Preparation method of (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives

Abstract

The present invention discloses a ( E The invention relates to a method for preparing a 4-aryl-2,2-difluoro-3-butenoic acid derivative, and belongs to the technical field of pharmaceutical intermediates and organic synthesis. E )-1-aryl-2-bromoethylene and 2,2-difluoro-2-bromoacetic acid derivatives as raw materials, a reductive coupling reaction occurs under the coordinated catalysis of an iron / palladium co-catalyst to generate ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives; the synthesized ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives contain geminal difluoroallyl structural units and can be used as potential drug candidates. They can also provide a new way to introduce geminal difluoroallyl groups.

Description

Technical Field

[0001] The present invention relates to a ( E The invention discloses a method for preparing 4-aryl-2,2-difluoro-3-butenoic acid derivatives, belonging to the technical field of pharmaceutical intermediates and organic synthesis. Background Art

[0002] Gem-difluoroallyl structural units are commonly found in biologically active molecules. The special properties of fluorine give them certain drug properties, including enhanced lipophilicity and metabolic stability, making them potential drug candidates (Hagmann, WKJ Med. Chem. 2008, 51, 4359.). Transition metal-catalyzed coupling reactions are one of the most effective methods for constructing carbon-carbon bonds and can be widely used in the synthesis of complex drugs and natural products (Nicolaou, KC, Bulger, PG, Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442; Dounay, AB, Overman, LE Chem. Rev. 2003, 103, 2945; Graening, T., Schmalz, H.-G. Angew. Chem. Int. Ed. 2003, 42, 2580; Nicolaou, KC, Bulger, PG, Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490; Magano, J., Dunetz, JR Chem. Rev. 2011, 111, 112). 2177.), currently the construction of geminal difluoroallyl compounds mainly relies on this method, especially the transition metal-catalyzed redox-neutral cross-coupling reaction (Q.-Q. Min, Z. Yin, Z. Feng, W.-H. Guo, X. Zhang, J. Am. Chem. Soc. 2014, 136, 1230; Y.-T. He, Q. Wang, L.-H. Li, X.-Y. Liu, P.-F. Xu, Y.-M. Liang, Org. Lett. 2015, 17, 5188.).

[0003] However, these synthetic methods have some disadvantages to a large extent, such as the need for sensitive organometallic reagents or expensive transition metals as catalysts. In contrast, the reductive coupling reaction has been rapidly developed because it avoids the use of unstable organometallic reagents (Weix, DJ Acc. Chem. Res. 2015, 48, 1767.; Poremba, KE; Dibrell, SE; Reisman, SE ACS Catal. 2020, 10, 8237.; Liu, J.; Ye,Y.; Sessler, JL; Gong, H. Acc. Chem. Res. 2020, 53, 1833.). The use of this method to construct geminal difluoroallyl compounds has the characteristics of simple operation and step economy. However, this method currently has certain limitations due to the use of equivalent transition metal Cu. Summary of the invention

[0004] In view of the problems in the prior art in synthesizing geminal difluoroallyl compounds, the present invention provides a highly efficient ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives, the method uses base metal as a catalyst to synthesize geminal difluoroallyl compounds, the method of the present invention is to ( E )-1-aryl-2-bromoethylene, 2,2-difluoro-2-bromoacetic acid derivatives, reducing agent, catalyst A, catalyst B, ligand, and additives are added to a solvent to obtain a reaction system, and the reaction is carried out under a protective atmosphere at 50°C to 100°C for 6 to 12 hours, and then 2,2-difluoro-2-bromoacetic acid derivatives and reducing agent are added, and the reaction is continued under a protective atmosphere at 50°C to 100°C for 6 to 12 hours, and the solvent is removed by reduced pressure distillation to obtain a crude product, and then separated and purified to obtain ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives.

[0005] In the reaction system ( E The molar ratio of )-1-aryl-2-bromoethylene, 2,2-difluoro-2-bromoacetic acid derivative, reducing agent, catalyst A, catalyst B, ligand, additive and solvent is 1: (1-4): (1-4): (0.05-0.3): (0.01-0.1): (0.1-0.3): (1-4): (10-100), wherein the initial addition amount of 2,2-difluoro-2-bromoacetic acid derivative is 25-75% of the total molar amount, and the initial addition amount of reducing agent is 25-75% of the total molar amount.

[0006] The catalyst A is ferrous chloride, ferric chloride, ferrous acetate, ferrous oxalate, ferrous acetylacetonate or ferrous trifluoromethanesulfonate.

[0007] The catalyst B is cuprous iodide, copper trifluoromethanesulfonate, nickel acetylacetonate, nickel bromide, bis(acetonitrile)palladium dichloride or bis(dibenzylideneacetone)palladium.

[0008] The reducing agent is manganese, zinc, magnesium, manganese, iron or indium.

[0009] The ligand is triphenylphosphine, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl or bis(diphenylphosphine)methane.

[0010] The additive is magnesium chloride, ammonium chloride, sodium iodide, potassium bromide, potassium fluoride or lithium chloride.

[0011] The solvent is toluene, acetonitrile, 1,4-dioxane, N , N -dimethylformamide, N -Methylpyrrolidone or tetrahydrofuran.

[0012] The protective atmosphere is argon or nitrogen.

[0013] The present invention synthesized ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives include ( E )-4-phenyl-2,2-difluoro-3-butenoic acid ethyl ester, ( E )-4-(4'-methylphenyl)-2,2-difluoro-3-butenoic acid ethyl ester, ( E )-4-(4'-isopropylphenyl)-2,2-difluoro-3-butenoic acid ethyl ester, ( E )-4-(4'-methoxyphenyl)-2,2-difluoro-3-butenoic acid ethyl ester, ( E )-4-(3'-methoxyphenyl)-2,2-difluoro-3-butenoic acid ethyl ester, ( E )-4-(2'-methoxyphenyl)-2,2-difluoro-3-butenoic acid ethyl ester, ( E )-4-(4'-fluorophenyl)-2,2-difluoro-3-butenoic acid ethyl ester, ( E )-4-(4'-chlorophenyl)-2,2-difluoro-3-butenoate, ( E )-4-(3-chlorophenyl)-2,2-difluoro-3-butenoate, ( E )-4-(2-chlorophenyl)-2,2-difluoro-3-butenoate, ( E )-4-(4'-bromophenyl)-2,2-difluoro-3-butenoate, ( E )-4-(4'-cyanophenyl)-2,2-difluoro-3-butenoate, (E )-4-(naphthalen-2'-yl)-2,2-difluoro-3-butenoic acid ethyl ester, ( E )-4-(thiophen-2'-yl)-2,2-difluoro-3-butenoic acid ethyl ester, ( E )-4-phenyl-2,2-difluoro-3-pentenoic acid ethyl ester, ( E )- N , N -Diethyl-4-phenyl-2,2-difluoro-3-butenamide, ( E )- N , N -dipropyl-4-phenyl-2,2-difluoro-3-butenamide, ( E )-4-phenyl-1-(pyrrolidin-1'-yl)-2,2-difluoro-3-butene-1-one, ( E )-4-phenyl-1-(piperidin-1'-yl)-2,2-difluoro-3-butene-1-one, ( E )-4-phenyl-1-(morpholin-4'-yl)-2,2-difluoro-3-butene-1-one, ( E )- N -n-pentyl-4-phenyl-2,2-difluoro-3-butenamide, ( E )- N -tert-butyl-4-phenyl-2,2-difluoro-3-butenamide, ( E )- N -cyclohexyl-4-phenyl-2,2-difluoro-3-butenamide, ( E )- N -benzyl-4-phenyl-2,2-difluoro-3-butenamide, ( E )-2-(3'-phenyl-1',1'-difluoroallyl)benzo[ d ]oxazole, ( E )-5-methyl-2-(3'-phenyl-1',1'-difluoroallyl)benzo[ d ]oxazole, ( E )-2-(3'-phenyl 1',1'-difluoroallyl)-5-chlorobenzo[ d ]Oxazole.

[0014] Beneficial effects of the present invention:

[0015] The present invention is based on ( E)-1-aryl-2-bromoethylene and 2,2-difluoro-2-bromoacetic acid derivatives are used as raw materials, and a reduction coupling reaction occurs under the coordinated catalysis of an iron / palladium co-catalyst to generate (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives. The (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives synthesized by the present invention contain geminal difluoroallyl structural units, can be used as potential candidate drugs, and can also provide a new way to introduce geminal difluoroallyl groups. DETAILED DESCRIPTION

[0016] The present invention is further described in detail below in conjunction with specific implementation methods, but the protection scope of the present invention is not limited to the described contents; if no specific technology or conditions are specified in the embodiments, the technology or conditions described in the literature in the field or the product instructions are used; if the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased.

[0017] Example 1: In this example, (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-phenyl-2,2-difluoro-3-butenoic acid ethyl ester 3aa, the structural formula is as follows:

[0018] ;

[0019] ( E The synthesis method of ethyl 4-phenyl-2,2-difluoro-3-butenoate 3aa is as follows:

[0020] according to( E )-1-phenyl-2-bromoethylene (1a), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. 0.4 mmol ( E)-1-phenyl-2-bromoethylene (1a), 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol manganese, 0.04mmol ferrous chloride, 0.004mmol bis(dibenzylideneacetone)palladium, 0.092mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8mmol sodium iodide, and 2.0mL acetonitrile were added to a Young's tube previously dried with a flame oven, and reacted at 80°C for 12h, and then 0.4mmol was added to the Young's tube in a glove box filled with argon. ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol manganese, continue to react at 80℃ for 12h; cool the reaction system to room temperature, remove the solvent by vacuum distillation at 45℃ to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel), the eluent of the column chromatography is ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:100), collect the eluate, and vacuum distill at 45℃ to obtain ( E )-4-phenyl-2,2-difluoro-3-butenoic acid ethyl ester 3aa, the yield is 61%;

[0021] The reaction equation is as follows:

[0022]

[0023] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.37 (dd, J = 7.8, 1.5Hz, 2H), 7.32-7.25 (m, 3H), 7.00 (dt, J = 16.2, 2.5 Hz, 1H), 6.23 (dt, J =16.2, 11.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H). 13 CNMR (151 MHz, CDCl3) δ 164.06 (t, J = 34.9 Hz), 136.95 (t, J = 9.4 Hz),134.17, 129.79, 128.97, 127.57, 118.88 (t, J = 25.0 Hz), 112.86 (t, J = 248.5Hz), 63.28, 14.08. 19F NMR (471 MHz, CDCl3) δ -103.23 (dd, J = 11.4, 2.5 Hz, 2F).

[0024] Example 2: In this example, (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(4'-methylphenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3ba, the structural formula of which is as follows:

[0025] ;

[0026] ( E The synthesis method of ethyl 4-(4'-methylphenyl)-2,2-difluoro-3-butenoate 3ba is as follows:

[0027] according to( E )-1-(4'-methylphenyl)-2-bromoethylene (1b), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. 0.4 mmol ( E )-1-(4'-methylphenyl)-2-bromoethylene (1b), 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol manganese, 0.04mmol ferrous chloride, 0.004mmol bis(dibenzylideneacetone)palladium, 0.092mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8mmol sodium iodide, and 2.0mL acetonitrile were added to a Young's tube previously dried by a flame oven and reacted at 80°C for 12h.

[0028] Then, 0.4 mmol of ethyl 2,2-difluoro-2-bromoacetate (2a) and 0.4 mmol of manganese were added to the Young's tube in an argon-filled glove box, and the reaction was continued at 80 °C for 12 h. The reaction system was cooled to room temperature, and the solvent was removed by vacuum distillation at 45 °C to obtain a crude product. The crude product was then subjected to column chromatography (200-300 mesh silica gel), and the eluent for column chromatography was ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether was 1:100). The eluate was collected and vacuum distilled at 45 °C to obtain ( E )-4-(4'-methylphenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3ba with a yield of 67%;

[0029] The reaction equation is as follows:

[0030]

[0031] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.34 (d, J = 8.1 Hz, 2H),7.18 (d, J = 7.9 Hz, 2H), 7.04 (dt, J = 16.2, 2.3 Hz, 1H), 6.25 (dt, J =16.2, 11.5 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.36 (t, J = 7.2Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 164.16 (t, J = 35.0 Hz), 140.01, 136.85 (t, J = 9.4 Hz), 131.42, 129.67, 127.52, 117.77 (t, J = 25.0 Hz), 112.99 (t, J = 248.4 Hz), 63.22, 21.49, 14.09. 19 F NMR (471 MHz, CDCl3) δ -103.02 (dd, J = 11.5, 2.1 Hz, 2F).

[0032] Example 3: In this example (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(4'-isopropylphenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3ca, the structural formula is as follows:

[0033] ;

[0034] ( E The synthesis method of ethyl 4-(4'-isopropylphenyl)-2,2-difluoro-3-butenoate 3ca is as follows:

[0035] according to( E)-1-(4'-isopropylphenyl)-2-bromoethylene (1c), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were sequentially added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. E )-1-(4'-isopropylphenyl)-2-bromoethylene (1c), 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4 mmol manganese, 0.04 mmol ferrous chloride, 0.004 mmol bis(dibenzylideneacetone)palladium, 0.092 mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8 mmol sodium iodide and 2.0 mL acetonitrile were added into a Young's tube which had been previously dried by a flame oven, and the mixture was reacted at 80°C for 12 h. Then, in a glove box filled with argon, 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4 mmol Manganese, continue to react at 80°C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel) with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:100) on the crude product. Collect the eluent and distill under reduced pressure at 45°C to obtain ( E )-4-(4'-isopropylphenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3ca with a yield of 61%;

[0036] The reaction equation is as follows:

[0037] ;

[0038] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.30 (d, J = 8.2 Hz, 2H),7.16 (t, J = 6.4 Hz, 2H), 6.98 (dt, J = 16.1, 2.2 Hz, 1H), 6.18 (dt, J =16.1, 11.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 2.87-2.79 (m, 1H), 1.27 (t, J =7.2 Hz, 3H), 1.17 (d, J= 7.0 Hz, 6H). 13 C NMR (151 MHz, CDCl3) δ 164.15 (t, J = 35.1 Hz), 150.94, 136.82 (t, J = 9.4 Hz), 131.81, 127.62, 127.06, 117.90 (t, J = 25.0 Hz), 112.99 (t, J = 248.3 Hz), 63.20, 34.11, 23.93, 14.07. 19 FNMR (471 MHz, CDCl3) δ -103.09 (dd, J = 11.5, 2.3 Hz, 2F).

[0039] Example 4: The structural formula of the (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives of this example is as follows (( E )-4-(4'-methoxyphenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3da):

[0040] ;

[0041] ( E The synthesis method of ethyl 4-(4'-methoxyphenyl)-2,2-difluoro-3-butenoate 3da is as follows:

[0042] according to( E )-1-(4'-methoxyphenyl)-2-bromoethylene (1d), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were sequentially added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. E)-1-(4'-methoxyphenyl)-2-bromoethylene (1d), 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol manganese, 0.04mmol ferrous chloride, 0.004mmol bis(dibenzylideneacetone)palladium, 0.092mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8mmol sodium iodide and 2.0mL acetonitrile were added into a Young's tube which had been previously dried by a flame oven, and the mixture was reacted at 80°C for 12h, and then 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol Manganese, continue to react at 80°C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel) with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:100) on the crude product. Collect the eluent and distill under reduced pressure at 45°C to obtain ( E )-4-(4'-methoxyphenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3da, the yield was 26%;

[0043] The reaction equation is as follows:

[0044]

[0045] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.32 (d, J = 8.7 Hz, 2H), 6.94 (dt, J = 16.2, 2.4 Hz, 1H), 6.85-6.78 (m, 2H), 6.08 (dt, J = 16.1, 11.5Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). 13 CNMR (151 MHz, CDCl3) δ 164.27 (t, J = 35.2 Hz), 160.87, 136.43 (t, J = 9.5Hz), 129.06, 126.90, 116.41 (t, J = 25.0 Hz), 114.34, 113.10 (t, J= 248.2Hz), 63.21, 55.50, 14.12. 19 F NMR (471 MHz, CDCl3) δ -102.72 (dd, J = 11.4,2.5 Hz, 2F).

[0046] Example 5: In this example (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(3'-methoxyphenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3ea, the structural formula of which is as follows:

[0047] ;

[0048] ( E The synthesis method of ethyl 4-(3'-methoxyphenyl)-2,2-difluoro-3-butenoate 3ea is as follows:

[0049] according to( E )-1-(3'-methoxyphenyl)-2-bromoethylene (1e), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. 0.4 mmol ( E )-1-(3'-methoxyphenyl)-2-bromoethylene (1e), 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol manganese, 0.04mmol ferrous chloride, 0.004mmol bis(dibenzylideneacetone)palladium, 0.092mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8mmol sodium iodide and 2.0mL acetonitrile were added into a Young's tube which had been previously dried by a flame oven, and the mixture was reacted at 80°C for 12h, and then 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol Manganese, continue to react at 80°C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel) with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:100) on the crude product. Collect the eluent and distill under reduced pressure at 45°C to obtain ( E )-4-(3'-methoxyphenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3ea, the yield was 50%;

[0050] The reaction equation is as follows:

[0051] ;

[0052] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.22 (t, J = 7.9 Hz, 1H), 6.98 (dd, J = 10.0, 5.4 Hz, 2H), 6.89 (s, 1H), 6.83 (dd, J = 8.2, 2.3 Hz,1H), 6.22 (dt, J = 16.1, 11.4 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 164.04 (t, J = 34.9Hz), 159.98, 136.89 (t, J = 9.4 Hz), 135.55, 129.99, 120.18, 119.19 (t, J =25.0 Hz), 115.48, 112.81 (t, J = 248.6 Hz), 112.66, 63.30, 55.42, 14.09. 19 FNMR (471 MHz, CDCl3) δ -103.30 (dd, J = 11.4, 2.4 Hz, 2F).

[0053] Example 6: In this example (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(2'-methoxyphenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3fa, the structural formula is as follows:

[0054]

[0055] ( E The synthesis method of ethyl 4-(2'-methoxyphenyl)-2,2-difluoro-3-butenoate 3fa is as follows:

[0056] according to( E)-1-(2'-methoxyphenyl)-2-bromoethylene (1f), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. 0.4 mmol ( E )-1-(2'-methoxyphenyl)-2-bromoethylene (1f), 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol manganese, 0.04mmol ferrous chloride, 0.004mmol bis(dibenzylideneacetone)palladium, 0.092mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8mmol sodium iodide and 2.0mL acetonitrile were added into a Young's tube which had been previously dried by a flame oven, and the mixture was reacted at 80℃ for 12h, and then 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol Manganese, continue to react at 80°C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel) with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:100) on the crude product. Collect the eluent and distill under reduced pressure at 45°C to obtain ( E )-4-(2'-methoxyphenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3fa, the yield was 50%;

[0057] The reaction equation is as follows:

[0058] ;

[0059] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.35 (dd, J = 7.6, 1.1Hz, 1H), 7.29 (dt, J = 16.3, 2.4 Hz, 1H), 7.26-7.22 (m, 1H), 6.88 (t, J = 7.5Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.33 (dt, J = 16.3, 11.5 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 164.28 (t, J= 35.1 Hz), 157.83, 132.32 (t, J = 9.9 Hz),130.92, 128.46, 123.03, 120.75, 119.36 (t, J = 24.8 Hz), 113.19 (t, J = 248.2Hz), 111.13, 63.14, 55.53, 14.07. 19 F NMR (471 MHz, CDCl3) δ -102.92 (dd, J =11.6, 2.5 Hz, 2F).

[0060] Example 7: In this example (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(4'-fluorophenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3ga, the structural formula is as follows:

[0061] ;

[0062] ( E The synthesis method of ethyl 4-(4'-fluorophenyl)-2,2-difluoro-3-butenoate 3ga is as follows:

[0063] according to( E )-1-(4'-fluorophenyl)-2-bromoethylene (1 g), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. 0.4 mmol ( E)-1-(4'-fluorophenyl)-2-bromoethylene (1 g), 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4 mmol manganese, 0.04 mmol ferrous chloride, 0.004 mmol bis(dibenzylideneacetone)palladium, 0.092 mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8 mmol sodium iodide, and 2.0 mL acetonitrile were added to a Young's tube previously dried with a flame oven, and the mixture was reacted at 80°C for 12 h. Then, 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4 mmol Manganese, continue to react at 80°C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel) with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:100) on the crude product. Collect the eluent and distill under reduced pressure at 45°C to obtain ( E )-4-(4'-fluorophenyl)-2,2-difluoro-3-butenoic acid ethyl ester 3ga, the yield was 59%;

[0064] The reaction equation is as follows:

[0065]

[0066] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.46-7.40 (m, 2H), 7.09-7.00 (m, 3H), 6.23 (dt, J = 16.2, 11.3 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H),1.36 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 164.01 (t, J = 34.9 Hz),163.59 (d, J = 250.1 Hz), 135.74 (t, J = 9.5 Hz), 130.40 (d, J = 3.2 Hz),129.39 (d, J = 8.4 Hz), 118.64 (td, J = 25.0, 2.2 Hz), 116.06 (d, J= 21.9Hz), 112.75 (t, J = 248.6 Hz), 63.33, 14.09. 19 F NMR (471 MHz, CDCl3) δ -103.24 (dd, J = 11.4, 2.0 Hz, 2F), -110.86 (s, 1F).

[0067] Example 8: In this example (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(4'-chlorophenyl)-2,2-difluoro-3-butenoate 3ha, the structural formula is as follows:

[0068] ;

[0069] ( E The synthesis method of 4-(4'-chlorophenyl)-2,2-difluoro-3-butenoate 3HA is as follows:

[0070] according to( E )-1-(4'-chlorophenyl)-2-bromoethylene (1h), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. 0.4 mmol ( E )-1-(4'-chlorophenyl)-2-bromoethylene (1h), 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol manganese, 0.04mmol ferrous chloride, 0.004mmol bis(dibenzylideneacetone)palladium, 0.092mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8mmol sodium iodide, and 2.0mL acetonitrile were added to a Young's tube previously dried with a flame oven, and the mixture was reacted at 80°C for 12h, and then 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol Manganese, continue to react at 80°C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel) with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:100) on the crude product. Collect the eluent and distill under reduced pressure at 45°C to obtain ( E )-4-(4'-chlorophenyl)-2,2-difluoro-3-butenoate 3HA, yield 68%;

[0071] The reaction equation is as follows:

[0072] ;

[0073] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.38 (d, J = 8.6 Hz, 2H), 7.36-7.32 (m, 2H), 7.03 (dt, J = 16.2, 2.4 Hz, 1H), 6.29 (dt, J = 16.2, 11.4Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 163.88 (t, J = 34.7 Hz), 135.66 (t, J = 9.4 Hz), 135.60, 132.65,129.18, 128.78, 119.47 (t, J = 25.0 Hz), 112.65 (t, J = 248.8 Hz), 63.35,14.06. 19 F NMR (471 MHz, CDCl3) δ -103.36 (dd, J = 11.3, 2.4 Hz, 2F).

[0074] Example 9: In this example (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(3-chlorophenyl)-2,2-difluoro-3-butenoate 3ia, the structural formula is as follows:

[0075]

[0076] ( E The synthesis method of 4-(3-chlorophenyl)-2,2-difluoro-3-butenoate 3ia is as follows:

[0077] according to( E)-1-(3'-chlorophenyl)-2-bromoethylene (1i), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were sequentially added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. E )-1-(3'-chlorophenyl)-2-bromoethylene (1i), 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol manganese, 0.04mmol ferrous chloride, 0.004mmol bis(dibenzylideneacetone)palladium, 0.092mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8mmol sodium iodide, and 2.0mL acetonitrile were added to a Young's tube previously dried with a flame oven, and the mixture was reacted at 80°C for 12h, and then 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol Manganese, continue to react at 80°C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel) with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:100) on the crude product. Collect the eluent and distill under reduced pressure at 45°C to obtain ( E )-4-(3-chlorophenyl)-2,2-difluoro-3-butenoate 3ia with a yield of 58%;

[0078] The reaction equation is as follows:

[0079]

[0080] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.44 (s, 1H), 7.36-7.28 (m, 3H), 7.02 (dt, J = 16.2, 2.5 Hz, 1H), 6.32 (dt, J = 16.2, 11.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ163.82 (t, J = 34.7 Hz), 135.97, 135.57 (t,J = 9.4 Hz), 134.96, 130.23,129.71, 127.38, 125.85, 120.40 (t, J = 25.0 Hz), 112.53 (t, J = 248.9 Hz), 63.40, 14.08. 19 F NMR (471 MHz, CDCl3) δ -103.58 (dd, J = 11.3, 2.4 Hz, 2F).

[0081] Example 10: In this example (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(2-chlorophenyl)-2,2-difluoro-3-butenoate 3ja, the structural formula is as follows:

[0082] ;

[0083] ( E The synthesis method of 4-(2-chlorophenyl)-2,2-difluoro-3-butenoate 3ja is as follows:

[0084] according to( E )-1-(2'-chlorophenyl)-2-bromoethylene (1j), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were sequentially added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. E)-1-(2'-chlorophenyl)-2-bromoethylene (1j), 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4 mmol manganese, 0.04 mmol ferrous chloride, 0.004 mmol bis(dibenzylideneacetone)palladium, 0.092 mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8 mmol sodium iodide and 2.0 mL acetonitrile were added into a Young's tube which had been previously dried by a flame oven, and the mixture was reacted at 80°C for 12 h. Then, in a glove box filled with argon, 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a) and 0.4 mmol Manganese, continue to react at 80°C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel) with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:100) on the crude product. Collect the eluent and distill under reduced pressure at 45°C to obtain ( E )-4-(2-chlorophenyl)-2,2-difluoro-3-butenoate 3ja with a yield of 63%;

[0085] The reaction equation is as follows:

[0086] ;

[0087] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.56 (dd, J = 7.0, 2.4Hz, 1H), 7.50 (dt, J = 16.2, 2.5 Hz, 1H), 7.43-7.38 (m, 1H), 7.32-7.25 (m, 2H), 6.32 (dt, J = 16.2, 11.1 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J =7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 163.82 (t, J = 34.6 Hz), 134.41,133.28 (t, J = 9.7 Hz), 132.46, 130.71, 130.17, 127.47, 127.22, 121.59 (t, J = 25.2 Hz), 112.60 (t,J = 248.8 Hz), 63.38, 14.09. 19 F NMR (471 MHz, CDCl3) δ-103.18 (dd, J = 11.1, 2.6 Hz, 2F).

[0088] Example 11: In this example, (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(4'-bromophenyl)-2,2-difluoro-3-butenoate 3ka, the structural formula is as follows:

[0089] ;

[0090] ( E The synthesis method of 4-(4'-bromophenyl)-2,2-difluoro-3-butenoate 3ka is as follows:

[0091] according to( E )-1-(4'-bromophenyl)-2-bromoethylene (1k), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were sequentially added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. E )-1-(4'-bromophenyl)-2-bromoethylene (1k), 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4 mmol manganese, 0.04 mmol ferrous chloride, 0.004 mmol bis(dibenzylideneacetone)palladium, 0.092 mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8 mmol sodium iodide, and 2.0 mL acetonitrile were added to a Young's tube previously dried by a flame oven, and the mixture was reacted at 80°C for 12 h. Then, in a glove box filled with argon, 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4 mmol Manganese, continue to react at 80°C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel) with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:100) on the crude product. Collect the eluent and distill under reduced pressure at 45°C to obtain ( E )-4-(4'-bromophenyl)-2,2-difluoro-3-butenoate 3ka with a yield of 54%;

[0092] The reaction equation is as follows:

[0093]

[0094] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 8.5 Hz, 2H),7.31 (d, J = 8.4 Hz, 2H), 7.02 (dd, J = 16.2, 2.3 Hz, 1H), 6.30 (dt, J =16.2, 11.3 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). 13 CNMR (151 MHz, CDCl3) δ 163.85 (t, J = 34.7 Hz), 135.74 (t, J = 9.4 Hz),133.08, 132.15, 129.03, 123.90, 119.59 (t, J = 25.0 Hz), 112.63 (t, J = 248.8Hz), 63.36, 14.07. 19 F NMR (471 MHz, CDCl3) δ -103.40 (dd, J = 11.3, 2.4 Hz, 2F).

[0095] Example 12: In this example, (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(4'-cyanophenyl)-2,2-difluoro-3-butenoate 3la, the structural formula is as follows:

[0096] ;

[0097] ( E The synthesis method of 4-(4'-cyanophenyl)-2,2-difluoro-3-butenoate 3la is as follows:

[0098] according to( E)-1-(4'-cyanophenyl)-2-bromoethylene (1l), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were sequentially added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. E )-1-(4'-cyanophenyl)-2-bromoethylene (1l), 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4 mmol manganese, 0.04 mmol ferrous chloride, 0.004 mmol bis(dibenzylideneacetone)palladium, 0.092 mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8 mmol sodium iodide and 2.0 mL acetonitrile were added into a Young's tube which had been previously dried by a flame oven, and the reaction was carried out at 80°C for 12 h. Then, in a glove box filled with argon, 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a) and 0.4 mmol manganese were added into the Young's tube, and the reaction was continued at 80°C. ℃ for 12h; the reaction system was cooled to room temperature, and the solvent was removed by vacuum distillation at 45℃ to obtain a crude product, which was then subjected to column chromatography (200-300 mesh silica gel), with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether was 1:20) as the eluent, and the eluent was collected and vacuum distilled at 45℃ to obtain ( E )-4-(4'-cyanophenyl)-2,2-difluoro-3-butenoate 3la with a yield of 62%;

[0099] The reaction equation is as follows:

[0100] ;

[0101] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2H),7.56 (d, J = 8.3 Hz, 2H), 7.10 (dt, J = 16.2, 2.2 Hz, 1H), 6.43 (dt, J =16.2, 11.2 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13CNMR (151 MHz, CDCl3) δ 163.57 (t, J = 34.3 Hz), 138.47, 135.08 (t, J = 9.4Hz), 132.77, 128.08, 122.59 (t, J = 25.1 Hz), 118.51, 113.09, 112.25 (t, J =249.4 Hz), 63.56, 14.08. 19 F NMR (471 MHz, CDCl3) δ -103.91 (dd, J = 11.2, 2.3Hz, 2F).

[0102] Example 13: In this example, (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(naphthalen-2'-yl)-2,2-difluoro-3-butenoic acid ethyl ester 3ma, the structural formula is as follows:

[0103]

[0104] ( E The synthesis method of ethyl 4-(naphthalene-2'-yl)-2,2-difluoro-3-butenoate 3ma is as follows:

[0105] according to( E )-1-(naphthalene-2'-yl)-2-bromoethylene (1m), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were sequentially added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. E)-1-(naphthalen-2'-yl)-2-bromoethylene (1m), 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4 mmol manganese, 0.04 mmol ferrous chloride, 0.004 mmol bis(dibenzylideneacetone)palladium, 0.092 mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8 mmol sodium iodide, and 2.0 mL acetonitrile were added to a Young's tube previously dried with a flame oven, and the reaction was carried out at 80 °C for 12 h. Then, in a glove box filled with argon, 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a) and 0.4 mmol manganese were added to the Young's tube, and the reaction was continued at 80 °C. ℃ for 12h; the reaction system was cooled to room temperature, and the solvent was removed by vacuum distillation at 45℃ to obtain a crude product, which was then subjected to column chromatography (200-300 mesh silica gel), with petroleum ether as the eluent for column chromatography, and the eluent was collected and vacuum distilled at 45℃ to obtain ( E )-4-(naphthalen-2'-yl)-2,2-difluoro-3-butenoic acid ethyl ester 3ma, the yield is 35%;

[0106] The reaction equation is as follows:

[0107] ;

[0108] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.73 (t, J = 7.0 Hz, 4H), 7.53-7.48 (m, 1H), 7.44-7.38 (m, 2H), 7.15 (d, J = 16.2 Hz, 1H), 6.33 (dt, J = 16.1, 11.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H). 13 CNMR (151 MHz, CDCl3) δ 164.11 (t, J = 35.0 Hz), 137.03 (t, J = 9.4 Hz),133.95, 133.36, 131.60, 128.98, 128.77, 128.48, 127.88, 127.10, 126.82,123.33, 119.02 (t, J = 25.0 Hz), 112.96 (t,J = 248.6 Hz), 63.32, 14.11. 19 FNMR (471 MHz, CDCl3) δ -103.03 (dd, J = 11.4, 2.3 Hz, 2F).

[0109] Example 14: In this example, (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-(thiophen-2'-yl)-2,2-difluoro-3-butenoic acid ethyl ester 3na, the structural formula is as follows:

[0110] ;

[0111] ( E The synthesis method of ethyl 4-(thiophene-2'-yl)-2,2-difluoro-3-butenoate 3na is as follows:

[0112] according to( E )-1-(thiophen-2'-yl)-2-bromoethylene (1n), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. 0.4 mmol ( E )-1-(thiophen-2'-yl)-2-bromoethylene (1n), 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol manganese, 0.04mmol ferrous chloride, 0.004mmol bis(dibenzylideneacetone)palladium, 0.092mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8mmol sodium iodide, and 2.0mL acetonitrile were added to a Young's tube previously dried with a flame oven, and the mixture was reacted at 80°C for 12h, and then 0.4mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4mmol Manganese, continue to react at 80°C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform column chromatography (200-300 mesh silica gel) with petroleum ether as the eluent for column chromatography; collect the eluent and distill under reduced pressure at 45°C to obtain ( E )-4-(thiophen-2'-yl)-2,2-difluoro-3-butenoic acid ethyl ester 3na, the yield is 24%

[0113] The reaction equation is as follows:

[0114] ;

[0115] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.32 (d, J = 5.1 Hz, 1H),7.19 (dt, J = 15.9, 2.4 Hz, 1H), 7.15 (d, J = 3.5 Hz, 1H), 7.02 (dd, J = 5.1,3.6 Hz, 1H), 6.11 (dt, J = 15.9, 11.5 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 163.95 (t, J = 35.0 Hz),139.02, 129.92 (t, J = 10.0 Hz), 129.62, 127.97, 127.44, 117.60 (t, J = 25.2Hz), 112.56 (t, J = 248.7 Hz), 63.33, 14.10. 19 F NMR (471 MHz, CDCl3) δ -102.99 (dd, J = 11.6, 2.2 Hz, 2F).

[0116] Example 15: In this example, (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-phenyl-2,2-difluoro-3-pentenoic acid ethyl ester 3oa, the structural formula is as follows:

[0117] ;

[0118] ( E The synthesis method of ethyl 4-phenyl-2,2-difluoro-3-pentenoate 3oa is as follows:

[0119] according to( E)-2-phenyl-1-bromo-1-propene (1o), ethyl 2,2-difluoro-2-bromoacetate (2a), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were sequentially added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. E )-2-phenyl-1-bromo-1-propene (1o), 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a), 0.4 mmol manganese, 0.04 mmol ferrous chloride, 0.004 mmol bis(dibenzylideneacetone)palladium, 0.092 mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8 mmol sodium iodide and 2.0 mL acetonitrile were added into a Young's tube which had been previously dried by a flame oven, and the reaction was carried out at 80°C for 12 h. Then, in a glove box filled with argon, 0.4 mmol ethyl 2,2-difluoro-2-bromoacetate (2a) and 0.4 mmol manganese were added into the Young's tube, and the reaction was continued at 80°C. ℃ for 12h; the reaction system was cooled to room temperature, and the solvent was removed by vacuum distillation at 45℃ to obtain a crude product, which was then subjected to column chromatography (200-300 mesh silica gel), with ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether was 1:100) as the eluent, and the eluent was collected and vacuum distilled at 45℃ to obtain ( E )-4-phenyl-2,2-difluoro-3-pentenoic acid ethyl ester 3oa, the yield is 67%

[0120] The reaction equation is as follows:

[0121] ;

[0122] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.41 (dt, J = 4.0, 2.2Hz, 2H), 7.39-7.32 (m, 3H), 5.92 (td, J = 14.0, 1.2 Hz, 1H), 4.35 (q, J = 7.1Hz, 2H), 2.26 (td, J = 2.6, 1.3 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 164.41 (t, J= 35.2 Hz), 147.85 (t, J = 7.2 Hz), 141.61,128.82, 128.61, 126.14, 118.77 (t, J = 26.8 Hz), 113.12 (t, J = 248.3 Hz), 63.14, 17.46, 14.07. 19 F NMR (471 MHz, CDCl3) δ -97.68 (dd, J = 14.0, 2.7 Hz, 2F).

[0123] Example 16: In this example, (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )- N , N -Diethyl-4-phenyl-2,2-difluoro-3-buteneamide 3ab, the structural formula is as follows:

[0124] ;

[0125] ( E )- N , N The synthesis method of diethyl-4-phenyl-2,2-difluoro-3-buteneamide 3ab is as follows:

[0126] according to( E )-1-phenyl-2-vinyl bromide (1a), N , N -diethyl-2,2-difluoro-2-bromoacetamide (2b), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, acetonitrile in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96, 0.4 mmol ( E )-1-phenyl-2-vinyl bromide (1a), N , N -Diethyl-2,2-difluoro-2-bromoacetamide (2b), 0.4 mmol manganese, 0.04 mmol ferrous chloride, 0.004 mmol bis(dibenzylideneacetone)palladium, 0.092 mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8 mmol sodium iodide, and 2.0 mL acetonitrile were added to a Young's tube previously dried with a flame gun, and reacted at 80 °C for 12 h, and then 0.4 mmol was added to the Young's tube in a glove box filled with argon. N ,N -diethyl-2,2-difluoro-2-bromoacetamide (2b), 0.4 mmol manganese, continue to react at 80°C for 12h; cool the reaction system to room temperature, distill under reduced pressure at 45°C to remove the solvent to obtain a crude product, and then perform gradient column chromatography (200-300 mesh silica gel), the eluent of the column chromatography is ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:60-1:30), collect the eluate, and distill under reduced pressure at 45°C to obtain ( E )- N , N -diethyl-4-phenyl-2,2-difluoro-3-butenamide 3ab, yield 60%;

[0127] The reaction equation is as follows:

[0128] ;

[0129] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 7.4 Hz, 2H), 7.35-7.25 (m, 3H), 6.93 (dd, J = 16.3, 2.5 Hz, 1H), 6.42 (dt, J = 16.3, 10.8Hz, 1H), 3.40 (dq, J = 30.6, 7.0 Hz, 4H), 1.15 (dt, J = 16.8, 7.1 Hz, 6H). 13 CNMR (151 MHz, CDCl3) δ 162.81 (t, J = 30.0 Hz), 135.34 (t, J = 9.8 Hz),134.43, 129.48, 128.87, 127.45, 120.60 (t, J = 24.8 Hz), 115.41 (t, J = 248.9Hz), 42.18 (t, J = 4.9 Hz), 41.57, 14.32, 12.43. 19 F NMR (471 MHz, CDCl3) δ -95.67 (d, J = 10.7 Hz, 2F).

[0130] Example 17: In this example, (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )-4-phenyl-1-(piperidin-1'-yl)-2,2-difluoro-3-butene-1-one 3ac, the structural formula is as follows:

[0131] ;

[0132] ( E The synthesis method of 4-phenyl-1-(piperidin-1'-yl)-2,2-difluoro-3-butene-1-one 3ac is as follows:

[0133] according to( E )-1-phenyl-2-bromoethylene (1a), 1-(piperidin-1-yl)-2,2-difluoro-2-bromoethane-1-one (2c), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96 were sequentially added in an argon-filled glove box. 0.4 mmol ( E )-1-phenyl-2-bromoethylene (1a), 1-(piperidin-1-yl)-2,2-difluoro-2-bromoethane-1-one (2c), 0.4 mmol manganese, 0.04 mmol ferrous chloride, 0.004 mmol bis(dibenzylideneacetone)palladium, 0.092 mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8 mmol sodium iodide, and 2.0 mL acetonitrile were added into a Young's tube previously dried by a flame oven, and reacted at 80 °C for 12 hours. Then, in a glove box filled with argon, 0.4 mmol 1-(piperidin-1-yl)-2,2-difluoro-2-bromoethane-1-one (2c) and 0.4 mmol manganese were added into the Young's tube, and the reaction was continued at 80 °C. ℃ for 12 hours; the reaction system was cooled to room temperature, and the solvent was removed by vacuum distillation at 45℃ to obtain a crude product, which was then subjected to gradient column chromatography (200-300 mesh silica gel), the eluent for column chromatography was ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether was 1:60-1:30), the eluent was collected, and vacuum distillation at 45℃ was performed to obtain ( E )-4-phenyl-1-(piperidin-1'-yl)-2,2-difluoro-3-buten-1-one 3ac in 56% yield;

[0134] The reaction equation is as follows:

[0135] ;

[0136] The characterization data of the product are as follows: 1H NMR (600 MHz, CDCl3) δ 7.37 (d, J = 6.1 Hz, 2H),7.28 (dd, J = 14.7, 7.3 Hz, 3H), 6.91 (d, J = 16.3 Hz, 1H), 6.44-6.32 (m,1H), 3.53 (d, J = 17.5 Hz, 4H), 1.63-1.48 (m, 6H). 13 C NMR (151 MHz, CDCl3) δ161.78 (t, J = 29.8 Hz), 135.46 (t, J = 9.7 Hz), 134.42, 129.51, 128.89,127.45, 120.55 (t, J = 24.8 Hz), 115.47 (t, J = 248.6 Hz), 47.16 (t, J = 5.2Hz), 44.55, 26.44, 25.72, 24.48. 19 F NMR (471 MHz, CDCl3) δ -94.94 (dd, J =10.4, 1.2 Hz, 2F) HRMS(ESI): mass found: 266.1353, calculated mass forC 15 H 18 F2NO + [M+H + ]: 266.1351.

[0137] Example 18: In this example (E)-4-aryl-2,2-difluoro-3-butenoic acid derivatives are ( E )- N -tert-Butyl-4-phenyl-2,2-difluoro-3-butenamide 3ad, the structural formula is as follows:

[0138] ;

[0139] ( E )- N The synthesis method of tert-butyl-4-phenyl-2,2-difluoro-3-buteneamide 3ad is as follows:

[0140] according to( E)-1-phenyl-2-vinyl bromide (1a), N -tert-butyl-2,2-difluoro-2-bromoacetamide (2d), manganese, ferrous chloride, bis(dibenzylideneacetone)palladium, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, sodium iodide, and acetonitrile were added in a glove box filled with argon in a molar ratio of 1:2:2:0.1:0.01:0.23:2:96. 0.4 mmol ( E )-1-phenyl-2-vinyl bromide (1a), N -tert-Butyl-2,2-difluoro-2-bromoacetamide (2d), 0.4 mmol manganese, 0.04 mmol ferrous chloride, 0.004 mmol bis(dibenzylideneacetone)palladium, 0.092 mmol 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.8 mmol sodium iodide, and 2.0 mL acetonitrile were added to a Young's tube previously dried with a flame oven, and reacted at 80 °C for 12 h. Then, 0.4 mmol was added to the Young's tube in an argon-filled glove box. N -tert-butyl-2,2-difluoro-2-bromoacetamide (2d), 0.4 mmol manganese, continue to react at 80 °C for 12 hours; cool the reaction system to room temperature, distill under reduced pressure at 45 °C to remove the solvent to obtain a crude product, and then perform gradient column chromatography (200-300 mesh silica gel), the eluent of the column chromatography is ethyl acetate / petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1:60-1:30), collect the eluate, and distill under reduced pressure at 45 °C to obtain ( E )- N -tert-Butyl-4-phenyl-2,2-difluoro-3-butenamide 3ad, yield 48%;

[0141] The reaction equation is as follows:

[0142] ;

[0143] The characterization data of the product are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.38 (d, J = 6.7 Hz, 2H), 7.33-7.24 (m, 3H), 6.98 (dd, J = 16.2, 2.5 Hz, 1H), 6.30 (dt, J = 16.2, 11.5Hz, 1H), 6.12 (s, 1H), 1.34 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 163.03 (t, J=29.3 Hz), 136.34 (t, J = 9.6 Hz), 134.40, 129.58, 128.90, 127.56, 119.33 (t, J = 25.1 Hz), 114.24 (t, J = 250.6 Hz), 52.17, 28.55. 19 F NMR (471 MHz, CDCl3)δ -102.06~-102.14 (m, 2F) HRMS(ESI): mass found: 276.1174, calculated massfor C 14 H 17 F2NONa + [M+Na + ]: 276.1170。

Claims

1. A ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives, characterized in that: Will( E )-1-aryl-2-bromoethylene, 2,2-difluoro-2-bromoacetic acid derivatives, reducing agent, catalyst A, catalyst B, ligand, and additives are added to a solvent to obtain a reaction system, and the reaction is carried out under a protective atmosphere at 50°C to 100°C for 6 to 12 hours, and then 2,2-difluoro-2-bromoacetic acid derivatives and reducing agent are added, and the reaction is continued under a protective atmosphere at 50°C to 100°C for 6 to 12 hours, and the solvent is removed by reduced pressure distillation to obtain a crude product, and then separated and purified to obtain ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives; The catalyst A is ferrous chloride, ferric chloride, ferrous acetate, ferrous oxalate, ferrous acetylacetonate or ferrous trifluoromethanesulfonate; the catalyst B is cuprous iodide, copper trifluoromethanesulfonate, nickel acetylacetonate, nickel bromide, bis(acetonitrile)palladium dichloride or bis(dibenzylideneacetone)palladium; the reducing agent is manganese, zinc, magnesium, manganese, iron or indium; the ligand is triphenylphosphine, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl or bis(diphenylphosphine)methane; the additive is magnesium chloride, ammonium chloride, sodium iodide, potassium bromide, potassium fluoride or lithium chloride; The 2,2-difluoro-2-bromoacetic acid derivatives are ethyl 2,2-difluoro-2-bromoacetate, N , N -diethyl-2,2-difluoro-2-bromoacetamide, 1-(piperidin-1-yl)-2,2-difluoro-2-bromoethane-1-one or N -tert-Butyl-2,2-difluoro-2-bromoacetamide.

2. According to claim 1 ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives, characterized in that: In the reaction system ( E The molar ratio of )-1-aryl-2-bromoethylene, 2,2-difluoro-2-bromoacetic acid derivatives, reducing agent, catalyst A, catalyst B, ligand, additive and solvent is 1: (1~4): (1~4): (0.05~0.3): (0.01~0.1): (0.1~0.3): (1~4): (10~100).

3. According to claim 2 ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives, characterized in that: The first added amount of the 2,2-difluoro-2-bromoacetic acid derivative is 25-75% of the total molar amount, and the first added amount of the reducing agent is 25-75% of the total molar amount.

4. According to claim 1 ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives, characterized in that: The solvents are toluene, acetonitrile, 1,4-dioxane, N , N -dimethylformamide, N -Methylpyrrolidone or tetrahydrofuran.

5. According to claim 1 ( E )-4-aryl-2,2-difluoro-3-butenoic acid derivatives, characterized in that: The protective atmosphere is argon or nitrogen.

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