CN116903493A - Method for synthesizing polysubstituted o-phenylphenol compound through nucleophilic reaction ring opening of dibenzofuran - Google Patents

Method for synthesizing polysubstituted o-phenylphenol compound through nucleophilic reaction ring opening of dibenzofuran Download PDF

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CN116903493A
CN116903493A CN202310774130.XA CN202310774130A CN116903493A CN 116903493 A CN116903493 A CN 116903493A CN 202310774130 A CN202310774130 A CN 202310774130A CN 116903493 A CN116903493 A CN 116903493A
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dibenzofuran
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polysubstituted
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phenylphenol
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黄良斌
余佳慧
林跃萍
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South China University of Technology SCUT
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/505—Preparation; Separation; Purification; Stabilisation
    • C07F9/5063—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds
    • C07F9/5072—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds from starting materials having the structure P-H
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a method for synthesizing a polysubstituted o-phenylphenol compound through nucleophilic reaction ring opening of dibenzofuran. The method comprises the following steps: under the atmosphere of protective gas, using an organic solvent as a reaction medium, and reacting the substituted dibenzofuran with a nucleophilic reagent under the action of an alkaline compound to obtain a polysubstituted o-phenylphenol compound; the nucleophilic reagent is alcohol, amine or phosphine; the structure is RX-H, and X is O, N, P. The method is simple, and the high-efficiency polysubstituted o-aryl phenol product is obtained under the condition of mild and no metal participation. The ring-opening reagent used in the method is a cheap bulk nucleophilic reagent, has higher industrialization possibility, realizes wider usability for the substrate range of dibenzofuran, and brings more convenience for industrial production without using a metal catalyst.

Description

Method for synthesizing polysubstituted o-phenylphenol compound through nucleophilic reaction ring opening of dibenzofuran
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing an o-phenylphenol derivative through ring opening of SNAr reaction of benzofuran under the action of a nucleophile.
Background
Dibenzofurans are a very common class of materials in chemical synthesis. O-phenylphenol and its derivatives have also found wide application in domestic production, for example, in inhibiting the growth of partial fungi, for the synthesis of certain building materials, leather materials, etc., and are also of great benefit for the synthesis of polymers.
Few reports have been made to date of the reaction of dibenzofuran cleavage of the ring opening of the C-O bond: the Wangquan group initially produced 6,6-substituted-6H-dibenzo [ b, d ] pyrans (Wang, B.; li, M.; xu, S.; song, H.; wang, B.A general synthetic route to, 6-substituted-6H-dibenzo [ b, d ] pyrans from dibenzo [ J.org.chem.2006, 71, 8291-8293) in good yields by refluxing dibenzo-benzofuran with metallic lithium in ether followed by addition of an alkyl ketone or aldehyde at-78℃and final hydrolysis and dehydration with hydrochloric acid. However, in the above reaction, 2.2 equivalents of lithium sheets are used as ring-opening reagent, the reaction conditions are severe, the operation steps are complicated, and in addition, the substrate range of the reaction is very limited, and only the substrate of dibenzofuran having no substitution on benzene ring is used at present.
The dibenzofuran is then cleaved by reductive cleavage by the method of activation of the silane by Robert H.Grubbs et al via path Yi Siji, and ring opening to give selectively ortho-silylated phenylphenol (A.Fedorov, A.A.Toutov, N.A.Swisher and R.H.Grubbs, lewis-base silane activation: from reductive cleavage of aryl ethers to selective ortho-hybridization, chem. Sci.,2013,4, 1640-1645). I.e. in the presence of potassium t-butoxide, an excess of triethylsilane in combination as reducing agent, while this transition metal free silylation process has potential application in organic synthesis, the reaction uses an excess of silane reagent, and does not rely on highly supported organosilanes for the actual commercial benzofuran conversion process, but generally uses commercially viable reducing agents. And the reaction has C-H activated byproducts, so that the reaction system is disordered and the later purification is difficult.
Ring opening of dibenzofurans by metal catalyzed grignard reagents is a very common way of ring opening of dibenzofurans, for example, naoto Chatani published a nickel catalyzed alkyl ring opening reaction of dibenzofurans, specifically operating as: in a glove box, bis- (1, 5-cyclooctadiene) nickel is used as a catalyst, 1, 2-bis (dicyclohexyl phosphorus) -ethane is used as a ligand, dibenzofuran and an alkyl format reagent are added into a bottle, after stirring is carried out for three minutes, diethyl ether in the system is removed, the residual residues are dissolved in toluene, and the reaction is carried out for 14 hours at 80 ℃ to obtain 2,2' -disubstituted biphenyl (Tobisu, M.; takahira, T.; morika, T.; chatani, N.Nickel-Catalyzed Alkylative Cross-Coupling of Anisoles with Grignard Reagents via C-O Bond activation J.am. Chem. Soc.2016, 138, 6711-6714) after the reaction is carried out. Atsuhiro Osuka published a nickel-catalyzed reaction involving an aryl-formatted reagent of dibenzofuran: firstly, using bis- (1, 5-cyclooctadiene) nickel for catalysis, reacting at 80 ℃ for 5 hours in tetrahydrofuran with nitrogen heterocyclic carbene as a ligand to obtain aryl substituted biphenyl, then adding trifluoromethanesulfonic anhydride into dichloromethane, using pyridine as a catalyst and neutralizing acid generated by the reaction, and reacting for two hours from 0 ℃ to room temperature to convert phenolic hydroxyl into trifluoromethanesulfonate. Finally, the triflic acid coupling was removed using tris (dibenzylideneacetone) dipalladium catalysis to give tristyrene (Kurata, y.; otsuka, s.; fukui, n.; nogi, k.; yolimitsu, h.; osuka, a. Aromatic metamorphosis of dibenzofurans into triphenylenes starting with nickel-catalyzed ring-opening C-O-actuation. Org. Lett.2017, 19, 1274-1277). Both reactions use grignard reagents for ring opening, which is not beneficial for industrial production, and has poor compatibility with the functional groups of the reaction substrate, and for the latter reaction, the current limitation of this catalytic alkylation reaction is also that the sensitivity to steric hindrance effect is high, and when the steric hindrance is large, the tension of the product ring is too high, resulting in extremely low or even undetectable yield of the product.
Chinese patent, publication No.: CN106495991a discloses a method for preparing biphenyl and o-phenylphenol by hydrofining industrial dibenzofuran, which comprises the steps of dissolving dibenzofuran in an organic solvent at 80-100 ℃, then carrying out hydrogenation reaction in a fixed bed reactor under the action of a selective hydrogenation catalyst, and then separating and purifying by a rectifying tower, wherein the selectivity is low, and the polysubstituted o-phenylphenol is not easy to prepare by the method.
Chinese patent application, publication No.: CN108947758A discloses a method for preparing biphenyl by catalyzing ring opening of dibenzofuran, which uses supported transition metal phosphide as a catalyst to carry out hydrogenation reaction to open the dibenzofuran, wherein the temperature is 200-280 ℃ and the hydrogen pressure is 1-4MPa, and alumina and silica are used as catalyst carriers. The method uses the recoverable catalyst with better stability, but the preparation process of the catalyst is complex, the steps are complicated, the reaction conditions are more severe, the method is unfavorable for industrial production, and the method is used for leading the dibenzofuran to open the ring to cause excessive C-O activation and breaking two C-O bonds to obtain biphenyl products, and only a small amount of phosphine phenylphenol products are obtained, and the yield is 12%.
At present, the reaction involving dibenzofuran ring opening mostly needs to use active metal coupling reagent, which brings great difficulty to industrial production, for example, the preparation and preservation of Grignard reagent are difficult, anhydrous and anaerobic are strictly required, and the reaction can be strongly exothermic, and the feeding is strictly controlled, so as to prevent temperature runaway or lower yield. There are high demands on industrial equipment or practical operations. The other method has the problem that the dibenzofuran is subjected to ring opening through hydrogenation reduction, but the selectivity of the method is lower, the yield of the o-phenylphenol is not more than 20%, and the method has very low efficiency because of excessive reduction. Therefore, a method for exploring the ring opening of dibenzofuran and obtaining a structure with an ortho-phenylphenol skeleton, which has the advantages of cheap and easily available raw materials, mild reaction conditions, high selectivity and environmental friendliness, is still a subject to be researched.
Disclosure of Invention
In order to solve the existing problem of ring opening of dibenzofuran and overcome the defects, the invention aims to provide a method for synthesizing polysubstituted o-phenylphenol compounds by ring opening through nucleophilic reaction of dibenzofuran. The invention adopts simple structureThe ring-opening reagent is easy to obtain, and the polysubstituted o-aryl phenol product with high efficiency is obtained under mild conditions and without metal participation. The ring-opening reagent used in the method is a cheap bulk nucleophilic reagent (oxygen, nitrogen, phosphorus and the like), avoids a plurality of difficulties and challenges of using a Grignard reagent, has higher industrialization possibility, realizes wider usability for the substrate range of dibenzofuran, brings more convenience for industrial production without using a metal catalyst, and is prepared by only one S N Ar reaction can simply realize the ring opening of dibenzofuran.
The aim of the invention is achieved by the following technical scheme:
a method for synthesizing polysubstituted o-phenylphenol compounds by nucleophilic reaction ring opening of dibenzofuran comprises the following steps:
under the atmosphere of protective gas, using an organic solvent as a reaction medium, and reacting the substituted dibenzofuran with a nucleophilic reagent under the action of an alkaline compound to obtain a polysubstituted o-phenylphenol compound;
the structure of the dibenzofuran is as follows:
the substitution sites of the substituent groups are more than one of 2, 3 and 4 substitutions;
the substituent EWG is an electron-withdrawing group, and specifically is more than one of cyano, trifluoromethyl, phenyl, aryl and carbonyl; or more than one of the above electron withdrawing groups and more than one of methyl, 1, 3-dioxolane groups;
the carbonyl group comprises aldehyde groups, ketone groups, amide groups, and ester groups.
The substituent is cyano, trifluoromethyl, phenyl, picolyl, N-methoxy phenyl amide.
The nucleophilic reagent is alcohol, amine or phosphine; the structure is RX-H, X is O, N, P;
the alcohol is one or more of ethanol, n-butanol, isopropanol, cyclobutylmethanol, 4-pentyne-1-alcohol, 4-pentene-1-alcohol, cyclopentanol, cyclohexanol and 2-heptanol;
the amine is one or more of dialkylamine (such as dimethylamine and diethylamine), morpholine, azetidine, azacyclopentane, azacyclohexane and nitrogen-substituted piperazine;
the phosphine is diphenyl phosphine.
Structure of the polysubstituted o-phenylphenol compound:
the alkaline compound is more than one of sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, n-butyllithium and bis (trimethylsilyl) aminopotassium.
If the nucleophile is an alcohol or diphenyl phosphine, the basic compound is preferably potassium tert-butoxide; if the nucleophile is an amine, the basic compound is preferably n-butyllithium.
The organic solvent is one or more of tetrahydrofuran, N-diethyl acetamide, 1, 4-dioxane, cyclopentyl methyl ether and dimethyl ether.
The molar ratio of the dibenzofuran to the nucleophile is 1: (1-3).
The molar ratio of benzofuran to basic compound is 1: (1-3).
The reaction condition is 40-100 ℃, and the reaction time is 8-12 hours.
After the reaction, the subsequent treatment is performed, wherein the subsequent treatment is that after the quenching reaction, ethyl acetate is used for extracting reaction liquid, an organic phase is collected, water and an organic solvent in the organic phase are removed, and the target product is separated and purified through column chromatography.
The method of the invention has the following advantages:
the method is a metal-free reaction method, raw material reagents are cheap and massive, the operation method is simple and safe, the substrate compatibility is good, the reaction is highly selective, green and efficient, and the requirements of industrial mass production are well met.
Drawings
Fig. 1: compound 3a hydrogen spectrum:( 1 H NMR：500MHz，CDCl 3 ) A figure;
fig. 2: carbon spectrum of compound 3 a: ( 13 C NMR：126MHz，CDCl 3 ) A figure;
fig. 3: compound 3b hydrogen spectrum: (1H NMR:500MHz,DMSO-d 6) diagram;
fig. 4: carbon spectrum of compound 3 b: ( 13 C NMR：126MHz，DMSO-d 6 ) A figure;
fig. 5: compound 3c hydrogen spectrum: ( 1 H NMR：500MHz，CDCl 3 ) A figure;
fig. 6: compound 3c carbon spectrum: ( 13 C NMR：126MHz，CDCl 3 ) A figure;
fig. 7: compound 3d hydrogen spectrum: ( 1 H NMR：500MHz，CDCl 3 ) A figure;
fig. 8: compound 3d carbon spectrum: ( 13 C NMR：101MHz，CDCl 3 ) A figure;
fig. 9: compound 3f hydrogen spectrum: (1H NMR:500MHz,DMSO-d 6) diagram;
fig. 10: compound 3f carbon spectrum: ( 13 C NMR：126MHz，DMSO-d 6 ) A drawing.
Detailed Description
The following description of the technical scheme of the present invention in detail with reference to specific examples is not to be construed as limiting the scope of the present invention, and the raw materials, reagents and solvents used in the present invention are all commercial industrial products.
Example 1: synthesis of 3- (2-hydroxy) phenyl-2-isopropoxy-benzonitrile (3 a)
57.9mg (0.3 mmol) of dibenzofuran-4-carbonitrile, 54.1mg (0.9 mmol) of isopropanol and 50.5mg (0.45 mmol) of potassium tert-butoxide were introduced under inert gas into a reaction flask, dissolved in 0.6mL of tetrahydrofuran and reacted at 80℃for 12 hours. After the reaction was completed, the reaction was quenched by adding a saturated sodium bicarbonate solution, extracted with 30mL of ethyl acetate, repeated three times, and the organic phases were combined, and the organic phase was removed by using anhydrous sodium sulfateThe residual water in the phase was distilled off under reduced pressure to remove the organic solvent, and the crude product was separated by flash column chromatography to give 57mg of the objective product in 75% yield. Product 3a nuclear magnetic resonance spectroscopy data: 1 H NMR(500MHz，CDCl 3 )：δ7.63(m，2H)，7.32(m，J＝21.1，13.6，7.6Hz，3H)，7.06(m，2H)，6.77(s，1H)，4.21(p，J＝6.1Hz，1H)，1.17(d，J＝6.2Hz，6H). 13 C NMR(126MHz，CDCl 3 )δ155.7，153.3，137.3，134.0，132.9，130.6，130.3，125.3，125.0，121.5，118.6，116.6，108.9，79.9，21.9.
fig. 1: compound 3a hydrogen spectrum: ( 1 H NMR：500MHz，CDCl 3 ) A figure; fig. 2: carbon spectrum of compound 3 a: ( 13 C NMR：126MHz，CDCl 3 ) A drawing.
Example 2: synthesis of 3- (2-hydroxy) phenyl-2- (cyclobutylmethoxy) benzonitrile (3 b)
57.9mg (0.3 mmol) of dibenzofuran-4-carbonitrile, 77.5mg (0.9 mmol) of cyclobutylmethanol and 50.5mg (0.45 mmol) of potassium tert-butoxide were introduced into a reaction flask under inert gas conditions, dissolved in 0.6mL of tetrahydrofuran and reacted at 80℃for 12 hours. After the reaction was completed, the reaction was quenched by adding a saturated sodium bicarbonate solution, extracted with 30mL of ethyl acetate, repeated three times, the organic phases were combined, residual moisture in the organic phases was removed by using anhydrous sodium sulfate, the organic solvent was removed by distillation under reduced pressure, and the crude product was isolated by flash column chromatography to give 67mg of the objective product in 80% yield. Product 3b nuclear magnetic resonance spectroscopy data: 1 H NMR(500MHz，DMSO-d 6 )δ9.56(s，1H)，7.73(dd，J＝7.7，1.7Hz，1H)，7.58(d，J＝7.7，1.7Hz，1H)，7.29(t，J＝7.7Hz，1H)，7.23(td，J＝7.7，1.8Hz，1H)，7.16(d，J＝7.6，1.7Hz，1H)，6.97(d，J＝8.2Hz，1H)，6.87(t，J＝7.4Hz，1H)，3.65(d，J＝6.5Hz，2H)，2.42(p，J＝7.4Hz，1H)，1.88-1.78(m，2H)，1.77-1.71(m，1H)，1.71-1.62(m，1H)，1.61-1.51(m，2H). 13 C NMR(126MHz，DMSO-d 6 )δ159.3，155.0，137.8，133.7，132.9，131.3，129.8，124.4，123.8，119.2，117.2，116.1，106.8，77.9，34.8，24.2，18.3.
fig. 3: compound 3b hydrogen spectrum: (1 HNMR:500MHz, DMSO-d 6); fig. 4: carbon spectrum of compound 3 b: ( 13 C NMR：126MHz，DMSO-d 6 ) A drawing.
Example 3: synthesis of 2-hydroxy-2 ' - (azetidin-1-yl) -3' - (4-methylpyridin-2-yl) -1,1' -bipyridine (3 c)
51.9mg (0.2 mmol) of 2- (4-dibenzofuran) -4-methylpyridine, 22.8mg (0.4 mmol) of azetidine and 25.6mg (0.4 mmol) of n-butyllithium were placed in a reaction flask under inert gas conditions, and after dissolution in 1mL of tetrahydrofuran, the mixture was reacted at 40℃for 12 hours. After the reaction was completed, the reaction was quenched by adding a saturated sodium bicarbonate solution, extracted with 30mL of ethyl acetate, repeated three times, the organic phases were combined, residual moisture in the organic phases was removed by using anhydrous sodium sulfate, the organic solvent was removed by distillation under reduced pressure, and the crude product was isolated by flash column chromatography to give 53mg of the objective product in 84% yield. Product 3b nuclear magnetic resonance spectroscopy data: 1 H NMR(500MHz，CDCl 3 )δ8.53(d，J＝5.0Hz，1H)，7.84(s，1H)，7.48(dd，J＝7.6，1.5Hz，1H)，7.33-7.29(m，2H)，7.28-7.24(m，1H)，7.21(s，1H)，7.06-6.95(m，4H)，3.23(d，J＝23.4Hz，4H)，2.39(s，3H)，1.84(p，J＝7.6Hz，2H). 13 C NMR(126MHz，CDCl 3 )δ159.4，154.3，148.9，148.3，146.9，133.0，131.3，130.3，129.3，128.9，128.8，126.7，125.7，122.7，120.5，120.3，117.0，57.3，21.1，16.9.
fig. 5: compound 3c hydrogen spectrum: ( 1 H NMR：500MHz，CDCl 3 ) A figure; fig. 6: compound 3c carbon spectrum: ( 13 C NMR：126MHz，CDCl 3 ) A drawing.
Example 4: synthesis of 2 '-hydroxy-N- (4-methoxyphenyl) -2-morpholin-1, 1' -bipyridyl-3-amide (3 d)
Under inert gas, 63.5mg (0.2 mmol) of N-p-methoxyphenyl-4-dibenzofuran amide, 34.8mg (0.4 mmol) of morpholine and 38.4mg (0.6 mmol) of N-butyllithium were charged into a reaction flask, and after dissolving them in 1mL of tetrahydrofuran, they were reacted at 40℃for 12 hours. After the reaction was completed, the reaction was quenched by adding a saturated sodium bicarbonate solution, extracted with 30mL of ethyl acetate, repeated three times, the organic phases were combined, residual moisture in the organic phases was removed by using anhydrous sodium sulfate, the organic solvent was removed by distillation under reduced pressure, and the crude product was isolated by flash column chromatography to give 71mg of the objective product in 88% yield. Product 3d nmr spectrum data: 1 H NMR(500MHz，CDCl 3 )δ9.12(s，1H)，8.37(s，1H)，7.55(d，J＝8.9Hz，3H)，7.34-7.28(m，2H)，7.22-7.14(m，2H)，7.01(d，J＝7.9Hz，2H)，6.89(d，J＝9.0Hz，2H)，3.81(s，3H)，3.59(s，4H)，3.03(s，4H). 13 C NMR(101MHz，CDCl 3 )δ167.0，156.6，153.0，145.9，136.9，135.5，132.7，131.2，131.0，129.6，129.2，128.1，125.0，121.7，121.0，117.7，114.3，66.9，59.2，55.5。
fig. 7: compound 3d hydrogen spectrum: ( 1 H NMR：500MHz，CDCl 3 ) A figure; fig. 8: compound 3d carbon spectrum: ( 13 C NMR：101MHz，CDCl 3 ) A drawing.
Example 5: synthesis of 6- (diphenylphosphorus) -2 '-hydroxy-1, 1' -biphenyl-3-carbonitrile (3 f)
Under inert gas conditions, the reaction flask was charged with 38.6mg (0.2 mmol) of 2-dibenzofuran carbonitrile, 37.2mg (0.2 mmol) of diphenylphosphine and 22.4mg (0.2 mmol) of potassium tert-butoxide, and after dissolving it by adding 0.2mL of N, N-diethylacetamide, the mixture was reacted at 100℃for 8 hours. After the reaction was completed, the reaction was quenched by adding a saturated sodium bicarbonate solution, extracted with 30mL of ethyl acetate, repeated three times, the organic phases were combined, residual moisture in the organic phases was removed by using anhydrous sodium sulfate, the organic solvent was removed by distillation under reduced pressure, and the crude product was isolated by flash column chromatography to give 69.7mg of the objective product in 92% yield. Product 3f nuclear magnetic resonance spectroscopy data: 1H NMR (500 MHz, DMSO-d 6) δ9.58 (s, 1H), 7.74 (dd, J=8.0, 1.9Hz, 1H), 7.66 (dd, J=3.8, 1.8Hz, 1H), 7.36 (d, J=5.0 Hz, 6H), 7.20-7.09 (m, 6H), 6.88 (d, J=8.0 Hz, 1H), 6.81 (dd, J=7.6, 1.7Hz, 1H), 6.65 (t, J=7.4 Hz, 1H) 13C NMR (126 MHz, DMSO-d 6) δ154.7, 146.3, 146.1, 144.7, 144.6, 136.8, 136.6, 134.6, 134.1, 134.1, 133.8, 133.6, 131.3, 131.0, 129.9, 129.4, 129.4, 129.1.7, 126.7, 7.7.9, 19.118, and 13.9.118.
Fig. 9: compound 3f hydrogen spectrum: (1 HNMR:500MHz, DMSO-d 6); fig. 10: compound 3f carbon spectrum: ( 13 C NMR：126MHz，DMSO-d 6 ) A drawing.
The method of the invention has the following main effects:
the method has the advantages of mild reaction conditions, no metal participation, safe and easily obtained reactants, convenient storage, environmental protection and industrial mass production. The reaction has high chemical selectivity and regioselectivity, and the product yield is high; the range of the reaction substrate is wide, and the compatibility of the functional group is strong.
Comparative example 1
Lithium (4 eq) was added to a solution of dibenzofuran (0.2 mmol) in diethyl ether and the reaction mixture was stirred at room temperature for 48h. After the resulting reddish brown suspension was filtered, the filtrate was added dropwise to a solution of phosphorus trichloride (0.2 mmol) in diethyl ether at 0 ℃. The reaction mixture was stirred at room temperature for 2h, then the solvent was evaporated under reduced pressure. Isolation by flash column chromatography gave a pale yellow solid (0.57 g, 85%). Phenyl grignard reagent (2.5 eq) was beaten into the pale yellow solid as above with a syringe, stirred at room temperature for 20 hours and then quenched with water to efficiently convert the reaction to 2-diphenylphosphine-2' -hydroxybiphenyl with a final yield of 70%.

Claims (7)

1. A method for synthesizing polysubstituted o-phenylphenol compounds by nucleophilic reaction ring opening of dibenzofuran is characterized in that: the method comprises the following steps:
under the atmosphere of protective gas, using an organic solvent as a reaction medium, and reacting the substituted dibenzofuran with a nucleophilic reagent under the action of an alkaline compound to obtain a polysubstituted o-phenylphenol compound;
the structure of the dibenzofuran is as follows:
the substitution sites of the substituent groups in the structure are more than one of 2, 3 and 4 substitutions;
the substituent EWG is an electron-withdrawing group, and specifically is more than one of cyano, trifluoromethyl, phenyl, aryl and carbonyl; or more than one of the above electron withdrawing groups and more than one of methyl, 1, 3-dioxolane groups;
the carbonyl group comprises an aldehyde group, a ketone group, an amide group, and an ester group;
the nucleophilic reagent is alcohol, amine or phosphine; the structure is RX-H, and X is O, N, P.
2. The method for synthesizing the polysubstituted o-phenylphenol compound by nucleophilic reaction ring opening of dibenzofuran according to claim 1, which is characterized in that: in dibenzofuran, the substituent is cyano, trifluoromethyl, phenyl, picolyl and N-methoxy phenyl amide;
in the nucleophile, the alcohol is more than one of ethanol, n-butanol, isopropanol, cyclobutylmethanol, 4-pentyne-1-alcohol, 4-pentene-1-alcohol, cyclopentanol, cyclohexanol and 2-heptanol;
the amine is one or more of dialkylamine, morpholine, azetidine, azacyclopentane, azacyclohexane and nitrogen-substituted piperazine;
the phosphine is diphenyl phosphine;
the alkaline compound is more than one of sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, n-butyllithium and bis (trimethylsilyl) aminopotassium.
3. The method for synthesizing the polysubstituted o-phenylphenol compound by nucleophilic reaction ring opening of dibenzofuran according to claim 2, which is characterized in that: when the nucleophilic reagent is alcohol or diphenyl phosphine, the alkaline compound is potassium tert-butoxide; when the nucleophile is an amine, the basic compound is n-butyllithium.
4. The method for synthesizing the polysubstituted o-phenylphenol compound by nucleophilic reaction ring opening of dibenzofuran according to claim 1, which is characterized in that: the mol ratio of the dibenzofuran to the nucleophile is 1:1-3;
the mol ratio of the benzofuran to the alkaline compound is 1:1-3;
the reaction condition is 40-100 ℃, and the reaction time is 8-12 hours.
5. The method for synthesizing the polysubstituted o-phenylphenol compound by nucleophilic reaction ring opening of dibenzofuran according to claim 1, which is characterized in that: the organic solvent is one or more of tetrahydrofuran, N-diethyl acetamide, 1, 4-dioxane, cyclopentyl methyl ether and dimethyl ether.
6. The method for synthesizing the polysubstituted o-phenylphenol compound by nucleophilic reaction ring opening of dibenzofuran according to claim 1, which is characterized in that:
after the reaction, the subsequent treatment is performed, wherein the subsequent treatment is that after the quenching reaction, ethyl acetate is used for extracting reaction liquid, an organic phase is collected, water and an organic solvent in the organic phase are removed, and the target product is separated and purified through column chromatography.
7. The method for synthesizing the polysubstituted o-phenylphenol compound by nucleophilic reaction ring opening of dibenzofuran according to claim 1, which is characterized in that: the structure of the polysubstituted o-phenylphenol compound:
CN202310774130.XA 2023-06-27 2023-06-27 Method for synthesizing polysubstituted o-phenylphenol compound through nucleophilic reaction ring opening of dibenzofuran Pending CN116903493A (en)

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