Method for directly preparing aryl ether compound from aromatic aldehyde, ketone and phenol

Abstract

The invention provides a method for preparing aryl ether compounds with various series structures and functions by directly reducing and etherifying carbonyl compounds such as aromatic aldehyde and ketone and phenol under the action of diaryl phosphine oxide for the first time. The method is simple and mild in condition, does not need protonic acid, lewis acid, transition metal catalyst, reducing agent and other conditions, and can be compatible with various polar and reducing functional groups which are difficult to be compatible in known reductive etherification reaction; the compounds can be aromatic halogens, cyano groups, diazo groups, alkyl hydroxyl groups, aromatic and alkyl ketone carbonyl groups, aromatic aldehyde groups, secondary amino groups, acylamino groups and the like. The method can also be used for later modification reaction of various aromatic ketones and phenols with biological activity, can also be directly used for efficient and high-selectivity synthesis of aryl ether drugs and intermediates, and has potential application prospects and values in the fields of organic synthesis and medicines.

Description

[Technical field]

[0001] The invention relates to the field of organic synthesis, and in particular to a method for directly preparing aromatic ether compounds from aromatic aldehydes, ketones and phenols. [Background technology]

[0002] Ether compounds are widely found in drugs and natural products. At the same time, they also play a pivotal role in the chemical industry and are widely used in bulk and fine chemistry. Many biologically active compounds, spices, condiments, solvents or polymers contain ether groups, and these diverse applications highlight the importance of this functional group. Therefore, the method of constructing ether bonds has always been a research hotspot in organic chemistry and related fields.

[0003] Traditionally, the Williamson reaction has been widely used in the synthesis of ether compounds. This reaction mainly involves nucleophilic substitution reactions of alcohols, phenols and alkyl halides. However, due to the inevitable competitive β-H elimination side reactions, this type of reaction is less efficient in the synthesis of secondary and tertiary ethers. At the same time, the Williamson etherification reaction also faces common problems such as the production of toxic halogen-containing wastes and cumbersome operating steps. Carbonyl reductive etherification is one of the most ideal methods for synthesizing ether compounds because it uses cheap, readily available, rich, structurally and functionally diverse carbonyl compounds such as aldehydes and ketones as starting materials. The mechanism of this reaction is similar to that of carbonyl reductive amination, and the key is the formation of an oxonium ion intermediate. In recent years, chemists have developed a variety of methods for the reductive etherification of carbonyl compounds, which has greatly promoted the development of synthetic ether chemistry and medicine.

[0004] Despite the important progress, carbonyl reductive etherification still faces many problems and challenges. The key oxonium ion intermediate in the reductive etherification reaction is extremely unstable, and the reported methods inevitably require the use of conditions such as proton acids, Lewis acids and transition metal catalysts. At the same time, this type of reaction also requires the addition of additional reducing agents, which also leads to such reactions usually facing harsh reaction conditions and limited substrate and functional group applicability. More importantly, the currently reported reductive etherification reaction substrates are only applicable to alcohols, while the reductive etherification involving phenols with weaker nucleophilicity has not yet been realized because it is more difficult to form oxonium ion intermediates. [References: (a) Lluna-Galán, C.; Izquierdo-Aranda, L.; Adam, R.; Cabrero-Antonino, JR Chem Sus Chem 2021,14,3744–3784.(b)Liu,B.;Li,Y.;Liu,Q.ChemCatal.2022,2,883–897.(c)Zhao,C.; Sojdak, CA; Myint, W.; Seidel, DJ Am. Chem. Soc. 2017, 139, 10224–10227. (d) Barluenga, J. Tomás-Gamasa, M.; Aznar, F.; Valdés, C. Angew. Chem., Int. Ed. 2010, 49, 4993–4996. (e) Wu, D.; Hernández, WY; Zhang, S.; Vovk, EI; Zhou, X.; Yang, Y.; Khodakov, AY; Ordomsky, VVACS Catal.2019,9,2940–2948.(f)Kalutharage,N.;Yi,CSOrg.Lett.2015,17,1778–1781.(g)Bakos,M.; Domján, A.; Soós, T. Angew. Chem., Int. Ed. 2017, 56, 5217–5221. (h) Pelosi, A.; Lanari, D.; Temperini, A.; Curini, M.; Rosati , O.Adv.Synth.Catal.2019,361,4527–4539. (i) Ouyang, L.; Xia, Y.; Miao, R.; Liao, J.; Luo, R. Iridium-catalyzedreductive Etherification of alpha,beta-unsaturated ketones and aldehydes with alcohols.Org.Biomol.Chem.2022,20,2621–2625.】

[0005] Based on this background, it is of great significance and research value to develop a simple, direct, efficient and universal method for the reductive etherification of carbonyl compounds such as aldehydes and ketones with phenols to achieve the universal synthesis of asymmetric ether compounds with diverse structures and functions. [Summary of the invention]

[0006] The purpose of the present invention is to develop a method for directly realizing reductive etherification of carbonyl compounds such as aromatic aldehydes and ketones with phenol under the action of diarylphosphine oxide, which can be used for the synthesis of a series of aromatic ether compounds with diverse structures and functions and related drug intermediates.

[0007] The objective of the present invention is achieved through the following technical solutions:

[0008] The invention discloses a method for directly preparing aromatic ether compounds from aromatic aldehydes, ketones and phenols. The synthetic raw materials of the aromatic ether compounds include aromatic aldehydes, ketones, phenols, diaryl phosphine oxides, bases and solvents.

[0009] The aromatic ether compound has the following structural formula:

[0010]

[0011] In the structural formula, R 1 is a substituent at any one or more positions on the benzene ring, and R 1 R is independently selected from one of H, alkyl, alkoxy, halogen, and difluoromethoxy; 2 One selected from H or alkyl; R 3 is a substituent at any one or more positions on the benzene ring, and R 3 Independently selected from one of H, alkyl, alkoxy, alkylthiol, amide, halogen, cyano, ester and carbonyl.

[0012] In the structural formula, R 1 is a substituent at any one or more positions on the benzene ring, and R 1 R is independently selected from one of H, methyl, tert-butyl, fluorine, chlorine, and difluoromethoxy; 2 is selected from one of H, methyl and ethyl; R 3 is a substituent at any one or more positions on the benzene ring, and R 3 Independently selected from one of H, ethyl, tert-butyl, tert-amyl, methoxy, methylmercapto, acetylamino, fluorine, chlorine, iodine, cyano, ester, phenylacyl and formyl.

[0013] The aromatic aldehyde or ketone is selected from benzaldehyde, p-methylbenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-iodobenzaldehyde, m-fluorobenzaldehyde, o-fluorobenzaldehyde, acetophenone, p-tert-butylacetophenone, p-chloroacetophenone, p-methylsulfonylacetophenone, p-methylpropiophenone, 3-pyridineacetophenone, salifene and tuna.

[0014] The phenol is selected from phenol, p-ethylphenol, p-isopropylphenol, p-tert-amylphenol, p-fluorophenol, p-methylmercaptophenol, p-acetaminophenol, p-formylphenol, o-chlorophenol, o-iodinephenol, 2,4-di-tert-butylphenol, 3-bromo-4-methoxyphenol, 4-(2-hydroxyethyl)phenol, (4-hydroxyphenyl)(phenyl)methanone, 6-bromo-2-naphthol, 6-cyano-2-naphthol, 6-formyl-2-naphthol, 6-hydroxy-2-naphthoic acid methyl ester, 6-hydroxy-3,4-dihydroquinoline-2(1H)-one, 3-hydroxypyridine, raspberry ketone, triclosan, estradiol, and estrone.

[0015] The diarylphosphine oxide is selected from one of diphenylphosphine oxide, bis(4-methylphenyl)phosphine oxide and bis(4-chlorophenyl)phosphine oxide.

[0016] The base is selected from one of cesium carbonate, potassium phosphate, potassium carbonate and sodium hydroxide.

[0017] Preferably, a method for directly preparing aromatic ether compounds from aromatic aldehydes, ketones and phenols comprises the following steps: mixing aromatic aldehydes, ketones, phenols, diarylphosphine oxides and a base; adding a solvent under an inert gas atmosphere, reacting to obtain an aromatic ether product.

[0018] Further preferably, a method for directly preparing aromatic ether compounds from aromatic aldehydes, ketones and phenols comprises the following steps: mixing aromatic aldehydes, ketones, phenols, diaryl phosphine oxides and a base; adding a solvent under an inert gas atmosphere for stirring reaction, cooling to room temperature after the reaction is completed, washing with saturated ammonium chloride, extracting, drying, and removing the organic solvent by reduced pressure distillation. The crude product is separated by column chromatography to obtain an aromatic ether product.

[0019] More preferably, a method for directly preparing aromatic ether compounds from aromatic aldehydes, ketones and phenols comprises the following steps: adding aromatic aldehydes, ketones, phenols, diarylphosphine oxides and bases to a reaction container in sequence and mixing; adding a solvent under an inert gas atmosphere, heating and stirring, cooling to room temperature after the reaction is completed, washing with saturated ammonium chloride, then extracting with dichloromethane, drying with anhydrous sodium sulfate, removing the organic solvent by reduced pressure distillation, and separating the crude product by column chromatography to obtain an aromatic ether product.

[0020] The molar ratio of the aromatic aldehyde, ketone, phenol, diarylphosphine oxide and base is (1-3):1:(1-3):(1-5);

[0021] Preferably, the molar ratio of the aromatic aldehyde, ketone, phenol, diarylphosphine oxide and base is (1-2):1:(1-2):(1-3).

[0022] More preferably, the molar ratio of the aromatic aldehyde, ketone, phenol, diarylphosphine oxide and base is 1.2:1:1.2:2.

[0023] The solvent is one of N,N-dimethylformamide, acetonitrile, dichloromethane, ethyl acetate and dimethyl sulfoxide.

[0024] The reaction temperature is 70-130°C; more preferably 120°C;

[0025] The reaction time is 8-24 hours, more preferably 12 hours.

[0026] The inert gas is nitrogen.

[0027] According to experimental research, the present invention provides a method for preparing a series of aromatic ether compounds with diverse structures and functions by direct reduction etherification of carbonyl compounds such as aromatic aldehydes and ketones with phenols under the action of diarylphosphine oxide for the first time. The method has simple and mild conditions, does not require conditions such as protonic acid, Lewis acid, transition metal catalyst and reducing agent, and can be compatible with a variety of polar and reducing functional groups that are difficult to be compatible in known reduction etherification reactions, such as aromatic halogens, cyano groups, diazo groups, alkyl hydroxyl groups, aromatic and alkyl ketone carbonyl groups, aromatic aldehyde groups, secondary amino groups and amide groups. The present invention can also be used for the late modification reactions of various aromatic ketones and phenols with biological activity, and can also be directly used for the efficient and highly selective synthesis of aromatic ether drugs and intermediates, and has potential application prospects and value in the fields of organic synthesis and medicine.

Brief Description of the Drawings

[0028] Figure 1 This is the reaction formula for preparing the aryl ether compound of the present invention. [Specific implementation method]

[0029] The synthesis method of the present invention is further described below in conjunction with the synthesis examples of the present invention. It should be noted that the examples do not limit the scope of protection claimed in the present invention.

[0030] This reaction may be achieved through the following ways:

[0031]

[0032] The nucleophilic substitution reaction of the above-mentioned benzyl diarylphosphonate intermediate with phenol has not been reported.

[0033] Synthesis example 1

[0034] Synthesis of 1-methyl-4-(phenoxymethyl)benzene

[0035] 0.24mmol p-methylbenzaldehyde, 0.2mmol phenol, 0.4mmol cesium carbonate, 0.24mmol bis(4-chlorophenyl)phosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 90%. 1 H NMR (400 MHz, CDCl 3 )δ7.40(dd,J=19.6,7.6Hz,4H),7.29(d,J=7.6Hz,2H),7.07(dd,J=13.4,7.6Hz,3H),5.10(s,2H),2.46(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ158.8,137.6,134.0,129.4,129.2,127.5,120.8,114.8,69.8,21.1.

[0036] Synthesis example 2

[0037] Synthesis of 1-ethyl-4-((4-methylbenzyl)oxy)benzene

[0038] 0.24mmol p-tolualdehyde, 0.2mmol p-ethylphenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 97%.

[0039] Synthesis example 2

[0040] Synthesis of 1-ethyl-4-((4-methylbenzyl)oxy)benzene

[0041] 0.24mmol p-tolualdehyde, 0.2mmol p-ethylphenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 97%. 1 H NMR (400 MHz, CDCl 3 )δ7.44(d,J=7.2Hz,2H),7.30(d,J=7.9Hz,2H),7.23(d,J=7.5Hz,2H),7.02(d,J=7.5H z,2H),5.10(s,2H),2.71(dd,J=14.4,7.0Hz,2H),2.47(s,3H),1.34(t,J=7.2Hz,3H). 13 CNMR (101MHz, CDCl 3 )δ156.9,137.5,136.5,134.2,129.2,128.6,127.5,114.7,69.9,27.9,21.1,15.8.

[0042] Synthesis example 3

[0043] Synthesis of 1-methyl-4-((4-(tert-amyl)phenoxy)methyl)benzene

[0044] 0.24mmol p-tolualdehyde, 0.2mmol p-tert-amylphenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 91%. 1 H NMR (400 MHz, CDCl 3)δ7.44(d,J=7.3Hz,2H),7.36(d,J=7.8Hz,2H),7.30(d,J=7.5Hz,2H),7.04(d,J=7.9Hz, 2H),5.11(s,2H),2.47(s,3H),1.74(q,J=7.1Hz,2H),1.38(s,6H),0.81(t,J=7.2Hz,3H).

[0045] Synthesis example 4

[0046] Synthesis of 1-fluoro-4-((4-methylbenzyl)oxy)benzene

[0047] 0.24mmol p-tolualdehyde, 0.2mmol p-fluorophenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 87%. 1 H NMR (400 MHz, CDCl 3 )δ7.38(d,J=7.4Hz,2H),7.26(d,J=7.5Hz,2H),7.03(t,J=8.0Hz,2H),7.00–6.94(m,2H),5.04(s,2H),2.43(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ157.3(d,J=238.3Hz),154.9(d,J=1.9Hz),137.8,133.8,129.2,127.6,115.9(d,J=3.9Hz),115.7(d,J=19.0Hz),70.5,21.1. 19 F NMR (377 MHz, CDCl 3 )δ-123.81.

[0048] Synthesis example 5

[0049] Synthesis of 1-chloro-2-((4-methylbenzyl)oxy)benzene

[0050] 0.24mmol p-tolualdehyde, 0.2mmol o-chlorophenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 90%. 1 H NMR (400 MHz, CDCl 3 )δ7.43(t,J=8.6Hz,3H),7.32–7.18(m,3H),7.02(d,J=8.2Hz,1H),6.95(t,J=7.6Hz,1H),5.17(s,2H),2.42(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ154.2,137.6,133.5,130.3,129.2,127.6,127.2,123.2,121.5,114.1,70.7,21.1.

[0051] Synthesis example 6

[0052] Synthesis of 1-iodo-2-((4-methylbenzyl)oxy)benzene

[0053] 0.24mmol p-tolualdehyde, 0.2mmol o-iodophenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction vessel. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 90%. 1 H NMR (400 MHz, CDCl 3 )δ7.86(d,J=7.7Hz,1H),7.45(d,J=7.4Hz,2H),7.32(t,J=7.7Hz,1H),7.26(d,J=7 .5Hz,2H),6.91(d,J=8.2Hz,1H),6.77(t,J=7.5Hz,1H),5.16(s,2H),2.43(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ157.2,139.4,137.5,133.4,129.3,129.2,127.0,122.7,112.7,86.8,70.7,21.1.

[0054] Synthesis Example 7

[0055] Synthesis of Methyl (4-((4-methylbenzyl)oxy)phenyl)sulfane

[0056] 0.24mmol p-methylbenzaldehyde, 0.2mmol p-methylmercaptophenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 85%. 1 H NMR (400 MHz, CDCl 3 )δ7.33(d,J=7.5Hz,2H),7.28(d,J=8.1Hz,2H),7.21(d,J=7.5Hz,2H),6.94(d,J=8.1Hz,2H),5.02(s,2H),2.46(s,3H),2.38(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ157.5,137.8,133.9,130.1,129.3,129.1,127.6,115.6,70.1,21.2,18.0.

[0057] Synthesis example 8

[0058] Synthesis of 1-bromo-1-methoxy-4-((4-methylbenzyl)oxy)benzene

[0059] 0.24mmol p-methylbenzaldehyde, 0.2mmol 3-bromo-4-methoxyphenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 96%. 1 H NMR (400 MHz, CDCl 3 )δ7.35(d,J=7.3Hz,2H),7.30–7.21(m,3H),6.93(d,J=8.9Hz,1H),6.86(d,J=8.9Hz,1H),4.99(s,2H),3.88(s,3H),2.42(s,3H). 13C NMR (101 MHz, CDCl 3 )δ153.1,150.3,137.7,133.6,129.2,127.5,120.1,114.6,112.7,111.8,70.7,56.7,21.1.

[0060] Synthesis example 9

[0061] Synthesis of 1-(4-(Benzyloxy)phenyl)-2-phenyldiazide

[0062] 0.24mmol benzaldehyde, 0.2mmol p-diazophenylphenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction vessel. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 90%. 1 H NMR (400 MHz, CDCl 3 )δ7.99(dd,J=13.7,8.2Hz,4H),7.65–7.27(m,8H),7.14(d,J=7.7Hz,2H),5.16(s,2H). 13 CNMR (101MHz, CDCl 3 )δ161.1,152.7,147.1,136.4,130.3,129.0,128.6,128.1,127.4,124.7,122.5,115.0,70.1.

[0063] Synthesis example 10

[0064] Synthesis of N-(4-(Benzyloxy)phenyl)acetamide

[0065] 0.24mmol benzaldehyde, 0.2mmol acetaminophenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 78%. 1 H NMR (400 MHz, CDCl 3 )δ7.52(s,1H),7.45–7.29(m,7H),6.91(d,J=8.0Hz,2H),5.02(s,2H),2.12(s,3H).13 C NMR (101 MHz, CDCl 3 )δ168.4,155.5,136.9,131.2,128.5,127.9,127.4,121.9,115.1,70.2,24.2.

[0066] Synthesis Example 11

[0067] Synthesis of 2-(4-((4-methylbenzyl)oxy)phenyl)ethan-1-ol

[0068] 0.24mmol p-methylbenzaldehyde, 0.2mmol 4-(2-hydroxyethyl)phenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 73%. 1 H NMR (400 MHz, CDCl 3 )δ7.34(d,J=7.9Hz,2H),7.21(d,J=7.8Hz,2H),7.15(d,J=8.5Hz,2H),6.94(d,J=8.5Hz, 2H),5.02(s,2H),3.82(t,J=6.6Hz,2H),2.81(t,J=6.6Hz,2H),2.38(s,3H),1.67(s,1H). 13 C NMR (101 MHz, CDCl 3 )δ157.6,137.7,134.1,130.7,130.0,129.3,127.6,115.0,70.0,63.8,38.3,21.2

[0069] Synthesis example 12

[0070] Synthesis of (4-((4-methylbenzyl)oxy)phenyl)(phenyl)methanone

[0071] 0.24mmol p-tolualdehyde, 0.2mmol p-benzoylphenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction vessel. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 95%. 1H NMR (400 MHz, CDCl 3 )δ7.87(d,J=8.3Hz,2H),7.80(d,J=7.2Hz,2H),7.60(t,J=7.2Hz,1H),7.51(t,J=7.3Hz,2H), 7.37(d,J=7.5Hz,2H),7.25(d,J=7.4Hz,2H),7.07(d,J=8.3Hz,2H),5.14(s,2H),2.41(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ195.4,162.4,138.2,138.0133.1,132.4,131.8,130.2,129.6,129.3,128.1,127.5,114.3,70.0,21.1.

[0072] Synthesis example 13

[0073] Synthesis of 4-((4-methylbenzyl)oxy)-N-phenylaniline

[0074] 0.24mmol p-tolualdehyde, 0.2mmol p-phenylaminophenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction vessel. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 92%. 1 H NMR (400 MHz, CDCl 3 )δ7.41(d,J=7.9Hz,2H),7.29(t,J=8.0Hz,4H),7.16–7.09(m,2H),7.00(dt,J= 7.6, 4.2Hz, 4H), 6.91 (t, J = 7.3Hz, 1H). 5.54 (s, 1H), 5.07 (s, 2H), 2.44 (s, 3H). 13 C NMR (101 MHz, CDCl 3 )δ154.4,145,137.6,135.9,134.1,129.2,129.2,127.6,121.9,119.6,115.7,115.7,70.3,21.2.

[0075] Synthesis example 14

[0076] Synthesis of 1-bromo-6-((3,4-dimethylbenzyl)oxy)naphthalene

[0077] 0.24mmol 3,4-dimethylbenzaldehyde, 0.2mmol 6-bromo-2-phenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 86%. 1 H NMR (400 MHz, CDCl 3 )δ7.96(s,1H),7.69(d,J=8.9Hz,1H),7.63(d,J=8.6Hz,1H),7.55(d,J=8.7Hz,1H),7.35–7.17(m,5H),5.14(s,2H),2.36(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ157.1,136.8,136.5,133.9,133.0,130.0,129.8,129.6,129.5,129.1,128.4,128.4,125.3,120.1,117.0,107.0,70.0,19.7,19.5.

[0078] Synthesis Example 15

[0079] Synthesis of 6-((4-methylbenzyl)oxy)-2-naphthoic acid methyl ester

[0080] 0.24mmol p-methylbenzaldehyde, 0.2mmol methyl 6-hydroxy-2-naphthoate, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction vessel. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 67%. 1 H NMR (400 MHz, CDCl 3 )δ8.51(s,1H),8.00(d,J=8.5Hz,1H),7.83(d,J=8.8Hz,1H),7.72(d,J=8.5Hz,1H),7.3 6(d,J=7.3Hz,2H),7.22(dd,J=16.1,8.3Hz,4H),5.13(s,2H),3.95(s,3H),2.36(s,3H). 13 CNMR (101MHz, CDCl 3)δ167.3,158.7,138.0,137.1,133.4,130.9,130.8,129.3,128.0,127.7,126.9,125.9,125.3,120.0,106.9,70.1,52.1,21.2.

[0081] Synthesis example 16

[0082] Synthesis of 1-Isopropyl-4-(1-phenylethoxy)benzene

[0083] 0.24mmol acetophenone, 0.2mmol p-isopropylphenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 87%. 1 H NMR (400 MHz, CDCl 3 )δ7.41(d,J=7.5Hz,2H),7.36(t,J=7.5Hz,2H),7.30–7.26(m,1H),7.08(d,J=8.5Hz,2H),6.82(d,J =8.5Hz,2H),5.29(q,J=6.5Hz,1H),2.89–2.77(m,1H),1.65(d,J=6.5Hz,3H),1.21(d,J=7.0Hz,6H). 13 C NMR (101 MHz, CDCl 3 )δ156.1,143.5,140.9,128.5,127.3,127.1,125.5,115.6,76.0,33.2,24.5,24.1.

[0084] Synthesis Example 17

[0085] Synthesis of 1-(Chloro)-4-(1-(4-isopropylphenylphenoxy)ethyl)benzene

[0086] 0.24mmol p-chlorobenzaldehyde, 0.2mmol p-isopropylphenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. Stirring was continued at 120°C for 12h under nitrogen atmosphere, the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 71%. 1H NMR (400 MHz, CDCl 3 )δ7.31(s,4H),7.06(d,J=8.7Hz,2H),6.77(d,J=8.7Hz,2H),5.24(q,J=6. 4Hz,1H),2.88–2.75(m,1H).,1.60(d,J=6.4Hz,3H),1.19(d,J=7.0Hz,6H). 13 C NMR (101 MHz, CDCl 3 )δ155.8,142.0,141.2,133.0,128.8,127.2,127.0,115.6,75.3,33.2,24.4,24.1.

[0087] Synthesis example 18

[0088] Synthesis of 6-(tert-butyl)-4-(1-(4-isopropylphenoxy)ethyl)-1,1-dimethyl-2,3-dihydro-1H-indene

[0089] 0.24mmol of salvi musk, 0.2mmol of p-isopropylphenol, 0.4mmol of cesium carbonate, 0.24mmol of diphenylphosphine oxide and 1ml of N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12 hours under a nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with a saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, and dried. The crude product was separated by column chromatography to obtain the target product with a yield of 85%. 1 H NMR (400 MHz, CDCl 3 )δ7.29(s,1H),7.06(d,J=7.9Hz,3H),6.79(d,J=8.5Hz,2H),5.32(q,J=6.4Hz,1H),2.99–2.77(m,3H),1 .94(t,J=7.2Hz,2H),1.61(d,J=6.4Hz,3H),1.30(s,9H),1.26(d,J=12.9Hz,6H),1.19(d,J=6.9Hz,6H). 13 C NMR (101 MHz, CDCl 3 )δ156.3,152.7,150.1,140.8,138.0,136.4,127.1,120.4,117.8,115.7,74.8,43.7,41.5,34.8,33.2,31.6,28.7,27.9,24.2,22.4.

[0090] Synthesis example 19

[0091] Synthesis of 6-(1-(4-isopropylphenoxy)ethyl)-1,1,2,4,4,7-hexamethyl-1,2,3,4-tetrahydronaphthalene

[0092] 0.24mmol of musk tonata, 0.2mmol of p-isopropylphenol, 0.4mmol of cesium carbonate, 0.24mmol of diphenylphosphine oxide and 1ml of N,N-dimethylformamide were added to the reaction container. The mixture was stirred at 120°C for 12h under nitrogen atmosphere, and then the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane. The solvent was removed by vacuum distillation and concentrated, and dried. The crude product was separated by column chromatography to obtain the target product with a yield of 80%. 1 H NMR (400 MHz, CDCl 3 )δ7.38(d,J=3.0Hz,1H),7.12(s,1H),7.08(d,J=8.6Hz,2H),6.81(dd,J=8.5,2.2Hz,2H),5.46–5.36(m,1H),2.84(dt,J=13.8,6.9Hz,1H) ,2.36(s,3H),1.94–1.78(m,1H),1.62(t,J=6.1Hz,3H),1.32(dd,J=16.4,9.0Hz,8H),1.22(s,6H),1.15(s,3H),1.07(s,3H),0.99(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ156.2,144.7,142.6,140.8,137.9,131.1,128.8,127.0,123.5,115.7,73.5 ,43.8,37.4,34.6,34.1,33.2,32.2,31.9,28.6,24.9,24.2,22.3,18.8,16.8.

[0093] Synthesis example 20

[0094] Synthesis of (8R,9S,13S,14S,17S)-3-((4-fluorobenzyl)oxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-17-ol

[0095] 0.24mmol p-fluorobenzaldehyde, 0.2mmol estradiol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction container. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 82%. 1 H NMR (400 MHz, CDCl 3 )δ7.49–7.36(m,2H),7.33–7.21(m,1H),7.10(dd,J=14.6,6.4Hz,2H),6.8 7–6.69(m,2H),5.03(d,J=13.2Hz,2H),4.69(d,J=13.2Hz,1H),3.76(dd,J= 14.6,6.7Hz,1H),2.91(s,2H),2.36(s,1H),2.29–2.07(m,2H),1.98(dd,J= 26.4,12.8Hz,2H),1.75(s,2H),1.59–1.07(m,6H),0.83(d,J=13.1Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ162.4(d,J=246.0Hz),156.5,138.0,133.0,129.0(t,J=32.5Hz),126.3,115.5,115.2,1 14.8,112.2,81.8,69.2,50.0,43.9,43.2,38.8,36.7,30.5,29.7,27.2,26.3,23.1,11.0. 19 F NMR (565MHz, CDCl 3 )δ-114.20.

[0096] Synthesis Example 21

[0097] Synthesis of 4-((3-fluorobenzyl)oxy)benzaldehyde

[0098] 0.24mmol m-fluorobenzaldehyde, 0.2mmol p-formylphenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction vessel. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 91%. 1H NMR (400 MHz, CDCl 3 )δ9.87(s,1H),7.83(d,J=8.7Hz,2H),7.35(dd,J=13.8,7.9Hz,1H),7.16(dd,J=19.2,8.6Hz,2H),7.09–6.98(m,3H),5.12(s,2H). 13 C NMR (101 MHz, CDCl 3 )δ190.6,163.3,162.9(d,J=246.6Hz),138.4(d,J=7.4Hz),131.9,130.3,130.2(d,J=2.1Hz ), 122.7 (d, J = 3.0Hz), 115.1 (d, J = 21.1Hz), 115.0, 114.1 (d, J = 22.2Hz), 69.2 (d, J = 1.9Hz). 19 FNMR (376MHz, CDCl 3 )δ-118.43.

[0099] Synthesis example 22

[0100] Synthesis of 6-((2-fluorobenzyl)oxy)-2-naphthaldehyde

[0101] 0.24mmol o-fluorobenzaldehyde, 0.2mmol 6-formyl-2-phenol, 0.4mmol cesium carbonate, 0.24mmol diphenylphosphine oxide and 1ml N,N-dimethylformamide were added to the reaction vessel. The reaction was stirred at 120°C for 12h under nitrogen atmosphere, and the reaction was stopped, cooled to room temperature, washed with saturated ammonium chloride solution, and then extracted with dichloromethane, concentrated by vacuum distillation to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 87%. 1 H NMR (400 MHz, CDCl 3 )δ10.08(s,1H),8.23(s,1H),7.90(t,J=9.1Hz,2H),7.79(d,J=8.5Hz,1H),7. 62–7.47(m,1H),7.39–7.24(m,3H),7.16(dt,J=18.4,8.4Hz,2H),5.26(s,2H). 13 C NMR (101 MHz, CDCl 3)δ192.0,160.6(d,J=247.2Hz),159.1,138.2,134.2,132.5,131.3,130.1(d,J=8.2 Hz),129.8(d,J=3.8 Hz),128.1,127.9,124.4(d,J=3.6 Hz),123.7,123.5(d,J=14.2 Hz),120.1,115.5(d,J=21.1 Hz),107.4,63.9(d,J=4.5 Hz). 19 F NMR (376 MHz, CDCl) 3 )δ-112.35.

Claims

1. A method for directly preparing aromatic ether compounds from aromatic aldehydes, ketones and phenols, characterized in that: The synthetic raw materials of the aromatic ether compound include: aromatic aldehyde, ketone, phenol, diarylphosphine oxide, base and solvent; The aromatic ether compound has the following structural formula: In the structural formula, R 1 is a substituent at any one or more positions on the benzene ring, and R 1 R is independently selected from one of H, alkyl, alkoxy, halogen, and difluoromethoxy; 2 One selected from H or alkyl; R 3 is a substituent at any one or more positions on the benzene ring, and R 3 Independently selected from one of H, alkyl, alkoxy, alkylthiol, amide, halogen, cyano, ester and carbonyl.

2. The method according to claim 1, characterized in that In the structural formula, R 1 is a substituent at any one or more positions on the benzene ring, and R 1 R is independently selected from one of H, methyl, tert-butyl, fluorine, chlorine, and difluoromethoxy; 2 One selected from H, methyl, ethyl; R 3 is a substituent at any one or more positions on the benzene ring, and R 3 Independently selected from one of H, ethyl, tert-butyl, tert-amyl, methoxy, methylmercapto, acetylamino, fluorine, chlorine, iodine, cyano, ester, phenylacyl and formyl.

3. The method according to claim 1 or 2, characterized in that The aromatic aldehyde or ketone is selected from benzaldehyde, p-methylbenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-iodobenzaldehyde, m-fluorobenzaldehyde, o-fluorobenzaldehyde, acetophenone, p-tert-butylacetophenone, p-chloroacetophenone, p-methylsulfonylacetophenone, p-methylpropiophenone, 3-pyridineacetophenone, salifene and tuna.

4. The method according to claim 1 or 2, characterized in that: The phenol is selected from phenol, p-ethylphenol, p-isopropylphenol, p-tert-amylphenol, p-fluorophenol, p-methylmercaptophenol, p-acetaminophenol, p-formylphenol, o-chlorophenol, o-iodinephenol, 2,4-di-tert-butylphenol, 3-bromo-4-methoxyphenol, 4-(2-hydroxyethyl)phenol, (4-hydroxyphenyl)(phenyl)methanone, 6-bromo-2-naphthol, 6-cyano-2-naphthol, 6-formyl-2-naphthol, 6-hydroxy-2-naphthoic acid methyl ester, 6-hydroxy-3,4-dihydroquinoline-2(1H)-one, 3-hydroxypyridine, raspberry ketone, triclosan, estradiol, and estrone.

5. The method according to claim 1 or 2, characterized in that: The following steps are involved: Aromatic aldehyde, ketone, phenol, diarylphosphine oxide and base are added to a reaction container in sequence and mixed; a solvent is added under an inert gas atmosphere, and the mixture is heated and stirred. After the reaction is completed, the mixture is cooled to room temperature, washed with saturated ammonium chloride, extracted with dichloromethane, dried with anhydrous sodium sulfate, and the organic solvent is removed by distillation under reduced pressure. The crude product is separated by column chromatography to obtain an aromatic ether product.

6. The method according to claim 5, characterized in that The diarylphosphine oxide is selected from one of diphenylphosphine oxide, bis(4-methylphenyl)phosphine oxide and bis(4-chlorophenyl)phosphine oxide.

7. The method according to claim 5, characterized in that The base is selected from one of cesium carbonate, potassium phosphate, potassium carbonate and sodium hydroxide.

8. The method according to claim 5, wherein the molar ratio of the aromatic aldehyde, ketone, phenol, diarylphosphine oxide and base is (1-3):1:(1-3):(1-5).

9. The method according to claim 5, characterized in that The solvent is one of N,N-dimethylformamide, acetonitrile, dichloromethane, ethyl acetate and dimethyl sulfoxide.

10. The method according to claim 5, characterized in that The reaction temperature is 70-130° C.; the reaction time is 8-24 hours; and the inert gas is nitrogen.

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