A method for preparing aromatic phosphine oxides catalyzed by nickel

Abstract

This invention discloses a nickel-catalyzed method for preparing aromatic phosphine oxides. The method includes the following steps: adding P(O)-H compounds, fluoroaromatic compounds, a nickel catalyst, and a base reagent to an organic solvent and mixing; stirring the mixture under heating conditions; and purifying and collecting the aromatic phosphine oxides. This reaction uses a nickel catalyst and a base reagent to synthesize intermediate organophosphorus (phosphonate) esters from P(O)-H compounds. These compounds then react with fluoroaromatics under the promotion of a nickel catalyst and a base to form corresponding aryl phosphine oxides. The nickel catalysis for generating intermediates lowers the activation energy for C-F bond breaking, increases the reaction yield, and achieves the phosphorylation of inert C-F bonds. Relatively inert fluorobenzenes and 4-methoxyfluorobenzenes, which are difficult to activate, exhibit good reaction results. The reaction can be scaled up to the gram level and can be used for the synthesis of fluorinated organophosphine compounds and the post-modification of fluorinated drug molecules, showing promising application prospects.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, specifically to a nickel-catalyzed method for preparing aromatic phosphine oxides and its reaction mechanism. Background Technology

[0002] Aromatic phosphine oxides have wide applications in organic synthesis, medicine, and materials. Brigatinib, an FDA-approved oral ALK inhibitor for lung cancer treatment, contains an aryl carbon-phosphorus bond in its structure (Huang WS, Liu S, Zou D, et al. Journal of Medicinal Chemistry, 2016, 59(10): 4948-4964). Aromatic phosphine oxides play an important role in flame retardants; for example, triphenylphosphine oxide is a novel environmentally friendly flame retardant. Phosphorus-containing polymers obtained by polymerizing fluorinated aromatic phosphine oxides as monomers with phenols or thiophenols can be used in proton exchange membranes for fuel cells (Ma X, Shen L, Zhang C, et al. Journal of Membrane Science, 2008, 310(1-2): 303-311; Ma X, Zhang C, Xiao G, et al. Journal of Power Sources, 2009, 188(1): 57-63). Therefore, developing efficient methods for synthesizing such compounds is of great value.

[0003] Traditionally, aromatic phosphine oxides are synthesized via nucleophilic substitution reactions of phosphine halides with organometallic reagents. However, this reaction is characterized by high toxicity of the starting materials, sensitivity to water and oxygen, and relatively harsh reaction conditions. Patent CN112125928 A discloses a method for synthesizing fluorinated aromatic phosphine oxides through a Grignard reagent reaction with diphenylphosphine chloride followed by an oxidation process; this method requires multiple steps. Using more environmentally friendly and stable P(O)-H compounds in cross-coupling reactions with haloaromatic hydrocarbons is an important route for preparing these compounds. For example, palladium or nickel catalysis can be used to achieve cross-coupling of P(O)-H compounds with iodoaryl, bromoaryl, or chloroaryl compounds to form important aromatic phosphine oxides (Rummelt S, Ranocchiari M, van Bokhoven J A. Organic Letters, 2012, 14(8): 2188-2190. Xu K, Yang F, Zhang G, et al. Green Chemistry, 2013, 15(4): 1055-1060). Sawamura et al. reported a method for preparing aromatic phosphine oxides by promoting the nucleophilic substitution reaction of dialkyl phosphine oxides with fluoroaryl compounds using KHMDS, where electron-donating fluorobenzenes are incompatible in the system (You Z, Higashida K, Iwai T, et al. Angewandte Chemie, 2021, 133(11): 5842-5846.). Holland et al. disclosed a method for preparing triarylphosphine by reacting ortho-amino-substituted fluoroaromatics with diphenylphosphine potassium salt under reflux or microwave-assisted conditions, and then preparing triarylphosphine oxide by oxidation reaction (Seipel KR, Platt ZH, Nguyen M, et al. The Journal of Organic Chemistry, 2008, 73(11): 4291-4294.).

[0004] The publicly disclosed methods for synthesizing aromatic phosphine oxides from fluoroaromatics mainly suffer from a relatively narrow range of applicable reaction substrates. They require relatively reactive fluoroaromatics and dialkyl phosphine oxides as raw materials, and fluoroaromatics with electron-donating or neutral electron-substituted groups are incompatible with these systems. Furthermore, the reactions all involve traditional nucleophilic substitution processes. For example, patent CN113512064A discloses a method for preparing aromatic phosphine oxides, which first reacts a P(O)-H compound with a base to form a phosphate salt, which then undergoes a nucleophilic substitution reaction with a fluoroaromatic at high temperature to obtain the corresponding aromatic phosphine oxide compound. In existing technology reports, there is currently no effective method to obtain aromatic phosphine oxides in high yield from less reactive fluoroaromatics. Summary of the Invention

[0005] Based on this, the present invention addresses the shortcomings of the prior art by providing a simple and efficient method for synthesizing aromatic phosphine oxides by reacting nickel-catalyzed fluoroaromatics with P(O)-H compounds. This method achieves efficient reaction of low-activity fluoroaromatics with P(O)-H compounds through the synergistic effect of nickel catalyst and alkaline reagent, thereby obtaining high-yield aromatic phosphine oxide products and avoiding the problem of poor substrate applicability in the prior art.

[0006] To achieve the above objectives, the present invention provides a method for preparing nickel-catalyzed aromatic phosphine oxide compounds, comprising the following steps: , Under an inert atmosphere, P(O)-H compounds, fluoroaromatic compounds, nickel catalysts, and alkaline reagents represented by Formula I are added to an organic solvent and mixed. The mixture is stirred under heating conditions, and the resulting aromatic phosphine oxides represented by Formula II are purified and collected. , Formula II; The P(O)-H compounds react with a base reagent to form organophosphate compounds under the catalysis of a nickel catalyst. The organophosphate compounds react with fluoroaromatic compounds to form aromatic phosphine oxide compounds under the promoting effect of a nickel catalyst and a base reagent. Wherein, R is one of hydrogen, methyl, methoxy, styryl, ester, or fluorine; R 1 and R 2 Each is independently selected from one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 1-naphthyl or alkoxy; The fluoroaromatic compound is one of fluorobenzene, 4-fluoroanisole, 4-fluorotoluene, 3-fluorotoluene, 2-fluorotoluene, 1-fluoronaphthalene, 4-styrylfluorobenzene, methyl 4-fluorobenzoate, 1,3,5-trifluorobenzene, 1-fluoronaphthalene, or (-)-trans-4-(4-fluorophenyl)-3-{[(3',4'-methylenedioxy)phenoxy]methyl}-N-benzylpiperidine; The alkaline reagent is one or two of lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0007] Preferably, the molar ratio of the P(O)-H compounds, fluorinated aromatic compounds, nickel catalyst and alkaline reagent is 1:1~2:0.01~0.2:1~2.

[0008] Preferably, the P(O)-H compound is one of diphenylphosphine oxide, bis(4-methylphenyl)phosphine oxide, bis(4-methoxyphenyl)phosphine oxide, bis(1-naphthyl)phosphine oxide, diethyl phosphite, diisopropyl phosphite, di-n-butyl phosphite, or ethyl phenylphosphonate.

[0009] Preferably, the nickel catalyst is one of bis(1,5-cyclooctadiene) nickel, nickel chloride, and nickel bromide.

[0010] Preferably, the organic solvent is one or more of toluene, 1,4-dioxane, and tetrahydrofuran.

[0011] Preferably, the stirring reaction conditions are: stirring at 60-140℃ for 10-24 hours.

[0012] Preferably, the purification and collection process is as follows: the mixed solution obtained after stirring reaction is washed and extracted to obtain an organic phase, and the organic phase is dried, distilled and then subjected to column chromatography to obtain aromatic phosphine oxide compounds.

[0013] The reaction mechanism in this preparation method is as follows: The P(O)-H compound, base, and catalyst first form intermediate organophosphorus (phosphonate) esters in an organic solution. These intermediate organophosphorus (phosphonate) esters then react with fluoroaromatics to form the corresponding aryl phosphine oxides under the facilitation of a nickel catalyst and a base. The nickel catalyst lowers the activation energy of the CF bond activation in the formation of the intermediate organophosphorus esters and fluoroaromatics. Under the action of the nickel catalyst, the reactivity of fluoroaromatic substrates that cannot directly react with P(O)-H compounds to form aryl phosphine oxides under alkaline conditions can be significantly improved, resulting in higher yields of the corresponding aromatic phosphine oxides.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The aromatic phosphine oxide preparation process provided by the present invention has simple reaction conditions. The reaction can be carried out efficiently under the promotion of a certain amount of alkaline reagent with nickel catalysis. Nickel catalysis can form intermediate products such as organophosphorus (phosphonic) esters and reduce the activation energy of CF bond breaking, thereby increasing the reaction yield and realizing the phosphorylation reaction of inert CF bonds. Inert fluoroaromatics and polyfluorosubstituted aromatics react well in this reaction system with high yield. 2. The aromatic phosphine oxide reaction intermediate provided by this invention is an organophosphate compound, so organophosphate compounds can also be synthesized by this method. It can also be used in the synthesis of fluorinated organophosphine compounds and the post-modification of drug molecules. This method avoids the problem of poor substrate applicability in the prior art, can be used for drug modification, and can be scaled up to the gram scale. 3. This invention provides a method for preparing aromatic phosphine oxides from nickel-catalyzed P(O)-H compounds and fluorinated aromatics in one step. The P(O)-H compounds used in the preparation process are simpler, more readily available, greener, and more stable than phosphorus halide reagents. Furthermore, the fluorinated aromatics used as reactants are widely available and have lower costs, thus showing good application prospects.

[0015] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and are not intended to limit this disclosure. Attached Figure Description

[0016] Figure 1 The 1H NMR spectrum of diphenyl(4-methoxyphenyl)phosphine oxide obtained in Example 1 of this invention; Figure 2 The phosphorus NMR spectrum of the intermediate product Ph2P(O)OBu-t obtained in Example 1 of this invention; Figure 3 This is the reaction formula for synthesizing aromatic phosphine oxide compounds according to the present invention; Figure 4 Ph2P(O)OBu- synthesized in Experimental Example 1 of this invention t 1H NMR spectrum; Figure 5 Ph2P(O)OBu- synthesized in Experimental Example 1 of this invention t Phosphorus NMR spectrum; Figure 6 The 1H NMR spectrum of triphenylphosphine oxide obtained in Example 2 of this invention; Figure 7 The 1H NMR spectrum of diphenyl(4-methylphenyl)phosphine oxide obtained in Example 3 of this invention; Figure 8 The 1H NMR spectrum of diphenyl(3-methylphenyl)phosphine oxide obtained in Example 4 of this invention; Figure 9 The 1H NMR spectrum of diphenyl(2-methylphenyl)phosphine oxide obtained in Example 5 of this invention; Figure 10 The 1H NMR spectrum of diphenyl(4-styryl-phenyl)phosphine oxide obtained in Example 6 of this invention; Figure 11 The 1H NMR spectrum of diphenyl(4-methyl carbamate-phenyl)phosphine oxide obtained in Example 7 of this invention; Figure 12 The 1H NMR spectrum of diphenyl(3,5-difluoro-phenyl)phosphine oxide obtained in Example 8 of this invention; Figure 13 The 1H NMR spectrum of bis(4-methylphenyl)(4-methoxyphenyl)phosphine oxide obtained in Example 9 of this invention; Figure 14The 1H NMR spectrum of tris(4-methoxyphenyl)phosphine oxide obtained in Example 10 of this invention; Figure 15 The 1H NMR spectrum of bis(1-naphthyl)(4-methoxyphenyl)phosphine oxide obtained in Example 11 of this invention; Figure 16 The 1H NMR spectrum of diethyl (1-naphthyl)phosphonate obtained in Example 12 of this invention; Figure 17 The 1H NMR spectrum of di-n-butyl (1-naphthyl)phosphonate obtained in Example 13 of this invention; Figure 18 The 1H NMR spectrum of (4-((3S,4R)-3-((1,3-benzodioxo-5-methoxy)methyl)-1-benzyl-4-piperidinyl)phenyl)diphenylphosphine oxide obtained in Example 14 of this invention. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0018] In this embodiment of the invention, the preparation process of aromatic phosphine oxide involves a reaction as shown in reaction formula (1).

[0019] (1), Wherein, R is one of hydrogen, methyl, methoxy, styryl, ester, or fluorine; R 1 or R 2 It is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 1-naphthyl or alkoxy.

[0020] In this embodiment of the invention, the synthetic steps for synthesizing aromatic phosphine oxides from P(O)-H compounds and fluoroaromatics under nickel catalysis are as follows: Under an inert atmosphere, P(O)-H compounds, fluoroaromatic compounds, nickel catalysts, and basic reagents are added to an organic solvent and mixed. The mixture is stirred at 60-140℃ for 10-24 hours and then cooled to obtain a mixed solution. The mixed solution was washed and extracted to obtain an organic phase, which was then dried, distilled, and subjected to column chromatography to obtain aromatic phosphine oxides.

[0021] The following is a further explanation using specific embodiments.

[0022] Example 1

[0023] This embodiment provides a method for preparing phenyl(4-methoxyphenyl)phosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of diphenylphosphine oxide, 0.40 mmol of 4-fluoroanisole, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to a reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and excess alkali and salts were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a yield of 81%. When the reaction was scaled up to 5 mmol, the reaction rate decreased slightly, but the target product could still be obtained in a yield of 75%. 1 H NMR (400 MHz CDCl3): δ 7.60–7.55 (m, 4H), 7.52–7.48 (m, 2H), 7.46–7.42(m, 2H), 7.38–7.34 (m, 4H), 6.88 (dd, J = 2.0 Hz, J = 8.8 Hz, 2H), 3.74 (s, 3H), the specific spectrum is as follows Figure 1 As shown.

[0024] The reaction mixture was monitored using phosphorus nuclear magnetic resonance spectroscopy. A peak with a chemical shift of 26.0 ppm was observed when 4-fluoroanisole, diphenylphosphine oxide, potassium tert-butoxide, and a catalytic amount of nickel catalyst were mixed in toluene and heated for 3 minutes. The specific spectrum is shown below. Figure 2 As shown, it is speculated that Ph₂P(O)OBu-t may be generated as an intermediate in the reaction, and its chemical reaction formula is as follows. Figure 3 As shown.

[0025] Experimental Example 1 According to the method reported in the literature (Williams DBG, Netshiozwi TE Tetrahedron, 2009, 65(48): 9973-9982): potassium tert-butoxide (5.5 mL, 1.0 M in THF) was added dropwise to diphenylphosphine chloride (1.0 mL, 1.22 g, 5.5 mmol) at 0 °C. After removing the ice bath, the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered and separated, and then oxidized with 30% hydrogen peroxide solution to prepare Ph2P(O)OBu- t ( 1 H NMR (400 MHz CDCl3): δ 7.80 (dd, J =6.8Hz, J=11.6Hz, 4H), 7.44–7.39 (m, 6H), 1.50 (s, 9H). 31 P NMR (162 MHz CDCl3): δ 25.71), the specific atlas is as follows Figures 4-5 As shown; using Ph2P(O)OBu- t By replacing diphenylphosphine oxide and directly heating it with 4-fluoroanisole in toluene at 130°C for 18 hours under nickel catalysis and potassium tert-butoxide promotion, bis(diphenyl(4-methoxyphenyl)phosphine oxide) in a yield of 48% can be obtained.

[0026] Replacing the 4-fluoroanisole in the above reaction with 1-fluoronaphthalene, and reacting it with the synthesized Ph₂P(O)OBu- under the same conditions... t The reaction yielded bis(1-naphthyl)phosphine oxide in a yield of over 70%.

[0027] The above results validate the reaction mechanism proposed by this preparation method, but the direct preparation of Ph₂P(O)OBu- t The reaction of nickel catalysis, potassium tert-butoxide promoting reaction with 4-fluoroanisole to prepare the target product bis(4-methoxyphenyl)phosphine oxide had a lower yield than that in Example 1. This was because the intermediate organophosphate compound Ph₂P(O)OBu- was directly synthesized in Example 1. t The synthesis reaction generates a tert-butyloxy anion, which inhibits the forward reaction with 4-fluoroanisole. In the reaction of Example 1, free H and the tert-butyloxy anion combine to form an alcohol, so the yield is lower than that of Example 1. This further verifies that the preparation method of the present invention reduces the reaction difficulty and increases the yield of the target product by synthesizing organophosphate intermediates.

[0028] Example 2

[0029] This embodiment provides a method for preparing triphenylphosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of diphenylphosphine oxide, 0.40 mmol of fluorobenzene, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to the reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and the excess alkali and salts generated in the reaction were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a separation yield of 75%. 1 H NMR (400 MHz CDCl3): δ7.70–7.65 (m, 6H), 7.53–7.49 (m, 3H), 7.45–7.41 (m, 6H), detailed spectra are as follows: Figure 6 As shown.

[0030] Example 3

[0031] This embodiment provides a method for preparing diphenyl(4-methylphenyl)phosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of diphenylphosphine oxide, 0.40 mmol of 4-fluorotoluene, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to a reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and the excess alkali and salts generated in the reaction were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a separation yield of 77%. 1 H NMR (400 MHz CDCl3): δ 7.69–7.64 (m, 4H), 7.58–7.51 (m, 4H), 7.47–7.43 (m, 4H), 7.28–7.26 (m, 2H), 2.40 (s, 3H), detailed spectrum as follows Figure 7 As shown.

[0032] Example 4

[0033] This embodiment provides a method for preparing diphenyl(3-methylphenyl)phosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of diphenylphosphine oxide, 0.40 mmol of 3-fluorotoluene, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to the reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and the excess alkali and salts generated in the reaction were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a separation yield of 60%. 1 H NMR (400 MHz CDCl3): δ 7.69–7.65 (m, 4H), 7.59–7.52 (m, 3H), 7.48–7.43 (m, 4H), 7.40–7.32 (m, 3H), 2.36 (s, 3H), detailed spectrum as follows Figure 8 As shown.

[0034] Example 5

[0035] This embodiment provides a method for preparing diphenyl(2-methylphenyl)phosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of diphenylphosphine oxide, 0.40 mmol of 2-fluorotoluene, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to a reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and excess alkali and salts were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a separation yield of 78%. 1 H NMR (400 MHz CDCl3): δ 7.57 (dd, J= 6.8 Hz, J= 12.0 Hz, 4H),7.48-7.45 (m, 2H), 7.41-7.37 (m, 4H), 7.36-7.32 (m, 1H), 7.20 (dd, J= 4.8 Hz, J= 7.2 Hz, 1H), 7.05 (t, J= 7.2 Hz, 1H), 6.94 (dd, J= 7.6 Hz, J= 14.0 Hz (1H), 2.37 (s, 3H), the specific spectrum is as follows Figure 9 As shown.

[0036] Example 6

[0037] This embodiment provides a method for preparing diphenyl(4-styrene-phenyl)phosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of diphenylphosphine oxide, 0.30 mmol of 4-styrene-fluorobenzene, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to the reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and the excess alkali and salts generated in the reaction were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a separation yield of 66%. 1 H NMR (400 MHz CDCl3): δ7.61–7.52 (m, 6H), 7.47–7.32 (m,10H), 7.23 (d, J = 7.6 Hz, 2H), 7.17–7.13 (m, 1H), 7.10–6.96 (m, 2H), the specific spectrum is as follows Figure 10 As shown.

[0038] Example 7

[0039] This embodiment provides a method for preparing diphenyl(4-methyl carbamate-phenyl)phosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of bis(4-methylphenyl)phosphine oxide, 0.40 mmol of methyl 4-fluorobenzoate, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to a reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and excess alkali and salts were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a yield of 63%. 1 H NMR (400 MHz CDCl3): δ 8.13–8.11 (m, 2H), 7.77 (dd, J = 8.4 Hz, J = 11.2 Hz, 2H), 7.69–7.64 (m, 4H), 7.59–7.55 (m, 2H), 7.50–7.47 (m, 4H), 3.94 (s, 3H), the specific spectrum is as follows Figure 11 As shown.

[0040] Example 8

[0041] This embodiment provides a method for preparing diphenyl(3,5-difluoro-phenyl)phosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of bis(4-methoxyphenyl)phosphine oxide, 0.40 mmol of 1,3,5-trifluorobenzene, 0.30 mmol of sodium tert-butoxide, and 1.5 mL of toluene solvent were added to a reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and excess alkali and salts were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a yield of 60%. 1¹H NMR (400 MHz, CDCl₃) δ 7.29–7.21 (m, 10H), 6.73–6.63 (m, 3H), detailed spectrum as follows: Figure 12 As shown.

[0042] Example 9

[0043] This embodiment provides a method for preparing bis(4-methylphenyl)(4-methoxyphenyl)phosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of bis(4-methylphenyl)phosphine oxide, 0.40 mmol of 4-methoxyfluorobenzene, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to a reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and excess alkali and salts were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a yield of 65%. 1 H NMR (400 MHz CDCl3): δ 7.59–7.51 (m, 6H), 7.27–7.24 (m, 4H), 6.96–6.93 (m, 2H), 3.83 (s, 3H), 2.39 (s, 6H), detailed spectra are as follows: Figure 13 As shown.

[0044] Example 10

[0045] This embodiment provides a method for preparing tris(4-methoxyphenyl)phosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of bis(4-methoxyphenyl)phosphine oxide, 0.40 mmol of 4-methoxyfluorobenzene, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to the reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and excess alkali and salts were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a separation yield of 50%. 1 H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 8.8 Hz, J =11.2 Hz, 6H), 6.95–6.93 (m, 6H), 3.81 (s, 9H), the specific spectrum is as follows Figure 14As shown.

[0046] Example 11

[0047] This embodiment provides a method for preparing bis(1-naphthyl)(4-methoxyphenyl)phosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of bis(1-naphthyl)phosphine oxide, 0.40 mmol of 4-methoxyfluorobenzene, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to the reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and the excess alkali and salts generated in the reaction were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a separation yield of 51%. 1 H NMR (400 MHz, CDCl3) δ 8.81 (d, J= 8.4 Hz, 2H), 7.99 (d, J= 8.0 Hz, 2H), 7.88 (d, J= 8.0 Hz, 2H), 7.62 (dd, J= 8.4 Hz, J= 11.2 Hz (2H), 7.51-7.43 (m, 4H), 7.33-7.23 (m, 4H), 6.96-6.93 (m, 2H), 3.81 (s, 3H), detailed spectrum as follows Figure 15 As shown.

[0048] Example 12

[0049] This embodiment provides a method for preparing diethyl (1-naphthyl)phosphonate, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.40 mmol of diethyl phosphite, 0.20 mmol of 1-fluoronaphthalene, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to a reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and excess alkali and salts were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product, with a yield of 82%. 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.4 Hz, 1H), 8.25 (dd, J=16.4, 6.8 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1 H), 7.62-7.49 (m, 3H), 4.24-4.16 (m, 2H), 4.13-4.03 (m, 2H), 1.31 (t, J = 7.2 Hz, 6H), the specific spectrum is as follows Figure 16 As shown.

[0050] Example 13

[0051] This embodiment provides a method for preparing (1-naphthyl)phosphonic acid di-n-butyl ester, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.40 mmol of di-n-butyl phosphite, 0.20 mmol of 1-fluoronaphthalene, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to a reactor. After sealing the tube, the mixture was heated to 120 °C and stirred continuously for 20 h. The reaction was then stopped, cooled to room temperature, and excess alkali and salts were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a separation yield of 85%. 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.4 Hz, 1H), 8.25 (dd, J = 16.4, 7.2 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1 H),7.62-7.52 (m, 3H), 4.18-4.10 (m, 2H), 4.04-3.96 (m, 2H), 1.67-1.60 (m, 4H),1.41-1.32 (m, 4H), 0.86 (t, J = 11.6 Hz, 6H), the specific spectrum is as follows Figure 17 As shown.

[0052] Example 14

[0053] This embodiment provides a method for preparing (4-((3S,4R)-3-((1,3-benzodioxo-5-methoxy)methyl)-1-benzyl-4-piperidinyl)phenyl)diphenylphosphine oxide, as detailed below: Under a nitrogen atmosphere, 0.01 mmol of bis(1,5-cyclooctadiene)nickel, 0.20 mmol of diphenylphosphine oxide, 0.40 mmol of (-)-trans-4-(4-fluorophenyl)-3-{[(3',4'-methylenedioxy)phenoxy]methyl}-N-benzylpiperidine, 0.30 mmol of potassium tert-butoxide, and 1.5 mL of toluene solvent were added to a reactor. After sealing the tube, the mixture was heated to 140 °C and stirred continuously for 48 h. The reaction was then stopped, cooled to room temperature, and excess alkali and salts were removed by washing with water. The aqueous phase was extracted with dichloromethane to obtain the organic phase, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography to obtain the target product with a yield of 55%. 1 H NMR (400 MHz, CDCl3): δ 7.68–7.63 (m, 4H), 7.58–7.44 (m, 9H), 7.35–7.29 (m, 6H), 6.60 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 6.08 (dd, J = 2.4 Hz, J =8.4 Hz, 1H), 5.87 (s, 2H), 3.69–3.53 (m, 3H), 3.44 (dd, J = 6.4 Hz, J = 8.8Hz, 1H), 3.26 (d, J = 10.0 Hz, 1H), 3.04 (d, J = 10.4 Hz, 1H), 2.60–2.55 (m, 1H), 2.30 (br, 1H), 2.23–2.09 (m, 2H), 1.93–1.80 (m, 2H), the specific spectrum is as follows. Figure 18 As shown.

[0054] As can be seen from the above embodiments, the preparation method of the present invention can efficiently synthesize aromatic phosphine oxide compounds. The reaction process is simple and efficient, the raw materials are widely available, the toxicity is low, and the substrates have a wide range of applicability. The use of nickel catalysis can reduce the activation energy of CF bond breaking, realize the activation of inert CF bonds, and improve the reaction yield. The reaction can be used for the synthesis of fluorinated organophosphine compounds and the post-modification of fluorinated drug molecules, and has strong application prospects.

[0055] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

Claims

1. A method for preparing nickel-catalyzed aromatic phosphine oxide compounds, characterized in that, Includes the following steps: ， Under an inert atmosphere, P(O)-H compounds, fluoroaromatic compounds, nickel catalysts, and basic reagents represented by Formula I are added to toluene and mixed. The mixture is stirred and reacted at room temperature or under heating conditions. The resulting aromatic phosphine oxide compounds are then purified and collected. The P(O)-H compounds react with a base reagent to form organophosphate compounds under the catalysis of a nickel catalyst. The organophosphate compounds react with fluoroaromatic compounds to form aromatic phosphine oxide compounds under the promoting effect of a nickel catalyst and a base reagent. The P(O)-H class compounds are one of diphenylphosphine oxide, bis(4-methylphenyl)phosphine oxide, bis(4-methoxyphenyl)phosphine oxide, bis(1-naphthyl)phosphine oxide, diethyl phosphite, diisopropyl phosphite, di-n-butyl phosphite, or ethyl phenylphosphonate. The fluoroaromatic compound is one of fluorobenzene, 4-fluoroanisole, 4-fluorotoluene, 3-fluorotoluene, 2-fluorotoluene, 4-styrylfluorobenzene, methyl 4-fluorobenzoate, 1,3,5-trifluorobenzene, and (-)-trans-4-(4-fluorophenyl)-3-{[(3',4'-methylenedioxy)phenoxy]methyl}-N-benzylpiperidine; The alkaline reagent is potassium tert-butoxide; The nickel catalyst is bis(1,5-cyclooctadiene) nickel.

2. The method for preparing aromatic phosphine oxide compounds catalyzed by nickel according to claim 1, characterized in that, The molar ratio of the P(O)-H compounds, fluorinated aromatic compounds, nickel catalyst and alkaline reagent is 1:1~2:0.01~0.2:1~2.

3. The method for preparing aromatic phosphine oxides catalyzed according to claim 1, characterized in that, The conditions for the stirring reaction are: stirring at 60-140℃ for 10-24 hours.

4. The method for preparing aromatic phosphine oxide compounds catalyzed by nickel according to claim 1, characterized in that, The purification and collection process is as follows: the mixed solution obtained after stirring reaction is washed and extracted to obtain an organic phase, and the organic phase is dried, distilled and then subjected to column chromatography to obtain aromatic phosphine oxide compounds.

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