Synthesis method and process of an allyl fluoroalkyl compound

Abstract

The invention discloses a synthesis method and process of allyl fluoroalkyl compounds, belonging to the technical field of organic chemistry. In this synthesis method, a fluoroalkyl compound and an olefin derivative undergo a substitution reaction under the catalysis of a cobalt oxime catalyst in an anaerobic and solution environment to generate an allyl fluoroalkyl compound. This method has a wide range of raw material selections. By using an inexpensive and easily available cobalt oxime catalyst under mild reaction conditions, allyl fluoroalkylation can be achieved with high site selectivity, solving the technical problems in the prior art that the reaction substrates are limited, relatively harsh reaction conditions are required, and it is also difficult to control the substitution site selectivity.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemistry, and particularly relates to a synthesis method and process of allyl fluoroalkyl compounds. Background Art

[0002] Fluorine is the element with the highest electronegativity in nature. Introducing fluorine atoms into organic compounds can significantly change the acidity, dipole moment, polarity, lipophilicity, and chemical and metabolic stability of the compounds. Since the first fluorine-containing drug, 5-fluorouracil, was synthesized and applied clinically in the 1960s of the last century, many highly bioactive fluorine-containing drugs have emerged one after another. So far, more than 200 drugs have been put on the market for sale, and fluorine-containing drugs account for about 20% of the entire drugs; in the field of pesticides, fluorine-containing pesticides have reached as high as 30%; the high bond energy of the C-F bond endows its compounds with better thermal stability, and this characteristic also enables fluorine-containing materials to have performance improvements that non-fluorine-containing materials cannot match in material chemistry. Therefore, fluorine-containing compounds have played an increasingly important role in the fields of life science, material chemistry, national defense industry, etc.

[0003] Alkenes, which are inexpensive and readily available bulk chemical products, can be functionalized at the allylic position to be converted into various high-value functional molecules, retaining the double bond of the alkene and also providing the possibility for further synthetic transformation. The classical allylic substitution reaction (such as the Tsuji-Trost reaction, etc.) has now become a powerful means for constructing complex organic molecules, but this reaction mode usually requires pre-functionalization, precious metal catalysts (such as Pd, Ir, Rh, etc.) and complex ligands, etc., which may limit the application prospects of the reaction. The allylic C-H bond functionalization reaction does not require pre-activation of the alkene and has step economy, which is a more attractive strategy. However, since there are usually multiple similar allylic C-H bonds in alkenes, it is usually difficult to control the site selectivity of this reaction mode. Introducing a fluorine-containing group at the allylic position can significantly improve the biological activity of the parent compound. Therefore, it is of great significance to develop a cheap and efficient synthesis method to achieve allylic C-H bond fluoroalkylation.

[0004] In 2010, the Shibata research group used trifluoromethanesulfonic acid to catalyze the intramolecular cyclization reaction of ortho-ethynylaryl trifluoromethyl sulfides to synthesize S-(trifluoromethyl)benzo[b]thiophenium salts (Umemoto-Type Reagents). Under the catalysis of copper, using a special active dicyanoalkene as the substrate, the allylation trifluoromethylation reaction was thus achieved.

[0005] In 2011 and in recent years, the Buchwald research group and the Wang Jianbo research group used copper as a catalyst and Togni's reagent as the CF3 source to achieve the allylic trifluoromethylation of alkenes. In the Buchwald research group's system, [(MeCN)4Cu]PF6 was used as the metal catalyst, while the Wang Jianbo research group used CuCl. However, in Buchwald's method, the substrates were limited to terminal alkenes, and 1,2-disubstituted alkenes and cyclic alkenes were not applicable. These substrates were compatible in the system developed by the Wang Jianbo research group, but required a relatively high temperature. For polysubstituted alkenes or some bioactive alkenes, neither system was applicable. Almost simultaneously, the Liu Lei research group also reported the realization of allylic trifluoromethylation of terminal alkenes by Cu catalysis, but the CF3 source used was Umemoto's reagent, and a product of direct addition to the alkene appeared, with the CF3 group at the α-carbon position of the terminal alkene.

[0006] In 2012, the Qing Fengling research group developed a Cu-catalyzed allylic trifluoromethylation reaction of terminal alkenes, using readily available and relatively inexpensive TMSCF3 as the CF3 source.

[0007] In 2022, the Bi Xihe research group of Northeast Normal University synthesized N-o-trifluoromethylbenzenesulfonylhydrazone as a fluoroalkyl precursor through a "one-pot two-step" method and achieved defluoroallylic fluoroalkylation under the catalysis of silver carbene.

[0008] In the current research on the fluoroalkylation of allylic C–H bonds, relatively expensive Togni's reagent and Umemoto's reagent or relatively complex imine fluoroalkyl precursors need to be synthesized. The substrates are limited and relatively harsh reaction conditions are required. Moreover, the control of site selectivity is also difficult. The fluoroalkyl group is not always at the allylic position and may also appear at the α-carbon position of the terminal alkene, resulting in a product of direct addition to the alkene. Summary of the Invention

[0009] In view of the above-mentioned defects of the prior art, in the first aspect of the present invention, a method for synthesizing an allylic fluoroalkyl compound with mild reaction conditions and precise fluoroalkyl substitution positions is provided, including the following steps:

[0010] The fluoroalkyl compound and the alkene derivative undergo a substitution reaction under the catalysis of a cobalt oxime catalyst in an anaerobic and solution environment to generate an allylic fluoroalkyl compound.

[0011] The inventive concept of the present invention lies in precisely synthesizing allyl fluoroalkyl compounds by using the halogen atom transfer ability (XAT) and hydrogen atom abstraction ability (HAT) of cobaloxime catalysts, and utilizing olefin derivatives and fluoroalkyl compounds. The selectivity of this strategy stems from the unique HAT mode of cobaloxime catalysts, which preferentially abstracts the allylic C-H bond with less steric hindrance, thereby providing excellent selectivity for this reaction. It has advantages such as mild reaction conditions, simple conditions, wide substrate applicability, high atom economy, and good site selectivity, and further provides an operable method for the demand of fluorine-containing building blocks in life and materials science.

[0012] Preferably, the specific operation of the synthesis method is as follows: In an anaerobic environment, a cobaloxime catalyst, a fluoroalkyl compound, an olefin derivative, a base scavenger, and an organic solvent are mixed and subjected to a substitution reaction. After the substitution reaction is completed, the organic solvent is removed, and the obtained crude product is purified to obtain an allyl fluoroalkyl compound.

[0013] More preferably, based on the amount of the fluoroalkyl compound being 1 eq, the amount of the olefin derivative is 3 - 6 eq, and the amount of N,N-diisopropylethylamine is 2 - 4 eq; in terms of mole percentage, the amount of the cobaloxime catalyst is 5 mol% - 13 mol%; in terms of molar concentration, the concentration of the organic solvent is 0.05 - 0.2 M.

[0014] Preferably, the fluoroalkyl compound includes any one of compounds with the general formula R f -X, Umemoto reagent, and Togni reagent; where R f represents a fluoroalkyl precursor, and X represents any one of chlorine, bromine, and iodine. The fluoroalkyl precursor includes any one of the following structural formulas:

[0015]

[0016] Preferably, the olefin derivative includes one of natural olefins, alkyl olefins, and their derivatives.

[0017] Further preferably, the olefin derivative includes one of nootkatone, limonene, carvone, perillaldehyde, isopulegol, dihydrocarvone, perilla alcohol, carveol, 3-carene, α-ionone, citronellol, rotenone, betulin acetate, betulinic acid, mandelic acid derivative, gemfibrozil derivative, cholesterol derivative, diacetone glucose derivative, indomethacin derivative, febuxostat derivative, 2,4-dichlorophenoxyacetic acid derivative, naproxen derivative, L-camphorsulfonic lactam derivative, 2,3-dimethyl-1-butene, 3-ethyl-2-methyl-1-pentene, (2-methylcyclohexyl)benzene, 2-methyl-1-pentene, 2,4-dimethyl-1-pentene, 2,4,4-trimethyl-1-pentene, ((3-methylcyclohexyl)methyl)benzene, 1-(3-methylcyclohexyl)-1H-imidazole, dimethyl 2-(3-methylcyclohexyl)malonate, isobutene, 2-methoxypropene, 1-propen-2-yl acetate, 2-ethyl-1-butene, methylenecyclohexane, α-methylstyrene, and trimethylethylene.

[0018] Preferably, the cobalt oxime catalyst is Co(dmgBF2)2(NCMe)2.

[0019] Preferably, the acid-binding agent is N,N-diisopropylethylamine or triethylamine.

[0020] Preferably, the organic solvent is at least one of dichloromethane, acetonitrile, chloroform, 1,2-dichloroethane, and acetone.

[0021] Preferably, the temperature of the substitution reaction is room temperature, and the reaction time is 24 to 48 h.

[0022] Preferably, after the substitution reaction is completed, the remaining organic solvent is removed by vacuum distillation, and the crude product is purified by column chromatography.

[0023] Further preferably, the column chromatography is purified using neutral alumina with a standard particle size of 200 to 300 mesh, and a mixture of petroleum ether and ethyl acetate is used as the eluent; by volume, the ratio of petroleum ether to ethyl acetate is 1 to 10:1.

[0024] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0025] The present invention provides a method for synthesizing an allyl fluoroalkyl compound. The raw materials of this method are widely selected. Using a cheap and easily available cobalt oxime catalyst under mild reaction conditions, allyl fluoroalkylation can be achieved with high site selectivity, solving the technical problems in the prior art that the reaction substrates are limited and require relatively harsh reaction conditions, and it is also difficult to control the substitution site selectivity. Detailed implementation manners

[0026] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0027] In the following examples:

[0028] Co(dmgBF2)2(NCMe)2 was synthesized by the method provided in the literature (Bakac, A., Brynildson, M. E. & Espenson, J. H. Characterization of the structure, properties, and reactivity of a cobalt(II) macrocyclic complex. Inorg. Chem. 25, 4108 - 4114, (1986). doi:10.1021 / ic00243a012);

[0029] Neutral alumina, with a standard mesh size between 200 and 300 meshes.

[0030] Example 1

[0031] Synthesis of ((4R,4aS)-6-(4,4-difluoro-5-morpholin-5-oxopent-1-en-2-yl)-4,4-dimethyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one):

[0032] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), (+)-nopinone (261.6 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove dichloromethane. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 66.3 mg of the target product was obtained with a yield of 87%; its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 5.77 (d, J = 1.9 Hz, 1H), 5.05 (s, 2H), 3.91–3.55 (m, 8H), 2.96 (t, J = 19.4 Hz, 2H), 2.58–2.35 (m, 3H), 2.34–2.18 (m, 2H), 2.12–1.91 (m, 3H), 1.41–1.23 (m, 1H), 1.11 (s, 3H), 1.06 (t, J = 12.9 Hz, 1H), 0.97 (d, J = 6.8 Hz, 3H). MS (EI): m / z 382.2180 [M+H] + 。

[0033] Example 2

[0034] (Preparation of ((R)-2,2-difluoro-4-(4-methylcyclohex-3-en-1-yl)-1-morpholin-4-en-1-one)):

[0035] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethanol-1-one (48.6 mg, 0.2 mmol), d-limonene (163.2 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to obtain 37.7 mg of the target product with a yield of 63%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.47–5.28 (m, 1H), 5.03 (d, J = 15.2 Hz, 2H), 3.92–3.49 (m, 8H), 2.94 (t, J = 19.5 Hz, 2H), 2.27–2.11 (m, 2H), 2.09–1.78 (m, 4H), 1.70–1.58 (m, 4H). MS (EI): m / z 300.1766 [M+H] + 。

[0036] Example 3

[0037] (Preparation of ((S)-5-(4,4-difluoro-5-morpholin-5-oxo-1-en-2-yl)-2-methylcyclohex-2-en-1-one)):

[0038] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 2.0 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (3 / 1, v / v) was used as the eluent to obtain 44.4 mg of the target product with a yield of 71%; its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 6.75 (m, 1H), 5.13 (d, J = 8.3 Hz, 2H), 3.77–3.61 (m, 8H), 2.96 (td, J = 19.3, 3.5 Hz, 2H), 2.88–2.77 (m, 1H), 2.66 (ddd, J = 16.1, 3.7, 1.7 Hz, 1H), 2.60–2.49 (m, 1H), 2.40–2.29 (m, 1H), 2.30–2.20 (m, 1H), 1.79 (dt, J = 2.8, 1.4 Hz, 3H). MS (EI): m / z 314.1556 [M+H] + .

[0039] Example 4

[0040] Preparation of ((R)-4-(4,4-difluoro-5-morpholino-5-oxopent-1-en-2-yl)cyclohex-1-ene-1-carbaldehyde):

[0041] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 2.0 mmol), (-)-perillaldehyde (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (3 / 1, v / v) was used as the eluent to obtain 47.6 mg of the target product with a yield of 76%; its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 6.96–6.71 (m, 1H), 5.09 (d, J = 6.5 Hz, 2H), 3.86–3.51 (m, 8H), 2.97 (t, J = 19.3 Hz, 2H), 2.66–2.52 (m, 1H), 2.51–2.29 (m, 2H), 2.30–2.05 (m, 2H), 2.05–1.93 (m, 1H), 1.51–1.36 (m, 1H). MS (EI): m / z 314.1553 [M+H] + 。

[0042] Example 5

[0043] (Preparation of (2,2-difluoro-4-((1R,2S,4S)-2-hydroxy-4-methylcyclohexyl)-1-morpholin-4-en-1-one)):

[0044] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethanol-1-one (48.6 mg, 0.2 mmol), (-)-isopulegol (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (1 / 1, v / v) as the eluent, and 50.0 mg of the target product was obtained with a yield of 79%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.13 (s, 2H), 3.88–3.47 (m, 9H), 3.02–2.69 (m, 3H), 2.12–1.88 (m, 2H), 1.79–1.60 (m, 2H), 1.57–1.42 (m, 1H), 1.33–1.16 (m, 1H), 1.10–0.84 (m, 5H). MS (EI): m / z 318.1868 [M+H] + 。

[0045] Example 6

[0046] (Preparation of (5-(4,4-difluoro-5-morpholino-5-oxopent-1-en-2-yl)-2-methylcyclohexan-1-one)):

[0047] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), dihydrocarvone (182.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to afford 48.5 mg of the target product in 77% yield. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.10 (s, 2H), 3.86–3.40 (m, 8H), 2.94 (td, J = 19.5, 3.6 Hz, 2H), 2.58–2.33 (m, 3H), 2.26 (td, J = 12.8, 1.2 Hz, 1H), 2.09 (m, 2H), 1.67–1.54 (m, 1H), 1.37 (m, 1H), 1.06 (dd, J = 20.3, 6.7 Hz, 3H). MS (EI): m / z 316.1713 [M+H] + .

[0048] Example 7

[0049] (Preparation of 2,2-difluoro-4-(4-(hydroxymethyl)cyclohex-3-en-1-yl)-1-morpholin-4-en-1-one):

[0050] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), perillyl alcohol (182.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to afford 54.8 mg of the target product in 87% yield. Its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 5.70 (dd, J = 4.5, 2.5 Hz, 1H), 5.05 (d, J = 11.7 Hz, 2H), 3.99 (s, 2H), 3.86–3.55 (m, 8H), 2.95 (t, J = 19.5 Hz, 2H), 2.35–2.16 (m, 2H), 2.20–2.03 (m, 2H), 2.02–1.83 (m, 3H), 1.56–1.37 (m, 1H). MS (EI): m / z 316.1718 [M+H] + 。

[0051] Example 8

[0052] (Preparation of (2,2-difluoro-4-(5-hydroxy-4-methylcyclohex-3-en-1-yl)-1-morpholin-4-en-1-one)):

[0053] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), carveol (182.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to obtain 55.4 mg of the target product with a yield of 88%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.53 (dd, J = 34.1, 5.3 Hz, 1H), 5.12–5.01 (m, 2H), 4.34–3.89 (m, 1H), 3.84–3.39 (m, 8H), 3.07–2.73 (m, 2H), 2.49–2.31 (m, 1H), 2.29–2.10 (m, 1H), 2.06–1.85 (m, 2H), 1.82–1.73 (m, 3H), 1.68–1.41 (m, 2H). MS (EI): m / z 316.1713 [M+H] + 。

[0054] Example 9

[0055] (Preparation of (2-(7,7-dimethyl-4-methylenebicyclo[4.1.0]heptan-3-yl)-2,2-difluoro-1-morpholinoethan-1-one)):

[0056] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 3-carene (163.2 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to obtain 43.6 mg of the target product with a yield of 73%; its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 4.92 (d, J = 18.8 Hz, 2H), 3.84–3.39 (m, 9H), 1.83–2.06 (m, 2H), 1.04–1.17 (m, 4H), 0.89 (s, 6H). MS (EI): m / z 300.1770 [M+H] + 。

[0057] Example 10

[0058] Preparation of ((E)-4-(5-(1,1-difluoro-2-morpholino-2-oxoethyl)-2,2-dimethyl-6-methylenecyclohexyl)but-3-en-2-one):

[0059] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), α-ionone (230.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to obtain 57.5 mg of the target product with a yield of 81%; its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 6.84 - 6.87 (m, 1H), 5.98 - 6.01 (m, 1H), 4.88 - 5.01 (m, 2H), 3.81–3.51 (m, 9H), 2.54–2.56 (m, 1H), 2.18 (s, 3H), 1.04–1.23 (m, 4H), 0.94 (s, 6H). MS (EI): m / z 356.2034 [M+H] + 。

[0060] Example 11

[0061] (Preparation of (6-(1,1-difluoro-2-morpholin-2-oxoethyl)-3,7-dimethyloct-7-en-1-yl) acetate):

[0062] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethanol-1-one (48.6 mg, 0.2 mmol), citronellol (187.2 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 27.4 mg of the target product was obtained with a yield of 38%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.02 (s, 1H), 4.88 (s, 1H), 4.19–4.00 (m, 2H), 3.79–3.51 (m, 8H), 3.00–2.74 (m, 1H), 2.04 (s, 3H), 1.77 (s, 3H), 1.75–1.38 (m, 5H), 1.36–1.23 (m, 1H), 1.20–1.05 (m, 1H), 0.92 (dd, J = 6.6, 2.7 Hz, 3H). MS (EI): m / z 362.2125 [M+H] + 。

[0063] Example 12

[0064] (Preparation of ((2R,6aS,12aS)-2-(4,4-difluoro-5-morpholin-5-oxopent-1-en-2-yl)-8,9-dimethoxy-1,2,12,12a-tetrahydromethano[3,4-b]furo[2,3-h]chromen-6(6aH)-one))

[0065] Under nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), rotenone (472.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to afford 54.6 mg of the target product with a yield of 49%. Its 1H NMR spectrum is as follows: 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.6 Hz, 1H), 6.78 (s, 1H), 6.53 (d, J = 8.6 Hz, 1H), 6.47 (s, 1H), 5.45 (s, 1H), 5.39 (t, J = 9.0 Hz, 1H), 5.28 (s, 1H), 4.95 (t, J = 3.2 Hz, 1H), 4.63 (dd, J = 12.1, 3.1 Hz, 1H), 4.20 (d, J = 12.1 Hz, 1H), 3.86 (d, J = 4.1 Hz, 1H), 3.82 (s, 3H), 3.80–3.70 (m, 10H), 3.69–3.63 (m, 2H), 3.41 (dd, J = 15.8, 9.8 Hz, 1H), 3.08–2.97 (m, 2H). MS (EI): m / z 558.1930 [M+H] + 。

[0066] Example 13

[0067] Preparation of methyl ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-1-(4,4-difluoro-5-morpholin-5-yl-5-oxopent-1-en-2-yl)-5a,5b,8,8,11a-pentamethyldecahydro-3aH-cyclopenta[a]chrysen-3a-yl)acetate):

[0068] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), methyl ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)eicosahydro-3aH-cyclopenta[a]chrysen-3a-yl)acetate (631.2 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 86.8 mg of the target product was obtained with a yield of 63%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.06 (s, 1H), 4.94 (s, 1H), 4.47 (dd, J = 10.1, 6.0 Hz, 1H), 4.34–4.16 (m, 1H), 3.89–3.56 (m, 9H), 2.89 (t, J = 19.6 Hz, 2H), 2.35 (s, 1H), 2.07 (s, 3H), 2.04 (s, 3H), 1.91–1.55 (m, 9H), 1.55–1.34 (m, 7H), 1.34–1.06 (m, 6H), 1.07–0.94 (m, 7H), 0.89–0.74 (m, 10H). MS (EI): m / z 690.4538 [M+H] + .

[0069] Example 14

[0070] Preparation of ((trimethylsilyl)methyl (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-1-(4,4-difluoro-5-morpholin-5-yl-5-oxopent-1-en-2-yl)-5a,5b,8,8,11a-pentamethyleicosahydro-3aH-cyclopenta[a]chrysen-3a-carboxylate):

[0071] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), (trimethylsilyl)methyl (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)eicosahydro-3aH-cyclopenta[a]chlorene-3a-carboxylate (700.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 125.5 mg of the target product was obtained with a yield of 84%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.82–5.77 (m, 2H), 5.10 (d, J = 7.9 Hz, 4H), 4.44–4.10 (m, 8H), 3.00–2.75 (m, 4H), 2.61–2.20 (m, 10H), 2.15–1.95 (m, 6H), 1.42 (t, J = 7.1 Hz, 12H), 1.40–1.22 (m, 6H), 1.13 (s, 6H), 1.08 (t, J = 12.9 Hz, 2H), 1.00 (s, 3H), 0.98 (s, 3H), 0.95–0.84 (m, 1H). MS (EI): m / z 748.4778 [M+H] + 。

[0072] Example 15

[0073] Preparation of (4,4-difluoro-2-methylidene-5-morpholino-5-oxopentyl) (S)-2-hydroxy-2-phenylacetate:

[0074] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2-methylallyl (S)-2-hydroxy-2-phenylacetate (247.2 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (2 / 1, v / v) was used as the eluent to obtain 39.8 mg of the target product with a yield of 54%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.46–7.30 (m, 5H), 5.22 (d, J = 4.6 Hz, 1H), 5.13 (d, J = 5.7 Hz, 2H), 4.84–4.56 (m, 2H), 3.92–3.45 (m, 9H), 2.93–2.67 (m, 2H). MS (EI): m / z 392.1278 [M+H] + .

[0075] Example 16

[0076] (Preparation of (4,4-difluoro-2-methylene-5-morpholino-5-oxopentyl-5-(2,5-dimethylphenoxy)-2,2-dimethylvalerate)):

[0077] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2-methylallyl 5-(2,5-dimethylphenoxy)-2,2-dimethylvalerate (364.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 55.1 mg of the target product with a yield of 59%. Its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 6.99 (d, J = 7.4 Hz, 1H), 6.83–6.39 (m, 2H), 5.28 (d, J = 53.2 Hz, 2H), 4.61 (s, 2H), 3.91 (s, 2H), 3.82–3.51 (m, 8H), 2.98 (t, J = 19.2 Hz, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.74 (s, 4H), 1.25 (s, 6H). MS (EI): m / z 468.2556 [M+H] + 。

[0078] Example 17

[0079] (4 - ((((3S, 8S, 9S, 10R, 13R, 14S, 17R)-10,13-Dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)methyl)-2,2-difluoro-1-morpholin-4-ene-1-one) Preparation:

[0080] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholin-4-ene-1-one (48.6 mg, 0.2 mmol), (3S, 8S, 9S, 10R, 13R, 14S, 17R)-10,13-dimethyl-3-((2-methylallyl)oxy)-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene (528.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 56.7 mg of the target product was obtained with a yield of 47%; its 1H nuclear magnetic resonance spectrum: 1HNMR (400 MHz, CDCl3) δ 5.34 (d, J = 3.8 Hz, 2H), 5.15 (s, 1H), 4.03 (s, 2H), 3.83–3.53 (m, 8H), 3.30–3.10 (m, 1H), 2.96 (t, J = 19.4 Hz, 2H), 2.43–2.31 (m, 1H), 2.29–2.16 (m, 1H), 2.08–1.75 (m, 5H), 1.72–1.40 (m, 8H), 1.41–1.22 (m, 5H), 1.22–1.02 (m, 6H), 1.00 (s, 4H), 0.98–0.80 (m, 10H), 0.68 (s, 3H). MS (EI): m / z 604.4533 [M+H] + 。

[0081] Example 18

[0082] Preparation of (4 - ((((3aR,5R,6S,6aR)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl)oxy)methyl)-2,2-difluoro-1-morpholin-4-yl-4-en-1-one):

[0083] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), (3aR,5R,6S,6aR)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-((2-methylallyl)oxy)tetrahydrofuro[2,3-d][1,3]dioxole (376.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 48.6 mg of the target product was obtained with a yield of 51%; its 1H NMR spectrum is as follows: 11H NMR (400 MHz, CDCl3) δ 5.88 (d, J = 3.6 Hz, 1H), 5.50–5.05 (m, 2H), 4.56 (d, J = 3.7 Hz, 1H), 4.32 (dt, J = 8.0, 5.9 Hz, 1H), 4.25–4.17 (m, 1H), 4.17–4.04 (m, 3H), 4.04–3.91 (m, 2H), 3.82–3.53 (m, 8H), 3.11–2.86 (m, 2H), 1.50 (s, 3H), 1.42 (s, 3H), 1.33 (d, J = 8.8 Hz, 6H). MS (EI): m / z 478.2245 [M+H] + 。

[0084] Example 19

[0085] (4,4-Difluoro-2-methylene-5-morpholino-5-oxopentyl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate) Preparation:

[0086] Under nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethanol-1-one (48.6 mg, 0.2 mmol), 2-methylallyl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate (493.2 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina with petroleum ether / ethyl acetate (2 / 1, v / v) as the eluent to obtain 42.5 mg of the target product with a yield of 37%; its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.75–7.60 (m, 2H), 7.57–7.42 (m, 2H), 6.96 (d, J = 2.5 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 6.67 (dd, J = 9.0, 2.6 Hz, 1H), 5.35–5.08 (m, 2H), 4.65 (s, 2H), 3.83 (s, 3H), 3.77–3.53 (m, 10H), 2.91 (t, J = 19.1 Hz, 2H), 2.39 (s, 3H). MS (EI): m / z 575.1757 [M+H] + 。

[0087] Example 20

[0088] (Preparation of 4,4-difluoro-2-methylene-5-morpholino-5-oxopentyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate):

[0089] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethanol-1-one (48.6 mg, 0.2 mmol), 2-methylallyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (444.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (3 / 1, v / v) as the eluent, and 46.9 mg of the target product was obtained with a yield of 44%. Its 1H NMR spectrum: 1 H NMR(400 MHz,CDCl3)δ8.18(d,J = 2.3 Hz,1H),8.09(dd,J = 8.9,2.3 Hz,1H),7.02(d,J = 8.9 Hz,1H),5.51–5.24(m,2H),4.85(s,2H),3.91(d,J = 6.5 Hz,2H),3.82–3.59(m,8H),3.05(t,J = 19.1 Hz,2H),2.77(s,3H),2.31–2.10(m,1H),1.10(d,J = 6.7 Hz,6H). MS(EI):m / z 534.1869[M+H] + 。

[0090] Example 21

[0091] (Preparation of 4,4-difluoro-2-methylene-5-morpholino-5-oxopentyl 2-(2,4-dichlorophenoxy)acetate):

[0092] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2-(2,4-dichlorophenoxy)acetic acid 2-methylallyl ester (328.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (3 / 1, v / v) as the eluent to afford 63.8 mg of the target product in 73% yield. Its 1H NMR spectrum is as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.8, 2.6 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.35 (s, 1H), 5.26 (s, 1H), 4.83–4.58 (m, 4H), 3.81–3.57 (m, 8H), 3.06–2.86 (m, 2H). MS (EI): m / z 438.0681 [M+H] + 。

[0093] Example 22

[0094] (Preparation of (S)-2-(6-methoxynaphthalen-2-yl)propanoic acid (4,4-difluoro-2-methylidene-5-morpholino-5-oxopentyl) ester):

[0095] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2-methylallyl (S)-2-(6-methoxynaphthalen-2-yl)propanoate (340.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (3 / 1, v / v) as the eluent to afford 53.6 mg of the target product in 60% yield. Its 1H NMR spectrum is as follows: 11H NMR (400 MHz, CDCl3) δ 7.78–7.60 (m, 3H), 7.41 (dd, J = 8.4, 1.9 Hz, 1H), 7.21–6.99 (m, 2H), 5.15 (d, J = 25.3 Hz, 2H), 4.61 (s, 2H), 4.06–3.81 (m, 4H), 3.82–3.47 (m, 8H), 3.04–2.62 (m, 2H), 1.59 (d, J = 7.1 Hz, 3H). MS (EI): m / z 448.1931 [M+H] + 。

[0096] Example 23

[0097] (Preparation of (4-(((7aR)-8,8-dimethyl-2,2-dioxotetrahydro-3H-3a,6-methylbenzo[c]isothiazol-1(4H)-yl)methyl)-2,2-fluoro-1-morpholinone-4-en-1-one)):

[0098] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethanol-1-one (48.6 mg, 0.2 mmol), (7aR)-8,8-dimethyl-1-(2-methylallyl)hexahydro-3H-3a,6-methylbenzo[c]isothiazole 2,2-dioxide (322.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (3 / 1, v / v) was used as the eluent to obtain 61.8 mg of the target product with a yield of 71%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.32 (d, J = 69.3 Hz, 2H), 3.81 (d, J = 14.3 Hz, 1H), 3.76–3.59 (m, 8H), 3.40 (d, J = 14.3 Hz, 1H), 3.15 (d, J = 1.2 Hz, 2H), 3.11–2.86 (m, 3H), 2.07–1.95 (m, 1H), 1.93–1.78 (m, 3H), 1.63 (dd, J = 12.9, 8.0 Hz, 1H), 1.43 (t, J = 9.2 Hz, 1H), 1.27 (t, J = 8.6 Hz, 1H), 1.16 (s, 3H), 0.93 (s, 3H). MS (EI): m / z 433.1965 [M+H]+ .

[0099] Example 24

[0100] Preparation of (2,2-difluoro-5-methyl-4-methylene-1-morpholinohexan-1-one):

[0101] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2,3-dimethylbut-1-ene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to afford 41.0 mg of the target product in 83% yield. Its 1H NMR spectrum: 1 H NMR(400MHz,CDCl3)δ5.01(d,J=34.0Hz,2H),4.01–3.40(m,8H),2.92(t,J=19.5Hz,2H),2.52–2.18(m,1H),1.05(d,J=6.9Hz,6H). MS(EI):m / z 248.1450[M+H] + .

[0102] Example 25

[0103] Preparation of (5-ethyl-2,2-difluoro-4-methylene-1-morpholinoheptan-1-one):

[0104] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 3-ethyl-2-methylpent-1-ene (134.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to afford 42.3 mg of the target product in 77% yield. Its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 5.03 (d, J = 34.4 Hz, 2H), 4.10–3.17 (m, 8H), 2.82 (t, J = 19.6 Hz, 2H), 2.07–1.81 (m, 1H), 1.56–1.17 (m, 4H), 1.10–0.06 (m, 6H). MS (EI): m / z 276.1763 [M+H] + 。

[0105] Example 26

[0106] Preparation of (2,2-difluoro-1-morpholino-3-(1,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)propan-1-one):

[0107] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), (2-methylcyclohexyl)benzene (206.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 57.0 mg of the target product was obtained with a yield of 85%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.33–7.24 (m, 2H), 7.23–7.10 (m, 3H), 6.42–5.39 (m, 1H), 3.80–3.41 (m, 9H), 2.86–2.43 (m, 2H), 2.34–1.94 (m, 3H), 1.71–1.42 (m, 1H). MS (EI): m / z 336.1769 [M+H] + 。

[0108] Example 27

[0109] Preparation of (2,2-difluoro-4-methylene-1-morpholinoheptan-1-one):

[0110] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2-methyl-1-pentene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 35.1 mg of the target product with a yield of 71%; its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.21–4.63 (m, 2H), 4.04–3.31 (m, 8H), 3.10–2.65 (m, 2H), 2.25–1.93 (m, 2H), 1.64–1.18 (m, 2H), 1.09–0.59 (m, 3H). MS (EI): m / z 248.1450 [M+H] + 。

[0111] Example 28

[0112] (Preparation of 2,2-difluoro-6-methyl-4-methylene-1-morpholinoheptan-1-one):

[0113] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2,4-dimethyl-1-pentene (117.6 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 39.1 mg of the target product with a yield of 75%; its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.15–4.84 (m, 2H), 3.81–3.55 (m, 9H), 2.86 (t, J = 19.5 Hz, 2H), 2.02 (d, J = 7.2 Hz, 2H), 0.88 (d, J = 6.6 Hz, 6H). MS (EI): m / z 262.1610 [M+H] + 。

[0114] Example 29

[0115] Preparation of (2,2-difluoro-6,6-dimethyl-4-methylene-1-morpholinohept-1-one):

[0116] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2,4,4-trimethylpent-1-ene (134.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to afford 45.1 mg of the target product with a yield of 82%; 1H NMR spectrum: 1 H NMR (400 MHz, CDCl3) δ 5.43–4.52 (m, 2H), 4.11–3.18 (m, 8H), 3.07–2.66 (m, 2H), 2.07 (s, 2H), 0.92 (s, 9H). MS (EI): m / z 276.1766 [M+H] + 。

[0117] Example 30

[0118] Preparation of (3-(5-benzylcyclohex-1-en-1-yl)-2,2-difluoro-1-morpholin-1-one):

[0119] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), ((3-methylcyclohexyl)methyl)benzene (223.2 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to afford 43.9 mg of the target product with a yield of 63%; 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 7.36–7.16 (m, 5H), 5.69–5.60 (m, 1H), 3.84–3.50 (m, 8H), 2.92–2.72 (m, 2H), 2.70–2.52 (2H), 2.22–1.99 (m, 3H), 1.97–1.63 (m, 3H), 1.36–1.15 (m, 1H). MS (EI): m / z 350.1916 [M+H] + 。

[0120] Example 31

[0121] (Preparation of 3-(5-(1H-pyrazol-1-yl)cyclohex-1-en-1-yl)-2,2-difluoro-1-morpholin-1-one):

[0122] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethanol-1-one (48.6 mg, 0.2 mmol), 1-(3-methylcyclohexyl)-1H-pyrazole (194.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 36.3 mg of the target product was obtained with a yield of 52%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 1.9 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 6.24 (t, J = 2.1 Hz, 1H), 5.72 (s, 1H), 4.59–4.29 (m, 1H), 3.90–3.43 (m, 8H), 3.01–2.82 (m, 2H), 2.61 (d, J = 6.8 Hz, 2H), 2.30–2.17 (m, 2H), 2.15–1.98 (m, 2H). MS (EI): m / z 326.1663 [M+H] + 。

[0123] Example 32

[0124] (Preparation of dimethyl 2-(3-(2,2-difluoro-3-morpholino-3-oxopropyl)cyclohex-3-en-1-yl)malonate):

[0125] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), dimethyl 2-(3-methylenecyclohexyl)malonate (271.2 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to afford 73.9 mg of the target product in 95% yield. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.65 (s, 1H), 4.35–4.02 (m, 4H), 3.82–3.55 (m, 8H), 3.33–3.16 (m, 1H), 2.79 (m, 2H), 2.49–2.31 (m, 1H), 2.25–1.84 (m, 4H), 1.83–1.63 (m, 1H), 1.27 (m, 7H). MS (EI): m / z 418.2015 [M + H] + 。

[0126] Example 33

[0127] (Preparation of (2,2-difluoro-4-methyl-1-morpholin-4-en-1-one)):

[0128] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), isobutene (dissolved in THF, concentration 2.4 M, 0.5 mL, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to afford 31.9 mg of the target product in 73% yield. Its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 4.97 (d, J = 46.0 Hz, 2H), 4.01–3.51 (m, 8H), 2.89 (t, J = 19.4 Hz, 2H), 1.85 (s, 3H). MS (EI): m / z 220.1140 [M+H] + 。

[0129] Example 34

[0130] (Preparation of (2,2-difluoro-4-(hydroxymethyl)-1-morpholin-4-en-1-one)):

[0131] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethanol-1-one (48.6 mg, 0.2 mmol), 2-methylallyl alcohol (86.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 28.8 mg of the target product with a yield of 61%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.30 (s, 1H), 5.14 (s, 1H), 4.13 (s, 2H), 3.98–3.46 (m, 8H), 2.98 (t, J = 18.5 Hz, 2H). MS (EI): m / z 236.1092 [M+H] + 。

[0132] Example 35

[0133] (Preparation of (2,2-difluoro-4-methoxy-1-morpholin-4-en-1-one)):

[0134] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2-methoxypropene (86.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 31.5 mg of the target product was obtained with a yield of 67%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 4.22–4.08 (m, 2H), 3.81–3.62 (m, 8H), 3.56 (s, 3H), 2.98 (t, J = 18.0 Hz, 2H). MS (EI): m / z 236.1092 [M+H] + .

[0135] Example 36

[0136] (Preparation of (2,2-difluoro-4-methoxy-1-morpholin-4-en-1-one)):

[0137] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), allyl acetate (120.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 29.5 mg of the target product was obtained with a yield of 56%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 5.52–4.65 (m, 2H), 3.84–3.50 (m, 8H), 3.18 (t, J = 17.8 Hz, 2H), 2.14 (s, 3H). MS (EI): m / z 264.1041 [M+H] + .

[0138] Example 37

[0139] Preparation of ((E)-4-ethyl-2,2-difluoro-1-morpholin-4-en-1-one):

[0140] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2-ethyl-1-butene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 38.0 mg of the target product with a yield of 77%; its 1H NMR spectrum: 1 H NMR(400MHz,CDCl3)δ5.41(q,J=6.8Hz,1H),3.82–3.56(m,8H),3.10–2.65(m,2H),2.27–2.02(m,2H),1.71–1.56(m,3H),1.15–0.74(m,3H). MS(EI):m / z248.1447[M+H] + 。

[0141] Example 38

[0142] Preparation of (3-(cyclohex-1-en-1-yl)-2,2-difluoro-1-morpholinopropan-1-one):

[0143] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), methylenecyclohexane (115.2 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 41.9 mg of the target product with a yield of 81%; its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 5.62 (d, J = 2.9 Hz, 1H), 4.11–3.18 (m, 8H), 2.78 (t, J = 19.6 Hz, 2H), 2.16–1.91 (m, 4H), 1.73–1.47 (m, 4H). MS (EI): m / z 260.1448 [M+H] + 。

[0144] Example 39

[0145] (Preparation of (2,2-difluoro-1-morpholin-4-ylpent-4-en-1-one)):

[0146] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), α-methylstyrene (141.6 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 43.8 mg of the target product was obtained with a yield of 78%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.47–7.37 (m, 2H), 7.37–7.20 (m, 3H), 5.57 (s, 1H), 5.33 (s, 1H), 3.74–3.52 (m, 8H), 3.41 (t, J = 18.8 Hz, 2H). MS (EI): m / z 282.1290 [M+H] + 。

[0147] Example 40

[0148] (Preparation of (2,2-difluoro-3,4-dimethyl-1-morpholin-4-ylbut-4-en-1-one)):

[0149] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 2-methyl-2-butene (84.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 23.3 mg of the target product with a yield of 50%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 4.92 (d, J = 18.8 Hz, 2H), 3.92–3.50 (m, 8H), 3.17–2.99 (m, 1H), 2.19–1.57 (m, 3H), 1.23 (d, J = 7.1 Hz, 3H). MS (EI): m / z 234.1291 [M+H] + 。

[0150] Example 41

[0151] (Preparation of 2,2-difluoro-4-(4-methoxyphenyl)-3-methyl-1-morpholin-4-en-1-one):

[0152] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-morpholinoethan-1-one (48.6 mg, 0.2 mmol), 1-(but-2-en-2-yl)-4-methoxybenzene (194.4 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 39.1 mg of the target product with a yield of 60%. Its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 7.45–7.26 (m, 2H), 7.01–6.67 (m, 2H), 5.33 (d, J = 41.2 Hz, 2H), 3.80 (d, J = 1.2 Hz, 3H), 3.78–3.53 (m, 8H), 3.53–3.38 (m, 1H), 1.37 (d, J = 6.9 Hz, 3H). MS (EI): m / z 326.1556 [M+H] + 。

[0153] Example 42

[0154] (Preparation of ((S)-2-methyl-5-(4,4,5,5,6,6,7,7-nonafluorohept-1-en-2-yl)cyclohex-2-en-1-one)):

[0155] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), perfluoroiodobutane (207.6 mg, 3.0 eq), (+)-carvone (30.0 mg, 0.2 mmol), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 48 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (10 / 1, v / v) as the eluent to afford 60.3 mg of the target product in 82% yield; its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 6.83–6.59 (m, 1H), 5.38–4.98 (m, 2H), 2.95–2.73 (m, 3H), 2.72–2.62 (m, 1H), 2.63–2.48 (m, 1H), 2.41–2.19 (m, 2H), 1.88–1.59 (m, 3H). MS (EI): m / z 369.0887 [M+H] + 。

[0156] Example 43

[0157] (Preparation of ((S)-2-methyl-5-(4,4,5,5,6,6,7,8,9,9-tridecafluoronon-1-en-2-yl)cyclohex-2-en-1-one)):

[0158] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), perfluoroiodohexane (267.6 mg, 3.0 eq), (+)-carvone (30.0 mg, 0.2 mmol), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 48 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (10 / 1, v / v) as the eluent, and 65.5 mg of the target product was separated with a yield of 70%; its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 6.94–6.57 (m, 1H), 5.50–4.93 (m, 2H), 2.93–2.74 (m, 3H), 2.71–2.64 (m, 1H), 2.61–2.49 (m, 1H), 2.41–2.21 (m, 2H), 1.88–1.69 (m, 3H). MS (EI): m / z 469.0828 [M+H] + 。

[0159] Example 44

[0160] (Preparation of (S)-2-methyl-5-(4,5,5,5-tetrafluoro-4-(trifluoromethyl)penta-1-en-2-yl)cyclohex-2-en-1-one):

[0161] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 1,1,1,2,3,3,3-heptafluoro-2-iodopropane (177.6 mg, 3.0 eq), (+)-carvone (30.0 mg, 0.2 mmol), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 48 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (10 / 1, v / v) as the eluent, and 24 mg of the target product was separated with a yield of 38%; its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 6.98–6.48 (m, 1H), 5.42–4.70 (m, 2H), 2.92–2.87 (m, 1H), 2.87–2.73 (m, 2H), 2.71–2.61 (m, 1H), 2.61–2.46 (m, 1H), 2.40–2.16 (m, 2H), 1.80 (dt, J = 2.7, 1.4 Hz, 3H). MS (EI): m / z 319.0925 [M+H] + 。

[0162] Example 45

[0163] (Preparation of ((S)-2-methyl-5-(4,4,4-trifluorobut-1-en-2-yl)cyclohex-2-en-1-one)):

[0164] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), S-(trifluoromethyl)dibenzothiophenium triflate (241.2 mg, 3.0 eq), (+)-carvone (30.0 mg, 0.2 mmol), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 48 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (10 / 1, v / v) as the eluent, and 20.1 mg of the target product was obtained with a yield of 46%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 6.89–6.50 (m, 1H), 5.41–4.86 (m, 2H), 2.92–2.72 (m, 3H), 2.71–2.62 (m, 1H), 2.61–2.47 (m, 1H), 2.42–2.17 (m, 2H), 1.80 (dt, J = 2.6, 1.4 Hz, 3H). MS (EI): m / z 219.0991 [M+H] + 。

[0165] Example 46

[0166] (Preparation of ((S)-2-methyl-5-(4,4,4-trifluorobut-1-en-2-yl)cyclohex-2-en-1-one)):

[0167] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (189.6 mg, 3.0 eq), (+)-carvone (30.0 mg, 0.2 mmol), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 48 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (10 / 1, v / v) as the eluent, and 12.2 mg of the target product was obtained with a yield of 28%; its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 6.89–6.50 (m, 1H), 5.41–4.86 (m, 2H), 2.92–2.72 (m, 3H), 2.71–2.62 (m, 1H), 2.61–2.47 (m, 1H), 2.42–2.17 (m, 2H), 1.80 (dt, J = 2.6, 1.4 Hz, 3H). MS (EI): m / z 219.0991 [M+H] + 。

[0168] Example 47

[0169] Preparation of ethyl ((S)-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)pent-4-enoate):

[0170] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), ethyl difluoroiodoacetate (50.0 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 42.4 mg of the target product was obtained with a yield of 78%; its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 6.78–6.72 (m, 1H), 5.10 (d, J = 4.7 Hz, 2H), 4.45–4.10 (m, 2H), 2.95–2.71 (m, 3H), 2.69–2.47 (m, 2H), 2.41–2.11 (m, 2H), 1.78 (s, 3H), 1.41–1.20 (m, 3H). MS (EI): m / z 273.1293 [M+H] + 。

[0171] Example 48

[0172] Preparation of ethyl ((S)-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)penta-4-enoate):

[0173] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), ethyl difluorobromoacetate (40.4 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 33.2 mg of the target product was obtained with a yield of 61%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 6.78–6.72 (m, 1H), 5.10 (d, J = 4.7 Hz, 2H), 4.45–4.10 (m, 2H), 2.95–2.71 (m, 3H), 2.69–2.47 (m, 2H), 2.41–2.11 (m, 2H), 1.78 (s, 3H), 1.41–1.20 (m, 3H). MS (EI): m / z 273.1293 [M+H] + 。

[0174] Example 49

[0175] Preparation of ethyl ((S)-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)penta-4-enoate):

[0176] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), ethyl difluorochloroacetate (31.6 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 11.9 mg of the target product with a yield of 22%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 6.78–6.72 (m, 1H), 5.10 (d, J = 4.7 Hz, 2H), 4.45–4.10 (m, 2H), 2.95–2.71 (m, 3H), 2.69–2.47 (m, 2H), 2.41–2.11 (m, 2H), 1.78 (s, 3H), 1.41–1.20 (m, 3H). MS (EI): m / z 273.1293 [M+H] + .

[0177] Example 50

[0178] (Preparation of diethyl ((S)-(1,1-difluoro-3-(4-methyl-5-oxocyclohex-3-en-1-yl)but-3-en-1-yl)phosphonate)):

[0179] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), diethyl (bromodifluoromethyl)phosphonate (53.2 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (2 / 1, v / v) was used as the eluent to obtain 44.3 mg of the target product with a yield of 66%. Its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 6.96–6.60 (m, 1H), 5.15 (d, J = 13.2 Hz, 2H), 4.53–4.00 (m, 4H), 2.97–2.73 (m, 3H), 2.72–2.45 (m, 2H), 2.39–2.11 (m, 2H), 1.84–1.65 (m, 3H), 1.38 (t, J = 7.1 Hz, 6H). MS (EI): m / z 337.1374 [M+H] + 。

[0180] Example 51

[0181] Preparation of ((S)-5-(4-bromo-4,4-difluorobut-1-en-2-yl)-2-methylcyclohex-2-en-1-one):

[0182] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), dibromodifluoromethane (124.8 mg, 3.0 eq), (+)-carvone (30.0 mg, 0.2 mmol), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 48 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (10 / 1, v / v) as the eluent to afford 15.5 mg of the target product in 28% yield; its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.13–6.44 (m, 1H), 5.22 (d, J = 7.0 Hz, 2H), 3.16 (t, J = 14.6 Hz, 2H), 2.89–2.76 (m, 1H), 2.74–2.60 (m, 1H), 2.60–2.47 (m, 1H), 2.43–2.14 (m, 2H), 1.92–1.64 (m, 3H). MS (EI): m / z 279.0190 [M+H] + 。

[0183] Example 52

[0184] Preparation of ((S)-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)pent-4-en-1-yl 4-methylbenzenesulfonate):

[0185] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoroethyl 4-methylbenzenesulfonate (62.8 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (3 / 1, v / v) as the eluent, and 20.7 mg of the target product was obtained with a yield of 27%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.96–7.67 (m, 2H), 7.38 (d, J = 8.1 Hz, 2H), 6.89–6.51 (m, 1H), 5.09 (d, J = 5.1 Hz, 2H), 4.10 (t, J = 11.2 Hz, 2H), 2.76–2.62 (m, 3H), 2.61–2.54 (m, 1H), 2.54–2.44 (m, 4H), 2.33–2.12 (m, 2H), 1.83–1.70 (m, 3H). MS (EI): m / z 385.1278 [M+H] + 。

[0186] Example 53

[0187] (Preparation of (S)-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)pent-4-enamide):

[0188] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoroacetamide (34.6 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (1 / 1, v / v) as the eluent, and 13.1 mg of the target product was obtained with a yield of 27%. Its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 6.83–6.63 (m, 1H), 6.33 (d, J = 51.9 Hz, 2H), 5.14 (d, J = 16.4 Hz, 2H), 2.88 (t, J = 17.3 Hz, 2H), 2.82–2.70 (m, 1H), 2.69–2.46 (m, 2H), 2.41–2.16 (m, 2H), 1.78 (d, J = 2.3 Hz, 3H). MS (EI): m / z 244.1139 [M+H] + 。

[0189] Example 54

[0190] ((S)-N-butyl-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)pent-4-enamide) Preparation:

[0191] Under nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-N-butyl-2,2-difluoroacetamide (45.8 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was evaporated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina with petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 32.2 mg of the target product was obtained with a yield of 54%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 6.92–6.64 (m, 1H), 6.36 (s, 1H), 5.10 (d, J = 18.3 Hz, 2H), 3.30 (q, J = 6.8 Hz, 2H), 2.89 (m, 2H), 2.75 (m, 1H), 2.67–2.47 (m, 2H), 2.33 (dd, J = 16.0, 13.1 Hz, 1H), 2.22 (m, 1H), 1.82–1.76 (m, 3H), 1.59–1.46 (m, 2H), 1.40–1.30 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). MS (EI): m / z 300.1761 [M+H] + 。

[0192] Example 55

[0193] Preparation of ((S)-2,2-difluoro-N-isopropyl-4-(4-methyl-5-oxocyclohex-3-en-1-yl)pent-4-enamide):

[0194] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-N-isopropylamide (43.0 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent to obtain 41.6 mg of the target product with a yield of 73%. Its 1H NMR spectrum: 1 H NMR(400 MHz, CDCl3)δ6.87–6.64(m, 1H), 6.34(s, 1H), 5.10(d, J = 18.6 Hz, 2H), 4.17–3.96(m, 1H), 2.95–2.81(m, 2H), 2.81–2.68(m, 1H), 2.66–2.46(m, 2H), 2.40–2.28(m, 1H), 2.29–2.16(m, 1H), 1.90–1.64(m, 3H), 1.19(d, J = 6.7 Hz, 6H). MS(EI): m / z 286.1602[M+H] + 。

[0195] Example 56

[0196] Preparation of ((S)-N-(tert-butyl)-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)pent-4-enamide):

[0197] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-N-(tert-butyl)-2,2-difluoroacetamide (45.8 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 43 mg of the target product was separated with a yield of 72%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 6.86–6.65 (m, 1H), 6.13 (s, 1H), 5.43–4.52 (m, 2H), 2.95–2.79 (m, 2H), 2.80–2.69 (m, 1H), 2.66–2.46 (m, 2H), 2.40–2.29 (m, 1H), 2.29–2.15 (m, 1H), 1.85–1.67 (m, 3H), 1.37 (s, 9H). MS (EI): m / z 300.1760 [M+H] + 。

[0198] Example 57

[0199] (Preparation of (S)-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)-N-phenylpent-4-enamide):

[0200] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-N-phenylacetamide (49.8 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 45.9 mg of the target product was separated with a yield of 72%. Its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.56 (dd, J = 7.9, 1.6 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 6.84–6.59 (m, 1H), 5.14 (d, J = 26.4 Hz, 2H), 2.97 (t, J = 17.3 Hz, 2H), 2.87–2.72 (m, 1H), 2.69–2.46 (m, 2H), 2.41–2.16 (m, 2H), 1.78 (s, 3H). MS (EI): m / z 320.1448 [M+H] + 。

[0201] Example 58

[0202] (2,2-difluoro-4-((S)-4-methyl-5-oxocyclohex-3-en-1-yl)-N-(1-phenylethyl)penta-4-enamide) Preparation:

[0203] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-N-(1-phenylethyl)acetamide (55.2 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 54.8 mg of the target product with a yield of 79%; its 1H nuclear magnetic resonance spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.39–7.33 (m, 2H), 7.33–7.24 (m, 3H), 6.78–6.66 (m, 1H), 6.65–6.52 (m, 1H), 5.18–5.05 (m, 1H), 5.01 (d, J = 1.2 Hz, 2H), 2.95–2.80 (m, 2H), 2.78–2.63 (m, 1H), 2.60–2.53 (m, 1H), 2.52–2.41 (m, 1H), 2.28 (dd, J = 16.0, 13.1 Hz, 1H), 2.23–2.09 (m, 1H), 1.84–1.73 (m, 3H), 1.53 (d, J = 7.0 Hz, 3H). MS (EI): m / z 348.1761 [M+H] + 。

[0204] Example 59

[0205] (Preparation of ((S)-N-cyclopropyl-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)pent-4-enamide)):

[0206] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), 2-bromo-N-cyclopropyl-2,2-difluoroacetamide (42.6 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 40.1 mg of the target product was obtained with a yield of 71%; its 1H NMR spectrum: 1 H NMR(400MHz,CDCl3)δ6.83–6.68(m,1H),6.49(s,1H),5.10(d,J=16.2Hz,2H),2.94–2.81(m,2H),2.79–2.68(m,2H),2.65–2.48(m,2H),2.38–2.28(m,1H),2.28–2.14(m,1H),1.89–1.59(m,3H),0.90–0.78(m,2H),0.65–0.45(m,2H). MS(EI):m / z284.1447[M+H] + 。

[0207] Example 60

[0208] (Preparation of ((S)-N-cyclopentyl-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)pent-4-enamide)):

[0209] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-N-cyclopentyl-2,2-difluoroacetamide (48.2 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 42.2 mg of the target product with a yield of 68%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.04–6.46 (m, 1H), 6.52–6.09 (m, 1H), 5.10 (d, J = 18.4 Hz, 2H), 4.19 (q, J = 7.0 Hz, 1H), 2.88 (td, J = 17.2, 2.7 Hz, 2H), 2.81–2.67 (m, 1H), 2.65–2.47 (m, 2H), 2.39–2.28 (m, 1H), 2.28–2.17 (m, 1H), 2.08–1.94 (m, 2H), 1.83–1.76 (m, 3H), 1.75–1.55 (m, 4H), 1.49–1.33 (m, 2H). MS (EI): m / z 312.1771 [M+H] + .

[0210] Example 61

[0211] (Preparation of (S)-N-cycloheptyl-2,2-difluoro-4-(4-methyl-5-oxocyclohex-3-en-1-yl)pent-4-enamide):

[0212] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-N-cycloheptyl-2,2-difluoroacetamide (53.8 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, and petroleum ether / ethyl acetate (5 / 1, v / v) was used as the eluent to obtain 42.0 mg of the target product with a yield of 62%. Its 1H NMR spectrum: 11H NMR (400 MHz, CDCl3) δ 6.87–6.67 (m, 1H), 6.38 (d, J = 8.2 Hz, 1H), 5.10 (d, J = 19.6 Hz, 2H), 4.04–3.82 (m, 1H), 2.98–2.80 (m, 2H), 2.80–2.68 (m, 1H), 2.65–2.47 (m, 2H), 2.40–2.28 (m, 1H), 2.28–2.16 (m, 1H), 1.99–1.84 (m, 2H), 1.82–1.74 (m, 3H), 1.66–1.42 (m, 10H). MS (EI): m / z 340.2072 [M+H] + 。

[0213] Example 62

[0214] Preparation of ((S)-5-(4,4-difluoro-5-oxo-5-(1,4-dioxo-8-azaspiro[4.5]decan-8-yl)pent-1-en-2-yl)-2-methylcyclohex-2-en-1-one):

[0215] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-(1,4-dioxo-8-azaspiro[4.5]decan-8-yl)ethan-1-one (59.8 mg, 0.2 mmol), (+)-carvone (180.0 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (3 / 1, v / v) as the eluent, to afford 50.9 mg of the target product in a yield of 69%; its 1H NMR spectrum is as follows: 1 1H NMR (400 MHz, CDCl3) δ 6.96–6.49 (m, 1H), 5.43–4.52 (m, 2H), 3.99 (s, 4H), 3.87–3.62 (m, 4H), 3.07–2.88 (m, 2H), 2.87–2.77 (m, 1H), 2.73–2.61 (m, 1H), 2.62–2.47 (m, 1H), 2.43–2.14 (m, 2H), 1.88–1.55 (m, 7H). MS (EI): m / z 370.1811 [M+H] + 。

[0216] Example 63

[0217] Preparation of (N-(adamantan-1-yl)-2,2-difluoro-5-methyl-4-methylhexanamide):

[0218] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), N-(adamantan-1-yl)-2-bromo-2,2-difluoroacetamide (61.4 mg, 0.2 mmol), 2,3-dimethylbut-1-ene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (10 / 1, v / v) as the eluent, and 48.5 mg of the target product was obtained with a yield of 78%. Its 1H NMR spectrum: 1 H NMR(400MHz,CDCl3)δ5.96(s,1H),5.43–4.38(m,2H),2.90–2.73(m,2H),2.37–2.19(m,1H),2.19–2.05(m,3H),2.00(d,J=3.5Hz,6H),1.69(t,J=3.1Hz,6H),1.04(d,J=6.8Hz,6H). MS(EI):m / z 312.2122[M+H] + 。

[0219] Example 64

[0220] Preparation of (2,2-difluoro-N-(((1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10-octahydroanthracen-1-yl)methyl)-5-methyl-4-methylenhexanamide):

[0221] Under nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-N-(((1S,4aR,10aS)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10-octahydroanthracen-1-yl)methyl)acetamide (88.2 mg, 0.2 mmol), 2,3-dimethylbut-1-ene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina with petroleum ether / ethyl acetate (10 / 1, v / v) as the eluent, and 56.9 mg of the target product was obtained with a yield of 64%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.1 Hz, 1H), 6.99 (dd, J = 8.1, 2.0 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.32 (s, 1H), 4.90 (s, 2H), 3.21 (t, J = 6.2 Hz, 2H), 2.99–2.58 (m, 5H), 2.37–2.13 (m, 2H), 1.94–1.82 (m, 1H), 1.80–1.68 (m, 3H), 1.47–1.35 (m, 3H), 1.32–1.12 (m, 10H), 1.03–0.89 (m, 9H). MS (EI): m / z 446.3216 [M+H] + .

[0222] Example 65

[0223] (Preparation of tert-butyl 3-(2,2-difluoro-5-methyl-4-methylideneoxy)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate):

[0224] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), tert-butyl 3-(2-bromo-2,2-difluoroacetyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (73.6 mg, 0.2 mmol), 2,3-dimethylbut-1-ene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, to afford 52.8 mg of the target product in a yield of 71%. Its 1H NMR spectrum is as follows: 1 1H NMR (400 MHz, CDCl3) δ 5.22–4.77 (m, 2H), 4.34–4.15 (m, 3H), 4.14–3.92 (m, 1H), 3.38 (s, 1H), 3.09–2.75 (m, 3H), 2.42–2.24 (m, 1H), 1.99–1.87 (m, 2H), 1.83–1.72 (m, 1H), 1.70–1.61 (m, 1H), 1.48 (s, 9H), 1.05 (d, J = 6.8 Hz, 6H). MS (EI): m / z 373.2286 [M+H] + .

[0225] Example 66

[0226] Preparation of (2-((1-(2,2-difluoro-5-methyl-4-methoxymethylene)piperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one):

[0227] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-((1-(2-bromo-2,2-difluoroacetyl)piperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (89.0 mg, 0.2 mmol), 2,3-dimethylbut-1-ene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (2 / 1, v / v) as the eluent, and 63.8 mg of the target product was obtained with a yield of 71%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 6.87 (s, 1H), 5.00 (d, J = 31.4 Hz, 2H), 4.63–4.47 (m, 1H), 4.32 (d, J = 14.1 Hz, 1H), 3.94 (d, J = 23.7 Hz, 6H), 3.28 (dd, J = 17.5, 8.1 Hz, 1H), 3.17–3.01 (m, 1H), 3.00–2.82 (m, 2H), 2.70 (dd, J = 12.4, 5.9 Hz, 3H), 2.36 (p, J = 6.8 Hz, 1H), 2.00–1.66 (m, 4H), 1.46–1.17 (m, 3H), 1.06 (d, J = 6.9 Hz, 6H). MS (EI): m / z 450.2437 [M+H] + 。

[0228] Example 67

[0229] (Preparation of 1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2,2-difluoro-5-methyl-4-methoxy-1-one):

[0230] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2,2-difluoroethan-1-one (93.2 mg, 0.2 mmol), 2,3-dimethylbut-1-ene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (3 / 1, v / v) as the eluent to obtain 69.5 mg of the target product with a yield of 74%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 8.51–8.24 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.23–7.05 (m, 4H), 5.00 (d, J = 31.2 Hz, 2H), 4.17–3.89 (m, 2H), 3.55–3.28 (m, 3H), 3.31–3.10 (m, 1H), 3.08–2.74 (m, 4H), 2.72–2.50 (m, 1H), 2.50–2.25 (m, 4H), 1.05 (d, J = 6.8 Hz, 6H). MS (EI): m / z 471.2002 [M+H] + 。

[0231] Example 68

[0232] (Preparation of 1-(3-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidin-1-yl)-2,2-difluoro-5-methyl-4-methylhexan-1-one):

[0233] Under nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 1-(3-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidin-1-yl)-2-bromo-2,2-difluoroethan-1-one (97.0 mg, 0.2 mmol), 2,3-dimethylbut-1-ene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. After sealing the reaction tube, it was stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina with petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, and 73.3 mg of the target product was obtained with a yield of 75%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 7.20–7.09 (m, 2H), 7.06–6.92 (m, 2H), 6.63 (d, J = 8.4 Hz, 1H), 6.36 (dd, J = 6.2, 2.5 Hz, 1H), 6.21–6.08 (m, 1H), 5.89 (s, 2H), 5.21–4.78 (m, 2H), 4.91–4.34 (m, 2H), 3.70–3.58 (m, 1H), 3.56–3.39 (m, 1H), 3.26–3.10 (m, 1H), 3.05–2.70 (m, 4H), 2.45–2.27 (m, 1H), 2.18–1.99 (m, 1H), 1.98–1.88 (m, 1H), 1.86–1.58 (m, 1H), 1.07 (d, J = 6.8 Hz, 6H). MS (EI): m / z 490.2188 [M+H] + 。

[0234] Example 69

[0235] (Preparation of N-(1-(2,2-difluoro-5-methyl-4-methoxymethylene)piperidin-3-yl)-3,4,5-trimethoxybenzamide):

[0236] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2 (12.1 mg, 13 mol%), 2-bromo-2,2-difluoro-1-(3-(2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl)piperidin-1-yl)ethan-1-one (89.8 mg, 0.2 mmol), 2,3-dimethylbut-1-ene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina using petroleum ether / ethyl acetate (1 / 1, v / v) as the eluent to afford 60.7 mg of the target product in a yield of 67%. Its 1H NMR spectrum: 1 1H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 4.1 Hz, 2H), 6.79–6.20 (m, 1H), 5.03 (s, 1H), 4.95 (d, J = 5.4 Hz, 1H), 4.26–4.13 (m, 1H), 3.89 (s, 3H), 3.87 (s, 6H), 3.76–3.51 (m, 3H), 3.06–2.81 (m, 2H), 2.33 (p, J = 6.8 Hz, 1H), 2.12–1.60 (m, 5H), 1.04 (d, J = 6.8 Hz, 6H). MS (EI): m / z 455.2327 [M+H] + 。

[0237] Example 70

[0238] Preparation of ((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 2,2-difluoro-5-methyl-4-ethylenedicarboxylate):

[0239] Under a nitrogen atmosphere, Co(dmgBF2)2(NCMe)2(12.1 mg, 13 mol%), (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl 2-bromo-2,2-difluoroacetate (136.4 mg, 0.2 mmol), 2,3-dimethylbut-1-ene (100.8 mg, 6.0 eq), dichloromethane (2.0 mL, 0.1 M), and N,N-diisopropylethylamine (51.6 mg, 2.0 eq) were successively added to a dry 10 mL reaction tube equipped with a magnetic stir bar. The reaction tube was sealed and stirred at room temperature for 24 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography on neutral alumina, using petroleum ether / ethyl acetate (5 / 1, v / v) as the eluent, to afford 53.7 mg of the target product in 85% yield. Its 1H NMR spectrum is as follows: 1 1H NMR (400 MHz, CDCl3) δ 4.99 (s, 1H), 4.93 (s, 1H), 4.80 (m, 1H), 2.90–2.67 (m, 2H), 2.31 (m, 1H), 2.06–1.95 (m, 1H), 1.87 (m, 1H), 1.77–1.63 (m, 3H), 1.49 (m, 2H), 1.12–1.00 (m, 8H), 0.91 (dd, J = 9.3, 6.8 Hz, 6H), 0.75 (d, J = 6.9 Hz, 3H). MS (EI): m / z 339.2108 [M+H] + .

[0240] The preferred specific embodiments of the present invention have been described in detail above. It should be understood that those of ordinary skill in the art can make many modifications and variations based on the concept of the present invention without creative efforts. Therefore, all technical solutions that can be obtained by those skilled in the art in the technical field of the present invention based on the concept of the present invention through logical analysis, reasoning, or limited experiments on the basis of the prior art should fall within the protection scope determined by the claims.

Claims

1. A method for synthesizing an allyl fluoroalkyl compound, characterized in that, It includes the following steps: in an anaerobic environment, a cobalt oxime catalyst, a fluoroalkyl compound, an olefin derivative, a base scavenger and an organic solvent are mixed and subjected to a substitution reaction. After the substitution reaction is completed, the organic solvent is removed, and the obtained crude product is purified to obtain an allyl fluoroalkyl compound; The fluoroalkyl compound is selected from compounds having the general formula R f -X or trifluoromethyl-1,2-benziodoxol-3(1H)-one; wherein R f represents a fluoroalkyl precursor and X represents any one of chlorine, bromine and iodine; The fluoroalkyl compound is R f -X, the olefin derivatives and their corresponding allyl fluoroalkyl compounds are shown in the following table: When the fluoroalkyl compound is trifluoromethyl-1,2-benzoiodoxol-3(1H)-one, the olefin derivative and its corresponding product, the allyl fluoroalkyl compound, are shown in the following table: The cobalt oxime catalyst is Co(dmgBF2)2(NCMe)2; the base scavenger is N,N-diisopropylethylamine or triethylamine; the organic solvent is at least one of dichloromethane, acetonitrile, chloroform, 1,2-dichloroethane, and acetone; Based on the amount of the fluoroalkyl compound being 1 eq, the amount of the olefin derivative is 3 - 6 eq, and the amount of N,N-diisopropylethylamine is 2 - 4 eq; based on the molar percentage, the amount of the cobalt oxime catalyst is 5 mol% - 13 mol%; The temperature of the substitution reaction is room temperature, and the reaction time is 24 - 48 h.

2. The method according to claim 1, characterized in that: After the substitution reaction is completed, the remaining organic solvent is removed by vacuum distillation, and the crude product is purified by column chromatography.

3. The method according to claim 2, wherein: The column chromatography is purified using neutral alumina with a standard particle size of 200 - 300 mesh, and a mixture of petroleum ether and ethyl acetate is used as the eluent; By volume ratio, the ratio of petroleum ether to ethyl acetate is 1 - 10:1.

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