A method for preparing polyfluorinated substituted alkane compounds

Abstract

This invention discloses a method for preparing polyfluorinated substituted alkane compounds, comprising: adding a monovalent copper catalyst and its ligand, an organic solvent, a polyfluorinated alkyl reagent, and an aliphatic haloalkane to a reaction vessel in a nitrogen-filled vacuum-protected apparatus; stirring; and reacting at 25–100°C for 6–48 hours to obtain the polyfluorinated substituted alkane compound. This method uses inexpensive copper as a catalyst, has mild reaction conditions, good selectivity, and broad functional group compatibility, and can be used for late-stage functionalization modification of drug molecules.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry and relates to a method for preparing polyfluorinated substituted alkane compounds. Background Technology

[0002] Incorporating fluorine atoms or fluorine-containing groups into organic compounds can significantly improve their physicochemical properties, such as bioavailability, metabolic stability, lipophilicity, and selective binding. Statistics show that fluorine-containing compounds account for a high proportion of agrochemicals, and more than 20% of pharmaceuticals contain fluorine atoms, including best-selling drugs such as ciprofloxacin, efornithine, and prozac.

[0003]

[0004] Over the past century, research on organofluorine compounds has developed rapidly, from early air conditioning refrigerants like Freon to the corrosion-resistant fluorine-containing shells of atomic bombs, and now to fluoride pesticides and fluoride toothpaste. Fluorine chemistry is closely related to our lives. Although fluorine compounds have a wide range of applications, they also present several problems: 1) The number of naturally occurring fluorine compounds is extremely small, and most need to be synthesized artificially. 2) The synthesis process of organofluorine compounds often involves problems such as toxicity, explosiveness, and atmospheric damage. For these reasons, more and more scientists have devoted themselves to the research of organofluorine chemistry, leading to its rapid development in the last fifty years.

[0005] In the course of research, there has been considerable focus on the difluoromethylation and trifluoromethylation of aromatic compounds, while research on aliphatic compounds has been less extensive, and perfluoroalkylation of other carbon numbers is rarely addressed. In the study of difluoromethylation of aliphatic compounds, researchers often use stoichiometric copper and excess difluoromethylating reagents to perform difluoromethylation reactions on aliphatic haloalkanes (J. Org. Chem. 2021.86, 2854); (Angew Chem Int Ed. 2022, 61, e202201064).

[0006]

[0007] For trifluoromethylation reactions, the reaction often requires an excess of raw materials and a variety of complex reaction conditions. For example, the report published in 2021 (Angew Chem Int Ed 2021, 60, 5467) and (Org Lett. 2021, 20, 702) shows that the reaction uses an extremely excess of alkanes and can only be completed under conditions of stoichiometric oxidant and light.

[0008] Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method that is simple to operate, low in cost, high in yield, environmentally friendly, and conducive to the large-scale preparation of polyfluorinated substituted alkane compounds.

[0010] This invention provides a method for preparing polyfluorinated substituted alkane compounds, comprising the following steps: first, coordinating a monovalent copper catalyst with a ligand; then, under monovalent copper catalysis, reacting an aliphatic haloalkane with a polyfluorinated alkylating agent in an organic solvent under mild conditions to obtain an aliphatic polyfluorinated alkyl compound, the reaction formula of which is as follows:

[0011]

[0012] In the above structural formulas of haloalkanes, R 1 It is aryl, allyl, propargyl, and amide; R 2 It can be hydrogen or an alkyl group. X can be chlorine, bromine, iodine, or tert-butyloxycarbonyl (OBoc); Rf can be a polyfluoroalkyl group.

[0013] The polyfluoroalkyl reagents used in this invention are: (DMPU)2Zn(CF2H)2, (DMPU)2Zn(CF3)2, (DMPU)2Zn(C2F5)2, (DMPU)2Zn(C3F7)2, (DMPU)2Zn(C4F9)2, and (DMPU)2Zn(C6F5)2. 13 )2, The molar ratio of aliphatic haloalkanes to polyfluoroalkylating agents is 1:0.6.

[0014] The solvents used in this invention are aprotic solvents such as DMSO, DMA, and DCE.

[0015] The catalyst used in this invention is a cuprous iodide, cuprous bromide, and cuprous trifluoromethanesulfonate benzene complex. The ligands of the catalyst are selected as α,α,α-terpyridine or 4,4′-di-tert-butyl-2,2′-dipyridine. Both of them act as ligands to coordinate with Cu, which promotes the reaction to proceed better. The molar ratio of aliphatic haloalkanes to catalyst is 1:0.2.

[0016] The reaction temperature of this invention is 25–100°C, preferably room temperature.

[0017] The reaction time of the present invention is 6 to 48 hours, preferably 6 hours.

[0018] In this invention, the concentration of aliphatic haloalkanes is 1 mol / L.

[0019] In this invention, a monovalent copper catalyst and its ligands are first added to an organic solvent and reacted for several minutes. Then, the polyfluoroalkylating reagent is added and reacted for several minutes. Finally, the aliphatic haloalkane is added to carry out the reaction. The reason for the different order of addition of the reagents is that in the catalytic reaction of this invention, the Cu catalyst and ligands first need to coordinate, then the ligands undergo metal transfer with the polyfluoroalkylating reagent, and only then can the polyfluoroalkylation reaction of the haloalkane proceed.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] 1. This invention does not require the use of relatively expensive metal reagents, but instead uses metallic copper as a catalyst, which is beneficial to environmental protection, reduces production costs, and is easy to scale up for production;

[0022] 2. In this invention, for aryl benzyl halides, the reaction occurs only at the benzyl position of the aryl group, exhibiting good chemoselectivity and regioselectivity;

[0023] 3. This invention occurs under relatively mild conditions, and the reaction yields the product at temperatures ranging from room temperature to 100°C;

[0024] 4. The products obtained by this invention can be widely used in medicine, pesticides, materials science and other fields;

[0025] 5. The substrates of this invention have a wide range of applications and are well applicable to the late-stage functionalization modification of drug molecules, and can be applied to drug research and development and production.

[0026] 6. The functional groups in this invention have strong compatibility, and the substituents can be alkyl, halogen, amino, ether, ester, aryl, substituted aryl or heteroaryl substituents, etc. Detailed Implementation

[0027] The method of the present invention will be described in detail below with reference to specific embodiments.

[0028] Example 1

[0029] In a glove box, CuBr (0.04 mmol, 5.7 mg, 20 mol%), α,α,α-terpyridine (0.06 mmol, 14.0 mg, 30 mol%), DMA (1 mL), and DMSO (1 mL) were added to a 5 mL reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(CF₂H)₂ (0.12 mmol, 50.6 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 1a (0.2 mmol, 45.2 mg, 1.0 equiv) was added to the reaction system and reacted at room temperature for 6 hours to obtain 1b. The reaction formula is as follows:

[0030]

[0031] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 1b, which is a yellow oil with a yield of 85%.

[0032] The product is characterized as follows:

[0033] 1 H NMR (400MHz, CDCl3) δ8.47 (s, 1H), 8.26 (d, J=8.9Hz, 2H), 8.05 (d, J=8.4Hz, 2H), 7.677. 56 (m, 2H), 7.557.38 (m, 2H), 6.20 (tt, J=56.6, 4.8Hz, 1H), 4.21 (td, J=16.2, 4.8Hz, 2H).

[0034] 13 C NMR (101MHz, CDCl3) δ131.6, 131.0, 129.5, 128.1, 126.6, 125.2, 124.2 (t, J=5.8Hz), 124.1, 116.9 (t, J=243.3Hz), 33.0 (t, J=22.8Hz).

[0035] 19 F NMR (376MHz, CDCl3) δ-112.25 (2F, dt, J=56.8, 16.1Hz).

[0036] HRMS(ESI)m / z calcd for C 16 H 13 F2[(M+H) + ]: 243.0980, found: 243.0984.

[0037] Example 2

[0038] In a glove box, CuBr (0.04 mmol, 5.7 mg, 20 mol%), terpy (0.06 mmol, 14.0 mg, 30 mol%), DMA (1 mL), and DMSO (1 mL) were added to a 5 mL reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(CF₂H)₂ (0.12 mmol, 50.6 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 2a (0.2 mmol, 56.8 mg, 1.0 equiv) was added to the reaction system and reacted at room temperature for 6 hours to obtain 2b. The reaction equation is as follows:

[0039]

[0040] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 2b, which was a white solid with a yield of 87%.

[0041] The product is characterized as follows:

[0042] 1 H NMR (400MHz, CDCl3) δ7.837.78 (m, 3H), 7.72 (s, 1H), 7.59 (dd, J=8.6, 1.7Hz, 1H), 7.507.43 (m, 2H), 6.73 (d , J=15.9Hz, 1H), 6.26 (dt, J=15.9, 7.3Hz, 1H), 6.065.76 (m, 1H), 2.82 (tddd, J=17.2, 7.2, 4.5, 1.3Hz, 2H).

[0043] 13 C NMR (101MHz, CDCl3) δ135.5, 134.2, 133.6, 133.2, 128.4, 128.1, 127.8, 126.5, 12 6.4, 126.1, 123.5, 120.0 (t, J=6.7Hz), 116.4 (t, J=240.8Hz), 38.3 (t, J=22.0Hz).

[0044] 19 F NMR (376MHz, CDCl3) δ-115.49 (2F, dt, J=56.8, 17.3Hz).

[0045] HRMS(ESI)m / z calcd for C 14 H 13 F2[(M+H) + ]: 219.0980, found: 219.0983.

[0046] Example 3

[0047] In a glove box, CuBr (0.04 mmol, 5.7 mg, 20 mol%), terpy (0.06 mmol, 14.0 mg, 30 mol%), DMA (1 mol), and DMSO (1 mol) were added to a 5 mL reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(CF₂H)₂ (0.12 mmol, 50.6 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 3a (0.2 mmol, 57.0 mg, 1.0 equiv) was added to the reaction system and reacted at 100 °C for 6 hours to obtain 3b. The reaction formula is as follows:

[0048]

[0049] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 3b, which was a white solid with a yield of 86%.

[0050] The product is characterized as follows:

[0051] 1 H NMR (400MHz, CDCl3) δ5.85 (td, J=56.6, 5.9Hz, 1H), 2.65-2.44 (m, 1H), 2.08 (s , 3H), 1.99 (d, J=2.5Hz, 6H), 1.67 (s, 6H), 1.61 (s, 1H), 1.23 (d, J=7.1Hz, 3H).

[0052] 13 C NMR (101MHz, CDCl3) δ168.9 (d, J=11.4Hz), 123.0-112.3 (m), 52.5, 46.7 (t, J=21.1Hz), 41.6, 36.4, 29.5, 11.5 (dd, J=6.8, 3.6Hz).

[0053] 19 F NMR (376MHz, CDCl3) δ-118.08 (F, ddd, J=11.2, 56.6, 280.3Hz), -124.83 (F, ddd, J=12.5, 56.9, 280.3Hz).

[0054] HRMS(ESI)m / z calcd for C 14 H 22 F2NO[(M+H) + ]: 258.1664, found: 258.1665.

[0055] Example 4

[0056] In a glove box, CuI (0.04 mmol, 7.6 mg, 20 mol%), 4,4′-di-tert-butyl-2,2′-dipyridine (dbbpy) (0.06 mmol, 16.1 mg, 30 mol%), and DMA (2 ml) were added to a 10 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(CF₃)₂ (0.12 mmol, 55.0 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 4a (0.2 mmol, 69.2 mg, 1.0 equiv) was added to the reaction system and reacted at room temperature for 48 hours to obtain 4b. The reaction equation is as follows:

[0057]

[0058] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 4b, which was a white solid with a yield of 80%.

[0059] The product is characterized as follows:

[0060] 1 H NMR (400MHz, CDCl3) δ7.62 (d, J=2.2Hz, 2H), 7.60 (d, J=1.7Hz, 2H), 7.48 (dd, J=10.3, 4.8Hz, 2H), 7.38 (dd, J=10.3, 4.4Hz, 3H), 3.43 (q, J=10.8Hz, 2H).

[0061] 13 C NMR (101MHz, CDCl3) δ141.2, 140.6, 130.7, 129.2 (dd, J=5.7, 2.9Hz), 129.0, 127.6, 127.5, 127.2, 125.9 (q, J=276.9Hz), 40.0 (q, J=29.7Hz).

[0062] 19 F NMR (376MHz, CDCl3) δ-65.81 (3F, t, J=11.0Hz).

[0063] HRMS(ESI)m / z calcd for C 14 H 12 F3[(M+H) + ]: 237.0886, found: 237.0885.

[0064] Example 5

[0065] In a glove box, CuI (0.04 mmol, 7.6 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DMA (2 ml) were added to a 5 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(CF₃)₂ (0.12 mmol, 55.0 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 5a (0.2 mmol, 69.2 mg, 1.0 equiv) was added to the reaction system and reacted at room temperature for 48 hours to obtain 5b. The reaction formula is as follows:

[0066]

[0067] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 5b, which is a yellow oil with a yield of 88%.

[0068] The product is characterized as follows:

[0069] 1 H NMR (400MHz, CDCl3) δ7.65-7.61 (m, 2H), 7.47 (d, J=8.3Hz, 2H), 6.63 (d, J=15.9Hz, 1H), 6.25 (dt, J=15.9, 7.3Hz, 1H), 3.04 (qdd, J=10.6, 7.3, 1.3Hz, 2H).

[0070] 13 C NMR (101MHz, CDCl3) δ140.6, 135.2, 132.6, 132.4-113.7 (m), 127.1, 121.4 (q, J=3.5Hz), 118.9, 111.6, 37.8 (q, J=30.1Hz).

[0071] 19 F NMR (376MHz, CDCl3) δ-65.94 (3F, t, J=10.4Hz).

[0072] HRMS(ESI)m / z calcd for C 11 H9F3N[(M+H) + ]: 212.0682, found: 212.0680.

[0073] Example 6

[0074] In a glove box, CuI (0.04 mmol, 7.6 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DMA (2 ml) were added to a 5 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(CF₃)₂ (0.12 mmol, 55.0 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 6a (0.2 mmol, 46.6 mg, 1.0 equiv) was added to the reaction system and reacted at room temperature for 48 hours to obtain 6b. The reaction formula is as follows:

[0075]

[0076] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 6b, which is a yellow oil with a yield of 83%.

[0077] The product is characterized as follows:

[0078] 1 H NMR (400MHz, CDCl3) δ7.67-7.61 (m, 2H), 7.52 (d, J=8.3Hz, 2H), 6.05 (dtt, J=10.5, 7.4, 3.0Hz, 1H), 1.91 (d, J=7.4Hz, 3H).

[0079] 13 C NMR (101MHz, CDCl3) δ206.0 (q, J=4.0Hz), 135.2, 132.5, 127.6, 123.1 (q, J=273.9Hz), 118.7, 111.6, 101.3-99.9 (m), 96.3, 13.2.

[0080] 19 F NMR (376MHz, CDCl3) δ-60.38 (3F, d, J=2.7Hz).

[0081] HRMS(ESI)m / z calcd for C 12 H9F3N[(M+H) + ]: 224.0682, found: 224.0685.

[0082] Example 7

[0083] In a glove box, (CuOTf)₂·C₆H₆ (0.04 mmol, 20.1 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DCE (2 ml) were added to a 10 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(C₂F₅)₂ (0.12 mmol, 67.0 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 7a (0.2 mmol, 72.8 mg, 1.0 equiv) was added to the reaction system, and the reaction was carried out at 50 °C for 48 hours to obtain 7b. The reaction formula is as follows:

[0084]

[0085] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 7b, which was a white solid with a yield of 83%.

[0086] The product is characterized as follows:

[0087] 1 H NMR (400MHz, CDCl3) δ7.94-7.85 (m, 2H), 6.95 (d, J=8.5Hz, 1H), 4.34 (q, J=7.1H z, 2H), 3.89 (s, 3H), 3.45 (t, J=18.2Hz, 2H), 2.76 (s, 3H), 1.38 (t, J=7.1Hz, 3H).

[0088] 13 C NMR (101MHz, CDCl3) δ169.3, 162.5, 161.2, 160.5, 130.9, 128.6, 125.8, 121.2, 118.9, 118.5116.7(m), 115.7-113.8(m), 111.1, 61.3, 56.0, 30.3(t, J=22.2Hz), 17.7, 14.5.

[0089] 19 F NMR (376MHz, CDCl3) δ-85.12 (3F, s), -116.57 (2F, t, J=18.1Hz).

[0090] HRMS(ESI)m / z calcdfor C 17 H 17 F5NO3S[(M+H) + ]: 410.0844, found: 410.0848.

[0091] Example 8

[0092] In a glove box, (CuOTf)₂·C₆H₆ (0.04 mmol, 20.1 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DCE (2 ml) were added to a 10 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(C₂F₅)₂ (0.12 mmol, 67.0 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 8a (0.2 mmol, 66.8 mg, 1.0 equiv) was added to the reaction system, and the reaction was carried out at room temperature for 48 hours to obtain 8b. The reaction formula is as follows:

[0093]

[0094] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 8b, which is a yellow oil with a yield of 88%.

[0095] The product is characterized as follows:

[0096] 1 H NMR (400MHz, CDCl3) δ8.07-7.99 (m, 2H), 7.38 (d, J=8.2Hz, 2H), 4.47 (t, J=6.0 Hz, 2H), 3.55 (t, J=6.5Hz, 2H), 3.38 (t, J=18.1Hz, 2H), 2.32 (p, J=6.3Hz, 2H).

[0097] 13 C NMR (101MHz, CDCl3) δ166.0, 134.4 (t, J=1.9Hz), 130.9, 130.1, 130.0, 118.6 (ddd , J=146.2, 73.2, 36.7Hz), 115.6-110.7 (m), 62.9, 37.1 (t, J=22.1Hz), 31.9, 29.5.

[0098] 19 F NMR (376MHz, CDCl3) δ-84.72 (3F, s), -116.74 (2F, t, J=18.1Hz).

[0099] HRMS(ESI)m / z calcd for C 13 H 13 BrF5O2[(M+H) +]: 375.0014, found: 375.0018.

[0100] Example 9

[0101] In a glove box, (CuOTf)₂·C₆H₆ (0.04 mmol, 20.1 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DCE (2 ml) were added to a 10 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(C₂F₅)₂ (0.12 mmol, 67.0 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 9a (0.2 mmol, 53.2 mg, 1.0 equiv) was added to the reaction system, and the reaction was carried out at room temperature for 48 hours to obtain 9b. The reaction formula is as follows:

[0102]

[0103] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 9b, which is a yellow oil with a yield of 81%.

[0104] The product is characterized as follows:

[0105] 1 H NMR (400MHz, CDCl3) δ8.05-7.98 (m, 2H), 7.49 (d, J=8.9Hz, 2H), 5.94 (qt, J=7.4, 4.8Hz, 1H), 3.92 (s, 3H), 1.88 (d, J=7.4Hz, 3H).

[0106] 13 C NMR (101MHz, CDCl3) δ207.6 (t, J=7.5Hz), 166.8, 135.6, 129.9, 129.8, 128.1, 119.1 (dt, J=286.9, 37.7Hz), 115.7-110.4 (m), 98.5 (t, J=26.8Hz), 94.7, 52.3, 13.2 (d, J=2.5Hz).

[0107] 19 F NMR (376MHz, CDCl3) δ-82.82 (3F, s), -108.29 (2F, d, J=16.6Hz).

[0108] HRMS(ESI)m / z calcdfor C 14 H 12 F5O2[(M+H)+ ]: 307.0752, found: 307.0753.

[0109] Example 10

[0110] In a glove box, (CuOTf)₂·C₆H₆ (0.04 mmol, 20.1 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DCE (2 ml) were added to a 10 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(C₃F₇)₂ (0.12 mmol, 79.0 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 10a (0.2 mmol, 92.0 mg, 1.0 equiv) was added to the reaction system, and the reaction was carried out at 75 °C for 48 hours to obtain 10b. The reaction formula is as follows:

[0111]

[0112] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 10b, which was a white solid with a yield of 75%.

[0113] The product is characterized as follows:

[0114] 1 H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 7.89 (dd, J=5.9, 8.4Hz, 2H), 7.77 (d, J=8.7Hz, 2H), 7.60 (d, J=2.2Hz, 1H), 7.54 (dd, J=2.3, 8.4Hz, 1 H), 7.41 (d, J=8.4Hz, 1H), 7.00 (d, J=8.4Hz, 1H), 3.91 (s, 3H), 3.53 (t, J=18.9Hz, 2H), 2.20 (d, J=2.1Hz, 6H), 2.12 (s, 3H), 1.82 (s, 6H).

[0115] 13 C NMR (101MHz, CDCl3) δ158.8, 139.7, 139.1, 133.4, 133.1, 132.2, 130.1, 128.7, 128.6, 128.3, 126.4, 126.1, 125.8, 1 24.9, 117.6-116.0 (m), 115.0-113.1 (m), 112.2, 110.6-108.5 (m), 55.3, 40.8, 37.3 (d, J=5.0Hz), 37.2, 37.0, 29.3.

[0116] 19 F NMR (377MHz, CDCl3) δ-80.37 (3F, t, J=9.9Hz), -113.74 (2F, tdt, J=9.7, 14.0, 19.4Hz), -127.10 (2F, d, J=4.8Hz).

[0117] HRMS(ESI)m / z calcd for C 31 H 30 F7O[(M+H) + ]: 551.2180, found: 551.2188.

[0118] Example 11

[0119] In a glove box, (CuOTf)₂·C₆H₆ (0.04 mmol, 20.1 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DCE (2 ml) were added to a 10 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(C₃F₇)₂ (0.12 mmol, 79.0 mg, 0.6 e quiv) was added and reacted for another 5 minutes. Finally, 11a (0.2 mmol, 102.8 mg, 1.0 e quiv) was added to the reaction system, and the reaction was carried out at room temperature for 48 hours to obtain 11b. The reaction formula is as follows:

[0120]

[0121] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 11b, which was a yellow solid with a yield of 86%.

[0122] The product is characterized as follows:

[0123] 1 H NMR (400MHz, CDCl3) δ7.18-7.11 (m, 9H), 7.11-7.03 (m, 10H), 3.29 (t, J=18.8Hz, 2H).

[0124] 13C NMR (101MHz, CDCl3) δ143.8, 143.7, 143.63, 143.58, 141.6, 140.4, 131.6, 131.4, 130.3, 127.9, 127.8, 127.0, 126 .70, 126.68, 120.1-118.1 (m), 116.5 (td, J=17.7, 31.0, 32.7Hz), 109.2 (dd, J=36.2, 74.0Hz), 36.8 (t, J=22.3Hz).

[0125] 19 F NMR (377MHz, CDCl3) δ-80.44 (3F, t, J=10.3Hz), -113.68--114.02 (2F, m), -127.10 (2F, s).HRMS (ESI) m / z calcd for C 30 H 22 F7[(M+H) + ]: 515.1604, found: 515.1607.

[0126] Example 12

[0127] In a glove box, (CuOTf)₂·C₆H₆ (0.04 mmol, 20.1 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DCE (2 ml) were added to a 10 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(C₄F₉)₂ (0.12 mmol, 121.3 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 12a (0.2 mmol, 85.0 mg, 1.0 equiv) was added to the reaction system, and the reaction was carried out at 50 °C for 48 hours to obtain 12b. The reaction formula is as follows:

[0128]

[0129] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 12b, which was a white solid with a yield of 89%.

[0130] The product is characterized as follows:

[0131] 1H NMR (400MHz, CDCl3) δ7.41 (s, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 6.96 (d, J=6.3Hz, 1H), 6.61 (s, 1H), 3.32 (t, J=19.0Hz, 2H), 1.52 (s, 9H).

[0132] 13 C NMR (101MHz, CDCl3) δ152.8, 138.8, 129.9, 129.3, 125.6, 120.9, 118.9 (t, J=25.3Hz), 118.3, 1 16.9 (t, J=31.5Hz), 116.1 (t, J=33.5Hz), 114.4 (t, J=31.1Hz), 80.9, 37.0 (t, J=22.1Hz), 28.4.

[0133] 19 F NMR (376MHz, CDCl3) δ-81.01-81.15 (3F, m), -113.40 (2F, dt, J=33.1, 16.1Hz), -123.87-123.97 (2F, m), -125.93-126.08 (2F, m).

[0134] HRMS(ESI)m / z calcd for C 16 H 17 F9NO2[(M+H) + ]: 425.1032, found: 425.1035.

[0135] Example 13

[0136] In a glove box, (CuOTf)₂·C₆H₆ (0.04 mmol, 20.1 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DCE (2 ml) were added to a 10 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(C₄F₉)₂ (0.12 mmol, 121.3 mg, 0.6 equiv) was added and reacted for another 5 minutes. Finally, 13a (0.2 mmol, 58.0 mg, 1.0 equiv) was added to the reaction system, and the reaction was carried out at 50 °C for 48 hours to obtain 13b. The reaction formula is as follows:

[0137]

[0138] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 13b, which was a white solid with a yield of 90%.

[0139] The product is characterized as follows:

[0140] 1 H NMR (400MHz, CDCl3) δ 8.17-8.04 (m, 2H), 7.55 (t, J=7.4Hz, 1H), 7.43 (t, J=7.7Hz, 2H), 7.27 (d, J=8.4Hz, 2H), 7.18-7.11 (m, 2H), 3.30 (t, J=18.8Hz, 2H).

[0141] 13 C NMR (101MHz, CDCl3) δ165.2, 151.1, 133.9, 132.1, 130.3, 129.5, 128.8, 126.6, 122.1, 119.8-1 19.2 (m), 118.9 (t, J = 22.2Hz), 116.9 (t, J = 31.4Hz), 116.1 (t, J = 33.3Hz), 36.5 (t, J = 22.3Hz).

[0142] 19 F NMR (376MHz, CDCl3) δ-70.35--90.97(3F,m), -110.29--118.51(2F,m), -122.16--124.83(2F,m), -124.83--127.26(2F,m).

[0143] HRMS(ESI)m / z calcd for C 18 H 12 F9O2[(M+H) + ]: 431.0688, found: 431.0689.

[0144] Example 14

[0145] In a glove box, (CuOTf)₂·C₆H₆ (0.04 mmol, 20.1 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DCE (2 ml) were added to a 10 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(C₆F)₂ was added. 13After reacting 14a (0.2 mmol, 44.2 mg, 1.0 equiv) for 5 minutes, 14b (0.2 mmol, 44.2 mg, 1.0 equiv) was added to the reaction system, and the reaction was carried out at 50 °C for 48 hours to obtain 14b. The reaction formula is as follows:

[0146]

[0147] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 14b, which was a yellow solid with a yield of 90%.

[0148] The product is characterized as follows:

[0149] 1 H NMR (400MHz, CDCl3) δ8.96 (dd, J=1.8, 4.2Hz, 1H), 8.15 (dd, J=1.8, 8.3Hz, 1H), 7.81 (d, J=8.1Hz, 1 H), 7.77 (d, J=7.1Hz, 1H), 7.57-7.51 (m, 1H), 7.41 (dd, J=4.1, 8.3Hz, 1H), 4.27 (t, J=19.5Hz, 2H).

[0150] 13 C NMR (101MHz, CDCl3) δ150.2, 147.4, 136.3, 132.0, 128.63, 128.56, 128.5, 126.1, 121.4, 120.9

[0151] 120.0(m), 119.5-118.3(m), 118.3-117.3(m), 116.5-115.2(m), 112.0-111.0(m), 109.3-107.9(m), 30.6(t, J=21.6Hz).

[0152] 19 F NMR (376MHz, CDCl3) δ-80.91 (3F, d, J=9.1Hz), -112.10--112.44 (2F, m), -121.76 (2F, h, J=13 .7Hz), -122.82--122.91(2F,m), -122.91--123.01(2F,m), -126.21(2F,td,J=5.1,15.2Hz).

[0153] HRMS(ESI)m / z calcd for C 16 H9F13 N[(M+H) + ]: 462.0522, found: 462.0518.

[0154] Example 15

[0155] In a glove box, (CuOTf)₂·C₆H₆ (0.04 mmol, 20.1 mg, 20 mol%), dbbpy (0.06 mmol, 16.1 mg, 30 mol%), and DCE (2 ml) were added to a 10 ml reaction flask and reacted at room temperature for 5 minutes. Then, (DMPU)₂Zn(C₆F)₂ was added. 13 After reacting 15a (0.2 mmol, 50.8 mg, 1.0 equiv) for another 5 minutes, 15b (0.2 mmol, 50.8 mg, 1.0 equiv) was added to the reaction system, and the reaction was carried out at room temperature for 48 hours to obtain 15b. The reaction formula is as follows:

[0156]

[0157] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated ammonium chloride aqueous solution. The organic layer was dried with anhydrous Na2SO4, the solid was filtered, the solvent was removed by vacuum distillation, and finally the obtained substance was subjected to column chromatography to obtain 15b, which was a yellow solid with a yield of 84%.

[0158] The product is characterized as follows:

[0159] 1 H NMR (400MHz, CDCl3) δ8.03-7.97 (m, 2H), 7.44 (d, J=8.4Hz, 2H), 6.66 (d, J=15.9Hz, 1H), 6.31-6.21 (m, 1H), 3.91 (s, 3H), 3.10-2.97 (m, 2H).

[0160] 13 C NMR (101MHz, CDCl3) δ166.9, 140.6, 136.5, 130.1, 129.7, 126.5, 120.4-119.4 (m), 119.0 (t, J=4.5Hz), 118.9 (d, J=33.3Hz), 117.4(t, J=30.1Hz), 116.6-115.0(m), 111.8-110.6(m), 110.8109.8(m), 52.3, 35.3(t, J=22.6Hz).

[0161] 19F NMR(376MHz,CDCl3)δ-80.87(3F,t,J=9.6Hz),-112.85(2F,dq,J=15.3,16.3,33.2Hz),-121.98(2F,p,J=15.5,16.2Hz),-122.85--122.98(2F,m),-123.04(2F,d,J=14.7Hz),-126.22(2F,dq,J=6.8,15.2Hz).

[0162] HRMS(ESI)m / z calcd for C 17 H 12 F 13 O2[(M+H) + ]:495.0624,found:495.0627。

Claims

1. A method for preparing polyfluorinated substituted alkane compounds, characterized in that, The method includes the following steps: First, add the monovalent copper catalyst and its ligands to the organic solvent and mix for several minutes. Then, add the polyfluoroalkyl reagent and mix for several minutes. Finally, add the aliphatic haloalkane to react. The reaction formula is as follows: ； The aliphatic haloalkanes for , , , , , , , , or ; The monovalent copper catalyst is selected from cuprous iodide, cuprous bromide or cuprous trifluoromethanesulfonate benzene complex; the ligand of the monovalent copper catalyst is selected from α,α,α-terpyridine or 4,4'-di-tert-butyl-2,2'-dipyridine. The polyfluoroalkyl reagents are: difluoromethyl reagent: (DMPU)2Zn(CF2H)2; trifluoromethyl reagent: (DMPU)2Zn(CF3)2; pentafluoroethyl reagent: (DMPU)2Zn(C2F5)2; heptafluoropropyl reagent: (DMPU)2Zn(C3F7)2; nonafluorobutyl reagent: (DMPU)2Zn(C4F9)2; tridecylfluorohexyl reagent: (DMPU)2Zn(C6F)2 13 )2; The molar ratio of the aliphatic haloalkane to the polyfluoroalkyl reagent is 1:0.

6.

2. The method according to claim 1, characterized in that: The molar ratio of the aliphatic halohydrocarbon to the monovalent copper catalyst is 1:0.

2.

3. The method according to claim 1, characterized in that: The organic solvent is an aprotic polar solvent, and the organic solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylacetamide or 1,2-dichloroethane.

4. The method according to claim 1, characterized in that: The concentration of the aliphatic haloalkane in the organic solvent is 1 mol / L.

5. The method according to claim 1, characterized in that: The reaction time is 6 to 48 hours.

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