Synthetic method of aryl phosphate
The one-pot synthesis of aryl phosphates solves the problems of harsh reaction conditions and low yield in existing arylation synthesis methods, and realizes efficient and simplified preparation of aryl phosphates, which is suitable for industrial production.
Patent Information
- Application Number
- CN202511024721.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-24
- Publication Date
- 2025-11-18
AI Technical Summary
Existing arylation synthesis methods suffer from problems such as harsh reaction conditions, safety hazards, high equipment requirements, cumbersome processes, low yields, and high costs, making it difficult to meet the needs of industrial production.
Aromatic phosphates were synthesized using a one-pot method. The amino phosphates were generated by reacting chlorophosphates with different types of amines, and then arylated with benzyne precursors under fluorination conditions.
The experimental procedure was simplified, the generation of by-product impurities was avoided, the yield was significantly improved, the operation was simple, no special equipment or catalysts were required, and the product quality and yield were stable.
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Abstract
Description
TECHNICAL FIELD
[0001] The application relates to the technical field of organic synthesis, and particularly relates to a synthesis method of aryl phosphate. BACKGROUND
[0002] Phosphorus is an essential element for life, such as genetic material ribonucleic acid (RNA), deoxyribonucleic acid (DNA) and high-energy phosphate compounds ATP all involve phosphorus elements; meanwhile, phosphorus-containing organic compounds are also applied in flame retardants, ligands, medicines, agricultural chemicals and other fields.
[0003] Aryl alkyne, as an important organic reactive intermediate, has been universally concerned, and the reaction participated by aryl alkyne is one of important methods for constructing carbon-carbon bond and carbon heteroatom bond, and is widely applied in the synthesis of natural products, alkaloids and drug intermediates. Since the reaction of aryl alkyne can avoid the use of transition metal catalysts, the reaction conditions are mild and the application range is wide, the reaction of aryl alkyne participating in organic phosphorus and organic sulfur compounds can solve some problems existing in traditional arylization methods, and effectively promotes the development of organic phosphorus and organic sulfur chemistry.
[0004] Traditional phosphorus arylization methods are usually cross-coupling reactions (Hirao reaction) of nucleophilic phosphorus-containing reagents and halogenated aromatic hydrocarbons and the like, but the reaction conditions are relatively harsh and have certain limitations. Later, organic chemists at home and abroad carried out a series of researches on the reaction of aryl alkyne and organic phosphorus compounds. Among them, aryl phosphine ligands can form homogeneous catalysts with various transition metals due to their unique spatial structure, and play an increasingly important role in catalytic reactions.
[0005] As an important class of organic phosphorus compounds, aryl phosphonate can be coordinated with transition metals or combined with biological receptors as ligands, so as to regulate physiological processes or material functions. The bond formation reaction of C-P bond is one of the most important methods for synthesizing organic phosphorus compounds and is widely applied in the fields of material chemistry, medicinal chemistry and synthetic chemistry, for example, phosphine ligands (R)-BINAP, Xanphos and Binao are often applied in organic synthesis reactions; phosphino aminomycin is a good antimalarial drug, and phosphorus silonol has a good effect on treating cardiovascular diseases; ADPPO and DAPPO in material chemistry can be used as flame retardants, and BCPO is a good photoelectric material.
[0006] Compared with traditional arylization methods, the reaction participated by aryl alkyne has the characteristics of greenness, mildness and high efficiency. In recent years, the development has realized the synthesis of aryl phosphine and aryl sulfur compounds with diversified structures, and especially the aryl alkyne insertion reaction of phosphorus-containing and sulfur-containing chemical bonds has been studied in detail.
[0007] At present, there are the following several kinds of phosphorus arylization reactions participated by aryl alkyne; In 2010, the Jugé group reported the direct arylation of chiral and achiral P(III) compounds with arynes at room temperature. In this reaction, the phosphorus atom with a lone pair attacks the aryne, and the generated aryl anion is quenched by the proton in the solvent to give the chiral or achiral aryl phosphonium salt. In addition, the reaction of triphenylarsine with phenylhydrazine also gives the phenylarsenic salt in high yield. The reaction is shown in Scheme 1. Figure 1
[0008] In 2005, the Yoshida and Kunai groups developed the aryne insertion into the C-P bond of phosphoryl acetonitrile. This reaction constructs the C-C and C-P bond in one step to give the ortho-substituted aryl phosphine in moderate yield. In this reaction, the active methylene loses a proton to generate the carbon anion, which then attacks the aryne to generate the aryl anion intermediate. The aryl anion further intramolecularly attacks the phosphorus atom to generate the unstable benzo-tetra-membered ring intermediate. Finally, the ring-opening of the tetra-membered ring leads to the cleavage of the C-P bond, and the protonation gives the target product. The reaction is shown in Scheme 2. Figure 1
[0009] In 2013, the Zhang group realized the aryne insertion into the P-N bond of phosphoramidate. The cesium carbonate can accelerate the deprotonation process of phosphoramidate, thus improving the nucleophilicity of phosphoramidate. Similar to the mechanism of the aryne insertion into the C-P bond, the reaction of aryne with phosphoramidate generates the unstable benzo-tetra-membered ring intermediate, which then undergoes ring-opening to lead to the cleavage of the P-N bond. Finally, the protonation gives the ortho-arylamine-substituted aryl phosphine oxide. It is worth mentioning that the reduction of the product gives the important bidentate nitrogen-phosphorus ligand. In 2016, the Guo and He groups reported the aryne insertion into the P-O bond of organophosphonic acid. Similar to the mechanism of the aryne insertion into the P-N bond, the reaction undergoes the ring-opening of the benzo-tetra-membered ring to cleave the P-O bond, giving the ortho-hydroxyl-substituted aryl phosphine oxide. When the aryne is in excess, the phenolic hydroxyl group in the product further undergoes arylation. The reaction is shown in Scheme 3. Figure 1
[0010] In 2019, the Gogoi group developed the aryne insertion into the P=O bond of tertiary phosphine oxide. In this reaction, the aryne first inserts into the stable P=O bond to form the benzo-tetra-membered ring intermediate, which then undergoes ring-opening to cleave the P-O bond to generate the 1,4-zwitterionic intermediate. Finally, the oxygen anion undergoes arylation with another molecule of aryne to give the ortho-aryloxy-substituted aryl phosphonium salt. The reaction is shown in Scheme 4. Figure 1
[0011] However, the above-mentioned existing synthesis methods have the problems of harsh reaction conditions, safety hazards, high requirements for equipment, complicated process, low yield, and high cost, which are not conducive to industrial production. Therefore, we propose a new synthesis method of aryl phosphates to solve the above problems. SUMMARY
[0012] The technical problem solved by the present application is to overcome the defects of the prior art. The present application provides a synthesis method of aryl phosphate, which has the characteristics of green, mild and high efficiency.
[0013] To solve the above technical problems, the technical scheme adopted by the present application is as follows: a synthesis method of aryl phosphate, comprising the following steps: S1, reacting chlorophosphonate (IV) with different kinds of amines to obtain aminophosphonate (II); S2, arylating aminophosphonate with different kinds of phenylacetylene precursors (I) under fluoride conditions to obtain aryl phosphate (III), and the corresponding structural formula is as follows, .
[0014] Further, the phosphite in step S1 includes one or more of dimethyl phosphite, diethyl phosphite, diisopropyl phosphite.
[0015] Further, the different kinds of amines in step S1 include one or more of tetrahydropyrrole, piperidine, n-butylamine, benzylamine, aniline, diethylamine, morpholine.
[0016] Further, the chlorophosphonate in step S1 is prepared according to the following steps, A dry and clean flask equipped with a magnetic rotor is added with phosphite and dichloromethane, and stirred under ice bath conditions; N-chlorosuccinimide is slowly added, and the molar ratio of the phosphite to N-chlorosuccinimide is 1:1.1. After all the N-chlorosuccinimide is added, the ice bath is removed and the mixture is stirred at room temperature for 6-8 hours; After thin layer tracking reaction is completed, petroleum ether is used for washing, filtration and concentration to obtain chlorophosphonate.
[0017] Further, the aminophosphonate in step S1 is prepared according to the following steps, A dry and clean flask equipped with a magnetic rotor is added with chlorophosphonate, dichloromethane is added, and the mixture is stirred under ice bath conditions; Triethylamine and different kinds of amines are added at a molar ratio of 1.5:1. After all the amines are added, the ice bath is removed and the mixture is reacted at room temperature for 0.5-1 hour; After thin layer tracking reaction is completed, water is added to quench the reaction, and dichloromethane is used for extraction three times, and the mixture is concentrated and dried, and column chromatography is used to collect aminophosphonate.
[0018] The preparation steps of the phenylacetylene precursor in step S2 are as follows, Substituted phenol and hexamethyl disilazane were heated in a 1:2 molar ratio in THF under reflux conditions overnight in a flask fitted with a reflux condenser; After completion of the thin layer tracking reaction, the resulting solution was directly concentrated on a rotary evaporator and further dried under vacuum conditions; The crude product was dissolved in anhydrous THF and cooled to -78°C under inert atmosphere dropwise added n-butyllithium, 1.5 h after the addition of triflic anhydride, the molar ratio of n-butyllithium to triflic anhydride was 1.5:1, 1 h after the addition of saturated sodium bicarbonate solution to quench, Extracted three times with petroleum ether, washed the organic layer with brine, concentrated and dried, column chromatography was collected to obtain the benzyne precursor.
[0019] Further, the fluoride in the step S2 includes one or more of potassium fluoride, cesium fluoride, tetrabutyl difluorotriphenyl silicate.
[0020] Further, the aryl phosphate preparation step in the step S2 is as follows, A dry and clean pressure-resistant tube was added with the benzyne precursor, the phosphoramidate, and the cesium fluoride in a molar ratio of 1:0.5:1.5, and then dissolved in a reaction solvent under an inert gas atmosphere, and stirred at 30-40°C for 8-24 h; After completion of the thin layer tracking reaction, saturated sodium bicarbonate was added to quench, and then extracted three times with ethyl acetate, concentrated and dried, and column chromatography was collected to obtain the aryl phosphate.
[0021] Further, the inert gas is nitrogen, and the gas is replaced at least three times.
[0022] Further, the reaction solvent is anhydrous acetonitrile or anhydrous tetrahydrofuran.
[0023] Compared with the prior art, the beneficial effects of the present application include: the present application can simplify the experimental operation process by one-pot method, avoid the generation of byproduct impurities, and greatly improve the yield through condition screening, which has a significant effect. Moreover, the preparation method provided by the present application is convenient and reliable, simple to operate, does not require special equipment, does not require a catalyst, and the quality and yield of the product in mass production are relatively stable. BRIEF DESCRIPTION OF DRAWINGS
[0024] The disclosure of the present application is explained with reference to the accompanying drawings. It should be appreciated that the drawings are only for illustrative purposes, and are not intended to limit the scope of protection of the present application. In the drawings, the same reference numerals are used to refer to the same parts. Among them: Figure 1 The prior synthesis process mentioned in the background art of the present application is schematically shown; Figure 2The synthesis of aryl phosphate ester mediated by the benzyne in the present application is shown in the following reaction formula: Figure 3 The synthesis of product IIIa and product IIIb in the embodiment of the present application is shown in the following reaction formula: 1 HNMR chart. DETAILED DESCRIPTION
[0025] It is easy to understand that, according to the technical solution of the present application, a person skilled in the art can propose various structural modes and implementation modes which can be replaced with each other without changing the essential spirit of the present application. Therefore, the following detailed description and the accompanying drawings are only exemplary description of the technical solution of the present application, and should not be regarded as the whole or regarded as the limitation or restriction of the technical solution of the present application.
[0026] According to an embodiment of the present application, the synthesis of aryl phosphate ester mediated by the benzyne is shown in the following reaction formula: Figures 1-3 The raw materials and reagents used in the reaction are commercially available.
[0027] The synthesis of aryl phosphate ester is shown in the following reaction formula: Figure 2 The synthesis of aryl phosphate ester is shown in the following reaction formula:
[0028] The technical solution and technical effect of the present application are further described below in combination with the embodiments.
[0029] In the present embodiment: For the preparation of phosphoramidate (compound II), the reaction formula is as follows: The reaction formula is as follows: A dry and clean flask equipped with a magnetic rotor is added with phosphite (5 g, 1.0 eq) and dichloromethane 40 mL, which is stirred under ice bath condition, and N-chlorosuccinimide (1.1 eq) is slowly added. After all the N-chlorosuccinimide is added, the ice bath is removed and the stirring is continued at room temperature for 6-8 h. The reaction is tracked by thin layer chromatography, and the chlorophosphonate (i.e. the compound 2 in the above formula) is obtained by petroleum ether washing, filtration and concentration, with a yield of 87%.
[0030] A dry and clean flask equipped with a magnetic rotor is added with chlorophosphonate (3 g, 1.0 eq) and dichloromethane 20 mL, which is stirred under ice bath condition, and triethylamine (1.5 eq) is added. Different kinds of amine (1.0 eq) are slowly added, and after all the amine is added, the ice bath is removed and the reaction is continued at room temperature for 0.5 h. The reaction is tracked by thin layer chromatography, and the reaction is quenched by adding water. The product II is collected by column chromatography after extraction with dichloromethane three times, concentration and drying, with a yield of 95%.
[0031] For the preparation of benzyne precursor (compound I), the reaction formula is as follows: Substituted phenol (1.0 eq) and hexamethyldisilazane (HMDS) (2.0 eq) in THF (40 mL) were heated under reflux conditions overnight in a 100 mL flask equipped with a reflux condenser. The reaction was followed by thin layer chromatography and the resulting solution was directly concentrated on a rotary evaporator and further dried under vacuum for 1 h. The crude product was dissolved in dry THF (40 mL) and cooled to -78 °C under inert atmosphere and n-butyllithium (2.5 M in hexanes, 1.5 eq) was added dropwise. After 1.5 h, triflic anhydride (Tf20) (1.0 eq) was added. After 1 h, the reaction was quenched by the addition of 15 mL of saturated sodium bicarbonate solution. The organic layer was extracted with 30 mL of petroleum ether three times. The organic layer was washed with brine (20 mL) and concentrated to dryness. The product I was collected by column chromatography in 73% yield over 3 steps.
[0032] For the preparation of aryl phosphonate (compound III), the reaction scheme is: To a dry and clean pressure tube equipped with a magnetic stirrer, kobayashi benzyne precursor (1.0 eq), phosphoramidite (0.5 eq), cesium fluoride (1.5 eq) were dissolved in 5 mL of dry acetonitrile, purged with nitrogen three times, stirred at 36 °C for 24 h, the reaction was followed by thin layer chromatography, quenched by the addition of 10 mL of saturated sodium bicarbonate, extracted with 10 mL of ethyl acetate three times, concentrated to dryness. The product was collected by column chromatography.
[0033] Product IIIa was obtained in 82% yield, which 1 H NMR chart is shown in Figure 3 Product IIIb was obtained in 78% yield, which 1 H NMR chart is shown in Figure 3 .
[0034] The characterization data of product IIIa are as follows: 1 H NMR (CDC13, 400 MHz): δ 7.26 (m, 1H), 6.65 (d, 1H), 6.53 (m, 1H), 4.19 (m, 4H), 3.47 (d, 4H), 2.02 (m, 4H), 1.32 (t, 6H).
[0035] The characterization data of product IIIb are as follows: 1 H NMR (CDC13, 400 MHz): δ 7.70 (ddd, 1H), 7.40 (m, 1H), 6.94 (m, 2H), 3.76 (d, 6H), 3.48 (m, 4H), 1.98 (m, 4H).
[0036] From the above examples, it can be seen that the present application can simplify the experimental operation process by one-pot method, avoid the generation of byproduct impurities, and greatly improve the yield through condition screening, which has a significant effect. Moreover, the method provided by the present application is convenient and reliable, simple to operate, does not require special equipment, and does not need a catalyst, and the quality and yield of the product in mass production are relatively stable.
[0037] The technical scope of the present application is not limited to the content in the above description, and those skilled in the art can make various modifications and changes to the above examples without departing from the technical idea of the present application, and these modifications and changes shall all belong to the protection scope of the present application.
Claims
1. A method for synthesizing an aryl phosphate ester, characterized in that, Includes the following steps: S1. Chlorophosphate (IV) is reacted with different types of amines to obtain aminophosphate (II); S2. The aminophosphate ester is reacted with different types of benzyne precursors (Ⅰ) under fluoride conditions to undergo arylation reaction to obtain aryl phosphate ester (Ⅲ), with the corresponding structural formulas as follows. 。 2. The method for synthesizing aryl phosphates according to claim 1, characterized in that: The phosphite in step S1 includes one or more of dimethyl phosphite, diethyl phosphite, and diisopropyl phosphite.
3. The method for synthesizing aryl phosphates according to claim 1, characterized in that: The different types of amines in step S1 include one or more of tetrahydropyrrole, piperidine, n-butylamine, benzylamine, aniline, diethylamine, and morpholine.
4. The method for synthesizing aryl phosphates according to claim 1, characterized in that: The specific preparation steps of the chlorophosphate in step S1 are as follows: Add phosphite and dichloromethane to a dry, clean flask equipped with a magnetic rotor, and stir under ice bath conditions; Slowly add N-chlorosuccinimide, wherein the molar ratio of the phosphite to N-chlorosuccinimide is 1:1.
1. After all the phosphite has been added, remove the ice bath and stir at room temperature for 6-8 hours. After the thin-layer chromatography reaction was completed, the product was washed with petroleum ether, filtered, and concentrated to obtain chlorophosphate.
5. The method for synthesizing aryl phosphates according to claim 4, characterized in that: The specific preparation steps of the aminophosphate ester in step S1 are as follows. Add chlorophosphate to a dry, clean flask containing a magnetic rotor, add dichloromethane, and stir under ice bath conditions; Triethylamine and different types of amines were added at a molar ratio of 1.5:
1. After all the amines were added, the ice bath was removed and the reaction was carried out at room temperature for 0.5-1 h. After the thin-layer chromatography reaction was completed, water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. After concentration and drying, aminophosphate was collected by column chromatography.
6. The method for synthesizing aryl phosphates according to claim 1, characterized in that: The preparation steps of the benzylene precursor in step S2 are as follows. In a flask equipped with a reflux condenser, phenol and hexamethyldisilamine were replaced in a 1:2 molar ratio and heated overnight under reflux in THF. After the thin-layer tracking reaction was completed, the resulting solution was concentrated directly on a rotary evaporator and further dried under vacuum conditions; The crude product was dissolved in anhydrous THF and cooled to -78°C under an inert atmosphere. Butyllithium was added dropwise, and after 1.5 h, trifluoromethanesulfonic anhydride was added. The molar ratio of butyllithium to trifluoromethanesulfonic anhydride was 1.5:
1. After 1 h, saturated sodium bicarbonate solution was added to quench the reaction. The benzylene precursor was obtained by three extractions with petroleum ether, washing the organic layer with brine, concentrating and drying, and collecting by column chromatography.
7. The method for synthesizing aryl phosphates according to claim 1, characterized in that: The fluoride in step S2 includes one or more of potassium fluoride, cesium fluoride, and tetrabutyl difluorotriphenyl silicate.
8. The method for synthesizing aryl phosphates according to claim 7, characterized in that: The preparation steps of the aryl phosphate ester in step S2 are as follows. Add benzylene precursor, aminophosphate, and cesium fluoride to a dry, clean, pressure-resistant tube equipped with a magnetic rotor at a molar ratio of 1:0.5:1.5, then dissolve them in a reaction solvent under an inert gas atmosphere and stir at 30-40°C for 8-24 h. After the thin-layer chromatography reaction was completed, saturated sodium bicarbonate was added to quench the reaction, followed by extraction with ethyl acetate three times. The mixture was then concentrated, dried, and collected by column chromatography to obtain aryl phosphate esters.
9. The method for synthesizing aryl phosphates according to claim 8, characterized in that: The inert gas is nitrogen, and the gas is evacuated at least 3 times.
10. The method for synthesizing aryl phosphates according to claim 8, characterized in that: The reaction solvent is anhydrous acetonitrile or anhydrous tetrahydrofuran.