol of 1, 10-phenanthroline, 0.02mmol of pyridine, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate, and 0.6mmol of manganese powder are sequentially added to a reaction tube, 1mL of a DMF solution in which 0.2mmol of furfuryl alcohol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate are dissolved is injected into the reaction tube, the reaction tube is closed, the reaction is left under inert gas protection at 80 ℃ for 30 hours, and after the reaction is completed, water is quenched, extraction is carried out with ethyl acetate, anhydrous sodium sulfate is dried, and then filtered and concentrated, the concentrate is chromatographed by a silica gel column to obtain the 4- (furan-2-ylmethyl) benzoic acid methyl ester.

3. The method according to claim 1, wherein the target compound is methyl 4- (benzo [ b ] thiophen-2-ylmethyl) benzoate, and the method comprises: adding 0.02mmol of nickel (II) bromide diethylene glycol dimethyl ether compound, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.02mmol of 1, 10-phenanthroline, 0.02mmol of pyridine, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution dissolved with 0.2mmol of 1-benzothiophene-2-methanol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the protection of inert gas, quenching with water after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on the concentrate to obtain the target compound.

4. The method for producing a diarylmethane structural compound according to claim 1, wherein the target compound is methyl 4- (pyridin-3-ylmethyl) benzoate, and the production method comprises: adding 0.02mmol of nickel (II) bromide diethylene glycol dimethyl ether compound, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.02mmol of 1, 10-phenanthroline, 0.02mmol of pyridine, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution dissolved with 0.2mmol of indole-7-methanol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the protection of inert gas, after the reaction is finished, quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and performing silica gel column chromatography on the concentrate to obtain the target compound.

5. The method for producing a diarylmethane structural compound according to claim 1, wherein the target compound produced is methyl 4- ((1H-indol-7-yl) methyl) benzoate, and the production is carried out: adding 0.02mmol of nickel (II) bromide diethylene glycol dimethyl ether compound, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.02mmol of 1, 10-phenanthroline, 0.02mmol of pyridine, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution in which 0.2mmol of indole-7-methanol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate are dissolved into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the protection of inert gas, after the reaction is finished, quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on the concentrate to obtain the methyl 4- ((1H-indole-7-yl) methyl) benzoate.

6. The method for preparing a diarylmethane structural compound according to claim 1, wherein the target compound is methyl 4- ((ferrocenyl) methyl) benzoate, and the preparation method comprises: adding 0.02mmol of nickel (II) bromide diethylene glycol dimethyl ether compound, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.02mmol of 1, 10-phenanthroline, 0.02mmol of pyridine, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate, 0.6mmol and manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution in which 0.2mmol of indole-7-methanol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate are dissolved into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the protection of inert gas, after the reaction is finished, quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on a concentrate to obtain the methyl 4- ((ferrocenyl) methyl) benzoate.

7. The method for preparing a diarylmethane structural compound according to claim 1, wherein the target compound is methyl 4- (4- (tributylstannyl) benzyl) benzoate, and the method comprises: adding 0.02mmol of (1,1 '-bis (diphenylphosphino) ferrocene) nickel dichloride, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.004mmol of 1, 10-phenanthroline, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution dissolved with 0.2mmol of 4- (tributylstannyl) benzyl alcohol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate into the reaction tube, closing the reaction tube, reacting for 30 hours at 80 ℃ under the condition of inert gas protection, quenching with water after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on the concentrate to obtain the methyl 4- (4- (tributylstannyl) benzyl) benzoate.

8. The method for preparing a diarylmethane structural compound according to claim 1, wherein the target compound is 6- (4-methoxybenzyl) -1H-indole, and the method comprises: adding 0.02mmol of (1,1 '-bis (diphenylphosphino) ferrocene) nickel dichloride, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.004mmol of 1, 10-phenanthroline, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a clean and dry reaction tube in sequence, then injecting 1mL of DM F solution dissolved with 0.2mmol of p-methoxybenzyl alcohol and 0.3mmol of 6-chloroindole into the reaction tube, sealing the reaction tube, reacting at 80 ℃ for 30 hours under the protection of inert gas, quenching with water after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on the concentrate to obtain the 6- (4-methoxybenzyl) -1H-indole.

9. The method according to claim 1, wherein the target compound is 2- (4-methoxybenzyl) -4, 6-lutidine, and the method comprises: adding 0.02mmol of (1,1 '-bis (diphenylphosphino) ferrocene) nickel dichloride, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.004mmol of 1, 10-phenanthroline, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution dissolved with 0.2mmol of p-methoxybenzyl alcohol and 0.3mmol of 2-chloro-4, 6-dimethylpyridine into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the condition of inert gas protection, after the reaction is finished, quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and performing silica gel column chromatography on the concentrate to obtain 2- (4-methoxybenzyl) -4, 6-dimethylpyridine.

10. The process according to claim 1, wherein the product is compound 3a of formula II, which is prepared according to formula II:

sequentially adding 0.25mmol of nickel bromide (II) diethylene glycol dimethyl ether compound, 0.25mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.25mmol of 1, 10-phenanthroline, 0.25mmol of pyridine, 10mmol of dimethyl oxalate, 15mmol of manganese powder and 200mg of manganese powder into a clean and dry 100mL round bottom flask with a stirrerAnd (2) injecting a 25mL of mixed solution of (4- (trimethylsilyl) benzyl alcohol 7.5mmol and compound 2a in the formula II dissolved in 25mL of mixed solution of (4- (trimethylsilyl) benzyl alcohol and compound 2a in the formula II into a reaction tube, closing a round-bottom flask, reacting at 80 ℃ for 40 hours under the condition of inert gas protection, quenching with water after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography on the concentrate to obtain compound 3 a.

Technical Field

The invention relates to a preparation method of a compound, in particular to a preparation method of a compound with a diarylmethane structure.

Background

Diarylmethanes are ubiquitous building blocks of many drug molecules and functional organic materials, have many unique properties, and are often used as subunit units of supramolecular structures, such as: macrocycles, catenules, rotaxanes, and the like. With the advent of high-throughput chemistry, there is a need for more practical and convenient methods for synthesizing various compounds containing diaryl structures.

The synthesis of diarylmethane compounds has long relied on Friedel-Crafts reactions of aromatic compounds with benzyl electrophiles (RSCAdv.,2014,4, 28317). The method is suitable for the benzylation reaction of the electron-rich aromatic hydrocarbon, and is difficult to realize for electron-deficient aromatic hydrocarbon; at the same time, regioselective control of the reaction has hitherto been problematic. In recent years, with the rise of transition metal catalyzed reactions, transition metal catalyzed coupling reactions provide a feasible way to achieve precise synthesis of diarylmethane compounds. Currently, research in this area has made significant progress in three areas (chem.soc.rev.,2008,37, 290). (1) Coupling reaction of aryl metal reagent with benzyl halohydrocarbon and the like; (2) coupling reaction of aryl electrophile and benzyl metal reagent; (3) reductive coupling reaction of an aryl electrophile with a benzyl electrophile. However, these methods require the preparation of an organometallic reagent or benzyl halogenated hydrocarbon or the like in advance. Such agents are highly active and difficult to preserve for long periods of time; the preparation process can greatly reduce the compatibility of the functional groups of the reaction, thereby limiting the practicability of the reaction; in addition, the preparation of benzyl halogenated hydrocarbon is accompanied by the generation of a large amount of halogen-containing waste, and is harmful to the environment. Benzyl alcohol and aryl electrophilic reagents are bulk commercial raw materials, have the characteristics of various types, stability, easy obtaining and the like, and can be introduced in the later stage of synthesis of complex compounds very simply and conveniently. The synthesis of the diarylmethane compound by taking benzyl alcohol and an aryl electrophilic reagent as raw materials has important theoretical significance and reagent application value. However, this synthetic strategy is still under development. The only successful case requires the use of equivalent titanium complexes as activators for alcohols and is primarily applicable to the conversion of iodoaromatic hydrocarbons. (org.Lett.2018,20,7846.)

Disclosure of Invention

The invention provides a preparation method for a diaryl methane structure compound, and the strategy provides a direct and efficient method with good functional group compatibility to synthesize the diaryl compound.

The preparation method of the diarylmethane structural compound is shown as a formula I, namely under the catalysis of nickel,

1,1' -bis (diphenylphosphino) ferrocene and 1, 10-phenanthroline are used as ligands, dimethyl oxalate is used as an additive, manganese powder is used as a reducing agent, N, N-Dimethylformamide (DMF) is used as a solvent, benzyl alcohol and an aryl electrophilic reagent react to prepare a target compound, wherein a ring A is any one of a benzene ring, a furan ring, a thiophene ring, a pyridine ring, an indole ring or ferrocene, and a ring B is a benzene ring or a pyridine ring; r¹，R²Each independently is alkyl or substituted alkyl or aryl or substituted aryl at different positions, and X is any one of chlorine, bromine, iodine or triflate.

Preferably, the preparation method of the diarylmethane structural compound of the present invention is as follows:

0.02mmol of nickel bromide (II) diethylene glycol dimethyl ether compound, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.02mmol of 1, 10-phenanthroline, 0.02mmol of pyridine, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder are sequentially added into a reaction tube, then 1mL of DMF solution dissolved with 0.2mmol of furfuryl alcohol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate is injected into a reaction tube, the reaction tube is sealed, under the condition of inert gas protection, reacting at 80 deg.C for 30h, quenching with water after reaction, extracting with ethyl acetate, drying with anhydrous sodium sulfate, then filtering and concentrating, and carrying out silica gel column chromatography on the concentrate to obtain the 4- (furan-2-ylmethyl) methyl benzoate.

The target compound is 4- (benzo [ b ] thiophene-2-ylmethyl) methyl benzoate, and the preparation method comprises the following steps: adding 0.02mmol of nickel (II) bromide diethylene glycol dimethyl ether compound, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.02mmol of 1, 10-phenanthroline, 0.02mmol of pyridine, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution dissolved with 0.2mmol of 1-benzothiophene-2-methanol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate into the reaction tube, sealing the reactor, reacting for 30 hours at 80 ℃ under the protection of inert gas, quenching with water after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on the concentrate to obtain the target compound.

The target compound is 4- (pyridine-3-ylmethyl) methyl benzoate, and the preparation method comprises the following steps: adding 0.02mmol of nickel (II) bromide diethylene glycol dimethyl ether compound, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.02mmol of 1, 10-phenanthroline, 0.02mmol of pyridine, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution dissolved with 0.2mmol of indole-7-methanol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the protection of inert gas, after the reaction is finished, quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and performing silica gel column chromatography on the concentrate to obtain the target compound.

The target compound is 4- ((1H-indol-7-yl) methyl) benzoic acid methyl ester, and is prepared by the following steps: adding 0.02mmol of nickel (II) bromide diethylene glycol dimethyl ether compound, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.02mmol of 1, 10-phenanthroline, 0.02mmol of pyridine, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution in which 0.2mmol of indole-7-methanol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate are dissolved into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the protection of inert gas, after the reaction is finished, quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on the concentrate to obtain the methyl 4- ((1H-indole-7-yl) methyl) benzoate.

The target compound is 4- ((ferrocenyl) methyl benzoate, and the preparation method comprises the following steps: adding 0.02mmol of nickel (II) bromide diethylene glycol dimethyl ether compound, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.02mmol of 1, 10-phenanthroline, 0.02mmol of pyridine, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate, 0.6mmol and manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution in which 0.2mmol of indole-7-methanol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate are dissolved into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the protection of inert gas, after the reaction is finished, quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on a concentrate to obtain the methyl 4- ((ferrocenyl) methyl) benzoate.

The target compound is 4- (4- (tributylstannyl) benzyl) methyl benzoate, and the preparation method comprises the following steps: adding 0.02mmol of (1,1 '-bis (diphenylphosphino) ferrocene) nickel dichloride, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.004mmol of 1, 10-phenanthroline, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution dissolved with 0.2mmol of 4- (tributylstannyl) benzyl alcohol and 0.3mmol of methyl 4- (trifluoromethanesulfonyloxy) benzoate into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the protection of inert gas, quenching with water after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on the concentrate to obtain the methyl 4- (4- (tributylstannyl) benzyl) benzoate.

The target compound is 6- (4-methoxybenzyl) -1H-indole, and the preparation method comprises the following steps: adding 0.02mmol of (1,1 '-bis (diphenylphosphino) ferrocene) nickel dichloride, 0.02mmol of 1' -bis (diphenylphosphino) ferrocene, 0.004mmol of 1, 10-phenanthroline, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a clean and dry reaction tube in sequence, then injecting 1mL of DMF solution dissolved with p-0.2 mmol of methoxybenzyl alcohol and 0.3mmol of 6-chloroindole into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the protection of inert gas, quenching with water after the reaction is finished, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on the concentrate to obtain 6- (4-methoxybenzyl) -1H-indole.

The target compound is 2- (4-methoxybenzyl) -4, 6-dimethylpyridine, and the preparation method comprises the following steps: adding 0.02mmol of (1,1 '-bis (diphenylphosphino) ferrocene) nickel dichloride, 0.02mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.004mmol of 1, 10-phenanthroline, 0.02mmol of aluminum trichloride, 0.36mmol of dimethyl oxalate and 0.6mmol of manganese powder into a reaction tube in sequence, then injecting 1mL of DMF solution dissolved with 0.2mmol of p-methoxybenzyl alcohol and 0.3mmol of 2-chloro-4, 6-dimethylpyridine into the reaction tube, sealing the reaction tube, reacting for 30 hours at 80 ℃ under the condition of inert gas protection, after the reaction is finished, quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and performing silica gel column chromatography on the concentrate to obtain 2- (4-methoxybenzyl) -4, 6-dimethylpyridine.

The target compound is 3a, and the preparation method is as formula II:

sequentially adding 0.25mmol of nickel bromide (II) diethylene glycol dimethyl ether compound, 0.25mmol of 1,1' -bis (diphenylphosphino) ferrocene, 0.25mmol of 1, 10-phenanthroline, 0.25mmol of pyridine, 10mmol of dimethyl oxalate, 15mmol of manganese powder, 200mg of manganese powder into a clean and dry 100mL round-bottom flask with a stirrerMolecular sieve, then injecting a 25mL DMF solution dissolved with 7.5mmol (4- (trimethylsilyl) benzyl alcohol and 5mmol compound 2a in formula II into a reaction tube, sealing a round-bottom flask, reacting at 80 ℃ for 40h under the protection of inert gas, after the reaction is finished, quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, then filtering and concentrating, and carrying out silica gel column chromatography on the concentrate to obtain the product 3 a.

The invention provides a synthetic method for efficiently synthesizing a diarylmethane structure. The method takes cheap and easily-obtained benzyl alcohol and aryl electrophilic reagents as raw materials, and realizes the construction of a diarylmethane structure through the catalytic process of a cheap nickel catalyst. The reaction substrate has wide practicability, wherein chloro, bromo and iodo aromatic hydrocarbons and aryl sulfonate can be coupled with benzyl alcohol to obtain a target product; the reaction selectivity is unique, and the method is suitable for preparing diarylmethane compounds substituted by various metals such as B, Si, Sn and the like; the reaction condition is mild, and most of active functional groups can be compatible; the reaction can realize gram-scale, and is simultaneously suitable for carrying out later modification on complex bioactive molecules containing substrates and similar structures. These advantages make the present invention highly practical for the synthesis of diarylmethane structures.

Drawings

FIG. 1 shows the hydrogen spectrum of compound 3a with 400M nuclear magnetization in deuterated chloroform (¹H NMR(400MHz,CDCl₃))；

FIG. 2 shows the carbon spectrum of compound 3a with 400M nuclear magnetization in deuterated chloroform (¹³C NMR(100MHz,CDCl₃))；

Detailed Description

The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.