CN116237068A - Preparation method of 2-phosphonomethyl phenol compound - Google Patents
Preparation method of 2-phosphonomethyl phenol compound Download PDFInfo
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- CN116237068A CN116237068A CN202310255265.5A CN202310255265A CN116237068A CN 116237068 A CN116237068 A CN 116237068A CN 202310255265 A CN202310255265 A CN 202310255265A CN 116237068 A CN116237068 A CN 116237068A
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
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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
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5333—Arylalkane phosphine oxides or thioxides
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
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Abstract
The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of a 2-phosphonomethyl phenol compound, which takes a simple and easily obtained salicyl alcohol compound and diaryl phosphine oxide as reaction raw materials, and can efficiently construct a benzyl C-P bond to obtain a target product under the condition of proper organic solvent, reaction temperature and reaction time under the combined catalysis of an iodine simple substance and an alkaline reagent. The method has the advantages of wide sources of raw materials, stable properties, few reaction steps, safe and mild reaction conditions, high atom economy, high yield, greenness, high efficiency and strong universality, has good application value in the fields of organic synthesis and drug synthesis, and provides an effective new way for synthesizing the organic phosphine compound.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 2-phosphonomethyl phenol compound.
Background
The organic phosphine is an organic compound containing carbon-phosphorus bonds, is an important synthon and a synthesis intermediate in the field of organic synthesis, and is widely applied to the fields of organometallic catalytic ligands, medicines, pesticides, materials, life sciences and the like. Among these, benzylphosphine structures are widely present, for example, in human prostaphospate A (J.Bioorg.Med. Chem. Lett.1996,6,311), calcium antagonistic active ingredient B (Eur.J.Med. Chem.1993,28,943), chemiluminescent material C (J.Org. Chem.2003,68,5950), but also in synthetic intermediates of the antimicrobial active species 2-hydroxybenzylphosphonium salt (QPS, wherein R is alkyl) (Bioorg Med Chem Lett.2020,30,127234). In view of the important uses of such compounds, development of novel synthetic methods for efficient and rapid preparation of such compounds has attracted attention from organic and pharmaceutical synthesis workers.
The common methods for constructing the C-P bond are mainly Arbuzov reaction, direct addition of P-H bond to olefin, coupling reaction catalyzed by metal catalyst and the like, but the methods have the defects of poor atom economy, harsh reaction conditions and small application range of substrates, and certain reactions are environment-friendly due to the need of catalyzing reaction by using noble metal catalyst or using metal reagent as reactant in the reactionPoor economy and limited application range. For example, xiangyang Wo et al reported using Ba (NTf 2 ) 2 And KPF 6 The catalyst compounded according to the molar ratio of 1:1 can catalyze Cha Erchun to react with diphenylphosphine oxide, and the organic phosphine compound is prepared by dehydration coupling (Chemical communication.2018,54 (79): 11132-11135), but the reaction can only be applied to alcohol with a specific structure, namely chalcol, namely, the alcoholic hydroxyl is simultaneously positioned on benzyl position and allyl position, while the reactivity of pure allyl alcohol or benzyl alcohol is poorer, therefore, the yield of the reaction is greatly influenced by the electronic effect of a substituent of a reaction substrate, and Ba (NTf) 2 ) 2 The catalyst is expensive (1926 yuan/1 g) and severely limits the commercial application of the above reaction.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for producing a 2-phosphonomethyl phenol compound which is highly economical, mild in reaction conditions, environmentally friendly, high in yield and highly versatile.
In order to achieve the above purpose, the invention adopts the following technical scheme:
according to a first aspect of embodiments of the present invention, there is provided the use of a catalyst composition for catalyzing the reaction of a salicylalcohol compound with a diaryl phosphine oxide to produce a 2-phosphonomethyl phenol compound, the catalyst composition comprising elemental iodine and an alkaline reagent, the alkaline reagent being at least one of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide or sodium hydroxide.
In the embodiment of the invention, the molar ratio of the iodine simple substance to the salicylalcohol compound is 0.9-1.1:1.
In an embodiment of the invention, the molar ratio of the alkaline reagent to the diaryl phosphine oxide is 1 to 1.1:1.
In an embodiment of the invention, the molar ratio of the salicyl alcohol compound to the diaryl phosphine oxide is 1:1-1.2.
In a second aspect, the present invention provides a process for preparing a 2-phosphonomethyl phenol compound, comprising the steps of: in an anhydrous and anaerobic environment, in the presence of a catalyst, salicyclic alcohol compounds react with diaryl phosphine oxides to prepare the 2-phosphonomethyl phenol compound.
In an embodiment of the present invention, the catalyst includes elemental iodine and an alkaline reagent that is at least one of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, or sodium hydroxide.
In the embodiment of the invention, the molar ratio of the iodine simple substance to the salicylalcohol compound is 0.9-1.1:1.
In an embodiment of the invention, the molar ratio of the alkaline reagent to the diaryl phosphine oxide is 1 to 1.1:1.
In an embodiment of the invention, the molar ratio of the salicyl alcohol compound to the diaryl phosphine oxide is 1:1-1.2.
In an embodiment of the present invention, the diaryl phosphine oxide has the structural formula: ar (Ar) 2 PHO, wherein Ar is substituted or unsubstituted phenyl or heteroaryl;
preferably, the substituents on the phenyl or heteroaryl groups are alkoxy, halogen substituted or unsubstituted alkyl;
more preferably, ar is any one of thienyl, 3-methoxyphenyl, p-trifluoromethylphenyl and phenyl.
In an embodiment of the present invention, the salicylalcohol compound has a structure represented by formula I:
wherein R is 1 Is any one of hydrogen atom, alkyl, alkoxy and aryl;
preferably, the carbon number of the alkyl is 1-6, the carbon number of the alkoxy is 1-10, and the aryl is a substituted or unsubstituted phenyl;
more preferably, R 1 Is any one of hydrogen atom, methyl, benzyloxy and phenyl.
In an embodiment of the invention, the reaction is carried out in an anhydrous solvent.
In an embodiment of the invention, the anhydrous solvent is anhydrous 1, 4-dioxane and/or anhydrous dichloromethane.
In an embodiment of the present invention, the ratio of the amount of the substance of the salicyl compound to the volume of the anhydrous solvent is 0.5 to 0.7:6 to 9, and the proportion relation is mol/L.
In the embodiment of the invention, the temperature of the reaction is 80-100 ℃ and the reaction time is 4-10 hours.
In the embodiment of the invention, after the reaction is completed, the reaction mixture is extracted by a mixed solvent of water and dichloromethane, the organic layers are combined, dried and concentrated, and the obtained crude product is purified by column chromatography to obtain a target product, wherein the volume ratio of the eluent is 1: ethyl acetate and petroleum ether in 2-5 weight portions.
In an embodiment of the invention, the diaryl phosphine oxide is prepared by reacting diethyl phosphonate with an aryl grignard reagent.
In an embodiment of the invention, the molar ratio of the aryl grignard reagent to the diethyl phosphonate is 2-2.2:1.
In an embodiment of the present invention, the halogen in the aryl grignard reagent is a bromine atom, and preferably the aryl grignard reagent is one of 2-thiophenylmagnesium bromide, 3-methoxyphenylmagnesium bromide and p-trifluoromethylphenylmagnesium bromide.
The reaction time of the aryl Grignard reagent and the diethyl phosphonate is 0.8-1.2 h.
In the embodiment of the invention, after the aryl Grignard reagent and the diethyl phosphonate are completely reacted, adding an acid solution to quench the reaction, extracting the reaction product by using an ether solvent, combining an organic layer, drying and concentrating the organic layer, purifying the obtained crude product by column chromatography to obtain the diaryl phosphine oxide, wherein the eluent is ethyl acetate and petroleum ether with the volume ratio of 1:1-3; the acid solution is hydrochloric acid and/or sulfuric acid.
The use of grignard reagents of aryl bromides is preferred in the present invention for two reasons: 1. compared with benzyl halide, the halogen atom in the aryl halide and the aromatic ring are directly connected to generate p-pi conjugated effect, so that the aryl halide has lower reactivity than the benzyl halide, and side reactions such as Wurz coupling and the like caused by severe heat release and improper drop acceleration control in the preparation process of the Grignard reagent are avoided; 2. the aryl bromide has stronger activity than aryl chloride, and the required aryl Grignard reagent can be prepared by controlling the dripping speed without adding an initiator (such as iodine simple substance) and heating when the Grignard reagent is prepared, so that a coupling product is not easy to generate.
The reaction mechanism of the invention is as follows:
salicyclic alcohol compounds form an intermediate 1 and HI under the action of iodine simple substances; the intermediate 1 is dehydrated by the action of HI to regenerate iodine simple substance, and simultaneously, an active intermediate 2 (ortho-methyl benzoquinone) is also generated; the diaryl phosphine oxide is dehydroionized under the action of an alkaline reagent to generate diaryl phosphine anions, and reacts with an intermediate 2 (o-methyl benzoquinone) to generate 2-phosphonomethyl phenol anions 3; the 2-phosphonomethylphenol anion 3 is protonated to produce the target product 2-phosphonomethylphenol compound.
Compared with the prior art, the technical scheme of the invention has the following advantages:
according to the preparation method of the 2-phosphonomethyl phenol compound, provided by the embodiment of the invention, the simple and easily obtained salicyl alcohol compound and diaryl phosphine oxide are used as reaction raw materials, and under the combined catalysis of the iodine simple substance and the alkaline reagent, a benzyl C-P bond can be efficiently constructed under the conditions of a proper organic solvent, a reaction temperature and a reaction time to obtain a target product. The method has the advantages of wide sources of raw materials, stable properties, few reaction steps, safe and mild reaction conditions, high atom economy, high yield, greenness, high efficiency and strong universality (the reaction substrate has no obvious influence on the yield), has good application value in the fields of organic synthesis and drug synthesis, and provides an effective new way for synthesizing the organic phosphine compound.
Detailed Description
The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments described herein, but are not intended to limit the scope of the invention, any product which is the same or similar to the present invention, whether in light of the present teachings or in combination with other prior art features, falls within the scope of the present invention.
The specific experimental procedures or conditions are not noted in the examples and may be followed by the operations or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
Example 1
A method for preparing 2- (di (2-thienyl) phosphonomethyl) -phenol, comprising the steps of:
(1) After Schlenk flask was evacuated-nitrogen-filled 3 times, 6mL of 2-thiophen magnesium bromide (available from Ann Ji Co., ltd., cat. No. W420268) was added at a concentration of 0.5mol/L, 1.5mmol of diethyl phosphonate was added dropwise to the flask under the protection of nitrogen gas with magnetic stirring, stirring was continued for 0.8 hours after the completion of the addition, then the reaction was quenched with 1N diluted hydrochloric acid until no bubbles were generated, 20mL of methyl t-butyl ether was added to the reaction mixture to extract 3 times, and the organic layer was combined, and dried over anhydrous Na 2 SO 4 Drying for 30min, filtering and distilling under reduced pressure to obtain a crude product, drying the crude product by using anhydrous sodium sulfate for 30min, and purifying by column chromatography (the eluent is ethyl acetate and petroleum ether, the volume ratio is 1:2), thus obtaining 1.38mmol of dithiopheneylphosphine oxide, and the yield of the step is 92%.
The specific reaction formula is:
(2) After Schlenk bottle is vacuumized and filled with nitrogen for 3 times, under the protection of nitrogen, 0.5mmol of salicyl alcohol, 0.5mmol of dithiopheneyl phosphine oxide, 0.5mmol of potassium tert-butoxide, 0.5mmol of elemental iodine and 6mL of anhydrous dichloromethane are sequentially added, under the condition of magnetic stirring, the oil bath is used for reacting for 4 hours at 80 ℃, TLC is used for tracking the reaction in the reaction process, after the reaction is monitored to be complete, the mixture is taken out and cooled to room temperature, 20mL of water and 20mL of dichloromethane are added for extracting the mixture after the reaction for 3 times, the organic layers are combined and distilled under reduced pressure, and the crude product is dried for 30min by using anhydrous sodium sulfate and then purified by column chromatography (the eluent is ethyl acetate and petroleum ether with the volume ratio of 1:3), so that 2- (bis (2-thienyl) phosphonomethyl) -phenol can be obtained, and the yield of the step is 91%; the overall yield of the two-stage reaction was calculated to be 84% based on diethyl phosphonate.
The specific reaction formula is:
the 2- (bis (2-thienyl) phosphonomethyl) -phenol prepared in this example was subjected to nuclear magnetic resonance hydrogen spectroscopy and high resolution mass spectrometry as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.44(s,1H),7.72(t,J＝4.5Hz,2H),7.57(dd,J＝7.3,3.6Hz,2H),7.13(dd,J＝16.9,9.2Hz,3H),6.99(d,J＝8.0Hz,1H),6.86(d,J＝7.5Hz,1H),6.73(t,J＝7.4Hz,1H),3.72(d,J＝13.9Hz,2H). 13 CNMR(101MHz,CDCl 3 )δ156.29(d,J＝4.6Hz),136.47(d,J＝10.1Hz),134.27(d,J＝5.1Hz),131.80(d,J＝6.6Hz),130.68(s),129.19(d,J＝3.0Hz),128.55(d,J＝14.3Hz),120.58(s),119.13(d,J＝2.7Hz),118.70(d,J＝9.0Hz),38.49(d,J＝75.9Hz). 31 P NMR(162MHz,CDCl 3 )δ26.37.
HRMS(m/z)(EI):calcd for C 15 H 13 O 2 PS 2 [M] + 320.0095; found 320.0100 example 2
A method for preparing 2- (di (3-methoxyphenyl) phosphonomethyl) -phenol, comprising the steps of:
(1) After Schlenk flask was evacuated-nitrogen-filled 3 times, 6mL of 0.5 mol/L3-methoxyphenylmagnesium bromide (available from Ann Ji Co., ltd., cat. No. W4201671000) was added, 1.5mmol of diethyl phosphonate was added dropwise to the flask under the protection of nitrogen and magnetic stirring, stirring was continued for 1 hour after the completion of the addition, and then the reaction was quenched with 1N of dilute hydrochloric acid until no bubbles were generated, 20mL of methyl t-butyl ether was added to the reaction mixture, extracted 3 times, and the organic layer was combined, and dried over anhydrous Na 2 SO 4 Drying for 30min, filtering and distilling under reduced pressure to obtain a crude product, drying the crude product with anhydrous sodium sulfate for 30min, and purifying by column chromatography (the eluent is ethyl acetate and petroleum ether, the volume ratio is 1:3) to obtain 1.32mmol of di-3-methoxyphenylphosphine oxide, wherein the yield of the step is 88%.
The specific reaction formula is:
(2) After Schlenk bottle is vacuumized and filled with nitrogen for 3 times, under the protection of nitrogen, 0.6mmol of salicyl alcohol, 0.66mmol of di-3-methoxy phenyl phosphine oxide, 0.66mmol of potassium tert-butoxide, 0.6mmol of elemental iodine and 7.2mL of anhydrous 1, 4-dioxane are sequentially added, under the magnetic stirring condition, the oil bath is at 80 ℃ for reaction for 10 hours, TLC is used for tracking reaction in the reaction process, after the reaction is monitored to be complete, the reaction is taken out and cooled to room temperature, 20mL of water and 20mL of methylene dichloride are added for extracting the mixture after the reaction for 3 times, the organic layers are combined and then decompressed and distilled, the crude product is dried for 30 minutes by using anhydrous sodium sulfate and then purified by column chromatography (the eluent is ethyl acetate and petroleum ether, the volume ratio is 1:3), and 2- (di (3-methoxy phenyl) phosphonomethyl) -phenol can be obtained, and the yield of the step is 77%; the total yield of the two-stage reaction was calculated to be 68% based on diethyl phosphonate.
The specific reaction formula is:
the 2- (bis (3-methoxyphenyl) phosphonomethyl) -phenol prepared in this example was subjected to nmr hydrogen spectroscopy and high resolution mass spectrometry, and the results were as follows:
1 H NMR(400MHz,DMSO,ppm)δ9.75(s,1H),7.47–7.39(m,3H),7.39–7.34(m,2H),7.33(d,J＝2.4Hz,1H),7.15(d,J＝7.6Hz,1H),7.10(dd,J＝8.3,1.8Hz,2H),7.00(t,J＝7.7Hz,1H),6.77(d,J＝7.9Hz,1H),6.66(t,J＝7.4Hz,1H),3.88(d,J＝13.9Hz,2H),3.76(s,6H). 13 C NMR(101MHz,DMSO)δ159.53(d,J＝14.4Hz),155.99(d,J＝5.3Hz),134.94(d,J＝96.4Hz),131.93(d,J＝5.2Hz),130.48(d,J＝13.5Hz),128.33(s),123.16(d,J＝9.1Hz),119.57(d,J＝1.8Hz),119.32(d,J＝8.0Hz),117.91(d,J＝2.3Hz),116.53(d,J＝1.7Hz),116.08(d,J＝10.6Hz),55.75(s),30.75(d,J＝67.9Hz). 31 P NMR(162MHz,DMSO)δ31.57.
HRMS(m/z)(ESI):calcd for C 21 H 22 O 4 P[M+H + ]369.1256; found 369.1255 example 3
A method for preparing 2- (di-p-trifluoromethyl phenyl phosphonic acid methyl) -phenol, which comprises the following steps:
(1) After Schlenk flask was evacuated-nitrogen-filled 3 times, 6mL of p-trifluoromethylphenylmagnesium bromide (available from Ann Ji Co., ltd., product No. W420404) was added, 1.5mmol of diethyl phosphonate was added dropwise to the flask under the condition of nitrogen protection and magnetic stirring, stirring was continued for 1.2 hours after the completion of the addition, and then the reaction was quenched with 1N diluted hydrochloric acid until no bubbles were generated, 20mL of methyl t-butyl ether was added to the reaction mixture to extract 3 times, and the organic layer was combined, and dried over anhydrous Na 2 SO 4 Drying for 30min, filtering and distilling under reduced pressure to obtain a crude product, drying the crude product by using anhydrous sodium sulfate for 30min, and purifying by column chromatography (the eluent is ethyl acetate and petroleum ether, the volume ratio is 1:1), thus obtaining 0.93mmol of di-p-trifluoromethyl phenyl phosphine oxide, and the yield of the step is 62%.
The specific reaction formula is:
(2) After Schlenk bottle is vacuumized and filled with nitrogen for 3 times, under the protection of nitrogen, 0.5mmol of salicyl alcohol, 0.6mmol of di-p-trifluoromethylphenyl phosphine oxide, 0.6mmol of potassium tert-butoxide, 0.45mmol of elemental iodine and 6mL of anhydrous 1, 4-dioxane are sequentially added, under the magnetic stirring condition, the reaction is carried out for 10 hours at the temperature of 100 ℃ in an oil bath, TLC is used for tracking the reaction in the reaction process, after the reaction is monitored to be complete, the reaction is taken out and cooled to room temperature, 20mL of water and 20mL of methylene dichloride are added for extracting the mixture after the reaction for 3 times, the organic layers are combined and then decompressed and distilled, the crude product is dried for 30 minutes by using anhydrous sodium sulfate and then subjected to column chromatography purification (the eluent is ethyl acetate and petroleum ether with the volume ratio of 1:5), and 2- (di-p-trifluoromethylphenyl methyl) -phenol can be obtained, and the yield of the step is 73%; the overall yield of the two-step reaction was calculated to be 45% based on diethyl phosphonate.
The specific reaction formula is:
the 2- (di-p-trifluoromethylphenyl-methyl) -phenol prepared in this example was subjected to nuclear magnetic resonance hydrogen spectrometry and high resolution mass spectrometry, and the results are shown below:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.31(s,1H),7.88(dd,J＝11.2,8.1Hz,4H),7.73(d,J＝6.3Hz,4H),7.09(t,J＝7.0Hz,1H),6.94(d,J＝8.1Hz,1H),6.82(d,J＝7.6Hz,1H),6.71(t,J＝7.4Hz,1H),3.81(d,J＝12.9Hz,2H). 13 CNMR(101MHz,CDCl 3 )δ156.63(d,J＝4.4Hz),135.61(s),134.97(dd,J＝33.0,2.8Hz),134.64(s),132.04(d,J＝9.9Hz),129.89(d,J＝2.8Hz),126.85–125.91(m),123.85(d,J＝273.2Hz),121.29(s),119.42(s),118.17(d,J＝8.8Hz),34.35(d,J＝68.0Hz). 31 P NMR(162MHz,CDCl 3 ,ppm)δ34.86. 19 F NMR(376MHz,CDCl 3 ,ppm)δ-63.60.
HRMS(m/z)(ESI):calcd for C 21 H 15 F 6 O 2 PNa[M+Na] + :467.0612；found:467.0607.
example 4
A method for preparing 2- (diphenyl phosphonomethyl) -phenol, comprising the following steps:
(1) After Schlenk flask was evacuated-filled with nitrogen 3 times, 6mL of phenylmagnesium bromide (available from Ann Ji Co., ltd., product No. W4200241000) was added, 1.5mmol of diethyl phosphonate was added dropwise to the flask under the protection of nitrogen gas with magnetic stirring, stirring was continued for 1 hour after the completion of the addition, and then the reaction was quenched with 1N diluted hydrochloric acid until no bubble was generated, and 20mL of methyl group was added to the reaction mixtureTertiary butyl ether extraction 3 times, combining organic layers, using anhydrous Na 2 SO 4 Drying for 30min, filtering and distilling under reduced pressure to obtain a crude product, drying the crude product by using anhydrous sodium sulfate for 30min, and purifying by column chromatography (the eluent is ethyl acetate and petroleum ether, the volume ratio is 1:1), thus obtaining 1.17mmol of diphenyl phosphine oxide, and the yield of the step is 78%.
The specific reaction formula is:
(2) After Schlenk bottle is vacuumized and filled with nitrogen for 3 times, under the protection of nitrogen, 0.5mmol of salicyl alcohol, 0.5mmol of diphenyl phosphine oxide, 0.5mmol of potassium tert-butoxide, 0.5mmol of elemental iodine and 6mL of anhydrous 1, 4-dioxane are sequentially added, under the condition of magnetic stirring, the reaction is carried out for 4 hours at the temperature of 100 ℃ in an oil bath, TLC is used for tracking the reaction in the reaction process, after the reaction is monitored to be complete, the reaction is taken out and cooled to room temperature, 20mL of water and 20mL of methylene dichloride are added to extract the mixture after the reaction for 3 times, the organic layers are combined and distilled under reduced pressure, the crude product is dried for 30 minutes by using anhydrous sodium sulfate and then subjected to column chromatography purification (the eluent is ethyl acetate and petroleum ether with the volume ratio of 1:2), and 2- (diphenylphosphinomethyl) -phenol can be obtained, and the yield of the step is 90%; the overall yield of the two-step reaction was calculated to be 70% based on diethyl phosphonate.
The specific reaction formula is:
the 2- (diphenylphosphinomethyl) -phenol prepared in this example was subjected to nuclear magnetic resonance hydrogen spectroscopy and high resolution mass spectrometry as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.79(s,1H),7.74(q,J＝1.6Hz,1H),7.73–7.68(m,2H),7.70(t,J＝1.8Hz,1H),7.58–7.50(m,2H),7.50–7.42(m,4H),7.14–7.06(m,1H),6.99(dd,J＝8.1,1.1Hz,1H),6.77(d,J＝7.6Hz,1H),6.69(t,J＝7.4Hz,1H),3.71(d,J＝12.9Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ156.55(d,J＝4.0Hz),132.47(d,J＝2.8Hz),131.65(d,J＝6.4Hz),130.98(d,J＝9.5Hz),129.97(s),128.97(d,J＝2.7Hz),128.82(d,J＝12.0Hz),120.61(d,J＝1.8Hz),119.56(d,J＝2.5Hz),119.34(d,J＝8.5Hz),35.35(d,J＝67.5Hz). 31 PNMR(162MHz,CDCl 3 ,ppm)δ38.22.
HRMS(m/z)(EI):calcd for C 19 H 17 O 2 P[M] + 308.0966; found 308.0960 example 5
A method for preparing 2- (diphenyl phosphonomethyl) -4-phenylphenol, comprising the following steps:
(1) Diphenylphosphines were prepared in the same manner as in example 4.
(2) After Schlenk bottle is vacuumized and filled with nitrogen for 3 times, under the protection of nitrogen, 0.5mmol of p-phenyl salicyl alcohol, 0.6mmol of diphenyl phosphino, 0.6mmol of potassium tert-butoxide, 0.5mmol of elemental iodine and 6mL of anhydrous 1, 4-dioxane are sequentially added, under the condition of magnetic stirring, the reaction is carried out for 4 hours at 90 ℃ in an oil bath, TLC is used for tracking the reaction in the reaction process, after the reaction is monitored to be complete, the reaction is taken out and cooled to room temperature, 20mL of water and 20mL of methylene dichloride are added for extracting the mixture after the reaction for 3 times, the organic layers are combined and distilled under reduced pressure, and the crude product is dried for 30min by using anhydrous sodium sulfate and then purified by column chromatography (the eluent is ethyl acetate and petroleum ether with the volume ratio of 1:5), so that 2- (diphenylphosphonomethyl) -4-phenylphenol can be obtained, and the yield of the step is 63%; the overall yield of the two-stage reaction was calculated to be 49% based on diethyl phosphonate.
The specific reaction formula is:
the 2- (diphenylphosphinomethyl) -4-phenylphenol prepared in this example was subjected to nuclear magnetic resonance hydrogen spectroscopy and high resolution mass spectrometry as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.90(s,1H),7.80–7.71(m,4H),7.59–7.52(m,2H),7.48(m,4H),7.38–7.28(m,5H),7.28–7.22(m,1H),7.06(d,J＝8.3Hz,1H),6.96(t,J＝1.9Hz,1H),3.76(d,J＝12.9Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ156.74(d,J＝4.0Hz),141.26(s),134.21(d,J＝1.9Hz),133.08(d,J＝2.7Hz),131.57(d,J＝9.6Hz),131.45(s),130.89(d,J＝6.4Hz),130.45(s),129.39(d,J＝12.0Hz),129.17(s),128.30(d,J＝2.7Hz),127.17(s),120.37(d,J＝2.4Hz),120.18(d,J＝8.5Hz),36.00(d,J＝67.1Hz). 31 P NMR(162MHz,CDCl 3 ,ppm)δ38.35.
HRMS(m/z)(ESI):calcd for C 25 H 22 O 2 P[M+H + ]385.1358; found 385.1356 example 6
A method for preparing 2- (diphenyl phosphonomethyl) -4-methylphenol, which comprises the following steps:
(1) Diphenylphosphines were prepared in the same manner as in example 4.
(2) After Schlenk bottle is vacuumized and filled with nitrogen for 3 times, under the protection of nitrogen, 0.7mmol of p-methyl salicyl alcohol, 0.7mmol of diphenyl phosphino, 0.7mmol of potassium tert-butoxide, 0.7mmol of elemental iodine and 8.4mL of anhydrous 1, 4-dioxane are sequentially added, under the magnetic stirring condition, the reaction is carried out for 4 hours at 90 ℃ in an oil bath, TLC is used for tracking the reaction in the reaction process, after the reaction is monitored to be complete, the reaction is taken out and cooled to room temperature, 20mL of water and 20mL of methylene dichloride are added for extracting the mixture after the reaction for 3 times, the organic layers are combined and distilled under reduced pressure, and the crude product is dried for 30min by using anhydrous sodium sulfate and then purified by column chromatography (the eluent is ethyl acetate and petroleum ether with the volume ratio of 1:2), so that 2- (diphenylphosphonomethyl) -4-methylphenol can be obtained, and the yield of the step is 70%; the total yield of the two-step reaction was calculated to be 55% based on diethyl phosphonate.
The specific reaction formula is:
the 2- (diphenylphosphinomethyl) -4-methylphenol prepared in this example was subjected to nuclear magnetic resonance hydrogen spectroscopy and high resolution mass spectrometry as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ7.74(s,1H),7.73–7.70(m,2H),7.69(d,J＝1.5Hz,1H),7.55(d,J＝1.4Hz,1H),7.53(dd,J＝7.4,1.5Hz,1H),7.46(m,4H),6.89(s,2H),6.57(s,1H),3.66(d,J＝12.9Hz,2H),2.09(d,J＝8.6Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ154.67(d,J＝4.1Hz),132.92(d,J＝2.7Hz),132.62(d,J＝6.4Hz),131.50(d,J＝9.5Hz),130.65(s),130.22(d,J＝1.9Hz),129.98(d,J＝2.8Hz),129.29(d,J＝12.0Hz),119.72(d,J＝2.6Hz),119.50(d,J＝8.6Hz),35.64(d,J＝67.5Hz),20.86(s). 31 P NMR(162MHz,CDCl 3 ,ppm)δ38.12.
HRMS(m/z)(EI):calcd for C 20 H 19 O 2 P[M] + 322.1123; found 322.1120 example 7
A method for preparing 2- (diphenylphosphinomethyl) -4-benzyloxy phenol, which comprises the following steps:
(1) Diphenylphosphines were prepared in the same manner as in example 4.
(2) After Schlenk bottle is vacuumized and filled with nitrogen for 3 times, under the protection of nitrogen, 0.5mmol of p-benzyloxy salicyl alcohol, 0.5mmol of diphenyl phosphino, 0.55mmol of potassium tert-butoxide, 0.55mmol of elemental iodine and 6mL of anhydrous 1, 4-dioxane are sequentially added, under the magnetic stirring condition, the reaction is carried out for 8 hours at the temperature of 80 ℃ in an oil bath, TLC is used for tracking the reaction in the reaction process, after the reaction is monitored to be complete, the reaction is taken out and cooled to room temperature, 20mL of water and 20mL of methylene dichloride are added for extracting the mixture after the reaction for 3 times, the organic layers are combined and distilled under reduced pressure, and the crude product is dried for 30min by using anhydrous sodium sulfate and then purified by using column chromatography (the eluent is ethyl acetate and petroleum ether with the volume ratio of 1:4), so that 2- (diphenylphosphonomethyl) -4-benzyloxy phenol can be obtained, and the yield of the step is 83%; the total yield of the two-step reaction was calculated to be 65% based on diethyl phosphonate.
The specific reaction formula is:
the 2- (diphenylphosphinomethyl) -4-benzyloxyphenol prepared in this example was subjected to nuclear magnetic resonance hydrogen spectroscopy and high resolution mass spectrometry as follows:
1 H NMR(400MHz,CDCl 3 ,ppm)δ9.35(br,1H),7.74–7.65(m,4H),7.53(td,J＝7.4,1.4Hz,2H),7.44(ddd,J＝9.4,5.8,2.0Hz,4H),7.37–7.26(m,5H),6.91(d,J＝8.8Hz,1H),6.74–6.68(m,1H),6.41(s,1H),4.81(s,2H),3.66(d,J＝12.9Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ153.10(s),151.03(d,J＝4.2Hz),137.68(s),132.97(d,J＝2.7Hz),131.47(d,J＝9.6Hz),130.48(s),129.33(d,J＝12.0Hz),129.05(s),128.41(s),127.95(s),120.84(d,J＝8.6Hz),120.55(d,J＝2.6Hz),118.76(d,J＝6.3Hz),115.61(d,J＝2.8Hz),71.21(s),35.67(d,J＝67.2Hz). 31 P NMR(162MHz,CDCl 3 ,ppm)δ38.12.
HRMS(m/z)(EI):calcd for C 26 H 23 O 3 P[M] + 414.1385; found 414.1390 comparative example 1
The preparation method of 2- (bis (2-thienyl) phosphonomethyl) -phenol provided in this comparative example is substantially the same as the reaction conditions of example 1, except that iodobenzene diacetic acid is used instead of elemental iodine in example 1.
As a result, it was found that the yield of this step was 11%; the overall yield of the two-step reaction was calculated to be 10% based on diethyl phosphonate.
Comparative example 2
The preparation of 2- (bis (2-thienyl) phosphonomethyl) -phenol provided in this comparative example was essentially the same as the reaction conditions of example 1, the only difference being that one of the existing potassium carbonates was used in place of the potassium t-butoxide in example 1.
As a result, it was found that no target product was produced, i.e., the yield was 0%.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (10)
1. The application of a catalyst composition in preparing 2-phosphonomethyl phenol compound by catalyzing the reaction of salicylalcohol compound and diaryl phosphine oxide is characterized in that the catalyst composition comprises iodine simple substance and alkaline reagent, and the alkaline reagent is at least one of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide or sodium hydroxide.
2. The use according to claim 1, wherein the molar ratio of the elemental iodine to the salicyl compound is between 0.9 and 1.1:1; and/or the number of the groups of groups,
the molar ratio of the alkaline reagent to the diaryl phosphine oxide is 1-1.1:1; and/or the number of the groups of groups,
the molar ratio of the salicylalcohol compound to the diaryl phosphine oxide is 1:1-1.2.
3. A process for the preparation of a 2-phosphonomethyl phenol compound comprising the steps of: in an anhydrous and anaerobic environment, in the presence of a catalyst, salicyclic alcohol compounds react with diaryl phosphine oxides to prepare 2-phosphonomethyl phenol compounds;
the catalyst comprises iodine simple substance and an alkaline reagent, wherein the alkaline reagent is at least one of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide or sodium hydroxide.
4. The method according to claim 3, wherein the molar ratio of the elemental iodine to the salicyl alcohol compound is 0.9 to 1.1:1; and/or the number of the groups of groups,
the molar ratio of the alkaline reagent to the diaryl phosphine oxide is 1-1.1:1; and/or the number of the groups of groups,
the molar ratio of the salicylalcohol compound to the diaryl phosphine oxide is 1:1-1.2.
5. The method of claim 3, wherein the diaryl phosphine oxide has the structural formula: ar (Ar) 2 PHO wherein Ar is substituted orUnsubstituted phenyl or heteroaryl;
preferably, the substituents on the phenyl or heteroaryl groups are alkoxy, halogen substituted or unsubstituted alkyl;
more preferably, ar is any one of thienyl, 3-methoxyphenyl, p-trifluoromethylphenyl and phenyl.
6. The method of any one of claims 3 to 5, wherein the salicyl alcohol compound has a structure represented by formula I:
wherein R is 1 Is any one of hydrogen atom, alkyl, alkoxy and aryl;
preferably, the carbon number of the alkyl is 1-6, the carbon number of the alkoxy is 1-10, and the aryl is a substituted or unsubstituted phenyl;
more preferably, R 1 Is any one of hydrogen atom, methyl, benzyloxy and phenyl.
7. The method of claim 6, wherein the reaction is carried out in an anhydrous solvent and has at least one of the following characteristics:
A. the anhydrous solvent is anhydrous 1, 4-dioxane and/or anhydrous dichloromethane;
B. the ratio of the mass of the salicyl alcohol compound to the volume of the anhydrous solvent is 0.5-0.7: 6 to 9, the proportion relation is mol/L;
C. the reaction temperature is 80-100 ℃ and the reaction time is 4-10 hours;
D. after the reaction is completed, extracting the reaction mixture by using a mixed solvent of water and dichloromethane, merging the organic layers, drying, concentrating, purifying the obtained crude product by column chromatography to obtain a target product, wherein the eluent is ethyl acetate and petroleum ether with the volume ratio of 1:2-5.
8. The method of claim 3, 4, 5 or 7, wherein the diaryl phosphine oxide is prepared by reacting diethyl phosphonate with an aryl grignard reagent.
9. The method of claim 8, wherein the molar ratio of the aryl grignard reagent to the diethyl phosphonate is 2-2.2:1; and/or the number of the groups of groups,
halogen in the aryl grignard reagent is a bromine atom; and/or the number of the groups of groups,
the reaction time of the aryl Grignard reagent and the diethyl phosphonate is 0.8-1.2 h.
10. The preparation method according to claim 8, wherein after the aryl grignard reagent and the diethyl phosphonate are reacted completely, adding an acid solution to quench the reaction, extracting the reaction product with an ether solvent, combining organic layers, drying and concentrating the reaction product, purifying the obtained crude product by column chromatography to obtain the diaryl phosphine oxide, wherein the eluent is ethyl acetate and petroleum ether with the volume ratio of 1:1-3.
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