A method for preparing phosphonyl dihydropyran derivatives

Abstract

The present patent application discloses a method for preparing a phosphonyl dihydropyran derivative, wherein 1,6-enyne compounds, diarylphosphine oxides, an inorganic base and a photocatalyst are dissolved in a solvent, and in an air atmosphere, under light and stirring at room temperature, an intermolecular free radical addition / cyclization reaction occurs to prepare a target product, and after the reaction is complete, the product is separated and purified by column chromatography to obtain the product, and then the product is obtained by 1 H NMR, 13 C NMR, 31 P NMR and HRMS were used to characterize and analyze the structure of the target product. This method does not require complex reaction conditions such as high temperature and transition metal catalysis, and has the advantages of mild reaction conditions, simple operation, convenient subsequent treatment, and easy availability of raw materials, which is in line with the concept of green environmental protection.

Description

Technical Field

[0001] The present patent application relates to the technical field of organic compound synthesis, and more specifically, to a method for preparing a phosphonyl dihydropyran derivative. Background Art

[0002] Organophosphorus compounds play a key role in organic preparation, pesticide chemistry, materials and catalysis. Many organophosphorus compounds have physiological activities such as antibacterial, anti-tumor, anti-inflammatory and analgesic. Dihydropyrans are commonly found in some natural products and drug molecules, and are also important intermediates for drug preparation. Therefore, the preparation of phosphonyl dihydropyran compounds is of great significance.

[0003] In the prior art, the reaction of free radical addition and cyclization initiated by the reaction of diaryl phosphorus oxide compounds to form phosphorus atom free radicals is mainly participated by transition metals such as silver and copper (Org. Lett., 2014, 16, 21, 5616-5619); the above reaction not only requires high temperature reaction conditions, but also requires high-valent metal ions or peroxides as oxidants, so the prepared heterocyclic compounds inevitably have heavy metal residues.

[0004] In summary, it is very important to develop a method for preparing phosphonyldihydropyran derivatives that starts from readily available raw materials, has mild reaction conditions, a wide range of applications, high yields, low costs, and meets the requirements of green chemistry.

[0005] Patent application content

[0006] The purpose of this patent application is to overcome at least one problem of the above-mentioned prior art and provide a simple method for preparing phosphonyl dihydropyran derivatives. The method is simple to operate, low in cost and high in yield.

[0007] In order to achieve the above purpose, the following technical solutions are adopted. The technical solutions adopted in this patent application are:

[0008] A preparation method of a phosphonyl dihydropyran derivative comprises: dissolving a 1,6-enyne compound, a diarylphosphine oxide, an inorganic base and a photocatalyst in a solvent, and causing a chemical reaction of the following reaction equation to occur in the air at room temperature under light and stirring to prepare a target product, and after the reaction is complete, separating and purifying the product by column chromatography to obtain the product:

[0009]

[0010] Wherein, R is halogen or alkyl.

[0011] Preferably, the photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate.

[0012] Preferably, the solvent is selected from any one or more of acetonitrile, dichloromethane, tetrahydrofuran and dimethyl sulfoxide.

[0013] More preferably, the solvent is dimethyl sulfoxide.

[0014] Preferably, the molar ratio of the 1,6-enyne compound to the diarylphosphine oxide is 1:(1.0-3.0).

[0015] Preferably, the inorganic base is selected from Cs 2 CO 3 、Na 2 CO 3 and NaHCO 3 Any one or more of them.

[0016] More preferably, the inorganic base is Cs 2 CO 3 .

[0017] Preferably, the reaction is carried out under visible light irradiation.

[0018] Preferably, the light source of visible light is any one of 6W blue light, 9W blue light, and 12W blue light.

[0019] More preferably, the visible light source is 12W blue light.

[0020] Compared with the prior art, this patent application has the following beneficial effects:

[0021] 1. The preparation method of the phosphonyl dihydropyran derivatives in this patent application uses a very small amount of low-toxic photocatalyst to replace the expensive and highly toxic transition metal-induced phosphorus free radicals, which is relatively more environmentally friendly.

[0022] 2. The preparation method of the phosphonyl dihydropyran derivatives in this patent application does not require high temperature and is in line with the concept of green environmental protection.

[0023] 3. The preparation method of the phosphonyl dihydropyran derivatives in this patent application is simple to operate and convenient for post-processing. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of (4-(3-bromophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 1.

[0025] Figure 2 This is the carbon nuclear magnetic resonance spectrum of (4-(3-bromophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 1.

[0026] Figure 3 This is the nuclear magnetic resonance phosphorus spectrum of (4-(3-bromophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 1.

[0027] Figure 4 This is a high-resolution mass spectrum of (4-(3-bromophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 1.

[0028] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of (4-(3-chlorophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 2.

[0029] Figure 6 This is the carbon nuclear magnetic resonance spectrum of (4-(3-chlorophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 2.

[0030] Figure 7 This is the nuclear magnetic resonance phosphorus spectrum of (4-(3-chlorophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 2.

[0031] Figure 8 This is a high-resolution mass spectrum of (4-(3-chlorophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 2.

[0032] Fig. 9 This is the hydrogen nuclear magnetic resonance spectrum of (4-(4-tert-butylphenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 3.

[0033] Fig.10 This is the carbon nuclear magnetic resonance spectrum of (4-(4-tert-butylphenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 3.

[0034] Fig.11 This is the nuclear magnetic resonance phosphorus spectrum of (4-(4-tert-butylphenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 3.

[0035] Fig.12 This is a high-resolution mass spectrum of (4-(4-tert-butylphenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide prepared in Example 3. DETAILED DESCRIPTION

[0036] The embodiments of the present patent application will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present patent application and should not be considered to limit the scope of the present patent application. If the specific conditions are not specified in the examples, they are carried out according to the normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0037] It should be noted that:

[0038] In this patent application, unless otherwise specified, all implementation methods and preferred implementation methods mentioned herein can be combined with each other to form a new technical solution.

[0039] In the present patent application, unless otherwise specified, percentage (%) or part refers to the weight percentage or weight part relative to the composition.

[0040] In this patent application, unless otherwise specified, the components or preferred components involved can be combined with each other to form a new technical solution.

[0041] In this patent application, unless otherwise specified, the numerical range "a-b" represents an abbreviation of any real number combination between a and b, where a and b are real numbers. For example, the numerical range "1-3" means that all real numbers between "1-3" have been listed in this document, and "1-3" is just an abbreviation of these numerical combinations.

[0042] The “range” disclosed in this patent application is in the form of a lower limit and an upper limit, which can be one or more lower limits, and one or more upper limits, respectively.

[0043] In this patent application, unless otherwise specified, each reaction or operation step can be carried out sequentially or in a sequential manner. Preferably, the reaction method herein is carried out sequentially.

[0044] Unless otherwise specified, the professional and scientific terms used herein are the same as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the described content may also be applied to this patent application.

[0045] The present patent application provides a method for preparing a phosphonyl dihydropyran derivative, comprising: dissolving a 1,6-enyne compound, a diarylphosphine oxide, an inorganic base and a photocatalyst in a solvent, and causing a chemical reaction of the following reaction equation to occur in the air at room temperature under light and stirring to prepare a target product, and after the reaction is complete, separating and purifying the product by column chromatography to obtain the product:

[0046]

[0047] Wherein, R is halogen or alkyl.

[0048] The preparation method of the phosphonyl dihydropyran derivative in the present patent application is to dissolve 1,6-enyne compounds, diarylphosphine oxide, inorganic base and photocatalyst in a solvent, and in an air atmosphere, under light and stirring at room temperature, intermolecular free radical addition and cyclization reaction occur to prepare the target product. Specifically: in an air atmosphere, under light and at room temperature, the photocatalyst catalyzes diarylphosphine oxide to form a phosphorus free radical, which undergoes intermolecular free radical addition with the triple bond of the 1,6-enyne compound, and then undergoes a cyclization reaction with the double bond to prepare the target product.

[0049] The preparation method of the phosphonyl dihydropyran derivatives in the present patent application uses a very small amount of low-toxic photocatalyst to replace the expensive and highly toxic transition metal-induced phosphorus free radicals, which is relatively more environmentally friendly; furthermore, the preparation method in the present patent application does not require high temperature, which is in line with the concept of green environmental protection; finally, the preparation method of the phosphonyl dihydropyran derivatives in the present patent application is simple to operate and convenient for post-processing.

[0050] In some embodiments, the photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate.

[0051] In some embodiments, the amount of the photocatalyst is 5 mol % of the 1,6-enyne compound.

[0052] In some embodiments, the solvent is selected from any one or more of acetonitrile, dichloromethane, tetrahydrofuran and dimethyl sulfoxide.

[0053] In some more preferred embodiments, the solvent is dimethyl sulfoxide.

[0054] In some embodiments, the molar ratio of the 1,6-enyne compound to the diarylphosphine oxide is 1:(1.0-3.0).

[0055] In some embodiments, the inorganic base is selected from Cs 2 CO 3 、Na 2 CO 3 and NaHCO 3 Any one or more of them.

[0056] In some preferred embodiments, the inorganic base is Cs 2 CO 3 .

[0057] In some embodiments, the reaction is performed under visible light irradiation.

[0058] In some embodiments, the light source of visible light is any one of 6W blue light, 9W blue light, and 12W blue light.

[0059] In some more preferred embodiments, the visible light source is 12W blue light.

[0060] Next, specific examples will be used to illustrate that the present patent application can efficiently synthesize phosphonodihydropyran derivatives.

[0061] Example 1 Preparation and Characterization of (4-(3-bromophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide

[0062] Weigh 1-(3-(allyloxy)prop-1-yn-1-yl)-3-bromobenzene 50.2mg (0.2mmol), diphenylphosphine 121.2mg (0.6mmol) and photocatalyst (4,4'-di-tert-butyl-2,2'-bipyridine) bis[(2-pyridyl)phenyl]iridium (III) hexafluorophosphate 9.1mg (5% mol) in a colorless transparent reaction tube, add 2ml of dimethyl sulfoxide solvent, stir and react under air and room temperature, and detect the reaction progress by thin layer chromatography (TLC). After about 12h, the reaction is complete, and the mixture is separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow oil. The yield of the preparation method is 62%, and the yield of the preparation method is high. The chemical reaction equation corresponding to this embodiment is as follows:

[0063]

[0064] The yellow oil prepared in Example 1 was characterized, and its hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, phosphorus nuclear magnetic resonance spectrum and high-resolution mass spectrum were as follows: Figure 1 , Figure 2 , Figure 3 and Figure 4 As shown. Figure 1 It can be seen 1 H NMR (400 MHz, CDCl 3)δ7.66-7.58(m,2H),7.55-7.46(m,4H), 7.42-7.35(m,3H),7.29(dd,J=7.6,3.0Hz,2H),7.10(ddd,J=8.0,2.0,1.1Hz,1H ),7.02(dt,J=7.7,1.4Hz,1H),6.95(t,J=1.8Hz,1H),6.88(t,J=7.8Hz,1H),4.29 (ddd, J = 16.7, 4.2, 1.6 Hz, 1H), 4.08 (dt, J = 16.7, 2.6 Hz, 1H), 3.86 (dd, J = 11.2, 4.0 Hz, 1H), 3.73 (dd, J = 11.2, 3.4 Hz, 1H), 2.45 (s, 1H), 0.96 (d, J = 7.1 Hz, 3H); molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 2 It can be seen that: 13 C NMR (100 MHz, CDCl 3 )δ154.8(d,J=3Hz),140.6(d,J=7.9Hz),132.1(d,J=102.3Hz),131.8(d, J=105.5Hz),131.7(d,J=2.5Hz),131.5(d,J=2.9Hz),131.32(d,J=9.8Hz),13 1.27,131.2(d,J=9.9Hz),130.5,129.1,128.5(d,J=11.9Hz),128.4(d,J=94.7 Hz), 128.2 (d, J = 12.2 Hz), 127.7, 121.7, 70.2, 68.0 (d, J = 18.5 Hz), 36.3 (d, J = 9.5 Hz), 16.9; the molecular carbon spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 3 It can be seen that: 31 P NMR (162 MHz, CDCl 3 )δ22.6. Figure 4 It can be seen that HRMS (ESI-Orbitrap) m / z: [M +H] + Calculate for C 24 H 22 B O 2 P 453.0614, found 453.0608. Combining the results of the above nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, nuclear magnetic resonance phosphorus spectrum and high-resolution mass spectrum, it can be seen that Example 1 successfully synthesized the compound (4-(3-bromophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl) diphenylphosphine oxide, and its molecular structure is as follows:

[0065]

[0066] The preparation method in this embodiment first uses a very small amount (only 9.1 mg, 5% mol) of low-toxic photocatalyst (4,4'-di-tert-butyl-2,2'-bipyridine) bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate to replace the expensive and highly toxic transition metal-induced phosphorus free radicals, which is relatively more environmentally friendly; then, the preparation method only needs to be stirred under air at room temperature under light to complete the reaction, does not require a high reaction temperature, avoids excessive energy consumption, and conforms to the concept of green environmental protection; finally, the preparation method in this embodiment only needs to be stirred under air at room temperature under light to complete the reaction in a colorless and transparent reaction tube, the operation is relatively simple, and the post-processing only needs thin layer chromatography (TLC) to detect the progress of the reaction, and then the final product is separated and purified by column chromatography, that is, the post-processing is convenient.

[0067] In order to obtain the best experimental conditions in the preparation method, the following comparative experiments were carried out.

[0068] 1. Comparison of solvent types

[0069] The reaction conditions were the same as in Example 1. When different types of reaction solvents were used, the product yields were as shown in the following table:

[0070] Table 1 Product yields in different types of reaction solvents

[0071] Solvents MeCN DCM THF DMSO Yield (%) 37 42 44 62

[0072] It can be seen from the above table that when other reaction conditions remain unchanged and the solvent is dimethyl sulfoxide, the yield of the product is the highest.

[0073] After further analysis, the applicant of the present patent found that the reaction substrates 1,6-enyne compounds, diarylphosphine oxides, inorganic bases and photocatalysts in the above experiment have better solubility in dimethyl sulfoxide (DMSO), which makes the preparation reaction more thorough in the colorless and transparent reaction tube. Therefore, when other reaction conditions remain unchanged and the solvent is dimethyl sulfoxide, the yield of the product phosphonyldihydropyran derivative is the highest.

[0074] 2. Comparison of reaction equivalents of phosphorus reagents

[0075] The reaction conditions were the same as in Example 1, and different equivalents of phosphorus reagent were used. The product yields are shown in the following table:

[0076] Table 2 Product yields at different equivalents of diphenylphosphine oxide

[0077] Diphenylphosphine oxide (equiv) 1.0 2.0 3.0 Yield (%) 31 50 62

[0078] It can be seen from the above table that when other reaction conditions remain unchanged and the amount of diphenylphosphine oxide is 3 times the equivalent of the 1,6-enyne compound, the yield of the product is the highest.

[0079] After further research, the applicant of the present patent application found that when the amount of diphenylphosphine oxide in the above preparation method is increased to 3 times the equivalent of 1,6-enyne compounds, the phosphorus free radicals formed by diarylphosphine oxide catalyzed by the photocatalyst under room temperature light in the reaction system are more likely to be generated, which is more conducive to the reaction to the right; but if the amount is further increased, due to the influence of chemical equilibrium, the excess reactant will inhibit the reaction from proceeding to the right. Therefore, when other reaction conditions remain unchanged and the amount of diphenylphosphine oxide is 3 times the equivalent of 1,6-enyne compounds, the yield of the product phosphonyl dihydropyran derivative is the highest.

[0080] 3. Comparison of types of inorganic bases

[0081] The reaction conditions were the same as in Example 1, and different types of inorganic bases were used. The product yields are shown in the following table:

[0082] Table 3 Product yields of different types of inorganic bases

[0083]

[0084]

[0085] From the above table, we can see that when other reaction conditions remain unchanged, the inorganic base is Cs 2 CO 3 The product yield is the highest.

[0086] The applicant of the present invention has found through further research that when the inorganic base is selected from Cs 2 CO 3 Compared with other inorganic bases, such as NaHCO 3 、Na 2 CO 3 etc., Cs 2 CO 3 It has a better promoting effect on the generation of phosphorus free radicals. Therefore, when other reaction conditions remain unchanged, the inorganic base is selected as Cs 2 CO 3 When , the yield of the product phosphonyl dihydropyran derivative is the highest.

[0087] 4. Comparison of light source types

[0088] The reaction conditions were the same as in Example 1, but different light sources were used. The product yields are shown in the following table:

[0089] Table 4 Product yields under different light sources

[0090] light source 6W blue light 9W blue light 12W blue light Yield (%) 55 51 62

[0091] It can be seen from the above table that when other reaction conditions remain unchanged and 12W blue light is used as the light source, the yield of the product is the highest.

[0092] The applicant of the present patent has found through further research that in the above preparation method, when the light source is 12W blue light, it has a better promoting effect on the generation of phosphorus free radicals compared with other powers of blue light, such as 6W blue light, 9W blue light, etc. Therefore, when other reaction conditions remain unchanged and the light source is 12W blue light, the yield of the product phosphonyl dihydropyran derivative is the highest.

[0093] Example 2 Preparation and Characterization of (4-(3-chlorophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide

[0094] The same method and reaction conditions as in Example 1 are used, and when the 1,6-enyne compound is 1-(3-(allyloxy)prop-1-yn-1-yl)-3-chlorobenzene, the following target product 2 is obtained. The yield of the preparation method is 60%, and the yield of the preparation method in this example is relatively high. The chemical reaction equation corresponding to this example is as follows:

[0095]

[0096] The yellow oil prepared in Example 2 was characterized, and its hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, phosphorus nuclear magnetic resonance spectrum and high-resolution mass spectrum were as follows: Figure 5 , Figure 6 , Figure 7 and Figure 8 As shown. Figure 5 It can be seen 1 H NMR (400 MHz, CDCl 3 )δ7.68-7.58(m,2H),7.56-7.44(m,3H), 7.42-7.34(m,1H),7.29(dd,J=7.8,3.1Hz,2H),7.00-6.91(m,3H),6.83-6.77(m,1H),4.30(ddd,J=16.7,4.1,1.6Hz,1H),4.08(dt,J=16.7,2.6Hz,1H),3.87(dd,J =11.2,4.0Hz,1H),3.73(dd,J=11.2,3.5Hz,1H),2.47(s,1H),0.96(d,J=7.1Hz, 3H); The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 6 It can be seen that: 13 C NMR (100MHz,CDCl3 )δ154.7(d,J=3.8Hz),140.4(d,J=8.1Hz),133.4,132.3(d,J =101.5Hz), 132.1(d, J=103.5Hz), 131.7(d, J=2.9Hz), 131.4(d, J=3.0Hz), 131.3(d, J=9.6Hz), 131.2(d, J=9.8Hz), 128.8, 128.48, 128.45(d, J=12Hz), 128.4(d, J=94.4Hz), 128.1(d, J=12.1Hz), 127.6, 127.2, 70.2, 68.0(d, J=18.6Hz), 36.3(d, J=9.5Hz), 16.9; The molecular carbon spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 7 It can be seen that: 31 PNMR (162MHz, CDCl 3 )δ22.4. Figure 8 It can be seen that: HRMS (ESI-Orbitrap) m / z: [M+H] + Calculate for C 24 H 22 C1O 2 P 409.1119, found 409.1115. Combining the results of the above nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, nuclear magnetic resonance phosphorus spectrum and high-resolution mass spectrum, it can be seen that Example 2 successfully synthesized the compound (4-(3-chlorophenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl) diphenylphosphine oxide, and its molecular structure is as follows:

[0097]

[0098] The preparation method in this embodiment first uses a very small amount (only 9.1 mg, 5% mol) of low-toxic photocatalyst (4,4'-di-tert-butyl-2,2'-bipyridine) bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate to replace the expensive and highly toxic transition metal-induced phosphorus free radicals, which is relatively more environmentally friendly; then, the preparation method only needs to be stirred under air at room temperature under light to complete the reaction, does not require a high reaction temperature, avoids excessive energy consumption, and conforms to the concept of green environmental protection; finally, the preparation method in this embodiment only needs to be stirred under air at room temperature under light to complete the reaction in a colorless and transparent reaction tube, the operation is relatively simple, and the post-processing only needs thin layer chromatography (TLC) to detect the progress of the reaction, and then the final product is separated and purified by column chromatography, that is, the post-processing is convenient.

[0099] Example 3 Preparation and Characterization of (4-(4-tert-butylphenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl)diphenylphosphine oxide

[0100] Using the same method and reaction conditions as in Example 1, when the 1,6-ene yne compound is 1-(3-(allyloxy)prop-1-yn-1-yl)-4-tert-butylbenzene, the following white solid product is obtained, and the yield of the preparation method is 61%. The yield of the preparation method in this example is relatively high. The chemical reaction equation corresponding to this example is as follows:

[0101]

[0102] The white solid product prepared in Example 3 was characterized and tested to have a melting point of 201-205° C. In addition, its hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, phosphorus nuclear magnetic resonance spectrum and high-resolution mass spectrum were tested as follows: Fig. 9 , Fig.10 , Fig.11 and Fig.12 As shown. Fig. 9 It can be seen 1 H NMR (400 MHz, CDCl 3 )δ7.65-7.58(m,2H),7.52-7.44(m,3H),7.40-7.32(m,1H), 7.19(dd,J=8.3,2.5Hz,2H),6.95-6.87(m,4H),4.33(ddd,J=16.4,4.2,1.5Hz,1H),4.10(dt,J=16.5,2.5Hz,1H),3.88(dd,J=11.1,4.0Hz,1H),3.75(dd,J=11.2, 3.2Hz,1H),2.52(s,1H),1.17(s,9H),0.97(d,J=7.1Hz,3H); The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Fig.10 It can be seen that: 13 C NMR (100 MHz, CDCl 3)δ 156.5(d,J=3.7Hz),150.0,135.7(d,J=8Hz),132.8(d,J=101.3Hz),132.6(d,J= 103.5Hz),131.4(d,J=9.5Hz),131.3(d,J=2.8Hz),131.2(d,J=9.8Hz),130.9(d, J=2.7Hz), 128.34, 128.28 (d, J=11.7Hz), 127.9 (d, J=12.2Hz), 126.7 (d, J=96.6Hz), 124.3, 70.4, 68.1 (d, J=18.9Hz), 36.4 (d, J=9.8Hz), 34.3, 31.1, 17.2; the molecular carbon spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Fig.11 It can be seen that: 31 P NMR (162 MHz, CDCl 3 )δ23.0. Fig.12 It can be seen that: HRMS (ESI-Orbitrap) m / z: [M+H] + Calculate for C 28 H 31 O 2 P 431.2134, found 431.2130. Combining the results of the above nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, nuclear magnetic resonance phosphorus spectrum and high-resolution mass spectrum, it can be seen that Example 3 successfully synthesized the compound (4-(4-tert-butylphenyl)-5-methyl-5,6-dihydro-dihydropyran-3-yl) diphenylphosphine oxide, and its molecular structure is as follows:

[0103]

[0104] The preparation method in this embodiment first uses a very small amount (only 9.1 mg, 5% mol) of low-toxic photocatalyst (4,4'-di-tert-butyl-2,2'-bipyridine) bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate to replace the expensive and highly toxic transition metal-induced phosphorus free radicals, which is relatively more environmentally friendly; then, the preparation method only needs to be stirred under air at room temperature under light to complete the reaction, does not require a high reaction temperature, avoids excessive energy consumption, and conforms to the concept of green environmental protection; finally, the preparation method in this embodiment only needs to be stirred under air at room temperature under light to complete the reaction in a colorless and transparent reaction tube, the operation is relatively simple, and the post-processing only needs thin layer chromatography (TLC) to detect the progress of the reaction, and then the final product is separated and purified by column chromatography, that is, the post-processing is convenient.

[0105] In summary, this patent application discloses a method for preparing a phosphono-substituted six-membered cyclic compound, wherein 1,6-enyne compounds, diarylphosphine oxides, inorganic bases and photocatalysts are dissolved in a solvent, and in an air atmosphere, under light and stirring at room temperature, intermolecular free radical addition / cyclization reactions occur to prepare the target product, and after the reaction is complete, the product is separated and purified by column chromatography, and then the product is obtained by 1 H NMR, 13 C NMR, 31 The structure of the target product was characterized and analyzed by P NMR and HRMS.

[0106] In addition, the preparation method of the patent application does not require complex reaction conditions such as high temperature and toxic transition metal catalysis, and can obtain phosphonyl dihydropyran derivatives with broad application prospects under mild reaction conditions (i.e., stirring under light at room temperature in air). That is, the preparation method has the advantages of mild reaction conditions, simple operation, convenient subsequent treatment, and easy availability of raw materials, which conforms to the concept of green environmental protection.

[0107] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiments or examples are included in at least one embodiment or example of this patent application. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0108] Although several embodiments of the present patent application have been shown and described, those skilled in the art will appreciate that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present patent application, and the scope of the present patent application is defined by the claims and their equivalents.

Claims

1. A method for preparing a phosphonyldihydropyran derivative, characterized in that: include: The 1,6-enyne compound represented by formula (I), the diarylphosphine represented by formula (II), an inorganic base and a photocatalyst are dissolved in a solvent, and a chemical reaction of the following reaction equation is carried out in air at room temperature under light and stirring to prepare the target product. After the reaction is complete, the product is separated and purified by column chromatography to obtain the phosphonodihydropyran derivative represented by formula (III): The reaction is carried out under visible light irradiation, and the visible light source is any one of 6W blue light, 9W blue light, and 12W blue light. The photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, and R is a halogen or an alkyl group.

2. The method for preparing the phosphonodihydropyran derivative according to claim 1, characterized in that: The solvent is selected from any one or more of acetonitrile, dichloromethane, tetrahydrofuran and dimethyl sulfoxide.

3. The method for preparing the phosphonodihydropyran derivative according to claim 2, characterized in that: The solvent is dimethyl sulfoxide.

4. The method for preparing the phosphonodihydropyran derivative according to claim 1, characterized in that: The molar ratio of the 1,6-eneyne compound to the diarylphosphine oxide is 1:(1.0-3.0).

5. The method for preparing the phosphonodihydropyran derivative according to claim 1, characterized in that: The inorganic base is selected from any one or more of Cs2CO3, Na2CO3 and NaHCO3.

6. The method for preparing the phosphonodihydropyran derivative according to claim 5, characterized in that: The inorganic base is Cs2CO3.

7. The method for preparing the phosphonodihydropyran derivative according to claim 1, characterized in that: The visible light source is 12W blue light.

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