Preparation method of difluoromethyl reagent and application of difluoromethyl reagent in synthesis of nickel-catalyzed alkyl difluoromethyl compound

Abstract

The invention discloses a preparation method of a difluoromethyl reagent and application of the difluoromethyl reagent in synthesis of a nickel-catalyzed alkyl difluoromethyl compound. The preparation method of the difluoromethyl reagent comprises the following steps: in an inert gas atmosphere, adding potassium iodide, cuprous iodide and a water-containing dimethylformamide solution into a reaction container, heating, dropwise adding difluorochloroacetic acid of DMF (Dimethyl Formamide) into a reaction system, collecting difluoroiodomethane, and supplementing a 1-methyl-2-pyrrolidone NMP (N-Methyl Pyrrolidone) solution into the system. The invention provides a difluoromethyl reagent which is simple and convenient to operate, low in cost, high in yield, environment-friendly and beneficial to large-scale preparation and application of the reagent in synthesis of difluoromethyl substituted alkane compounds.

Description

Technical Field

[0001] This invention relates to difluoromethyl reagents and their preparation methods, specifically to a method for preparing difluoromethyl reagents and their application in the nickel-catalyzed synthesis of alkyl difluoromethyl compounds. Background Technology

[0002] Fluorine atoms play an irreplaceable role in drug molecule design due to their unique physicochemical properties. Introducing fluorine-containing groups can significantly enhance the lipophilicity and metabolic stability of compounds, making organofluorine chemistry a crucial branch driving drug development, materials science, and pesticide innovation. Difluoromethyl (CF2H), as a key fluorine-containing building block, exhibits multiple advantages in medicinal chemistry: First, the CF2H group can effectively prolong the drug's half-life by enhancing metabolic oxidative resistance; second, its lipophilic nature can optimize drug absorption and distribution in vivo; more importantly, CF2H can act as a bioisostere for hydroxyl (-OH), amino (-NH2), and thiol (-SH) groups, significantly improving chemical stability and bioavailability while maintaining drug-target interactions. This unique dual property makes the CF2H group an ideal alternative to traditional hydrogen bond donors. It not only acts as a hydrogen bond donor to maintain the interaction of pharmacodynamic groups but also improves pharmacokinetic properties by enhancing cell membrane permeability. The anti-obstructive pulmonary disease drug roflumilast significantly improves metabolic stability by substituting hydroxyl groups with CF2H; in addition, the development of the insecticide benzo[a]flufenicol further demonstrates the significant advantages of the CF2H group in improving compound performance.

[0003]

[0004] Difluorohalomethanes are common electrophilic difluoromethylating agents and a direct or indirect source of other difluoromethylating agents. Since difluorobromomethane and difluorochloromethane are commercially available, current research mainly focuses on these two gases. However, difluoroiodomethane is expensive and currently unavailable, resulting in relatively less research on this reagent. Furthermore, in terms of reactivity, difluoroiodomethane exhibits stronger electrophilicity than the other two reagents.

[0005] In research, there has been considerable focus on the difluoromethylation of aromatic halides, with less research on aliphatic halides, particularly the difluoromethyl substitution reactions of secondary halides. In studies of aliphatic difluoromethylation, researchers often use stoichiometric copper and excess difluoromethylating agents to perform difluoromethylation reactions on aliphatic halogenated hydrocarbons. J. Org. Chem. 2021. 86 ,2854); ( Angew Chem Int Ed. 2022, 61, e202201064 ); ( Chem. Sci. 2024, 15 , 11550–11556).

[0006] Summary of the Invention

[0007] Purpose of the invention: 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 difluoromethyl reagents, as well as the application of this reagent in the synthesis of difluoromethyl-substituted alkane compounds.

[0008] Technical solution: The preparation method of the difluoromethyl reagent of the present invention includes the following steps: Under an inert gas atmosphere, potassium iodide, cuprous iodide, and a solution of dimethylformamide containing water were added to a reaction vessel. After heating, difluorochloroacetic acid dissolved in DMF was added to the reaction system. After the reaction was completed, difluoroiodomethane was collected, and then 1-methyl-2-pyrrolidone solution was added to the system to prepare difluoromethyl reagent.

[0009] Furthermore, the molar ratio of potassium iodide, cuprous iodide and difluorochloroacetic acid is 0.2-0.3:0.09-0.15:0.1-0.15.

[0010] Furthermore, the molar ratio of potassium iodide, cuprous iodide, and difluorochloroacetic acid is 0.3:0.15:0.15.

[0011] The difluoromethyl reagent is prepared by the method described above.

[0012] The application of the difluoromethyl reagent in the nickel-catalyzed synthesis of alkyl difluoromethyl compounds.

[0013] Furthermore, the method for synthesizing the nickel-catalyzed alkyl difluoromethyl compound is as follows: Under an inert gas atmosphere, a catalyst, ligand, solvent, difluoromethyl reagent, and haloalkanes or unactivated alkenes are added to a reaction vessel and stirred to allow for complete reaction, yielding difluoromethyl compounds, as shown in the following reaction formula:

[0014] Wherein, X is chlorine, bromine, iodine or p-toluenesulfonyl; R is H or CH3.

[0015] The catalyst is NiBr2, and the ligand is L4, 2-trifluoromethylpyridine, or bipyridine.

[0016] The amount of NiBr2 used is 5-20 mol of the substrate, preferably 10 mol of the substrate; the amount of the ligand used is 10-20 mol of the substrate.

[0017] The solvent is 1-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMA), or 1,4-dioxane, or any mixture thereof.

[0018] Compared with the prior art, the present invention has the following advantages: 1. This invention enables the large-scale preparation of difluoromethyl reagents and solves the difficulties of difluoroiodomethane reagents being gaseous at room temperature, having a low boiling point, and being difficult to store.

[0019] 2. This invention does not require the use of relatively expensive metal reagents, but uses metallic nickel as a catalyst, which is beneficial to environmental protection, reduces production costs, and is easy to scale up.

[0020] 3. In this invention, our experimental design strives for simplicity. The synthesis of most raw materials and intermediates requires only 1-2 steps. By controlling the reaction conditions, the rapid and efficient construction of alkyl difluoromethyl groups can be precisely achieved.

[0021] 4. This invention occurs under relatively mild conditions, and the reaction yields the product at temperatures ranging from room temperature to 60°C.

[0022] 5. The products obtained by this invention can be widely used in medicine, pesticides, materials science and other fields.

[0023] 6. 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.

[0024] 7. The functional groups in this invention have strong compatibility and a wide range of substrates. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of the present invention clearer, the technical solutions of the present invention will be further described below.

[0026] The method of the present invention will be described in detail below with reference to specific embodiments.

[0027] The preparation method of the difluoromethyl reagent in this embodiment is characterized by including the following steps: Under an argon protective atmosphere, potassium iodide (49.8 g, 0.3 mol), cuprous iodide (28.5 g, 0.15 mol), and 80 mL of dimethylformamide (DMF) solution containing 1.5 mL of water were added sequentially to a 250 mL three-necked round-bottom flask equipped with a reflux condenser with a -78°C cold trap.

[0028] After heating to 90℃, difluorochloroacetic acid (19.6 g, 0.15 mol) dissolved in 15 mL DMF was added dropwise to the reaction system over 1.0 h.

[0029] After the addition was complete, the temperature was raised to 150°C and refluxed for 24 h. After the reaction was completed, difluoroiodomethane was collected by low-temperature distillation to obtain 5.3 g of product, with a yield of 20%.

[0030] Considering the low boiling point of difluoroiodomethane (21–23℃, 20℃, 1 atm), 3.0 mL of N-1-methyl-2-pyrrolidone NMP solution was added to the system. The concentration of this solution (9.5 mol / L) was determined by... 19 Determined by F nuclear magnetic resonance spectroscopy.

[0031] The difluoromethyl reagent prepared above was used in the following examples.

[0032] Example 1 In a glove box, NiBr2 (10 mol%, 0.01 mmol), L4 (0.01 mmol, 10 mol%), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), K2CO3 (2.0 eq, 0.2 mmol, 27.6 mg), and tetrabutylammonium iodide (2.0 eq, 0.2 mmol, 58 mg) were added to a 5 mL reaction flask. Alkyl bromide 1a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone (0.4 mL) were added. The reaction was carried out at 60 °C for 12 hours to give 3. The reaction formula is as follows:

[0033] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 3, which was a white solid with a yield of 89%.

[0034] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.86 – 7.83 (m, 2H), 7.74 – 7.70 (m,2H), 5.80 (tt, J = 56.8, 4.4 Hz, 1H), 3.71 (t,J = 7.1 Hz, 2H), 1.96 – 1.81(m, 2H), 1.79 – 1.71 (m, 2H), 1.55 – 1.41 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 168.4, 134.0, 132.1, 123.3, 117.0(t, J = 238.9 Hz), 37.5, 33.6 (t, J = 21.0 Hz), 28.1, 19.5 (t, J = 5.8 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -115.96 (dt, J = 56.8, 17.8 Hz, 2F). Example 2 In a glove box, NiBr2 (10 mol%, 0.01 mmol), L4 (0.01 mmol, 10 mol%), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), K2CO3 (2.0 eq, 0.2 mmol, 27.6 mg), and tetrabutylammonium iodide (2.0 eq, 0.2 mmol, 58 mg) were added to a 5 mL reaction flask. Alkyl bromide 2a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone (0.4 mL) were added. The reaction was carried out at 60 °C for 12 hours to yield 4. The reaction equation is as follows:

[0035] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 4, which was a white solid with a yield of 86%.

[0036] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d) δ 7.87 – 7.79 (m, 2H), 7.75 – 7.67 (m,2H), 5.92 (tt, J = 55.9, 4.3 Hz, 1H), 3.87 (t, J = 6.9 Hz, 2H), 2.31 – 2.16(m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 168.1, 134.2, 132.0, 123.5, 115.8(t, J = 239.5 Hz), 33.2 (t, J = 21.5 Hz), 31.7 (t, J = 7.0 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -116.34 (dt, J = 55.9, 17.2 Hz, 2F). Example 3 In a glove box, NiBr2 (10 mol%, 0.01 mmol), L4 (0.01 mmol, 10 mol%), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), K2CO3 (2.0 eq, 0.2 mmol, 27.6 mg), and tetrabutylammonium iodide (2.0 eq, 0.2 mmol, 58 mg) were added to a 5 mL reaction flask. Alkyl bromide 3a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone (0.4 mL) were added. The reaction was carried out at 60 °C for 12 hours to obtain 5. The reaction formula is as follows:

[0037] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 5, which was a white solid with a yield of 81%.

[0038] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform-d ) δ 8.08 (d, J = 7.7 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.28 – 7.18 (m, 2H), 5.75 (tt, J =56.0, 4.4 Hz, 1H), 4.48 (t, J = 6.9 Hz, 2H), 2.46 – 2.28 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 140.0, 126.1, 123.2, 120.7, 119.5,115.7 (t, J = 239.1 Hz), 108.4, 36.5 (t, J = 6.9 Hz), 33.6 (t, J = 21.5 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -117.80 (dt, J = 56.1, 17.2 Hz, 2F). Example 4 In a glove box, NiBr2 (10 mol%, 0.01 mmol), L4 (0.01 mmol, 10 mol%), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), K2CO3 (2.0 eq, 0.2 mmol, 27.6 mg), and tetrabutylammonium iodide (2.0 eq, 0.2 mmol, 58 mg) were added to a 5 mL reaction flask. Alkyl bromide 4a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone (0.4 mL) were added. The reaction was carried out at 60 °C for 12 hours to yield 6. The reaction equation is as follows:

[0039] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 6, which is a yellow oil with a yield of 77%.

[0040] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.04 (dd, J = 8.3, 1.4 Hz, 2H), 7.60– 7.54 (m, 1H), 7.49 – 7.41 (m, 2H), 5.91 (tt, J = 56.2, 3.9 Hz, 1H), 4.38(t, J = 6.0 Hz, 2H), 2.11 – 1.92 (m, 4H). 13 C NMR (101 MHz, Chloroform- d ) δ 166.6, 133.2, 130.1, 129.7, 128.6,116.9 (t, J = 239.1 Hz), 64.0, 31.1 (t, J = 21.4 Hz), 21.7 (t, J = 5.5 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -116.27 (dt, J = 56.2, 16.9 Hz, 2F). Example 5 In a glove box, NiBr2 (10 mol%, 0.01 mmol), L4 (0.01 mmol, 10 mol%), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), K2CO3 (2.0 eq, 0.2 mmol, 27.6 mg), and tetrabutylammonium iodide (2.0 eq, 0.2 mmol, 58 mg) were added to a 5 mL reaction flask. Alkyl bromide 5a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone (0.4 mL) were added. The reaction was carried out at 60 °C for 12 hours to yield 7. The reaction equation is as follows:

[0041] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 7, which was a colorless oil with a yield of 79%.

[0042] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.43 – 7.35 (m, 2H), 7.29 – 7.20 (m,1H), 7.13 – 7.04 (m, 2H), 5.88 (tt, J = 56.4, 4.0 Hz, 1H), 2.66 (t, J = 7.0Hz, 2H), 2.10 – 1.86 (m, 4H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.5, 150.7, 129.6, 126.1, 121.6,116.97 (t, J = 239.1 Hz), 33.3 (t, J = 21.7 Hz), 17.6 (t, J = 5.9 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -116.05 (dt, J= 56.8, 16.8 Hz, 2F). Example 6 In a glove box, NiBr2 (10 mol%, 0.01 mmol), 2-trifluoromethylpyridine (20 mol%, 0.02 mmol), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), Na2CO3 (2.5 equiv, 0.2 mmol, 26.5 mg), tetrabutylammonium iodide (2.0 eq, 0.2 mmol, 58 mg), and KF (2.0 equiv, 0.2 mmol, 11.6 mg) were added to a 5 mL reaction flask. Alkyl iodide 6a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone / N,N-dimethylacetamide (DMA) (1 / 1, 0.4 mL) were added. The reaction was carried out at 60 °C for 48 hours to obtain 8. The reaction formula is as follows:

[0043] After the reaction was completed, the mixture was extracted with ethyl acetate and saturated sodium 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 8, which was a colorless oil with a yield of 88%.

[0044] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.32 – 7.27 (m, 2H), 7.23 – 7.17 (m,3H), 5.63 (td, J = 57.0, 3.6 Hz, 1H), 2.80 – 2.70 (m, 1H), 2.66 – 2.56 (m,1H), 1.97 – 1.84 (m, 2H), 1.60 – 1.49 (m,1H), 1.05 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 141.7, 128.6, 128.5, 126.2, 119.3(t, J = 242.2 Hz), 36.8 (t, J= 19.3 Hz), 33.0, 31.6 (t, J = 10.1 Hz), 12.4(t, J = 5.3 Hz). 19 F NMR (376 MHz, CDCl3) δ -122.03 – -124.72 (m, 2F). Example 7 In a glove box, NiBr2 (10 mol%, 0.01 mmol), 2-trifluoromethylpyridine (20 mol%, 0.02 mmol), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), Na2CO3 (2.5 equiv, 0.2 mmol, 26.5 mg), tetrabutylammonium iodide (2.0 eq, 0.2 mmol, 58 mg), and KF (2.0 equiv, 0.2 mmol, 11.6 mg) were added to a 5 mL reaction flask. Alkyl iodide 7a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone / N,N-dimethylacetamide (1 / 1, 0.4 mL) were added. The reaction was carried out at 60 °C for 48 hours to obtain 9. The reaction formula is as follows:

[0045] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 9, which was a colorless oil with a yield of 75%.

[0046] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.10 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.63 (td, J = 57.0, 3.7 Hz, 1H), 3.79 (s, 3H), 2.79 – 2.62 (m,1H), 2.62 – 2.46 (m, 1H), 2.01 – 1.77 (m, 2H), 1.54 – 1.46 (m, 1H), 1.04 (d,J = 6.8 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 158.0, 133.8, 129.4, 119.4 (t, J =242.2 Hz), 114.0, 55.4, 36.7 (t, J = 19.2 Hz), 32.0, 31.8 (t, J = 4.4 Hz), 12.4 (t, J = 5.2 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -121.96 – -124.71 (m, 2F). Example 8 In a glove box, NiBr2 (10 mol%, 0.01 mmol), 2-trifluoromethylpyridine (20 mol%, 0.02 mmol), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), Na2CO3 (2.5 equiv, 0.2 mmol, 26.5 mg), tetrabutylammonium iodide (2.0 eq, 0.2 mmol, 58 mg), and KF (2.0 equiv, 0.2 mmol, 11.6 mg) were added to a 5 mL reaction flask. Alkyl iodide 8a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone / N,N-dimethylacetamide (1 / 1, 0.4 mL) were added. The reaction was carried out at 60 °C for 48 hours to obtain 10. The reaction formula is as follows:

[0047] After the reaction was completed, the mixture was extracted with ethyl acetate and saturated sodium 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 10, which was a colorless oil with a yield of 82%.

[0048] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d) δ 7.73 – 7.63 (m, 4H), 7.51 – 7.35 (m, 6H), 5.71 (td, J = 57.1, 3.6 Hz, 1H), 3.83 – 3.63 (m, 2H), 2.28 – 2.06 (m,1H), 1.94 – 1.77 (m, 1H), 1.52 – 1.36 (m, 1H), 1.07 (s, 9H), 0.98 (d, J = 6.9Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 135.7, 133.8 (d, J = 3.0 Hz), 129.8, 127.8,121.8, 119.4 (t, J = 241.7 Hz), 117.0, 61.2, 34.3 (t, J = 19.6 Hz), 32.6 (t, J = 5.4, 4.4 Hz), 27.0, 19.3, 12.1 (t, J = 5.3 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -120.40 – -126.71 (m, 2F). Example 9 In a glove box, NiBr2 (10 mol%, 0.01 mmol), 2-trifluoromethylpyridine (20 mol%, 0.02 mmol), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), Na2CO3 (2.5 equiv, 0.2 mmol, 26.5 mg), tetrabutylammonium iodide (2.0 eq, 0.2 mmol, 58 mg), and KF (2.0 equiv, 0.2 mmol, 11.6 mg) were added to a 5 mL reaction flask. Alkyl iodide 9a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone / N,N-dimethylacetamide (1 / 1, 0.4 mL) were added. The reaction was carried out at 60 °C for 48 hours to obtain 11. The reaction formula is as follows:

[0049] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 11, which was a colorless oil with a yield of 72%.

[0050] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.6 (s, 1H), 7.2 (d, J = 3.5 Hz, 1H), 6.5 (dd, J = 3.5, 1.7 Hz, 1H), 5.7 (td, J = 56.7, 3.5 Hz, 1H), 4.5 – 4.3(m, 2H), 2.2 – 1.9 (m, 2H), 1.7 – 1.6 (m, 1H), 1.1 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 158.7, 146.6, 144.6, 118.9 (t, J =242.4 Hz), 118.2, 112.0, 62.4, 34.7 (t, J = 20.0 Hz), 28.9 (t, J = 4.6 Hz), 12.5 (t, J = 5.3 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -123.59 (dd, J = 56.7, 15.0 Hz, 2F). Example 10 In a glove box, NiBr2 (10 mol%, 0.01 mmol), 2-trifluoromethylpyridine (20 mol%, 0.02 mmol), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), Na2CO3 (2.5 equiv, 0.2 mmol, 26.5 mg), tetrabutylammonium iodide (2.0 eq, 0.2 mmol, 58 mg), and KF (2.0 equiv, 0.2 mmol, 11.6 mg) were added to a 5 mL reaction flask. Alkyl iodide 10a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone / N,N-dimethylacetamide (1 / 1, 0.4 mL) were added. The reaction was carried out at 60 °C for 48 hours to obtain 12. The reaction formula is as follows:

[0051] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 12, which is a yellow oil with a yield of 70%.

[0052] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 5.62 (tt, J = 56.9, 3.6 Hz, 1H),3.61 – 3.42 (m, 2H), 3.41 – 3.10 (m, 2H), 2.05 – 1.72 (m, 4H), 1.63 – 1.50(m, 2H), 1.44 (s, 9H), 1.33 – 1.25 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 155.5, 118.7 (t, J = 242.1 Hz), 79.5, 79.5,46.9, 46.3, 45.0, 44.6, 43.0 (t, J = 18.8 Hz), 42.6 (t, J = 19.0 Hz), 28.6, 27.4 (t, J = 241.9 Hz), 27.2 (t,J = 241.9 Hz), 26.9, 26.8, 25.9 (t, J = 4.4Hz), 25.7 (t, J = 4.3 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -121.49 – -124.26 (m, 2F). Example 11 In a glove box, NiBr2 (10 mol%, 0.01 mmol), bipyridine (20 mol%, 0.02 mmol), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), and LiOMe (2.5 equiv., 0.25 mmol, 9.5 mg) were added to a 5 mL reaction flask. Unsaturated olefin 11a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone / 1,4-dioxane (2 / 1, 0.4 mL) were added. The reaction was carried out at 60 °C for 12 hours to give 13. The reaction formula is as follows:

[0053] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 13, which was a white solid with a yield of 94%.

[0054] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.50 (d, J = 7.9 Hz, 3H), 7.33 (t, J = 7.9 Hz, 2H), 7.25 (s, 1H), 7.12 (t, J = 7.4 Hz, 1H), 5.83 (td, J = 56.8,2.8 Hz, 1H), 2.69 – 2.53 (m, 2H), 2.32 – 2.22 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 168.9, 137.6, 129.2, 124.7, 120.1,118.3 (t, J = 242.2 Hz), 37.4 (t, J = 4.4 Hz), 34.6 (t, J = 20.3 Hz), 12.8(t, J = 5.1 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -124.64 (ddd, J = 56.7, 33.8, 15.4Hz, 2F). Example 12 In a glove box, NiBr2 (10 mol%, 0.01 mmol), bipyridine (20 mol%, 0.02 mmol), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), and LiOMe (2.5 equiv., 0.25 mmol, 9.5 mg) were added to a 5 mL reaction flask. Unsaturated olefin 12a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone / 1,4-dioxane (2 / 1, 0.4 mL) were added. The reaction was carried out at 60 °C for 12 hours to give 14. The reaction equation is as follows:

[0055] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 14, which was a white solid with a yield of 86%.

[0056] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.47 – 7.40 (m, 3H), 7.00 (t, J =8.6 Hz, 2H), 5.81 (td, J= 56.7, 2.8 Hz, 1H), 2.65 – 2.51 (m, 2H), 2.31 –2.21 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 169.1, 159.6 (d, J = 244.1 Hz), 133.6 (d, J = 2.8 Hz), 122.1 (d, J = 8.0 Hz), 118.2 (t, J = 242.3 Hz), 115.8 (d, J = 22.5 Hz), 37.4 (t, J = 4.4 Hz), 34.6 (t, J = 20.2 Hz), 12.8 (t, J =5.1 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -117.24 – -117.72 (m, 1F), -123.30 –-125.83 (m, 2F). Example 13 In a glove box, NiBr2 (10 mol%, 0.01 mmol), bipyridine (20 mol%, 0.02 mmol), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), and LiOMe (2.5 equiv., 0.25 mmol, 9.5 mg) were added to a 5 mL reaction flask. Unsaturated olefin 13a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone / 1,4-dioxane (2 / 1, 0.4 mL) were added. The reaction was carried out at 60 °C for 12 hours to give 15. The reaction formula is as follows:

[0057] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 15, which was a white solid with a yield of 72%.

[0058] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.02 – 6.97 (m, 2H), 6.92 – 6.87 (m,2H), 5.82 (td, J = 56.6, 3.3 Hz, 1H), 3.80 (s, 3H), 2.85 – 2.76 (m, 1H), 2.64– 2.47 (m, 2H), 1.16 (d, J = 6.6 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 170.7, 157.5, 144.1, 122.3, 118.1(t, J = 242.4 Hz), 114.6, 55.7, 34.58 (t, J = 4.8 Hz), 34.6 (t, J = 20.5 Hz), 13.0 (t, J = 5.0 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -123.12 – -125.35 (m, 2F). Example 14 In a glove box, NiBr2 (10 mol%, 0.01 mmol), bipyridine (20 mol%, 0.02 mmol), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), and LiOMe (2.5 equiv., 0.25 mmol, 9.5 mg) were added to a 5 mL reaction flask. Unsaturated olefin 14a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone / 1,4-dioxane (2 / 1, 0.4 mL) were added. The reaction was carried out at 60 °C for 12 hours to yield 16. The reaction equation is as follows:

[0059] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 16, which was a white solid with a yield of 70%.

[0060] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.97 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 5.85 (td, J = 57.0, 3.0 Hz, 1H), 3.23 (dd, J = 17.6, 4.9 Hz, 1H), 2.95 (dd, J = 17.6, 8.0 Hz, 1H), 2.82 – 2.64(m, 1H), 1.10 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 169.3, 137.7, 129.2, 124.7, 120.1,118.0 (t, J = 242.2 Hz), 39.2 (t, J = 19.2 Hz), 35.5 (t,J = 4.3 Hz), 30.4 (dd, J = 5.3, 2.9 Hz), 20.1, 14.3. 19 F NMR (376 MHz, Chloroform- d ) δ -124.43 (ddd, J = 57.0, 25.5, 16.0Hz, 2F). Example 15 In a glove box, NiBr2 (10 mol%, 0.01 mmol), bipyridine (20 mol%, 0.02 mmol), Bis(neopentyl glycolato)diboron (2.0 eq, 0.2 mmol, 45.0 mg), and LiOMe (2.5 equiv., 0.25 mmol, 9.5 mg) were added to a 5 mL reaction flask. Unsaturated olefin 15a (1.0 eq, 0.1 mmol), difluoroiodomethane (2.0 eq, 0.2 mmol dissolved in NMP), and 1-methyl-2-pyrrolidone / 1,4-dioxane (2 / 1, 0.4 mL) were added. The reaction was carried out at 60 °C for 12 hours to give 17. The reaction formula is as follows:

[0061] After the reaction was complete, the mixture was extracted with ethyl acetate and saturated sodium 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 17, which was a white solid with a yield of 87%.

[0062] The product is characterized as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.20 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.95 (tt, J = 56.8, 4.2 Hz, 1H), 5.69 (s, 1H), 4.37 (d, J =5.6 Hz, 2H), 3.80 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H), 2.30 – 2.13 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 170.7, 159.3, 130.1, 129.4, 116.5(t, J = 239.0 Hz), 55.5, 43.4, 29.8 (t, J = 21.8 Hz), 28.6 (t, J = 5.5 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -117.52 (dt, J = 56.8, 17.5 Hz, 2F). The above are merely preferred embodiments of the present invention and do not constitute any limitation on the present invention. Any equivalent substitutions or modifications made by those skilled in the art to the technical solutions and content disclosed in the present invention without departing from the scope of the present invention shall be deemed to have remained within the protection scope of the present invention.

Claims

1. A method for preparing a difluoromethyl reagent, characterized in that, Includes the following steps: Under an inert gas atmosphere, potassium iodide, cuprous iodide, and a solution of dimethylformamide containing water were added to a reaction vessel. After heating, difluorochloroacetic acid dissolved in DMF was added to the reaction system. After the reaction was completed, difluoroiodomethane was collected, and then 1-methyl-2-pyrrolidone NMP solution was added to the system to prepare the difluoromethyl reagent.

2. The method according to claim 1, characterized in that, The molar ratio of potassium iodide, cuprous iodide and difluorochloroacetic acid is 0.2-0.3:0.09-0.15:0.1-0.

15.

3. The method according to claim 2, characterized in that, The molar ratio of potassium iodide, cuprous iodide, and difluorochloroacetic acid is 0.3:0.15:0.

15.

4. A difluoromethyl reagent prepared by the method according to any one of claims 1-3.

5. The application of the difluoromethyl reagent according to claim 4 in the nickel-catalyzed synthesis of alkyl difluoromethyl compounds.

6. The application according to claim 5, characterized in that, The nickel-catalyzed synthesis method of the alkyl difluoromethyl compound is as follows: Under an inert gas atmosphere, a catalyst, ligand, solvent, difluoromethyl reagent, and haloalkanes or unactivated alkenes are added to a reaction vessel and stirred to allow for complete reaction, yielding difluoromethyl compounds, as shown in the following reaction formula: ； Wherein, X is chlorine, bromine, iodine or p-toluenesulfonyl; R is H or CH3.

7. The application according to claim 6, characterized in that, The catalyst is NiBr2, and the ligand is L4, 2-trifluoromethylpyridine, or bipyridine.

8. The application according to claim 7, characterized in that, The amount of NiBr2 used is 5-20 mol of the substrate, preferably 10 mol of the substrate; the amount of the ligand used is 10-20 mol of the substrate.

9. The application according to claim 7 or 8, characterized in that, The solvent is 1-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMA), or 1,4-dioxane, or any mixture thereof.

Images