Method for preparing alkynyl phosphonate by mechanochemical method

Abstract

The invention discloses a method for preparing alkynyl phosphonate by a mechanochemical method, and relates to the technical field of organic synthesis. Comprising the following steps: 1, dissolving dibenzothiophene 5-oxide in an organic solvent under the protection of nitrogen, adding trifluoromethanesulfonic anhydride at-60 to-50 DEG C, uniformly stirring, adding TMS-alkyne, carrying out an addition reaction, removing the solvent after the reaction is finished, and washing a solid product to obtain alkynyl sulfonium salt; and step 2, adding the alkynyl sulfonium salt obtained in the step 1 and phosphite ester into a ball milling tank, carrying out vibration ball milling for reaction, and after the reaction is completed, carrying out column chromatography purification to obtain a target product. According to the present invention, the mechanochemical method is adopted to prepare the alkynyl phosphonate, the solvent and the metal catalyst are not required, the target product is obtained at the good yield within the short reaction time, and the problems of high solvent requirement, low cost and the like in the traditional synthesis method are solved; the preparation process is complicated and unstable when an alkynyl iodized salt reagent is used as a precursor reagent for electrophilic alkynylation reaction.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing alkynyl phosphonate by a mechanochemical method. Background Art

[0002] Mechanochemistry refers to the method of introducing mechanical force into the chemical reaction process to change the reaction path, accelerate the reaction rate or synthesize materials with special properties. This method combines the principles of mechanical mechanics and chemical reactions. Through mechanical means such as grinding, ball milling, and high-pressure extrusion, the reactants are subjected to mechanical stress in solid or liquid states, thereby inducing or promoting the breaking and reorganization of chemical bonds. Mechanochemical reactions generally require no or only a trace amount of solvents. Therefore, mechanochemistry has a good application prospect in green synthesis methodology.

[0003] Organophosphine compounds have shown great value in the fields of medicine and chemical biology research, and the synthesis of organophosphine compounds has always been a hot topic in organic chemistry. Among them, alkynyl phosphonates are important precursors for the synthesis of drug molecules and bioactive molecules such as anti-hypocholesterolemia bisphosphonates and progesterone receptor antagonists containing phosphorus 17β side chains of mifepristone analogs. Since alkynyl phosphonates are triple-bond compounds, various phosphine-containing molecules can also be synthesized through hydration reactions, reduction reactions, conjugate addition reactions, cycloaddition reactions, etc. However, traditional methods have the problem of large demand for solvents and cumbersome subsequent treatment. In the early days, the Michaelis-Arbuzov reaction was the main method for synthesizing phosphorus-containing compounds. However, the reaction has the disadvantages of poor substrate applicability and complex and harsh reaction conditions, which limits its application in the synthesis of organophosphorus compounds. In recent years, transition metal-catalyzed coupling reactions have become one of the powerful tools for constructing carbon-carbon, carbon-hetero bonds and carbon-phosphorus bonds, but transition metal catalysts are expensive and difficult to completely remove in later reactions. Moreover, in the preparation process, alkynyl iodide salt reagents are often used as general precursor reagents for electrophilic alkynylation reactions, which have the problems of complex preparation process and easy decomposition of trivalent iodine under heat. Therefore, how to synthesize alkynyl phosphonates in a greener and more economical way is a problem with practical application value. To solve this problem, the present invention provides a method for preparing alkynyl phosphonates by mechanochemical method. Summary of the invention

[0004] The purpose of the present invention is to provide a method for preparing alkynyl phosphonates by a mechanochemical method, so as to solve the problems mentioned in the above background technology that the traditional method for synthesizing phosphide-containing compounds has a large demand for solvents, cumbersome post-processing, and is not in line with the concept of green economy, and that alkynyl iodide salt reagents are used as general precursor reagents for electrophilic acetylenylation reactions, and the preparation process is complicated and trivalent iodine is easily decomposed under heat.

[0005] To achieve the above object, the present invention provides a method for preparing alkynyl phosphonate by mechanochemical method, comprising the following steps:

[0006] Step 1, under nitrogen protection, dissolving dibenzothiophene 5-oxide in an organic solvent, adding trifluoromethanesulfonic anhydride at -60 to -50°C, stirring evenly, adding TMS-alkyne for addition reaction, removing the solvent after the reaction, washing the solid product, and obtaining an alkynyl sulfonium salt;

[0007] Step 2: Add the alkynyl sulfonium salt and phosphite obtained in step 1 into a ball mill, tighten the lid, and perform a vibration ball milling reaction. After the reaction is completed, separate and purify by column chromatography to obtain the target product.

[0008] Preferably, in step 1, the molar ratio of dibenzothiophene 5-oxide, trifluoromethanesulfonic anhydride and TMS-alkyne is 1:1:1.

[0009] Preferably, in step 1, the organic solvent is any one of tetrahydrofuran, dichloromethane and ethyl acetate; and the concentration of dibenzothiophene 5-oxide in the organic solvent is 0.1-0.2 mol / L.

[0010] Preferably, in the step 1, the structural formula of the alkynyl sulfonium salt prepared is as shown in Chemical Formula I,

[0011]

[0012] Wherein, R1 is any one of hydrogen, C1-C5 lower alkyl, halogen substituent, and ester group.

[0013] Preferably, R1 is any one of a methyl group, a tert-butyl group, a chlorine atom, and a methyl formate group.

[0014] Preferably, in step 1, the addition reaction time is 12-16 hours; the solvent used for washing the solid product is one or more of anhydrous n-hexane, anhydrous n-pentane, and anhydrous ether.

[0015] Preferably, in step 2, the structural formula of the phosphite is as shown in Chemical Formula II,

[0016]

[0017] Wherein, R2 is any one of methoxy, ethoxy and propoxy.

[0018] Preferably, in step 2, the molar ratio of the alkynyl sulfonium salt to the phosphite is 1:1-1:2.

[0019] Preferably, in step 2, the vibration frequency of the vibration ball mill is 30-60 Hz; and the ball milling time is 15-25 min.

[0020] Preferably, in step 2, the eluent used for column chromatography separation is a mixed solution of n-hexane and ethyl acetate, wherein the volume ratio of n-hexane to ethyl acetate is 20:1-5:1.

[0021] Therefore, the present invention provides a method for preparing alkynyl phosphonates by a mechanochemical method. By using the mechanochemical method, an alkynyl sulfonium salt is used as an electrophilic alkynylation reaction reagent without the participation of a reaction solvent and a transition metal. Since the sulfonium salt carries a positive charge, a carbon-sulfonium bond undergoes homolysis during the single-electron reduction process to generate a sulfonium free radical, which further undergoes a coupling reaction with an alkyl phosphonate to generate an alkynyl phosphonate.

[0022] The technical solution of the present invention is further described in detail below through embodiments. DETAILED DESCRIPTION

[0023] The present invention is further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention. Any other changes, modifications, substitutions, combinations, simplifications made without violating the spirit and principle of the present invention should all be equivalent replacement methods and are included in the protection scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application, and all belong to the scope of protection of the present invention.

[0024] Reference to "embodiment" herein means that the specific features, structures or characteristics described in conjunction with the embodiment may be included in at least one embodiment of the present application. The term "embodiment" appearing in various places in the specification does not necessarily refer to the same embodiment, nor does it particularly limit its independence or association with other embodiments. In principle, in the present application, as long as there is no technical contradiction or conflict, the various technical features mentioned in the embodiments can be combined in any way to form a corresponding implementable technical solution.

[0025] Unless otherwise defined, the technical terms used in this document have the same meanings as those generally understood by those skilled in the art to which this application belongs; the use of relevant terms in this document is only for describing specific embodiments and is not intended to limit this application.

[0026] Unless otherwise specified in the present invention, the reagents, instruments, and equipment used are those commonly used by technicians in this field.

[0027] Example 1

[0028] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0029] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 10 mL of ethyl acetate in a reaction flask, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -60°C, stirred evenly, phenylethynyltrimethylsilane (174.3 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 16 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S1.

[0030] Step 2: Add alkynyl sulfonium salt S1 (434.4 mg, 1 mmol, 1 equiv.) and phosphite R1 (186.1 mg, 1.5 mmol, 1.5 equiv.) to a 2.5 mL vibrating ball mill under air conditions, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 20:1 was used for silica gel column chromatography to obtain a yellow oily target product P1 with a mass of 199.7 mg and a yield of 95%. The reaction formula is shown in Equation I.

[0031]

[0032]

[0033] The NMR characterization results of P1 obtained are as follows: 1 HNMR (500MHz, CDCl3): δ = 7.55 (d, J = 7.1Hz, 2H), 7.44 (t, J = 7.5Hz, 1H), 7.35 (t, J = 7.6Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H). 13 CNMR (126MHz, CDCl3): δ = 132.8 (d, J = 2.6Hz), 131.0, 128.7, 119.4 (d, J = 5.7Hz), 100.1 (d, J = 53.3Hz), 76.9 (d, J = 302.5Hz), 53.6, 53.5. 31 PNMR (202MHz,CDCl3):δ=2.12.

[0034] Example 2

[0035] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0036] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 10 mL of ethyl acetate in a reaction flask, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -60°C, stirred evenly, 4-methylphenylethynyltrimethylsilane (188.4 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 16 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S2.

[0037] Step 2: Add alkynyl sulfonium salt S2 (448.4 mg, 1 mmol, 1 equiv.) and phosphite R1 (186.1 mg, 1.5 mmol, 1.5 equiv.) to a 2.5 mL vibrating ball mill under air conditions, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 20:1 was used for silica gel column chromatography to obtain a colorless oily target product P2 with a mass of 204 mg and a yield of 91%. The reaction formula is shown in Equation II.

[0038]

[0039] The NMR characterization results of P2 obtained are as follows: 1 HNMR (500MHz, CDCl3): δ = 7.46 (d, J = 8.2Hz, 2H), 7.18 (d, J = 7.7Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.38 (s, 3H). 13 CNMR (126MHz, CDCl3): δ = 141.7, 132.8 (d, J = 2.5Hz), 129.5, 116.3 (d, J = 5.7Hz), 100.6 (d, J = 53.7Hz), 76.4 (d, J = 303.8Hz), 53.5, 53.5, 21.8. 31 PNMR (202MHz,CDCl3):δ=1.82.

[0040] Example 3

[0041] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0042] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 10 mL of ethyl acetate in a reaction flask, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -60°C, stirred evenly, 4-tert-butylphenylethynyltrimethylsilane (230.4 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 16 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S3.

[0043] Step 2: Add alkynyl sulfonium salt S3 (452.4 mg, 1 mmol, 1 equiv.) and phosphite R1 (186.1 mg, 1.5 mmol, 1.5 equiv.) to a 2.5 mL vibrating ball mill under air conditions, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 20:1 was used for silica gel column chromatography to obtain a yellow oily target product P3 with a mass of 198.5 mg and a yield of 87%. The reaction formula is shown in Equation III.

[0044]

[0045] The NMR characterization results of P3 obtained are as follows: 1 HNMR (500MHz, CDCl3): δ = 7.57 (dd, J = 8.7, 5.3Hz, 2H), 7.25 (s, 1H), 7.07 (t, J = 8.6Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H). 13 CNMR(151MHz,CDC l3): δ = 164.1 (d, J = 254.1Hz), 135.2 (dd, J = 9.0, 2.5Hz), 116.4, 116.3, 115. 6(dd,J=5.6,3.3Hz),98.9(d,J=53.6Hz),77.1(d,J=302.9Hz),53.6,53.6. 19 FNMR (565MHz, CDCl3): δ = -105.68. 31 PNMR (243MHz,CDCl3):δ=2.29.

[0046] Example 4

[0047] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0048] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 10 mL of ethyl acetate in a reaction flask, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -60°C, stirred evenly, 4-chlorophenylethynyltrimethylsilane (208.8 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 16 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S4.

[0049] Step 2: Add alkynyl sulfonium salt S4 (468.9 mg, 1 mmol, 1 equiv.) and phosphite R1 (186.1 mg, 1.5 mmol, 1.5 equiv.) to a 2.5 mL vibrating ball mill under air conditions, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 20:1 was used as an eluent, and the ethyl acetate solution was transferred to a silica gel column for separation to obtain a yellow oily target product P4 with a mass of 215.2 mg and a yield of 88%. The reaction formula is shown in Equation IV.

[0050]

[0051] The NMR characterization results of P4 obtained are as follows: 1 HNMR (500MHz, CDCl3): δ = 7.50 (d, J = 8.4Hz, 2H), 7.36 (d, J = 8.6Hz, 2H), 3.86 (s, 3H), 3.84 (s, 3H). 13 CNMR (126MHz, CDCl3): δ = 137.4, 134.0 (d, J = 2.5Hz), 129.2, 117.9 (d, J = 5.7Hz), 98.6 (d, J = 53.1Hz), 78.1 (d, J = 301.6Hz), 53.6, 53.6. 31 PNMR (202MHz,CDCl3):δ=2.52.

[0052] Example 5

[0053] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0054] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 5 mL of dichloromethane in a reaction bottle, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -50°C, stirred evenly, 4-methylformate phenylethynyltrimethylsilane (232.4 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 12 h. The solvent was removed and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S5.

[0055] Step 2: Add alkynyl sulfonium salt S5 (492.4 mg, 1 mmol, 1 equiv.) and phosphite R1 (186.1 mg, 1.5 mmol, 1.5 equiv.) to a 2.5 mL vibrating ball mill under air conditions, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 10:1 was used for silica gel column chromatography to obtain a yellow oily target product P5 with a mass of 249.4 mg and a yield of 93%. The reaction formula is shown in Equation V.

[0056]

[0057] The NMR characterization results of P5 obtained are as follows: 1 HNMR (500MHz, CDCl3): δ = 8.02 (d, J = 8.3Hz, 2H), 7.62 (d, J = 8.3Hz, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H). 13 CNMR (126MHz, CDCl3): δ = 166.0, 132.7 (d, J = 2.9Hz), 132.0, 129.7, 123.7 (d, J = 5.6Hz), 98.4 (d, J = 52.7Hz), 79.5 (d, J = 299.8Hz), 53.7, 53.6, 52.6. 31 PNMR (202MHz,CDCl3):δ=2.87.

[0058] Example 6

[0059] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0060] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 5 mL of dichloromethane in a reaction flask, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -50°C, stirred evenly, 3-methylphenylethynyltrimethylsilane (188.4 mg, 1 mmol, 1 equiv.) was added, and the reaction was continued for 12 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S6.

[0061] Step 2: Add alkynyl sulfonium salt S6 (448.5 mg, 1 mmol, 1 equiv.) and phosphite R1 (186.1 mg, 1.5 mmol, 1.5 equiv.) to a 2.5 mL vibrating ball mill under air conditions, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 20:1 was used for silica gel column chromatography to obtain a yellow oily target product P6 with a mass of 199.6 mg and a yield of 89%. The reaction formula is shown in Equation VI.

[0062]

[0063] The NMR characterization results of P6 obtained are as follows: 1 HNMR (500MHz, CDCl3): δ=7.41–7.37(m,2H),7.28–7.26(m,2H),3.87(s,3H),3.85(s,3H),2.36(s,3H). 13 CNMR (126MHz, CDCl3): δ = 138.6, 133.3 (d, J = 2.5Hz), 131.9, 130.0 (d, J = 2.3Hz), 128 .6,119.2(d,J=5.7Hz),100.5(d,J=53.3Hz),76.6(d,J=302.9Hz),53.6,53.5,21.3. 31 PNMR (202MHz,CDCl3):δ=1.98.

[0064] Example 7

[0065] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0066] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 5 mL of dichloromethane in a reaction flask, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -50°C, stirred evenly, 3-chlorophenylethynyltrimethylsilane (208.1 mg, 1 mmol, 1 equiv.) was added, and the reaction was continued for 12 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S7.

[0067] Step 2: Under air conditions, add alkynyl sulfonium salt S7 (468.9 mg, 1 mmol, 1 equiv.) and phosphite R1 (186.1 mg, 1.5 mmol, 1.5 equiv.) to a vibrating ball mill with a volume of 2.5 mL, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, the reactants were transferred using ethyl acetate, and a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 5:1 was used for silica gel column chromatography separation to obtain a yellow oily target product P7 with a mass of 212.7 mg and a yield of 87%. The reaction formula is shown in Equation VII.

[0068]

[0069] The NMR characterization results of P7 obtained are as follows: 1 HNMR (500MHz, CDCl3): δ=7.53(t,J=1.9Hz,1H),7.46–7.40(m,2H),7.31(t,J=7.9Hz,1H),3.85(s,3H),3.83(s,3H). 13 CNMR(126MHz,CD Cl3): δ = 134.6, 132.5 (d, J = 2.6Hz), 131.3, 130.9 (d, J = 2.5Hz), 130.0, 121.1 (d, J = 5.7Hz), 97.9 (d, J = 53.0Hz), 78.2 (d, J = 300.2Hz), 53.7, 53.6. 31 PNMR (202MHz,CDCl3):δ=2.81.

[0070] Example 8

[0071] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0072] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 10 mL of tetrahydrofuran in a reaction flask, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -50°C, stirred evenly, 2-methylphenylethynyltrimethylsilane (188.4 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 14 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S8.

[0073] Step 2: Add alkynyl sulfonium salt S8 (502.5 mg, 1 mmol, 1 equiv.) and phosphite R1 (186.1 mg, 1.5 mmol, 1.5 equiv.) to a 2.5 mL vibrating ball mill under air conditions, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, the reactants were transferred using ethyl acetate, and a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 5:1 was used for silica gel column chromatography separation to obtain a yellow oily target product P8 with a mass of 236.5 mg and a yield of 85%. The reaction formula is shown in Equation VIII.

[0074]

[0075] The NMR characterization results of P8 obtained are as follows: 1 HNMR (500MHz, CDCl3): δ=7.74–7.72(m,1H),7.71–7.69(m,1H),7.60–7.53(m,2H),3.86(s,3H),3.84(s,3H). 13 CNMR (151MHz, CDCl3): δ = 135.2 (d, J = 2.9Hz), 132.9 (q, J = 31.3, 30.9Hz), 131.9, 130.8, 126.3 (q ,J=5.0Hz),123.1(q,J=273.5Hz),117.6,95.1(d,J=52.0Hz),82.4(d,J=295.6Hz),53.7,53.7. 19 FNMR (565MHz, CDCl3): δ = -61.78. 31 PNMR (243MHz,CDCl3):δ=3.36.

[0076] Example 9

[0077] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0078] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 5 mL of tetrahydrofuran in a reaction bottle, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -50°C, stirred evenly, 2-chlorophenylethynyltrimethylsilane (188.4 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 14 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S9.

[0079] Step 2: In air, add alkynyl sulfonium salt S9 (468.9 mg, 1 mmol, 1 equiv.) and phosphite R1 (186.1 mg, 1.5 mmol, 1.5 equiv.) to a 2.5 mL vibrating ball mill, cover and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, the reactants are transferred using ethyl acetate, and a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 10:1 is used for silica gel column chromatography separation to obtain a yellow oily target product P9 with a mass of 190.4 mg and a yield of 81%. The reaction formula is shown in Equation IX.

[0080]

[0081] The NMR characterization results of P9 obtained are as follows: 1 HNMR (500MHz, CDCl3): δ=7.61 (dd, J=7.7, 1.7Hz, 1H), 7.46 (dd, J=8.2, 1.3Hz, 1H),7.41(td,J=7.8,1.6Hz,1H),7.32–7.27(m,1H),3.91(s,3H),3.88(s,3H). 13 CNMR (126MHz, CDCl3): δ = 137.2 (d, J = 2.9Hz), 134.5 (d, J = 2.5Hz), 132.0, 129.7, 126.9, 119.8 (d, J = 5.7Hz), 96.2 (d, J = 52.6Hz), 81.9 (d, J = 297.9Hz), 53.8, 53.7. 31 PNMR (202MHz,CDCl3):δ=2.78.

[0082] Example 10

[0083] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0084] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 5 mL of tetrahydrofuran in a reaction bottle, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -50°C, stirred evenly, phenylethynyltrimethylsilane (174.3 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 14 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S1.

[0085] Step 2: In air, add alkynyl sulfonium salt S1 (434.4 mg, 1 mmol, 1 equiv.) and phosphite R2 (249.3 mg, 1.5 mmol, 1.5 equiv.) to a 2.5 mL vibrating ball mill, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 5:1 was used for silica gel column chromatography to obtain a yellow oily target product P. 10 The mass is 216.8 mg and the yield is 91%. The reaction formula is shown in equation X.

[0086]

[0087] The obtained P 10 The NMR characterization results: 1 HNMR (500MHz, CDCl3): δ = 7.55 (d, J = 7.0Hz, 2H), 7.45–7.42 (m, 1H), 7.36 (t, J = 7.6Hz, 2H), 4.25–4.18 (m, 4H), 1.39 (t, J = 7.1Hz, 6H). 13 CNM R (126MHz, CDCl3): δ = 132.7 (d, J = 2.5Hz), 130.8, 128.67, 119.7 (d, J = 5.6Hz), 99.1 (d, J = 52.8Hz), 78.5 (d, J = 299.6Hz), 63.3, 63.3, 16.3, 16.2. 31 PNMR (202MHz, CDCl3): δ = -5.39.

[0088] Embodiment 11

[0089] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0090] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 5 mL of tetrahydrofuran in a reaction bottle, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -50°C, stirred evenly, 4-methylformate phenylethynyltrimethylsilane (232.4 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 14 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S5.

[0091] Step 2: In air, add alkynyl sulfonium salt S1 (492.5 mg, 1 mmol, 1 equiv.) and phosphite R3 (416.4 mg, 2 mmol, 2 equiv.) to a 2.5 mL vibrating ball mill, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 60 Hz for 25 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 5:1 was used for silica gel column chromatography to obtain a yellow oily target product P. 11 The mass is 260.7 mg and the yield is 88%. The reaction formula is shown in equation ⅩⅠ.

[0092]

[0093] The obtained P 11 The NMR characterization results: 1 HNMR (500MHz, CDCl3): δ = 8.02 (d, J = 8.3Hz, 2H), 7.61 (d, J = 8.4Hz, 2H), 4.26–4.17 (m, 4H), 3.91 (s, 3H), 1.39 (t, J = 7.1Hz, 6H). 13 CNMR (151MHz, CDCl3): δ = 166.1, 132.7 (d, J = 2.5Hz), 131.9, 129.7, 124.1 (d, J = 5.7Hz),97.5(d,J=52.1Hz),81.1(d,J=296.9Hz),63.5,63.5,52.5,16.3,16.2. 31 PNMR (243MHz, CDCl3): δ = -6.11.

[0094] Example 12

[0095] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0096] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 5 mL of tetrahydrofuran in a reaction bottle, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -50°C, stirred evenly, 4-chlorophenylethynyltrimethylsilane (218.4 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 14 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S4.

[0097] Step 2: In air, add alkynyl sulfonium salt S1 (492.5 mg, 1 mmol, 1 equiv.) and phosphite R3 (416.4 mg, 2 mmol, 2 equiv.) to a 2.5 mL vibrating ball mill, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 45 Hz for 25 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 5:1 was used for silica gel column chromatography to obtain a yellow oily target product P. 12 The mass is 226.3 mg and the yield is 83%. The reaction formula is shown in equation XII.

[0098]

[0099] The obtained P 12 The NMR characterization results: 1 HNMR (500MHz, CDCl3): δ = 8.02 (d, J = 8.3Hz, 2H), 7.61 (d, J = 8.4Hz, 2H), 4.26–4.17 (m, 4H), 3.91 (s, 3H), 1.39 (t, J = 7.1Hz, 6H). 13 CNMR (151MHz, CDCl3): δ = 166.1, 132.7 (d, J = 2.5Hz), 131.9, 129.7, 124.1 (d, J = 5.7Hz),97.5(d,J=52.1Hz),81.1(d,J=296.9Hz),63.5,63.5,52.5,16.3,16.2. 31 PNMR (243MHz, CDCl3): δ = -6.11.

[0100] Embodiment 13

[0101] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0102] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 5 mL of tetrahydrofuran in a reaction bottle, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -50°C, stirred evenly, phenylethynyltrimethylsilane (174.3 mg, 1 mmol, 1 equiv.) was added, and the reaction was carried out for 16 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S1.

[0103] Step 2: In air, add alkynyl sulfonium salt S1 (434.4 mg, 1 mmol, 1 equiv.) and phosphite R3 (416.4 mg, 2 mmol, 2 equiv.) to a 2.5 mL vibrating ball mill, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 30 Hz for 20 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 5:1 was used for silica gel column chromatography to obtain a yellow oily target product P. 13 The mass is 210.5 mg and the yield is 79%. The reaction formula is shown in equation XIII.

[0104]

[0105] The obtained P 13 The NMR characterization results: 1 HNMR (500MHz, CDCl3): δ = 7.55 (d, J = 7.0Hz, 2H), 7.45–7.42 (m, 1H), 7.36 (t, J = 7.6Hz, 2H), 4.25–4.18 (m, 4H), 4.15–4.04 (m, 4H), 1.39 (t, J = 7.1Hz, 6H). 13 CNMR (126MHz, CDCl3): δ = 132.7 (d, J = 2.5Hz), 130.8, 128.67, 119.7 (d, J = 5.6Hz) ),99.1(d,J=52.8Hz),78.5(d,J=299.6Hz),68.9,68.9,63.3,63.3,16.3,16.2. 31 PNMR (202MHz, CDCl3): δ = -6.71.

[0106] Embodiment 14

[0107] This embodiment provides a method for preparing an alkynyl phosphonate by promoting an alkynyl sulfonium salt and an alkyl phosphonate by a mechanochemical method, comprising the following steps:

[0108] Step 1. Under nitrogen protection, dibenzothiophene 5-oxide (200.3 mg, 1 mmol, 1 equiv.) was dissolved in 50 mL of ethyl acetate in a reaction flask, trifluoromethanesulfonic anhydride (282.1 mg, 1 mmol, 1 equiv.) was added at -50°C, stirred evenly, phenylethynyltrimethylsilane (174.3 mg, 1 mmol, 1 equiv.) was added, and the reaction was continued for 12 h. The solvent was removed, and the solid product was washed with anhydrous n-hexane to obtain the alkynyl sulfonium salt product S1.

[0109] Step 2: In air, add alkynyl sulfonium salt S1 (434.4 mg, 1 mmol, 1 equiv.) and phosphite R1 (124.1 mg, 1 mmol, 1 equiv.) to a 2.5 mL vibrating ball mill, close the lid and tighten the ball mill, and perform mechanical ball milling reaction at a vibration frequency of 30 Hz for 15 minutes. After the reaction, a mixed solvent of n-hexane and ethyl acetate with a volume ratio of 20:1 was used for silica gel column chromatography to obtain a yellow oily target product P. 14 , mass 178.3 mg, yield 85%.

[0110] The obtained P 14 The NMR characterization results: 1 HNMR (500MHz, CDCl3): δ = 7.55 (d, J = 7.1Hz, 2H), 7.44 (t, J = 7.5Hz, 1H), 7.35 (t, J = 7.6Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H). 13 CNMR (126MHz, CDCl3): δ = 132.8 (d, J = 2.6Hz), 131.0, 128.7, 119.4 (d, J = 5.7Hz), 100.1 (d, J = 53.3Hz), 76.9 (d, J = 302.5Hz), 53.6, 53.5. 31 PNMR (202MHz,CDCl3):δ=2.12.

[0111] Therefore, the present application provides a method for preparing alkynyl phosphonates by a mechanochemical method. The reaction pathway is economical and environmentally friendly. Only two reactants, an alkynyl sulfonium salt and a phosphite, need to be added. No solvent and a metal catalyst are required. The target product can be obtained in a good yield after a short reaction time. The problem of large solvent demand and cumbersome post-treatment in traditional synthesis methods and the complex preparation process and instability of alkynyl iodide reagents as general transfer reagents for electrophilic alkynylation reactions is solved.

[0112] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for preparing alkynyl phosphonates by mechanochemical method, characterized in that: The following steps are involved: Step 1, under the protection of inert gas, dissolve dibenzothiophene 5-oxide in an organic solvent, add trifluoromethanesulfonic anhydride at -60 to -50°C, stir evenly, add TMS-alkyne for addition reaction, remove the solvent after the reaction, wash the solid product, and obtain an alkynyl sulfonium salt; Step 2: Add the alkynyl sulfonium salt and phosphite obtained in step 1 into a ball mill, tighten the lid, and perform a vibration ball milling reaction. After the reaction is completed, separate and purify the target product by column chromatography.

2. The method for preparing alkynyl phosphonates by mechanochemical method according to claim 1, characterized in that: In the step 1, the molar ratio of dibenzothiophene 5-oxide, trifluoromethanesulfonic anhydride and TMS-alkyne is 1:1:

1.

3. The method for preparing alkynyl phosphonate by mechanochemical method according to claim 1, characterized in that: The organic solvent is any one of tetrahydrofuran, dichloromethane and ethyl acetate; the concentration of dibenzothiophene 5-oxide in the organic solvent is 0.1-0.2 mol / L.

4. The method for preparing alkynyl phosphonates by mechanochemical method according to claim 1, characterized in that: In the step 1, the structural formula of the prepared alkynyl sulfonium salt is shown in Chemical Formula I, Wherein, R1 is any one of hydrogen, C1-C5 lower alkyl, halogen substituent, and ester group.

5. The method for preparing alkynyl phosphonates by mechanochemical method according to claim 4, characterized in that: R1 is any one of a methyl group, a tert-butyl group, a chlorine atom, and a methyl formate group.

6. The method for preparing alkynyl phosphonates by mechanochemical method according to claim 1, characterized in that: In the step 1, the time of the addition reaction is 12-16 hours; the solvent used for washing the solid product is one or more of anhydrous n-hexane, anhydrous n-pentane, and anhydrous ether.

7. The method for preparing alkynyl phosphonates by mechanochemical method according to claim 1, characterized in that: In the step 2, the structural formula of the phosphite is shown in Chemical Formula II, Wherein, R2 is any one of methoxy, ethoxy and propoxy.

8. The method for preparing alkynyl phosphonates by mechanochemical method according to claim 1, characterized in that: In the step 2, the molar ratio of the alkynyl sulfonium salt to the phosphite is 1:1-1:

2.

9. The method for preparing alkynyl phosphonates by mechanochemical method according to claim 1, characterized in that: In the step 2, the vibration frequency of the vibration ball mill is 30-60 Hz; and the ball milling time is 15-25 min.

10. The method for preparing alkynyl phosphonate by mechanochemical method according to claim 1, characterized in that: In the step 2, the eluent used for column chromatography separation is a mixed solution of n-hexane and ethyl acetate, wherein the volume ratio of n-hexane to ethyl acetate is 20:1-5:1.

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