阅读说明：本技术 可循环铋络合物催化的不对称n-二芳基甲基取代的杂环化合物的合成方法 (Method for synthesizing asymmetric N-diarylmethyl substituted heterocyclic compound catalyzed by recyclable bismuth complex ) 是由 许海燕 刘冬兰 杭懿 陆鸿飞 于 2020-11-27 设计创作，主要内容包括：本发明公开了可循环铋络合物催化的不对称N-二芳基甲基取代的杂环化合物的合成方法,以对亚甲基苯醌或其衍生物和吡唑为原料,(C_5H_6N_4O)(C_5H_5N_4O)_3(C_5H_4N_4O)[Bi_2Cl_(11)]Cl_2为催化剂,一步反应制得不对称N-二芳基甲基取代的杂环化合物,相比较于现有技术,本发明的合成方法操作简便,反应时间短；催化剂活性高且可以多次回收重复使用；底物范围宽,生产成本低；目标化合物产率高；环境友好,工业生产前景广阔。(The invention discloses a method for synthesizing an asymmetric N-diaryl methyl substituted heterocyclic compound catalyzed by a recyclable bismuth complex, which takes p-methylene benzoquinone or derivatives thereof and pyrazole as raw materials (C) 5 H 6 N 4 O)(C 5 H 5 N 4 O) 3 (C 5 H 4 N 4 O)[Bi 2 Cl 11 ]Cl 2 Compared with the prior art, the synthesis method has the advantages of simple and convenient operation and short reaction time; the catalyst has high activity and can be recycled for multiple times; the substrate range is wide, and the production cost is low; the yield of the target compound is high; environment-friendly and has wide industrial production prospect.)

1. a process for synthesizing the unsymmetrical N-diarylmethyl substituted heterocyclic compound catalyzed by cyclic bismuth complex features that the P-methylenebenzoquinone or its derivative and pyrazole are used as raw materials₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂As a catalyst, preparing an asymmetric N-diaryl methyl substituted heterocyclic compound by one-step reaction; the reaction formula is shown as follows:

wherein R is¹Is selected from-H, -CH₃、-OCH₃、-NO₂Any one of-F, -Br, -Cl and benzene ring.

2. The method of claim 1, wherein the solvent for the one-step reaction is selected from the group consisting of 1,4-dioxane, tolumene, MeOH, dichloromethane, CH, and mixtures thereof₃One of CN.

3. The method of claim 1, wherein the solvent for the one-step reaction is preferably CH₃CN。

4. The method of claim 1, wherein the molar ratio of p-methylenebenzoquinone or derivative thereof to pyrazole is 1: 1-2.

5. The method of claim 1, wherein the catalyst (C) is selected from the group consisting of₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂The dosage of the p-methylene benzoquinone or the derivative thereof is 4 to 5 percent of the mol of the material.

6. The method for synthesizing the asymmetric N-diarylmethyl-substituted heterocyclic compound catalyzed by the recyclable bismuth complex as claimed in claim 1, wherein the reaction temperature of the one-step reaction is 25-30 ℃ and the reaction time is 4-8 h.

7. The method of claim 1, wherein the catalyst (C) is added after the reaction is completed₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂And is washed by filtration, dried and reused.

8. An asymmetric N-diarylmethyl substituted heterocyclic compound synthesized by the method of synthesizing an asymmetric N-diarylmethyl substituted heterocyclic compound catalyzed by a recyclable bismuth complex as described in claim 1, having a structural formula:

wherein R is¹Is selected from-H, -CH₃、-OCH₃、-NO₂Any one of-F, -Br, -Cl and benzene ring.

Technical Field

The invention belongs to the field of synthesis research of organic intermediates, and particularly relates to a method for synthesizing an asymmetric N-diaryl methyl substituted heterocyclic compound catalyzed by a recyclable bismuth complex.

Background

The formation of carbon-nitrogen bonds is an important area of modern organic synthesis. Through the generation of C-N bond, amine and its derivative, nitrogen-containing heterocycle and the like can be prepared, and many of them are compounds with biological and medicinal activities and some important intermediates. There are many proposals for forming C-N bonds in the literature, including direct functionalization of C-H bonds in aromatics or alkanes, and metal-catalyzed coupling with palladium, copper, etc., to obtain C-N bonds. The asymmetric N-diarylmethyl substituted heterocyclic compound is a substance containing C-N bonds, and is a core skeleton of various bioactive compounds, natural and non-natural alkaloids, N-heterocyclic scaffold, amino acids, lactam drugs and the like. Therefore, in recent years, considerable attention has been paid to the development of methods for efficiently synthesizing asymmetric N-diarylmethyl-substituted heterocyclic compounds. Various catalytic amounts of lewis acid (activating LUMO to reduce energy) or strong base (activating HOMO to increase energy) can promote the reaction, but these synthetic methods all show that the reaction conditions are harsh, the yield is not high, the catalyst cannot be recycled, the pollution is serious, and the industrial production cost is high.

Disclosure of Invention

The purpose of the invention is as follows: aiming at the problems in the prior art, the invention provides a brand-new method for synthesizing an asymmetric N-diaryl methyl substituted heterocyclic compound catalyzed by a recyclable bismuth complex. The asymmetric N-diaryl methyl substituted heterocyclic compound is synthesized by a one-step method, the whole method is simple and convenient to operate, and the reaction time is short; the catalyst has high activity and can be recycled for multiple times; the substrate range is wide, and the production cost is low; the yield of the target compound is high; environment-friendly and has wide industrial production prospect.

The technical scheme is as follows: in order to achieve the above object, the present invention provides a method for synthesizing an asymmetric N-diarylmethyl-substituted heterocyclic compound catalyzed by a recyclable bismuth complex, which comprises using p-methylenebenzoquinone or its derivative and pyrazole as raw materials, (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂As a catalyst, preparing an asymmetric N-diaryl methyl substituted heterocyclic compound by one-step reaction; the reaction formula is shown as follows:

wherein R is¹Is selected from-H, -CH₃、-OCH₃、-NO₂Any one of-F, -Br, -Cl and benzene ring.

Wherein the reaction solvent of the one-step reaction is selected from 1,4-dioxane, tolumene, MeOH, dichloromethane and CH₃One of CN.

Preferably, the reaction solvent of the one-step reaction is CH₃CN。

Wherein the molar ratio of the p-methylene benzoquinone or the derivative thereof to the pyrazole is 1: 1-2.

Preferably, the catalyst (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂The amount of the p-methylene benzoquinone or the derivative thereof is 4-5 mol percent of the amount of the p-methylene benzoquinone or the derivative thereof.

Most preferably, the p-methylenequinone or derivative thereof, pyrazole and catalyst (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂In a molar ratio of 1:1.1: 0.05.

Wherein the reaction temperature of the one-step reaction is 25-35 ℃, and the reaction time is 4-8 h.

Wherein the catalyst (C) is used after the reaction is completed₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂And is washed by filtration, dried and reused.

The structural formula of the asymmetric N-diarylmethyl substituted heterocyclic compound synthesized by the method for synthesizing the asymmetric N-diarylmethyl substituted heterocyclic compound catalyzed by the recyclable bismuth complex is as follows:

wherein R is¹Is selected from-H, -CH₃、-OCH₃、-NO₂Any one of-F, -Br, -Cl and benzene ring.

Catalyst (C) in the present invention₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂The structure is as follows:

(C₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂chemical formula (II)

Catalyst (C) after completion of the reaction₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂And is washed by filtration, dried and reused.

The raw material p-QMs (p-methylene benzoquinone or derivatives thereof) used in the invention is a compound simultaneously containing a zwitterionic resonance structure of cyclohexadienyl and carbonyl coupling, the special structure of the compound enhances the electrophilic characteristic of para position, and the compound is easy to perform 1, 6-addition reaction with N-nucleophilic reagent. The p-QMs and pyrazole with strong reactivity are used as reaction substrates, the reaction is easy to occur, and the method has the characteristics of short reaction time, high reaction yield, mild reaction conditions and the like.

Has the advantages that: compared with the prior art, the invention has the following advantages:

1. the invention develops a method for synthesizing an asymmetric N-diaryl methyl substituted heterocyclic compound by designing and optimizing a preparation method. The specific synthesis step is to efficiently synthesize the N-diaryl methyl substituted heterocyclic compound by taking p-methylene benzoquinone or derivatives thereof as raw materials through 1, 6-conjugate addition one-step reaction.

2. The invention has mild condition, and the target product can be obtained by one step under the condition of stirring at room temperature. And the reaction time is relatively short, the yield of the target compound is high, the substrate range is wide, the production cost is low, and the industrial prospect is wide.

3. Most of the existing technologies for synthesizing carbon-nitrogen bonds use polluting Lewis acid or strong base as a catalyst, and the catalyst provided by the invention has the characteristics of environmental friendliness and sustainable utilization. The catalyst is a complex formed by metal bismuth, and when the catalyst is applied to 1, 6-addition reaction of p-QMs and pyrazole heterocyclic compound, the catalyst shows good catalytic effect and high yield.

4. p-QMs is a ubiquitous structural backbone found widely in bioactive molecules, natural products and drugs. The final product obtained by the invention is that a nitrogen-containing bracket is inserted into the p-QMs organic matter, and finally a carbon-nitrogen bond is formed. The study of the properties of carbon-nitrogen bonds is a hotspot in organic chemistry, organometallic chemistry and biochemistry. For example, interconversion between proteins and amino acids does not separate the formation and cleavage of carbon-nitrogen bonds, and is important for human life activities. In addition, the asymmetric N-diaryl methyl substituted heterocyclic compound is a core skeleton of various bioactive compounds, natural and non-natural alkaloids, N-heterocyclic scaffolds, amino acids, lactam drugs and the like, and provides a new scheme and a raw material for synthesis and scientific research of a plurality of drugs.

In conclusion, the present invention has developed a method for synthesizing asymmetric N-diarylmethyl-substituted heterocyclic compounds. The target product is an important step in the synthesis of various substances. Compared with the prior art, the method has the advantages of simple operation, short reaction time, high catalyst activity and repeated recovery and reuse; wide substrate range, low production cost, high yield, environmental protection and wide industrial production prospect.

Detailed Description

The present invention will be further described with reference to the following specific examples.

The experimental methods described in the examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.

Raw materials: synthesis of p-methylene benzoquinone and its derivatives:

wherein R is¹Is selected from-H, -CH₃、-OCH₃、-NO₂Any one of-F, -Br, -Cl and benzene ring.

The experimental steps are as follows: 2, 6-di-tert-butylphenol (1.238g, 6mmol), benzaldehyde (0.59mL, 5mmol) or a corresponding amount of a benzaldehyde derivative, toluene (20mL), piperidine (0.988mL, 10mmol) were added in this order to a reaction flask, and the mixture was stirred under nitrogen₂Stirring, heating and refluxing under protection. TLC tracking reaction till the raw material point without benzaldehyde is 1: 30 (V (ethyl acetate) to V (petroleum ether)]About 12 h; after the reaction is finished, adding acetic anhydride (0.945mL, 10mmol) for dehydration for 15min, and cooling to room temperature; the reaction was quenched by the addition of methanol (5mL) and the toluene was removed by distillation under the reduced pressure. Dichloromethane (20mL) was added to dissolve the mixture, and the mixture was washed with saturated aqueous sodium bicarbonate (2 × 10mL), distilled water (20mL) and saturated brine (20mL), the organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the solvent was distilled off to obtain a crude product, which was then subjected to silica gel column chromatography to obtain p-methylenequinone and its derivatives as starting materials. References may be made to: [ [ J ]]The science and technology university journal of Jiangsu (Nature science edition), 2019, 33(2): 103-]。

Other reagents (e.g., pyrazole, bismuth trichloride, piperidine) are commercially available from Shanghai pure chemical Co., Ltd. Catalyst (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂The specific synthetic procedures of (a) can be as described in the following documents: X.Zhang, X.Y.Gu, Y.H.Gao, S.P.Nie, H.F.Lu.appl.organometc. chem.2016,31(4):1-10.

Example 1

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25ml one-necked flask were charged, in order, the previously prepared 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.00025mol, 73.55mg), pyrazole (0.000275mol, 18.711mg) and the previously prepared (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(0.0000125mol, 19.53mg) and finally 2.5mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, dried and recovered catalyst, then the concentrated filtrate was rotary evaporated and separated by column chromatography (EA: PE: 3:100) to give 82.41mg of a single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 91 percent of the total weight of the mixture,¹H NMR(400MHz,Chloroform-d)δ7.59(s,1H),7.35–7.25(m,3H),7.23(s,1H),7.05(s,2H),6.89(s,2H),6.70(s,1H),6.25(s,1H),5.23(s,1H),1.35(s,18H).¹³C NMR(101MHz,Chloroform-d)δ153.54,140.29,139.49,135.95,129.82,129.38,128.48,127.97,127.72,125.22,105.13,69.76,34.33,30.21ppm.

example 2

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, (naphthalen-1-yl) methyl) pyrazole (B) is carried out by the following synthetic route:

into a 25ml one-necked flask were charged, in order, the previously prepared 2, 6-di-t-butyl-4- (naphthalen-1-ylmethylene) cyclohexa-2, 5-dien-1-one (0.00025mol, 86.05mg), pyrazole (0.000275mol, 18.711mg) and the previously prepared(C₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(0.0000125mol, 19.53mg) and finally 2.5mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether ═ 1:20) followed the reaction until no starting material was present and stopped, filtered, washed, oven dried to recover the catalyst, then concentrated by rotary evaporation, and separated by column chromatography (EA: PE ═ 3:100) to give 91.6mg of single product B: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, (naphthalen-1-yl) methyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, (naphthalen-1-yl) methyl) pyrazole (B): yield: 88 percent of the total weight of the mixture,¹H NMR(400MHz,Chloroform-d)δ7.98–7.83(m,3H),7.65(d,J＝1.8Hz,1H),7.54–7.40(m,4H),7.15(d,J＝2.3Hz,1H),6.93(d,J＝7.1Hz,1H),6.87(s,2H),6.24(t,J＝2.0Hz,1H),5.24(s,1H),1.37(s,18H).¹³C NMR(101MHz,Chloroform-d)δ153.48,139.63,136.05,135.79,133.80,131.51,129.62,128.96,128.70,126.75,126.73,125.81,125.17,124.63,123.39,105.17,66.59,34.33,30.23ppm.

example 3

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, 4-bromophenyl) pyrazole (C) comprises the following steps:

into a 25ml single-necked flask were charged, in order, the previously prepared 2, 6-di-t-butyl-4- (4-bromobenzylidene) cyclohexa-2, 5-dien-1-one (0.00025mol, 93.03mg), pyrazole (0.000275mol, 18.711mg) and the previously prepared (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(0.0000125mol, 19.53mg) and finally 2.5mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether: 1:20) to follow the reaction until no material point exists, stopping the reaction, filtering and washingThe catalyst was recovered by washing, drying, and then the concentrated filtrate was rotary evaporated and separated by column chromatography (EA: PE ═ 3:100) to give 104.2mg of single product C: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, 4-bromophenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, 4-bromophenyl) pyrazole (C) yield: the content of the waste water is 94%,¹H NMR(400MHz,Chloroform-d)δ7.62(d,J＝1.8Hz,1H),7.50–7.45(m,2H),7.26(d,J＝2.3Hz,1H),6.98–6.90(m,4H),6.68(s,1H),6.30(t,J＝2.1Hz,1H),5.29(s,1H),1.39(s,18H).¹³C NMR(101MHz,Chloroform-d)δ153.75,139.66,139.52,136.16,131.61,129.61,129.37,129.16,125.21,121.75,105.39,69.17,34.35,30.20ppm.

example 4

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, 4-nitrophenyl) pyrazole (D) comprises the following steps:

into a 25ml one-necked flask were charged, in order, the previously prepared 2, 6-di-t-butyl-4- (4-nitrobenzylidene) cyclohexa-2, 5-dien-1-one (0.00025mol, 84.80mg), pyrazole (0.000275mol, 18.711mg) and the previously prepared (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(0.0000125mol, 19.53mg) and finally 2.5mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether ═ 1:20) followed the reaction until no starting material was present and stopped, filtered, washed, dried and recovered catalyst, then concentrated filtrate was rotary evaporated and separated by column chromatography (EA: PE ═ 3:100) to give 93.3mg of single product D: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, 4-nitrophenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, 4-nitrophenyl) pyrazole (D) yield: 91 percent of the total weight of the mixture,¹H NMR(400MHz,Chloroform-d)δ8.23–8.18(m,2H),7.66(d,J＝1.9Hz,1H),7.28(s,1H),7.22–7.15(m,2H),6.97(s,2H),6.79(s,1H),6.34(t,J＝2.1Hz,1H),5.36(s,1H),1.39(s,18H).¹³C NMR(101MHz,Chloroform-d)δ154.16,148.00,147.31,140.10,136.52,129.60,128.49,128.13,125.67,123.70,105.78,69.15,34.40,30.16ppm.

example 5

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, 4-methoxyphenyl) pyrazole (E) comprises the following steps:

into a 25ml one-necked flask were charged, in order, the previously prepared 2, 6-di-t-butyl-4- (4-methoxybenzylidene) cyclohexa-2, 5-dien-1-one (0.00025mol, 81.05mg), pyrazole (0.000275mol, 18.711mg) and the previously prepared (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(0.0000125mol, 19.53mg) and finally 2.5mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether: 1:20) followed the reaction until no starting material was present and stopped, filtered, washed, dried and recovered catalyst, then concentrated filtrate was evaporated and separated by column chromatography (EA: PE: 3:100) to give 92mg of single product E.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, 4-methoxyphenyl) pyrazole: yield: in the proportion of 93%,¹H NMR(400MHz,Chloroform-d)δ7.66–7.59(m,1H),7.26(d,J＝2.3Hz,1H),7.05(d,J＝8.7Hz,2H),6.89(t,J＝4.3Hz,4H),6.70(s,1H),6.28(t,J＝2.1Hz,1H),5.23(s,1H),3.82(s,3H),1.38(s,18H).¹³C NMR(101MHz,Chloroform-d)δ159.10,153.40,139.43,135.89,132.38,130.23,129.41,129.24,124.82,113.88,105.05,69.23,55.28,34.32,30.22ppm.

example 6

Catalyst species screening

Comparative example 1

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25ml one-necked flask were charged, in order, the previously prepared 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.000125mol, 36.78mg), pyrazole (0.0001375mol, 9.36mg) and the previously prepared (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(0.00000625mol, 9.76mg) and finally 1.5mL of CH were added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether ═ 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, oven dried and catalyst recovered, then the filtrate was concentrated by rotary evaporation and separated by column chromatography (EA: PE ═ 3:100) to give 40.7mg of single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 89.9 percent.

Comparative example 2

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25mL one-necked flask were charged previously prepared 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.000125mol, 36.78mg) and pyrazole ((0.0001375mol, 9.36mg) in this order, and finally 1.5mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether ═ 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, oven dried and catalyst recovered, then the filtrate was concentrated by rotary evaporation and separated by column chromatography (EA: PE ═ 3:100) to give 3.4mg of single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 7 percent.

Comparative example 3

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

in a 25mL one-necked flask, previously prepared 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.000125mol, 36.78mg), pyrazole (0.0001375mol, 9.36mg) and nickel trifluoromethanesulfonate (0.00000625mol, 2.23mg) were sequentially added, and finally 1.5mL of acetonitrile was added as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether ═ 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, oven dried and catalyst recovered, then the filtrate was concentrated by rotary evaporation and separated by column chromatography (EA: PE ═ 3:100) to give 6.7mg of single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 14 percent.

Comparative example 4

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25mL single-necked flask were charged previously prepared 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.000125mol, 36.78mg), pyrazole (0.0001375mol, 9.36mg) and scandium trifluoromethanesulfonate (0.00000625mol, 3.08mg) in this order, and finally 1.5mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether ═ 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, oven dried and catalyst recovered, then the filtrate was concentrated by rotary evaporation and separated by column chromatography (EA: PE ═ 3:100) to give 36.3mg of single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 80 percent.

Comparative example 5

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25mL single-necked flask were charged in the order of 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.000125mol, 36.78mg), pyrazole (0.0001375mol, 9.36mg) and bismuth trichloride (0.00000625mol, 1.97mg) prepared in advance, and finally 1.5mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether ═ 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, oven dried and catalyst recovered, then the filtrate was concentrated by rotary evaporation and separated by column chromatography (EA: PE ═ 3:100) to give 35.4mg of single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 78 percent.

As can be seen from the comparison of comparative examples 1 to 5, the yield of the final product is significantly reduced without using the catalyst of the present invention or replacing some of the existing catalysts.

Example 7

Comparison of catalyst amounts

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25ml single-necked flask were charged, in order, previously prepared 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.00025mol, 73.55mg), pyrazole (0.000275mol, 18.711mg) and previously prepared (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(0.0000025mol, 3.9mg), the catalyst added this time was 1% by mol of the amount of the substance p-methylenequinone and its derivatives. Finally, 2.5mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether ═ 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, oven dried and catalyst recovered, then the filtrate was concentrated by rotary evaporation and separated by column chromatography (EA: PE ═ 3:100) to give 69.7mg of single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 77 percent.

Comparison of example 1 and example 7 shows that 5 mol% of the amount of p-methylenequinone and its derivatives is used as a catalyst in the reaction.

Example 8

Recycling of the catalyst

Cycle 1

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25ml one-necked flask were charged, in order, the previously prepared 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.0002mol, 58.84mg), pyrazole (0.00022mol, 14.97mg) and the previously prepared (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(0.00001mol, 15.62mg) and finally 2.0mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether: 1:20) was followed until no starting material was present, the reaction was stopped, the solid was washed and dried after filtration to recover the catalyst, the filtrate was concentrated by rotary evaporation and column chromatography (EA: PE: 3:100) was performed to obtain 65.9mg of mono-merA product A: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 91 percent.

The dried and recovered catalyst mass was 15.2 mg.

Cycle 2

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25ml single-necked flask were charged, in order, previously prepared 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.0002mol, 58.84mg), pyrazole (0.00022mol, 14.97mg) and the catalyst (C) recovered by circulation-1 oven drying₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(15.2mg) and finally 2.0mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, dried and recovered catalyst, then the concentrated filtrate was rotary evaporated and separated by column chromatography (EA: PE: 3:100) to give 63.68mg of a single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 87.9 percent.

The dried and recovered catalyst mass was 15.1 mg.

Cycle 3

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

a25 ml single-neck flask was charged with the previously prepared 4-benzylidene-26-di-tert-butylcyclohexa-2, 5-dien-1-one (0.0002mol, 58.84mg), pyrazole (0.00022mol, 14.97mg) and recycle 2 oven-dried recovered catalyst (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(15.1mg) and finally 2.0mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether ═ 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, oven dried and catalyst recovered, then the filtrate was concentrated by rotary evaporation and separated by column chromatography (EA: PE ═ 3:100) to give 63.46mg of single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 87.6 percent.

The dried and recovered catalyst mass was 14.9 mg.

Cycle 4

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25ml single-necked flask were charged, in order, previously prepared 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.0002mol, 58.84mg), pyrazole (0.00022mol, 14.97mg) and the catalyst (C) recovered by circulation-3 oven drying₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(14.9mg) and finally 2.0mL of CH was added₃CN is used as a solvent. Stirring at 30 ℃ for about 4h, stopping the reaction when no raw material is present by TLC (ethyl acetate: petroleum ether: 1:20) following the reaction, filtering, washing the solid, drying to recover the catalyst, concentrating the filtrate by rotary evaporation, and separating by column chromatography (EA: PE: 3:100) to obtain 63.10mg of a single product A: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 87.1 percent.

The dried and recovered catalyst mass was 14.7 mg.

Cycle 5

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25ml single-necked flask were charged, in order, previously prepared 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.0002mol, 58.84mg), pyrazole (0.00022mol, 14.97mg) and the catalyst (C) recovered by drying with recycle 4 (C)₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(14.7mg) and finally 2.0mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, dried and recovered catalyst, then the concentrated filtrate was rotary evaporated and separated by column chromatography (EA: PE: 3:100) to give 62.81mg of a single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 86.7 percent.

The dried and recovered catalyst mass was 14.3 mg.

Cycle 6

The synthesis of 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole (A) comprises the following steps:

into a 25ml single-necked flask were charged in the order of 4-benzylidene-2, 6-di-t-butylcyclohexa-2, 5-dien-1-one (0.0002mol, 58.84mg), pyrazole (0.00022mol, 14.97mg) prepared in advance, and 5-bake was circulatedCatalyst (C) recovered in dry form₅H₆N₄O)(C₅H₅N₄O)₃(C₅H₄N₄O)[Bi₂Cl₁₁]Cl₂(14.3mg) and finally 2.0mL of CH was added₃CN is used as a solvent. Stirring was carried out at 30 ℃ and the reaction was carried out for about 4 h. TLC (ethyl acetate: petroleum ether ═ 1:20) followed the reaction until no starting material was present and stopped, after filtration the solid was washed, dried and recovered catalyst, then the filtrate was concentrated by rotary evaporation and separated by column chromatography (EA: PE ═ 3:100) to give 62.02mg of single product a: 1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole.

1-methyl (3, 5-di-tert-butyl-4-hydroxyphenyl, phenyl) pyrazole: yield: 85.6 percent.

The circulation 1-6 proves that the catalyst can be recycled, is beneficial to environmental protection and realizes green development.

Example 9

Example 9 was prepared in the same manner as example 1 except that R was¹Is selected from-CH₃The reaction solvent is 1,4-dioxane, and the molar ratio of the p-methylene benzoquinone derivative to the pyrazole to the catalyst is 1: 1: 0.04, the reaction temperature of the one-step reaction is 30 ℃, and the reaction time is 8 h.

Example 10

Example 10 was prepared in the same manner as example 1, except that R¹Is selected from-OMe, the reaction solvent is dichloromethane, the mol ratio of the p-methylene benzoquinone derivative to the pyrazole to the catalyst is 1: 2: 0.05.