Phosphine-containing oxapentacyclic heterocyclic compounds and methods for their preparation

Abstract

The application discloses a phosphine-containing oxypentacyclic compound and a preparation method thereof, relates to the technical field of organic synthesis, and discloses a high-efficiency radical hydrophosphonylation reaction of 1,6-alkenyl alkyne and a secondary phosphine oxide compound through visible light oxidation-reduction catalysis. Under simple operation and mild conditions without alkali, various pentacyclic compounds containing a secondary phosphine oxide group are obtained. The preparation method has good regioselectivity, is easy to expand, and the prepared phosphine-containing oxypentacyclic compound has a good inhibitory effect on mouse colon cancer cells MC38.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to phosphine-oxygen five-membered heterocyclic compounds and their preparation methods. Background Technology

[0002] Heterocyclic skeletons are widely found in natural products and exhibit excellent pharmacological properties. Therefore, the efficient synthesis of heterocyclic compounds and their derivatives has attracted great attention from chemists in the development of new drugs. 1,6-Enyne derivatives are widely used as synthons for synthesizing complex molecular structures, such as complex carbocyclic rings, heterocyclic rings, and bridged rings, and occupy an extremely important position in the fields of materials science, organometallic chemistry, and biochemistry.

[0003] In existing technologies, five-membered heterocyclic compounds can be rapidly constructed via the visible-light-catalyzed hydrophosphonylation of 1,6-enyne. This method uses 1,6-enyne and diarylphosphine oxides as substrates, Eosin Y as a photocatalyst, and proceeds sequentially through three pathways: radical addition, cyclization, and hydrogen atom transfer, ultimately yielding phosphonyl-substituted five-membered nitrogen heterocyclic compounds. Another method utilizes nitrogen-containing heterocyclic carbazoles with diarylphosphine oxides to directly achieve oxidative cross-dehydrogenation coupling via green electrochemistry under oxidant-free conditions. This reaction yields various carbazole and indole compounds containing phosphonyl substitutions in moderate to excellent yields. Furthermore, the phosphonylation and cyclization of alkenylaminopyridines or acylaminopyridines with secondary phosphine oxides via Pd-catalyzed transition metal coupling can synthesize phosphonyl-azoquinolines and α-azooxyindole. This reaction uses alkyl, alkoxy, and aryl secondary phosphine oxides as phosphine sources, exhibiting a broad substrate range and good functional group compatibility.

[0004] Although these methods yield five-membered nitrogen heterocyclic phosphine oxides with relatively good yields and functional group tolerance, their substrate scope is narrow. The use of metal catalysts and other conditions leaves room for us to find more direct and effective new methods to obtain five-membered nitrogen heterocyclic compounds containing phosphine oxide groups. Summary of the Invention

[0005] To address the aforementioned shortcomings of the prior art, this invention provides a phosphine-oxygen five-membered heterocyclic compound and its preparation method.

[0006] To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows:

[0007] Provided are phosphine-oxygen five-membered heterocyclic compounds, including compounds of the following general formula III(a):

[0008]

[0009] In the formula, R 1 R is aryl; R is phenyl; R 2is methyl, and X is p-toluenesulfonamide (NTs).

[0010] Furthermore, the aryl group is phenyl, substituted phenyl, naphthyl, or pyridyl;

[0011] The substituted phenyl group is a bromo-substituted phenyl group, a methoxycarbonyl-substituted phenyl group, or a methoxy-substituted phenyl group;

[0012] The specific structural formulas of different aryl compounds are as follows:

[0013]

[0014] Among them, R in equation III-1 1 It is phenyl; R of formula III-2 1 It is a bromine-substituted phenyl; R of formula III-3 1 It is a methoxycarbonyl-substituted phenyl; R of formula III-4 1 It is 2-naphthyl; R of formula III-5 1 It is 2-pyridyl; R of formula III-6 1 It is a methoxy-substituted phenyl group.

[0015] Another type of phosphine-oxygen five-membered heterocyclic compound includes compounds of formula III(b) as follows:

[0016]

[0017] A method for preparing a phosphine-oxygen five-membered heterocyclic compound of general formula III(a) using a 1,6-enyne substrate of general formula I(a);

[0018]

[0019] The specific steps are as follows: A 1,6-enyne substrate of general formula I(a), blue fluorescent material 4CzFCN, and diphenylphosphine oxide are mixed. Dichloroethane (DCE) is added under argon atmosphere. After deoxygenation by freezing, the mixture is stirred continuously for 24 hours under the illumination of a 40W blue LED lamp to obtain a phosphine-oxygen five-membered heterocyclic compound of general formula III(a). The reaction process is as follows:

[0020]

[0021] Among them, R 2 X is methyl, and R is p-toluenesulfonamide (NTs). 1 R is phenyl, substituted phenyl, naphthyl, or pyridyl; and the substituted phenyl is a bromosubstituted phenyl, a methoxycarbonylsubstituted phenyl, or a methoxysubstituted phenyl; R is phenyl.

[0022] A method for preparing a phosphine-oxygen five-membered heterocyclic compound of general formula III(b) using a 1,6-enyne substrate of formula I(b);

[0023]

[0024] The specific steps are as follows: 1,6-enyne substrate of formula I(b), blue fluorescent material 4CzFCN, and diphenylphosphine oxide are mixed, and dichloroethane (DCE) is added under argon atmosphere. After deoxygenation by freezing, the mixture is stirred continuously for 24 hours under the illumination of a 40W blue LED lamp to obtain the phosphine-oxygen five-membered heterocyclic compound of general formula III(b). The reaction process is as follows:

[0025]

[0026] Among them, R 2 X is methyl, and R is p-toluenesulfonamide (NTs). 1 R is phenyl; R is phenyl.

[0027] When preparing the phosphine oxide five-membered heterocyclic compound of general formula III(a) or III(b), the concentration of dichloroethane (DCE) is 0.1 mol / L; the molar ratio of the 1,6-enyne substrate to diphenylphosphine oxide is 1:3.

[0028] Furthermore, the freezing deoxygenation process specifically involves freezing the mixed solution, then evacuating it under vacuum, and then thawing it, repeating this process three times.

[0029] Furthermore, the molar ratio of the 1,6-enyne substrate to diphenylphosphine oxide is 1:3.

[0030] Furthermore, after the light exposure is complete, concentration and purification are required. The specific steps are as follows: the crude product is obtained by vacuum concentration, and the crude product is separated and purified by column chromatography; during purification, petroleum ether: ethyl acetate = 1:1 is used.

[0031] Furthermore, the method for preparing the 1,6-enyne substrate of general formula I(a) is as follows:

[0032] A1: Take p-toluenesulfonamide and potassium carbonate, add acetonitrile to obtain a mixed solution, add propargyl bromide to the mixed solution, stir at 80℃ for 14 hours, concentrate under reduced pressure, and then separate and purify the crude product by column chromatography using petroleum ether:ethyl acetate = 5:1 to obtain intermediate product S2.

[0033] A2: Dissolve 2-methyl-3-bromopropene and potassium carbonate in acetone, add intermediate S2, heat under reflux for 5 hours, then stir at room temperature for 16 hours; after concentration under reduced pressure, dissolve the crude product in ethyl acetate, wash three times with water, and then wash with saturated brine; after washing, dry with anhydrous sodium sulfate, distill the dried product under reduced pressure, and then purify by column chromatography using petroleum ether:ethyl acetate = 10:1 to obtain intermediate S3.

[0034] A3: Intermediate S3, palladium dichloride bis(triphenylphosphine), cuprous iodide, and R... 1 The iodinated compounds were mixed, and the solvent Et3N was added under argon atmosphere. The mixture was stirred at 50°C for 12 hours. After stirring, the mixture was cooled to room temperature, filtered, washed with EA, and concentrated under vacuum. The crude mixture obtained by concentration was purified by column chromatography to obtain the 1,6-enyne substrate of product formula I(a).

[0035] The reaction process is as follows:

[0036]

[0037] Furthermore, the method for preparing the 1,6-enyne substrate of formula I(b) is as follows:

[0038] A1: Take p-toluenesulfonamide and potassium carbonate, add acetonitrile to obtain a mixed solution, add propargyl bromide to the mixed solution, stir at 80℃ for 14 hours, concentrate under reduced pressure, and then separate and purify the crude product by column chromatography using petroleum ether:ethyl acetate = 5:1 to obtain intermediate product S2.

[0039] A2: After dissolving intermediate S2 in DCM, diisopropylethylamine was added, the mixture was cooled to 0°C, and methacryloyl chloride was slowly added dropwise. Then the temperature was raised to room temperature and stirred for 1 hour at room temperature. After stirring, the reaction was quenched with water, then extracted with DCM and dried with anhydrous sodium sulfate. The dried product was concentrated under reduced pressure, and the crude product obtained by concentration was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 to obtain intermediate S4.

[0040] A3: Intermediate S4, palladium dichloride bis(triphenylphosphine), cuprous iodide, and R... 1 The iodinated compounds were mixed, and the solvent Et3N was added under argon atmosphere. The mixture was stirred at 50°C for 12 hours. After stirring, the mixture was cooled to room temperature, filtered, washed with EA, and concentrated under vacuum. The crude mixture obtained by concentration was purified by column chromatography to obtain the 1,6-enyne substrate of product formula I(b).

[0041] The reaction process is as follows:

[0042]

[0043] The beneficial effects of this invention are as follows:

[0044] This invention develops a highly efficient radical hydrophosphonylation reaction of 1,6-enyne with secondary phosphoxy compounds via visible light redox catalysis. Various five-membered heterocyclic compounds containing secondary phosphoxy groups are obtained under simple operation and mild conditions without the need for bases. The preparation method of this invention exhibits good regioselectivity, is easily expandable, and the obtained phosphoxy-containing five-membered heterocyclic compounds show good inhibitory effects on mouse colon cancer cells MC38. Detailed Implementation

[0045] The specific embodiments of the present invention are described below to enable those skilled in the art to understand the present invention. However, it should be understood that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, various changes are obvious as long as they are within the spirit and scope of the present invention as defined and determined by the appended claims. All inventions utilizing the concept of the present invention are protected.

[0046] Example 1

[0047] Detailed information on each raw material for the preparation of 1,6-enyne substrates is shown in Table 1.

[0048] Table 1

[0049] Drug Name brand Item number p-Toluenesulfonamide Aladdin T102875-500g Potassium carbonate Myriel M20447-500G 3-Bromopropyne Adamas 13127AF Methacryl chloride Aladdin M109517-100g Diisopropylethylamine TCI D1599-500ML bis(triphenylphosphine)palladium dichloride J&K 242195 Cuprous iodide 3A Chemicals A00108

[0050] The specific steps are as follows: A1: Take 40 mmol of p-toluenesulfonamide and 96 mmol of potassium carbonate and place them in a 250 mL round-bottom flask. Add 80 mL of acetonitrile to obtain a mixed solution. Add 40 mmol of propargyl bromide to the mixed solution and stir at 80 °C for 14 hours. After concentration under reduced pressure, the crude product is separated and purified by column chromatography. During purification, petroleum ether: ethyl acetate = 5:1 is used to obtain 8.1 g of intermediate product S2.

[0051] A2: 32 mmol of 2-methyl-3-bromopropene and 32 mmol of potassium carbonate were dissolved in 60 mL of acetone. 4.185 g of intermediate S2 was added, and the mixture was heated under reflux for 5 hours, followed by stirring at room temperature for 16 hours. After concentration under reduced pressure, the crude product was dissolved in ethyl acetate, washed three times with water, and then washed with saturated brine. After washing, the product was dried with anhydrous sodium sulfate, and the dried product was distilled under reduced pressure and then purified by column chromatography using petroleum ether:ethyl acetate = 10:1 to obtain 2.7 g of intermediate S3.

[0052] A3: Dissolve 2.09 g of intermediate product S2 in 50 mL of DCM, add 15 mmol of diisopropylethylamine, cool the mixture to 0 °C, slowly add 12 mmol of methacryloyl chloride, then heat to room temperature and stir for 1 hour at room temperature; after stirring, perform water quenching reaction, then extract with DCM and dry with anhydrous sodium sulfate, concentrate the dried product under reduced pressure, and purify the crude product obtained by column chromatography using petroleum ether:ethyl acetate = 5:1 to obtain 1.3 g of intermediate product S4;

[0053] A4: Take intermediate product S3 (3 mmol, 1 equiv.) or intermediate product S4 (3 mmol, 1 equiv.), 2.0 mol% of bis(triphenylphosphine)palladium dichloride, 5.0 mol% of cuprous iodide and different aryl iodides (3.3 mmol, 1.1 equiv.), add 0.25 M solvent Et3N under argon atmosphere, and stir at 50 °C for 12 hours. After stirring, cool to room temperature, filter, wash with EA and concentrate under vacuum. Purify the crude mixture obtained by column chromatography to obtain the 1,6-enyne substrate of formula I(a) or formula I(b);

[0054] Example 2

[0055] The 1,6-enyne substrate of formula I-1 was prepared according to the method of Example 1;

[0056]

[0057] Phosphine-containing oxygen five-membered heterocyclic compounds of formula III-1 were prepared using 1,6-enyne substrates of formula I-1.

[0058]

[0059] The specific steps are as follows: 0.4 mmol of compound I-1, 1.2 mmol of diphenylphosphine oxide, and 3.0 mol% of blue fluorescent material 4CzFCN were dissolved in 4 mL of dichloroethane (DCE) solvent. After deoxygenation, the mixture was stirred at room temperature under blue light irradiation for 24 h. The reaction was confirmed by TLC to be complete. After the reaction of compound I-1 was completed, the solvent was evaporated under reduced pressure, and the mixture was loaded onto a silica gel column for column chromatography separation at a ratio of petroleum ether:ethyl acetate = 1:1. The chromatographic solution was removed under reduced pressure to obtain the phosphine-oxygen five-membered heterocyclic compound III-1 (106.1 mg, E:Z = 3.2:1).

[0060] Its main configuration product is a pale yellow oily substance; 1H NMR (400MHz, CDCl3) δ7.66 (d, J=7.9Hz, 2H), 7.47-7.40 (m, 4H), 7.40-7.35 (m, 4H), 7.35-7.27 (m, 6H), 7.13 (d, J=6.9Hz, 2H), 6.46 (s, 1H), 4.03 (d, J=13.6Hz, 1H), 3.79 (d, J=14.7Hz, 1H), 3.32 (s, 2H), 2.56 (dd, J=15.3, 8.9Hz, 1H), 2.41 (s, 3H), 2.17 (dd, J=15.3, 12.4Hz, 1H), 1.15 (s, 3H); 13 C NMR (100MHz, CDCl3) δ145.9 (d, J C-P =12.5Hz), 143.4, 136.6, 134.7 (d, J C-P =97.7Hz), 134.1 (d, J) C-P =96.6Hz), 132.0, 131.28 (d, J C-P =2.1Hz), 131.26 (d, J) C-P =2.3Hz), 130.2 (d, J) C-P =9.0Hz), 129.9 (d, J) C-P =9.1Hz), 129.5, 128.8, 128.4 (d, J C-P =11.4Hz), 128.3 (d, J) C-P =11.5Hz), 128.1, 127.9, 127.1, 122.9, 60.8 (d, J C-P =1.9Hz), 52.9, 44.6 (d, J) C-P =4.1Hz), 37.8 (d, J) C-P =67.6Hz), 25.8 (d, J) C-P =3.2Hz), 21.4; 31 P NMR (162MHz, CDCl3) δ26.7. (80.8mg, 37% yield)

[0061] Secondary configuration product: pale yellow oily substance; 1H NMR (400MHz, CDCl3) δ7.77-7.60 (m, 6H), 7.51-7.40 (m, 3H), 7.39-7.27 (m, 5H), 7.25-7.14 (m, 3H), 6.80 (d, J=7.2Hz, 2H), 6.35 (s, 1H), 3.95 (dd, J= 14.8, 2.7Hz, 1H), 3.78 (dd, J=14.9, 2.3Hz, 1H), 3.50 (d, J=9.4Hz, 1H), 2. 84-2.68 (m, 2H), 2.51 (dd, J=15.1, 12.6Hz, 1H), 2.39 (s, 3H), 1.50 (s, 3H); 13 C NMR (100MHz, CDCl3) δ143.7, 141.9 (d, J C-P =7.2Hz), 135.7, 135.0 (d, J C-P =98.1Hz), 133.7 (d, J) C-P =97.8Hz), 132.8, 131.5 (d, J C-P =2.8Hz), 131.1 (d, J) C-P =2.9Hz), 130.5 (d, J) C-P =9.0Hz), 130.3 (d, J) C-P =9.0Hz), 129.7, 128.7 (d, J C-P =11.8Hz), 128.5 (d, J) C-P =12.0Hz), 128.3, 128.2, 127.7, 127.2, 124.2, 59.9 (d, J C-P =8.8Hz), 50.5, 46.0 (d, J) C-P =70.3Hz), 38.4 (d, J) C-P =2.6Hz), 24.0, 21.5; 31 P NMR (162MHz, CDCl3) δ26.7.

[0062] Example 3

[0063] The 1,6-enyne substrate of formula I-2 was prepared according to the method of Example 1.

[0064]

[0065] Phosphine-containing oxygen five-membered heterocyclic compounds of formula III-2 were prepared using 1,6-enyne substrates of formula I-2.

[0066]

[0067] The specific steps are as follows: 0.3 mmol of compound I-2, 0.9 mmol of diphenylphosphine oxide, and 3.0 mol% of blue fluorescent material 4CzFCN were dissolved in 3 mL of dichloroethane (DCE) solvent. After deoxygenation, the mixture was stirred at room temperature under blue light irradiation for 24 h. The reaction was confirmed by TLC to be complete. After the reaction of compound I-2 was completed, the solvent was evaporated under reduced pressure, and the mixture was loaded onto a silica gel column for column chromatography separation with a petroleum ether:ethyl acetate ratio of 1:1. The chromatographic solution was removed under reduced pressure to obtain the phosphine-oxygen five-membered heterocyclic compound III-2 (76.1 mg).

[0068] Its main configuration product is a pale yellow oily substance; 1 H NMR (400MHz, CDCl3) δ7.65 (d, J=8.2Hz, 2H), 7.51-7.45 (m, 4H), 7.45-7.43 (m, 2H), 7.43-7.36 (m, 6H), 7.30 (d, J=8.0Hz, 2H), 7.00 (d, J=8.0Hz, 2H ), 6.36 (s, 1H), 3.97 (dd, J=13.9, 2.1Hz, 1H), 3.81 (dd, J=13.8, 2.1Hz, 1H), 3.38 (d, J=9.8Hz, 1H), 3.22 (d, J=9.8Hz, 1H), 2.45 (dd, J=15.2, 8.8Hz 1H), 2.42(s, 3H), 2.23(dd, J=15.3, 12.3Hz, 1H), 1.13(s, 3H); 13 C NMR (100MHz, CDCl3) δ146.8 (d, J C-P =12.0Hz), 143.6, 135.5, 135.5 (d, J C-P =98.0Hz), 133.9 (d, J) C-P =96.5Hz), 131.9, 131.48, 131.45, 131.2, 130.6, 130.3 (d, J C-P =9.1Hz), 130.0 (d, J) C-P =9.2Hz), 129.6, 128.53 (d, J C-P =11.6Hz), 128.48 (d, J) C-P =11.6Hz), 127.9, 121.8, 121.1, 60.6 (d, J C-P =2.1Hz), 53.1, 44.7 (d, J) C-P =4.0Hz), 36.9 (d, J) C-P =67.2Hz), 25.8 (d, J) C-P =3.5Hz), 21.5;31 P NMR (162MHz, CDCl3) δ26.6.

[0069] Example 4

[0070] 1,6-enyne substrates of formula I-3 were prepared according to the method in Example 1.

[0071]

[0072] Phosphine-oxygen five-membered heterocyclic compounds of formula III-3 were prepared using 1,6-enyne substrates of formula I-3.

[0073]

[0074] The specific steps are as follows: 0.3 mmol of compound I-3, 0.9 mmol of diphenylphosphine oxide, and 3.0 mol% of blue fluorescent material 4CzFCN were dissolved in 3 mL of dichloroethane (DCE) solvent. After removing oxygen, the mixture was stirred at room temperature under blue light irradiation for 24 h. The reaction of the raw material was confirmed by TLC. After the reaction of compound I-3 was completed, the solvent was evaporated under reduced pressure, and the mixture was loaded onto a silica gel column for column chromatography separation with a petroleum ether:ethyl acetate ratio of 1:1. The chromatographic solution was removed under reduced pressure to obtain the phosphine-oxygen five-membered heterocyclic compound III-3 (71.9 mg).

[0075] Its main configuration product is a pale yellow oily substance; 1 H NMR (400MHz, CDCl3) δ7.99 (d, J=8.1Hz, 2H), 7.66 (d, J=8.1Hz, 2H), 7.51-7.40 (m, 5H), 7.40- 7.33 (m, 5H), 7.30 (d, J=8.1Hz, 2H), 7.21 (d, J=8.1Hz, 2H), 6.45 (s, 1H), 4.01 (dd, J=14.0, 1. 6Hz, 1H), 3.96 (s, 3H), 3.84 (dd, J=14.0, 1.7Hz, 1H), 3.40 (d, J=9.8Hz, 1H), 3.24 (d, J=9.8Hz , 1H), 2.46 (dd, J=15.2, 8.8Hz, 1H), 2.42 (s, 3H), 2.24 (dd, J=15.0, 12.6Hz, 1H), 1.13 (s, 3H); 13 C NMR (100MHz, CDCl3) δ166.5, 147.3 (d, J C-P =12.0Hz), 143.6, 141.5, 134.5 (d, J C-P =98.1Hz), 134.0 (d, J) C-P=96.8Hz), 132.1, 131.47, 131.45, 130.3 (d, J C-P =9.0Hz), 130.0 (d, J) C-P =9.3Hz), 129.6, 129.3, 129.0, 128.9, 128.5 (d, J C-P =11.5Hz), 128.4 (d, J) C-P =11.6Hz), 127.9, 122.0, 60.7 (d, J C-P =2.0Hz), 53.1, 52.1, 44.8 (d, J C-P =4.0Hz), 36.9 (d, J) C-P =67.4Hz), 25.7 (d, J) C-P =3.5Hz), 21.4; 31 P NMR (162MHz, CDCl3) δ26.5.

[0076] Example 5

[0077] 1,6-enyne substrates of formula I-4 were prepared according to the method in Example 1.

[0078]

[0079] Phosphine-containing oxygen five-membered heterocyclic compounds of formula III-4 were prepared using 1,6-enyne substrates of formula I-4.

[0080]

[0081] The specific steps are as follows: 0.3 mmol of compound I-4, 0.9 mmol of diphenylphosphine oxide, and 3.0 mol% of blue fluorescent material 4CzFCN were dissolved in 3 mL of dichloroethane (DCE) solvent. After deoxygenation, the mixture was stirred at room temperature under blue light irradiation for 24 h. The reaction of the raw material was confirmed by TLC. After the reaction of compound I-4 was completed, the solvent was evaporated under reduced pressure, and the mixture was loaded onto a silica gel column for column chromatography separation with a petroleum ether:ethyl acetate ratio of 1:1. The chromatographic solution was removed under reduced pressure to obtain the phosphine-oxygen five-membered heterocyclic compound III-4 (51.4 mg).

[0082] Its main configuration product is a pale yellow oily substance; 1H NMR (400MHz, CDCl3) δ7.93-7.86 (m, 1H), 7.82 (d, J=8.4Hz, 1H), 7.80-7.74 (m, 1H), 7.69 (d, J= 7.9Hz, 2H), 7.60(s, 1H), 7.59-7.52(m, 2H), 7.44-7.36(m, 1H), 7.35-7.22(m, 8H), 7.17-7.07( m, 2H), 7.06-6.95 (m, 2H), 6.62 (s, 1H), 4.07 (d, J = 14.1Hz, 1H), 3.85 (d, J = 13.8Hz, 1H), 3.34 ( s, 2H), 2.55 (dd, J=15.3, 8.6Hz, 1H), 2.43 (s, 3H), 2.16 (dd, J=15.6, 12.8Hz, 1H), 1.16 (s, 3H); 13 C NMR (100MHz, CDCl3) δ146.7 (d, J C-P =12.4Hz), 143.5, 134.9 (d, J C-P =97.8Hz), 134.2, 134.0 (d, J C-P =96.6Hz), 133.0, 132.3 (d, J C-P =1.7Hz), 131.3 (d, J) C-P =2.7Hz), 131.2 (d, J) C-P =2.8Hz), 130.2 (d, J) C-P =9.0Hz), 130.0 (d, J) C-P =9.1Hz), 129.6, 128.4 (d, J C-P =11.5Hz), 128.3 (d, J) C-P =11.5Hz), 128.1, 127.79, 127.75, 127.70, 127.1, 126.6, 126.3, 123.1, 60.9 (d, J C-P =1.3Hz), 53.1, 44.8 (d, J) C-P =3.9Hz), 37.0 (d, J) C-P =67.6Hz), 26.0 (d, J) C-P =3.4Hz), 21.5; 31 PNMR (162MHz, CDCl3) δ26.6.

[0083] Example 6

[0084] 1,6-enyne substrates of formula I-5 were prepared according to the method in Example 1.

[0085]

[0086] Phosphine-containing oxygen five-membered heterocyclic compounds of formula III-5 were prepared using 1,6-enyne substrates of formula I-5.

[0087]

[0088] The specific steps are as follows: 0.3 mmol of compound I-5, 0.9 mmol of diphenylphosphine oxide, and 3.0 mol% of blue fluorescent material 4CzFCN were dissolved in 3 mL of dichloroethane (DCE) solvent. After deoxygenation, the mixture was stirred at room temperature under blue light irradiation for 24 h. The reaction was confirmed by TLC to be complete. After the reaction of compound I-5 was completed, the solvent was evaporated under reduced pressure, and the mixture was loaded onto a silica gel column for column chromatography separation at a ratio of petroleum ether:ethyl acetate = 1:1. The chromatographic solution was removed under reduced pressure to obtain the phosphine-oxygen five-membered heterocyclic compound III-5 (76.4 mg, E:Z = 2.2:1).

[0089] Its main configuration product is a white solid; 1 H NMR (400MHz, CDCl3) δ8.45 (d, J=4.2Hz, 1H), 7.77-7.61 (m, 6H), 7.55-7.40 (m, 4H), 7.28 (d, J=8.2Hz, 2H), 7.26-7.21 (m, 2H), 7.09-6.86 (m , 2H), 6.32 (s, 1H), 4.34-4.14 (m, 2H), 3.45 (d, J=9.4Hz, 1H), 2.85-2.71 (m, 2H), 2.54 (dd, J=15.1, 12.5Hz, 1H), 2.39 (s, 3H), 1.50 (s, 3H); 13 C NMR (100MHz, CDCl3) δ155.0, 149.0, 148.1 (d, J C-P =13.8Hz), 143.5, 135.7, 134.9 (d, J C-P =97.5Hz), 133.6 (d, J) C-P =97.9Hz), 132.7, 131.5 (d, J C-P =2.8Hz), 130.9 (d, J) C-P =2.7Hz), 130.4 (d, J) C-P =9.0Hz), 130.3 (d, J) C-P =9.1Hz), 129.6, 128.6 (d, J C-P =11.5Hz), 128.4 (d, J) C-P=11.5Hz), 127.9, 124.0, 122.1, 120.9, 59.8 (d, J C-P =8.4Hz), 52.4, 46.1 (d, J) C-P =3.6Hz), 38.6 (d, J) C-P =70.0Hz), 24.0, 21.4; 31 P NMR (162MHz, CDCl3) δ27.2.

[0090] Secondary configuration product: white solid; 1 H NMR (400MHz, CDCl3) δ8.57 (d, J=4.2Hz, 1H), 7.93-7.81 (m, 2H), 7.71 (d, J=8 .1Hz, 2H), 7.60 (m, 1H), 7.51 (m, 5H), 7.41 (t, J=7.3Hz, 1H), 7.35-7.27 (m, 4H ), 7.16-7.02(m, 2H), 6.21(s, 1H), 3.98-3.85(m, 2H), 3.85-3.71(m, 2H), 3.2 0 (d, J=9.8Hz, 1H), 2.89 (dd, J=15.2, 11.7Hz, 1H), 2.43 (s, 3H), 1.33 (s, 3H); 13 C NMR (100MHz, CDCl3) δ154.8, 150.3 (d, J C-P =11.8Hz), 148.5, 143.6, 136.3, 135.2 (d, J C-P =95.5Hz), 134.8 (d, J) C-P =98.5Hz), 131.9, 131.32, 131.18, 130.9 (d, J C-P =8.8Hz), 130.4 (d, J) C-P =9.3Hz), 129.6, 128.34 (d, J C-P =11.8Hz), 128.30 (d, J) C-P =10.6Hz), 128.2, 125.3, 121.9, 121.3, 61.0, 55.1, 45.3, 35.3 (d, J C-P =68.3Hz), 23.4 (d, J) C-P =2.6Hz), 21.5; 31 P NMR (162MHz, CDCl3) δ28.3.

[0091] Example 7

[0092] 1,6-enyne substrates of formula I-6 were prepared according to the method in Example 1.

[0093]

[0094] Phosphine-containing oxygen five-membered heterocyclic compounds of formula III-6 were prepared using 1,6-enyne substrates of formula I-7.

[0095]

[0096] The specific steps are as follows: 0.3 mmol of compound I-7, 0.9 mmol of diphenylphosphine oxide, and 3.0 mol% of blue fluorescent material 4CzFCN were dissolved in 3 mL of dichloroethane (DCE) solvent. After deoxygenation, the mixture was stirred at room temperature under blue light irradiation for 24 h. The reaction was confirmed by TLC to be complete. After the reaction of compound I-7 was completed, the solvent was evaporated under reduced pressure, and the mixture was loaded onto a silica gel column for column chromatography separation with a petroleum ether:ethyl acetate ratio of 1:1. The chromatographic solution was removed under reduced pressure to obtain the phosphine-oxygen five-membered heterocyclic compound III-7 (41.1 mg).

[0097] Its main configuration product is a white solid; 1 H NMR (400MHz, CDCl3) δ7.67 (d, J=8.2Hz, 2H), 7.51-7.41 (m, 4H), 7.32-7.27 (m, 7H), 7.29 ( d, J=8.1Hz, 2H), 7.07 (d, J=7.2, 1H), 6.95 (t, J=7.6Hz, 1H), 6.89 (d, J=8.3Hz, 1H), 6.29 (s , 1H), 4.03 (dd, J=13.7, 2.1Hz, 1H), 3.83 (dd, J=13.7, 2.1Hz, 1H), 3.72 (s, 3H), 3.33 (s, 2H ), 2.60 (dd, J=15.3, 8.8Hz, 1H), 2.42 (s, 3H), 2.21 (dd, J=15.4, 12.5Hz, 1H), 1.08 (s, 3H); 13 C NMR (100MHz, CDCl3) δ156.7, 146.1 (d, J C-P =13.0Hz), 143.4, 135.0 (d, J C-P =97.4Hz), 134.4 (d, J) C-P =96.4Hz), 132.4, 131.31 (d, J C-P =5.2Hz), 131.29 (d, J) C-P =5.5Hz), 130.8, 130.4 (d, J C-P =9.0Hz), 130.1 (d, J)C-P =9.1Hz), 129.6, 129.0, 128.5 (d, J C-P =11.5Hz), 128.4 (d, J) C-P =11.5Hz), 128.0, 125.6, 120.1, 119.3, 110.4, 60.7 (d, J C-P =1.8Hz), 55.2, 52.8, 44.6 (d, J C-P =4.1Hz), 36.1 (d, J) C-P =67.7Hz), 25.1 (d, J) C-P =2.8Hz), 21.5; 31 P NMR (162MHz, CDCl3) δ26.9.

[0098] Example 8

[0099] The 1,6-enyne substrate of formula I(b) was prepared according to the method of Example 1.

[0100]

[0101] Phosphine-oxygen five-membered heterocyclic compounds of formula III-7 were prepared using 1,6-enyne substrates of formula I(b).

[0102]

[0103] The specific steps are as follows: 0.3 mmol of compound I(b), 0.9 mmol of diphenylphosphine oxide, and 3.0 mol% of blue fluorescent material 4CzFCN were dissolved in 3 mL of dichloroethane (DCE) solvent. After deoxygenation, the mixture was stirred at room temperature under blue light irradiation for 27 h. The reaction was confirmed by TLC to be complete. After the reaction of compound I(b) was completed, the solvent was evaporated under reduced pressure, and the mixture was loaded onto a silica gel column for column chromatography separation at a ratio of petroleum ether:ethyl acetate = 1:1. The chromatographic solution was removed under reduced pressure to obtain the phosphine-oxygen five-membered heterocyclic compound III-7 (111.6 mg, E:Z = 1.3:1).

[0104] Its main configuration product is a pale yellow oily substance; 1H NMR (400MHz, CDCl3) δ7.99 (d, J=8.3Hz, 2H), 7.48-7.35 (m, 4H), 7.35-7.17 (m, 8H), 7.15-7.07 (m, 1H), 7.06-6.98 (m, 2H), 6.83 (d, J=7.8 Hz, 2H), 6.54 (s, 1H), 4.90 (dd, J=13.2, 2.2Hz, 1H), 4.65 (dd, J=13.2, 2.0Hz, 1H), 2.83-2.54 (m, 2H), 2.43 (s, 3H), 1.41 (d, J=2.4Hz, 3H); 13 C NMR (100MHz, CDCl3) δ175.9 (d, J C-P =2.5Hz), 144.5, 135.9 (d, J C-P =1.6Hz), 135.5, 134.9, 134.44 (d, J C-P =98.7Hz), 134.2 (d, J) C-P =97.8Hz), 131.3 (d, J) C-P =2.7Hz), 131.1 (d, J) C-P =2.9Hz), 130.3 (d, J) C-P =9.5Hz), 130.2 (d, J) C-P =9.1Hz), 129.2, 128.8, 128.5, 128.3 (d, J C-P =11.7Hz), 128.0 (d, J) C-P =11.9Hz), 127.9, 127.0, 126.3, 52.0, 47.7 (d, J C-P =4.4Hz), 37.0 (d, J) C-P =69.8Hz), 28.6 (d, J) C-P =13.7Hz), 21.6; 31 P NMR (162MHz, CDCl3) δ25.6. (111.6mg, 67% yield, E:Z=1.3:1)

[0105] Secondary configuration product: pale yellow oily substance; 11H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 2H), 7.72 - 7.54 (m, 2H), 7.52 - 7.44 (m, 2H), 7.44 - 7.36 (m, 2H), 7.36 - 7.27 (m, 7H), 7.26 - 7.16 (m, 2H), 6.87 (d, J = 7.1 Hz, 2H), 6.34 (t, J = 2.8 Hz, 1H), 4.84 - 4.49 (m, 2H), 2.90 (dd, J = 15.4, 9.4 Hz, 1H), 2.69 (dd, J = 15.4, 9.5 Hz, 1H), 2.42 (s, 3H), 1.46 (d, J = 1.6 Hz, 3H); 13 13C NMR (100 MHz, CDCl3) δ 175.3 (d, J C-P = 5.5 Hz), 144.9, 135.0, 134.9, 134.1 (d, J C-P = 98.4 Hz), 133.8 (d, J C-P = 2.5 Hz), 133.6 (d, J C-P = 99.1 Hz), 131.42, 131.40, 130.6 (d, J C-P = 9.6 Hz), 130.5 (d, J C-P = 9.6 Hz), 129.4, 128.5 (d, J C-P = 11.8 Hz), 128.44, 128.42 (d, J C-P = 11.8 Hz), 128.32, 128.29, 127.5, 126.7, 50.1, 49.0 (d, J C-P = 3.8 Hz), 38.7 (d, J C-P = 71.1 Hz), 27.2 (d, J C-P = 9.8 Hz), 21.6; 31 31P NMR (162 MHz, CDCl3) δ 26.2.

[0106] Example 9

[0107] The phosphine-containing oxygen five-membered heterocyclic compound III-(1-7) prepared in Examples 2-8 was used as the experimental subject to detect the inhibitory effect of the phosphine-containing oxygen five-membered heterocyclic compound on mouse colon cancer cells (MC38). The inhibitory effect of compound III-(1-7) on cell proliferation was detected using the CCK-8 cell viability assay kit on mouse colon cancer cells (MC38). First, MC38 cells were dispersed in serum-containing medium and evenly seeded in 96-well plates at a density of 3000 cells / well. After 24 hours, different concentrations of each compound (0, 0.5, 1, 2, 5, 10, 20, 50, 100 μM) were set, with 6 replicates per group. The cells were incubated at 37°C for 48 hours. After 48 hours, the medium in the plates was discarded, and 100 μL of fresh medium containing 10% CCK8 reagent was added to each well. The cells were incubated at 37°C for another 2 hours. The absorbance at 450 nm was then measured using a microplate reader, and the cell viability of each compound at different concentrations was detected. The half-maximal inhibitory rate (WHM) of each compound against mouse colon cancer cells (MC38) was calculated based on the cell viability at different concentrations. The results are shown in Table 2.

[0108] Table 2

[0109] compound III-1 III-2 III-3 III-4 III-5 III-6 III-7 <![CDATA[Semi-inhibitory rate IC 50 > 94.48μM 122.0μM 62.94μM 100.4μM 85.97μM 109.3μM 28.62μM

[0110] As shown in Table 1, except for compound III-7, all compounds showed a half-maximal inhibition rate of more than 60 μM against mouse colon cancer cells (MC38).

[0111] This invention utilizes a visible light catalytic strategy to achieve, for the first time, the radical phosphonyl addition cyclization reaction of 1,6-enyne compounds, directly and efficiently synthesizing phosphonyl-substituted pyrrolidine compounds with potential applications.

Claims

1. A phosphine-oxygen five-membered heterocyclic compound, characterized in that, Compounds having the following general formula III(a): Ⅲ（a）； In the formula, R 1 R is phenyl, substituted phenyl, naphthyl, or pyridyl; the substituted phenyl is a bromosubstituted phenyl, a methoxycarbonylsubstituted phenyl, or a methoxysubstituted phenyl; R is phenyl; R 2 is methyl, X is p-toluenesulfonamide (NTs); Ar is phenyl.

2. The phosphine-oxygen five-membered heterocyclic compound according to claim 1, characterized in that, The specific structural formula of the compound is as follows: 。 3. A phosphine-oxygen five-membered heterocyclic compound, characterized in that, Compounds having the following formula Ⅲ(b): Ⅲ（b）。 4. A method for preparing the phosphine-oxygen five-membered heterocyclic compound according to claim 1, characterized in that, Preparation was carried out using 1,6-enyne substrates of general formula I(a); Ⅰ（a）； The specific steps are as follows: A 1,6-enyne substrate of general formula I(a), blue fluorescent material 4CzFCN, and diphenylphosphine oxide are mixed. Dichloroethane (DCE) is added under argon atmosphere. After deoxygenation by freezing, the mixture is stirred continuously for 24 hours under the illumination of a 40W blue LED lamp to obtain a phosphine-oxygen five-membered heterocyclic compound of general formula III(a); wherein, R... 2 X is methyl, and R is p-toluenesulfonamide (NTs). 1 It is phenyl, substituted phenyl, naphthyl or pyridyl; and the substituted phenyl is bromosubstituted phenyl, methoxycarbonylsubstituted phenyl or methoxysubstituted phenyl.

5. A method for preparing the phosphine-oxygen five-membered heterocyclic compound according to claim 3, characterized in that, Preparation was carried out using a 1,6-enyne substrate of formula I(b); Ⅰ（b）； The specific steps are as follows: 1,6-enyne substrate of formula I(b), blue fluorescent material 4CzFCN, and diphenylphosphine oxide are mixed, and dichloroethane (DCE) is added under argon atmosphere. After deoxygenation by freezing, the mixture is stirred continuously for 24 hours under 40W blue LED light to obtain the phosphine-oxygen five-membered heterocyclic compound of general formula III(b); wherein, R 2 X is methyl, and R is p-toluenesulfonamide (NTs). 1 It is a phenyl group.

6. The preparation method according to any one of claims 4 or 5, characterized in that, The molar ratio of the 1,6-enyne substrate to diphenylphosphine oxide is 1:

3.

7. The preparation method according to any one of claims 4 or 5, characterized in that, The freezing and deoxygenation process specifically involves freezing the mixed solution, evacuating it under vacuum, and then thawing it, repeating this process three times.

8. The preparation method according to any one of claims 4 or 5, characterized in that, After the light exposure is complete, concentration and purification are required. The specific steps are as follows: the crude product is obtained by concentration under reduced pressure, and the crude product is separated and purified by column chromatography. The purification method uses petroleum ether:ethyl acetate = 1:

1.

9. The preparation method according to claim 4, characterized in that, The method for preparing the 1,6-enyne substrate of general formula I(a) is as follows: A1: Take p-toluenesulfonamide and potassium carbonate, add acetonitrile to obtain a mixed solution, add propargyl bromide to the mixed solution, stir at 80℃ for 14 hours, concentrate under reduced pressure, and then separate and purify the crude product by column chromatography using petroleum ether:ethyl acetate = 5:1 to obtain intermediate product S2. A2: Dissolve 2-methyl-3-bromopropene and potassium carbonate in acetone, add intermediate S2, heat under reflux for 5 hours, then stir at room temperature for 16 hours; after concentration under reduced pressure, dissolve the crude product in ethyl acetate, wash three times with water, and then wash with saturated brine; after washing, dry with anhydrous sodium sulfate, distill the dried product under reduced pressure, and then purify by column chromatography using petroleum ether:ethyl acetate = 10:1 to obtain intermediate S3. A3: Intermediate S3, palladium dichloride bis(triphenylphosphine), cuprous iodide, and R... 1 The iodinated compounds were mixed, and the solvent Et3N was added under argon atmosphere. The mixture was stirred at 50°C for 12 hours. After stirring, the mixture was cooled to room temperature, filtered, washed with EA, and concentrated under vacuum. The crude mixture obtained by concentration was purified by column chromatography to obtain the 1,6-enyne substrate of product formula I(a).

10. The preparation method according to claim 5, characterized in that, The method for preparing the 1,6-enyne substrate of formula I(b) is as follows: A1: Take p-toluenesulfonamide and potassium carbonate, add acetonitrile to obtain a mixed solution, add propargyl bromide to the mixed solution, stir at 80℃ for 14 hours, concentrate under reduced pressure, and then separate and purify the crude product by column chromatography using petroleum ether:ethyl acetate = 5:1 to obtain intermediate product S2. A2: After dissolving intermediate S2 in DCM, diisopropylethylamine was added, the mixture was cooled to 0°C, and methacryloyl chloride was slowly added dropwise. Then the temperature was raised to room temperature and stirred for 1 hour at room temperature. After stirring, the reaction was quenched with water, then extracted with DCM and dried with anhydrous sodium sulfate. The dried product was concentrated under reduced pressure, and the crude product obtained by concentration was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 to obtain intermediate S4. A3: Intermediate S4, palladium dichloride bis(triphenylphosphine), cuprous iodide, and R... 1 The iodinated compounds were mixed, and the solvent Et3N was added under argon atmosphere. The mixture was stirred at 50°C for 12 hours. After stirring, the mixture was cooled to room temperature, filtered, washed with EA, and concentrated under vacuum. The crude mixture obtained by concentration was purified by column chromatography to obtain the 1,6-enyne substrate of product I(b).

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