Three-component coupling method of a class of aromatic trifluoroalkyl compounds, conjugated olefins and nucleophiles

Abstract

The application discloses a three-component coupling method of aromatic trifluoroalkyl compounds, conjugated olefins and nucleophilic reagents, under the condition of room temperature and inert atmosphere, the aromatic trifluoroalkyl compounds generate aromatic difluoroalkyl-palladium complexes under the condition of a palladium catalyst, a phosphine ligand, an organic solvent, a base and light; the aromatic difluoroalkyl-palladium complexes are added to the conjugated olefins, and then added to amine or 1,3-dicarbonyl compounds to obtain difluoroalkyl functionalization products. The method has the advantages of easy availability of raw materials, simple operation, mild reaction conditions, wide substrate applicability and the like, meets the development requirements of green chemistry, and is expected to be widely applied in the modification of drug molecules or natural product molecules.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a three-component coupling method for a class of aromatic trifluoroalkyl compounds, conjugated olefins, and nucleophiles. Background Technology

[0002] Difluoroalkyl functional groups are widely found in various natural products, bioactive molecules, and drug molecules. They can serve as bioisosteres of functional groups such as carbonyl groups and oxygen atoms. For example, highly selective β2 receptor agonists such as Abediterol, HCV NS3 / 4A protease inhibitors such as Glecaprevir and Voxilaprevir, and antifungal agents such as Oteseconazole all possess difluoroalkyl functional groups. Therefore, developing green and efficient synthetic methods to construct molecules containing difluoroalkyl functional groups is of great significance.

[0003]

[0004] Aromatic trifluoroalkyl compounds, as inexpensive and readily available chemical raw materials, are an ideal precursor for constructing aromatic difluoroalkyl functional groups.

[0005] Traditional methods for generating aromatic difluoroalkyl functional groups typically require structurally reactive compounds as starting materials, such as RCF2-X (R = aryl, carbonyl), which generate aromatic difluoroalkyl functional groups through the cleavage of CF2-X (X = Cl, Br, I) bonds. However, these compounds are either expensive or difficult to prepare. The resurgence of visible light photocatalysis has provided a milder and more efficient method for constructing aromatic difluoroalkyl functional groups, and has seen rapid development in recent years.

[0006] The generation of aromatic difluoroalkyl functional groups via visible light catalysis, followed by three-component coupling with conjugated olefins and nucleophiles (amines or 1,3-dicarbonyl compounds), is a highly efficient method for constructing structurally complex fluorinated functional molecules. Currently reported intermediates for the defluorination of aromatic trifluoroalkyl compounds to generate aromatic difluoroalkyl functional groups mainly fall into four categories: aromatic difluoroalkyl cations, aromatic difluoroalkyl anions, aromatic difluoroalkyl radicals, and aromatic difluoroalkyl-metal complexes. Among these, the bicomponent coupling reactions of aromatic difluoroalkyl radicals with other coupling agents are relatively well-studied; however, multicomponent coupling reactions mediated by metal catalysts are less frequently reported.

[0007] The two currently reported metal-catalyzed defluorination coupling reactions of aromatic trifluoroalkyl compounds are both two-component processes: Ni-mediated defluorination hydrogenation and Pd-mediated defluorination Suzuki coupling, both involving the formation of aromatic difluoroalkyl-metal complex intermediates. Both methodologies suffer from limitations such as simple substrate structures, limited substrate scope, and low conversion and yield, thus restricting their application potential. Therefore, developing an economical, efficient, and widely applicable multi-component defluorination coupling reaction for aromatic trifluoroalkyl compounds is of great significance. Summary of the Invention

[0008] This invention provides a three-component coupling method for aromatic trifluoroalkyl compounds, conjugated olefins, and nucleophiles (amines or 1,3-dicarbonyl compounds), which solves the problems of simple substrate structure, limited substrate types, and low conversion and yield in current defluorination coupling reactions of aromatic trifluoroalkyl compounds.

[0009] The technical solution of the present invention is as follows:

[0010] A three-component coupling method for a class of aromatic trifluoroalkyl compounds, conjugated alkenes, and nucleophiles includes:

[0011] (1) Aromatic trifluoroalkyl compounds generate difluoroalkyl-palladium complexes under the conditions of palladium catalyst, phosphine ligand, organic solvent, alkali and light under an inert atmosphere at room temperature.

[0012] (2) The aromatic difluoroalkyl-palladium complex is added to a conjugated olefin, and then added to an amine or a 1,3-dicarbonyl compound to give a difluoroalkyl-functionalized product.

[0013] The aromatic trifluoroalkyl compounds are as shown in formula (I) or formula (II), the amines are as shown in formula (III) or formula (IV), and the 1,3-dicarbonyl compounds are as shown in formula (V) or formula (VI); the aromatic difluoroalkyl functionalized products are selected from the compounds shown in formulas (V)-(XIV).

[0014]

[0015] Where X is carbon or nitrogen; Y is carbon or oxygen; n = 1, 2 or 3;

[0016] R 1 The group is selected from hydrogen, phenyl, alkoxy, amino, cyano, alkyl with any substitution, N-indolyl, N-carbazolyl, N-pyrazolyl, 3-pyridyl, aryloxy;

[0017] R 2 The group is selected from hydrogen, any substituted alkyl, cyano, methoxycarbonyl, any substituted phenyl, any substituted phenoxy, 2-naphthoxy; R3 The radical group is selected from hydrogen, methoxy, fluorine, and amino.

[0018] R 2 Group and R 3 The groups are not both hydrogen;

[0019] R 4 R 5 The group is independently selected from hydrogen, C1-C10 alkyl or cycloalkyl, benzyl, or R. 4 R 5 It can form 4-8 membered nitrogen heterocycles with N in any substitutional form;

[0020] R 6 The group is selected from hydrogen, formamido, or any substituted C3-C7 alkyl group;

[0021] R 7 R 8 The group is independently selected from any substituted alkyl group, any substituted alkoxy group, or R group. 9 The group can be hydrogen or any substituted alkyl group;

[0022] R 10 The group is selected from any substituted alkyl or any substituted alkoxy group.

[0023] Preferably, X is carbon; R 3 The radical is hydrogen; R 2 The groups are selected from trifluoromethyl, cyano, methoxycarbonyl, p-trifluoromethylphenyl, and p-hydroxymethylphenyl.

[0024] Preferably, X is nitrogen; R 3 The radical is hydrogen; R 2 The group is selected from hydrogen, cyano, phenoxy, 3-methyl-4-fluorophenoxy, p-cyclohexylphenoxy, 2-naphthoxy, p-hydroxymethylphenoxy, and 2,4-difluorophenyl.

[0025] Preferably, X is nitrogen; R 2 The radical is hydrogen; R 3 The radical group is selected from methoxy, fluorine, and amino.

[0026] More preferably, the aromatic trifluoroalkyl compound is selected from the compounds listed below:

[0027]

[0028] More preferably, the amine is selected from the following compounds:

[0029]

[0030] More preferably, the 1,3-dicarbonyl compound is selected from the compounds listed below:

[0031]

[0032] Preferably, the conjugated olefin is 1,3-butadiene.

[0033] Preferably, based on the molar amount of amine or 1,3-dicarbonyl compound, the amount of palladium catalyst is 1.0-1.5%; the molar amount of phosphine ligand is 4-8%; the molar amount of aromatic trifluoroalkyl compound is 100-300%; and the molar amount of 1,3-butadiene is 100-200%.

[0034] Preferably, based on the molar amount of the amine or 1,3-dicarbonyl compound, the molar amount of the base is 100-300%; and the molar amount of the organic solvent is 10,000-30,000%.

[0035] Preferably, the palladium catalyst is at least one of tetra(triphenylphosphine)palladium, bis(triphenylphosphine)chlorine (II), bis(acetylacetone)palladium (II), dichlorobis(di-tert-butylphenylphosphine)palladium (II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium (II), and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II); and the phosphine ligand is at least one of 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (XantPhos) and bis(2-methoxyphenyl)(phenyl)phosphine.

[0036] Preferably, an additive is added in step (1); the additive is at least one of magnesium trifluoromethanesulfonate (Mg(OTf)2) and zinc trifluoromethanesulfonate (Zn(OTf)2).

[0037] Preferably, the molar amount of the additive is 10-20% based on the molar amount of the amine or 1,3-dicarbonyl compound.

[0038] Preferably, the organic solvent is at least one of tetrahydrofuran (THF), acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and 2-methyltetrahydrofuran.

[0039] Preferably, the base is at least one of lithium hydroxide, potassium phosphate, tetramethylguanidine (TMG), and 1,8-diazacyclo[5,4,0]undecene-7 (DBU).

[0040] Preferably, the light wavelength is 370–467 nm, the reaction temperature is room temperature, and the reaction time is 6–24 h.

[0041] The wavelength can be selected from 370, 390, 427, 440, 456, 467 nm, etc. The illumination power is 10-50W.

[0042] This invention enables the efficient generation of aromatic difluoroalkyl-palladium complexes by activating aromatic trifluoroalkyl compounds under conditions of palladium catalyst, phosphine ligand, base, with or without additives, and organic solvent. These complexes can then be used to add to conjugated olefins and, upon nucleophilic substitution with different amines or 1,3-dicarbonyl compounds, yield the corresponding functionalized products.

[0043] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0044] (1) This invention provides a three-component coupling reaction method for a class of aromatic trifluoroalkyl compounds, conjugated alkenes, and amines / 1,3-dicarbonyl compounds. Using inexpensive and readily available aromatic trifluoroalkyl compounds as raw materials, the aromatic trifluoroalkyl compounds are activated by light in the presence of palladium catalysts, phosphine ligands, bases, organic solvents, etc., and aromatic difluoroalkyl-palladium complexes are generated efficiently. Then, the conjugated alkenes are added to them and subsequently replaced by a wide range of nucleophiles to obtain the corresponding functionalized products.

[0045] (2) The method of the present invention has the advantages of simple and readily available raw materials, simple operation, mild reaction conditions and wide applicability of substrates, which meet the development requirements of green chemistry.

[0046] (3) The method of the present invention utilizes aromatic trifluoroalkyl compounds to generate aromatic difluoroalkyl functional groups, which are then added to conjugated olefins and subsequently substituted by amines or 1,3-dicarbonyl compounds to form functionalized products. This structure is novel, and the difluoroalkyl functional groups are widely present in drug molecules. Therefore, this method is expected to be widely used in the modification of drug molecules. Attached Figure Description

[0047] Figure 1 This is a schematic diagram of the three-component coupling reaction in an embodiment of the present invention;

[0048] Figure 2 This is a reaction mechanism diagram of the three-component coupling reaction in the embodiments of the present invention. Detailed Implementation

[0049] To make the objectives, technical solutions, and technical advantages of the present invention clearer, the following description, in conjunction with specific embodiments and with reference to the accompanying drawings, further illustrates the three-component coupling method of an aromatic trifluoroalkyl compound, a conjugated olefin, and a nucleophile (amine or 1,3-dicarbonyl compound) provided by the present invention.

[0050] This invention provides a three-component coupling reaction method using an aromatic trifluoroalkyl compound as a starting material with a conjugated olefin and an amine / 1,3-dicarbonyl compound. The method includes: the aromatic trifluoroalkyl compound, in the presence of a palladium catalyst, a phosphine ligand, a base, an additive, and an organic solvent, undergoes photocatalytic activation to generate an aromatic difluoroalkyl-palladium complex, which then adds to the conjugated olefin, followed by substitution by different nucleophiles to obtain the aromatic difluoroalkyl functionalized product. The reaction process is as follows: Figure 1 As shown.

[0051] The three-component coupling reaction method involving aromatic trifluoroalkyl compounds, conjugated olefins, and nucleophiles (amines or 1,3-dicarbonyl compounds) comprises the following steps:

[0052] In step S101, the aromatic trifluoroalkyl compound is activated by photocatalysis in the presence of a palladium catalyst, a phosphine ligand, a base, an additive, and an organic solvent to generate an aromatic difluoroalkyl-palladium complex.

[0053] In step S102, the aromatic difluoroalkyl-palladium complex undergoes addition with a conjugated olefin, and is then coupled with an amine or a 1,3-dicarbonyl compound to obtain the corresponding functionalized product.

[0054] According to an embodiment of the present invention, in step S101, the aromatic trifluoroalkyl compound includes general aryl trifluoroalkyl compounds and heteroaryl trifluoroalkyl compounds, R 1 Groups include hydrogen, phenyl, alkoxy, amino, cyano, etc., R 2 Groups include trifluoromethyl, cyano, methoxycarbonyl, p-cyclohexylphenoxy, 2-naphthoxy, etc.; R 3 Groups include methoxy, fluorine, amino, etc.

[0055]

[0056] According to an embodiment of the present invention, in step S102, the nucleophile comprises an amine and a 1,3-dicarbonyl compound, wherein the amine includes aliphatic amines and aromatic amines, R 4 R 5 Groups include methyl, benzyl, C2-C10 alkyl, hydrogen, etc., R 6 The group can be selected from formamide, C3-C7 alkyl, hydrogen, etc., R 7 The radical group can be selected from methoxy, ethoxy, methyl, etc., R 8 The group can be selected from methoxy, ethoxy, tert-butoxy, etc., R 9 The group can be selected from alkyl, hydrogen, etc. R 10 The functional group can be selected from methyl, methoxy, ethoxy, etc.

[0057] According to embodiments of the present invention, the palladium catalyst comprises at least one of the following: tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)chlorine palladium(II), bis(acetylacetone)palladium(II), dichlorobis(di-tert-butylphenylphosphine)palladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium(II), and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II).

[0058] According to embodiments of the present invention, the phosphine ligands are 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (XantPhos) and bis(2-methoxyphenyl)(phenyl)phosphine.

[0059] According to embodiments of the present invention, the base includes at least one of the following: lithium hydroxide, potassium phosphate, tetramethylguanidine (TMG), and 1,8-diazacyclo[5,4,0]undecene-7 (DBU).

[0060] According to embodiments of the present invention, the solvent includes at least one of the following: tetrahydrofuran (THF), acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and 2-methyltetrahydrofuran.

[0061] According to embodiments of the present invention, the additives include at least one of the following: magnesium trifluoromethanesulfonate (Mg(OTf)2) and zinc trifluoromethanesulfonate (Zn(OTf)2).

[0062] According to embodiments of the present invention, the molar amount of palladium catalyst is 1.0% to 1.5% of the molar amount of the reaction substrate; the molar amount of phosphine ligand is 4% to 8% of the molar amount of the reaction substrate; the molar amount of additive is 10% to 20% of the molar amount of the reaction substrate; the molar amount of base is 100% to 300% of the molar amount of the reaction substrate; and the molar amount of organic solvent is 10000% to 30000% of the molar amount of the reaction substrate.

[0063] According to an embodiment of the present invention, the conditions for carrying out the photocatalytic reaction at room temperature using an inert gas as a protective gas include: the light wavelength range of the photocatalytic reaction is 370 nm to 467 nm, and the light wavelength can be selected from 370, 390, 427, 440, 456, 467 nm, etc.; the reaction time is 6 h to 24 h.

[0064] Through the embodiments of the present invention, aromatic trifluoroalkyl compounds, which are inexpensive and readily available, can be used as starting materials. Under the conditions of palladium catalyst, phosphine ligand, base, organic solvent, additive, and light irradiation, aromatic difluoroalkyl-palladium complexes can be generated efficiently and added to conjugated olefins. Then, under the substitution of different nucleophiles, the corresponding functionalized products are obtained.

[0065] Taking m-difluorotoluene and N-phenylpiperazine as examples, the three-component coupling reaction mechanism of aromatic trifluoroalkyl compounds, conjugated olefins, and nucleophiles (amines or 1,3-dicarbonyl compounds) in the embodiments of the present invention is as follows: Figure 2 As shown, the excited-state palladium catalyst and m-difluorotoluene undergo a single-electron transfer and carbon-fluorine bond cleavage to obtain aryldifluoromethyl-palladium complex II. Subsequently, 1,3-butadiene undergoes radical addition or migration insertion to obtain allyl palladium species V or VI. Finally, allyl palladium is nucleophilically substituted by an amine to obtain the final product VII or VIII. The zero-valent palladium catalyst returns to the reduced state to complete the catalytic cycle.

[0066] To facilitate the implementation of the technical solution of the present invention, the three-component coupling reaction method of the aromatic trifluoroalkyl compound, conjugated olefin, and amine / 1,3-dicarbonyl compound of the present invention will be further described.

[0067] General Procedure A:

[0068] In an 8 mL reaction flask equipped with a magnetic stirrer, Pd(PPh3)4 (2.6 mg, 0.0046 mmol), XantPhos (0.024 mmol), (o-OMe)Ph2PPh (0.024 mmol), LiOH (0.3 x mmol), an aromatic trifluoroalkyl compound (0.9 mmol), and THF (3 mL) were added sequentially. The cap was tightened, and the flask was bubbled with nitrogen for 10 minutes. Then, under nitrogen atmosphere, a fatty amine or 1,3-dicarbonyl compound (0.3 mmol) was injected using a microsyringe (if the amine or 1,3-dicarbonyl compound used is solid, it should be added to the reaction flask before bubbling). Next, a solution of 1,3-butadiene (0.3 mL of 2.0 M THF solution) was injected. The flask was sealed with a sealing film, and the mixture was stirred at room temperature for 12 hours under a 40 W, 440 nm Kessil lamp. After the reaction was complete, illumination and stirring were stopped. The reaction solution was concentrated under reduced pressure, and the product was obtained by column chromatography. The general reaction formula is as follows:

[0069]

[0070] Among them, R 1 -R 10 The definition is as described above.

[0071] General Procedure B:

[0072] In an 8 mL reaction flask equipped with a magnetic stirrer, Pd(PPh3)4 (2.6 mg, 0.0046 mmol), XantPhos (0.024 mmol), Mg(OTf)2 (0.06 mmol), LiOH (0.3 mmol), an aromatic trifluoroalkyl compound (0.9 mmol), and THF (3 mL) were added sequentially. The flask was then capped and bubbled with nitrogen for 10 minutes. Then, under nitrogen atmosphere, amine (0.3 mmol) was injected using a microsyringe (if the amine used is solid, it should be added to the reaction flask before bubbling). Next, a solution of 1,3-butadiene (0.3 mL of 2.0 M THF solution) was injected. The flask was sealed with a sealing film and irradiated and stirred at room temperature for 12 hours using a 40 W, 440 nm Kessil lamp. After the reaction was complete, the light and stirring were stopped, the reaction solution was concentrated under reduced pressure, and the product was obtained by column chromatography. The general reaction formula is as follows:

[0073]

[0074] Among them, R 1 -R 10 The definition is as described above.

[0075] General Procedure C:

[0076] In an 8 mL reaction flask equipped with a magnetic stirrer, Pd(OH)₂ / C (20 wt%), the three-component coupling product of an aromatic difluoroalkyl-1,3-butadiene-amine / 1,3-dicarbonyl compound (0.1 mmol), THF (1 mL), and hexafluoroisopropanol (HFIP, 1 mL) were added sequentially. The flask was then capped tightly, and the mixture was continuously bubbled into the reaction solution at 55 °C using a hydrogen balloon (3–6 bubbles per second) while stirring for 1 h. After the reaction was complete, bubbling and stirring were stopped, the reaction solution was concentrated under reduced pressure, and the product was obtained by column chromatography.

[0077] General Procedure D:

[0078] In an 8 mL reaction flask equipped with a magnetic stirrer, Pd(OH)₂ / C (20 wt%), the three-component coupling product of aromatic difluoroalkyl-1,3-butadiene-amine (0.1 mmol), THF (1 mL), and hexafluoroisopropanol (HFIP, 1 mL) were added sequentially. The flask was then capped tightly, and the reaction mixture was continuously bubbled into the reaction solution at room temperature using a hydrogen balloon (3–6 bubbles per second) while stirring for 1 h. After the reaction was completed, bubbling and stirring were stopped, the reaction solution was concentrated under reduced pressure, and the product was obtained by column chromatography.

[0079] The general formula for the reaction between C and D is as follows:

[0080]

[0081] Among them, R 1-R 10 The definition is as described above.

[0082] To make the objectives, technical solutions, and advantages of the present invention clearer, the following specific embodiments are used to further illustrate the three-component coupling method of the present invention, which involves aromatic trifluoroalkyl compounds, conjugated olefins, and nucleophiles (amines or 1,3-dicarbonyl compounds). (For ease of characterization, the NMR spectra and high-resolution characterization data of the compounds after hydrogenation saturation treatment (0.1 mmol scale) are generally shown, while the yields of the unhydrogenated and hydrogenated compounds are listed separately, and the product mass is the weight of the compound obtained after hydrogenation.)

[0083] Example 1: 1-(5,5-difluoro-5-(5-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)pentyl)-4-phenylpiperazine

[0084]

[0085] Using S1 and S28 as raw materials, a colorless liquid was obtained by following the general procedure A and C. The product was 1-(5,5-difluoro-5-(5-(trifluoromethyl)-[1,1'-diphenyl]-3-yl)pentyl)-4-phenylpiperazine (46 mg, 91%, 92%). 1 H NMR (400MHz, CDCl3) δ7.80 (s, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.51 (d, J = 7.5Hz ,2H),7.39(t,J=7.4Hz,2H),7.33(t,J=7.3Hz,1H),7.17(t,J=7.6Hz,2H),6.82 (d,J=8.1Hz,2H),6.76(t,J=7.3Hz,1H),3.08(t,J=5.0Hz,4H),2.48(t,J=4.9H z,4H),2.29(t,J=7.1Hz,2H),2.13(tt,J=15.9,7.4Hz,2H),1.58–1.37(m,4H). 13C NMR(101MHz, CDCl3)δ151.34,142.72,139.11(t,J=27.4Hz),138.99,131.65( q,J=32.7Hz),129.18,129.12,128.55,127.29,127.10(t,J=5.9Hz),125.25, 123.82(q,J=274.7Hz),122.40(t,J=243.3Hz),120.70(d,J=4.1Hz),119.71, 116.06,58.16,53.29,49.13,38.93(t,J=27.1Hz),26.41,20.49(t,J=3.9Hz). 19 F NMR(376MHz, CDCl3)δ-62.54,-95.81(t,J=16.4Hz).HRMS(ESI-TOF)m / zcalcd.for C 28 H 30 F5N2([M+H) + ):489.2324,found:489.2299.

[0086] Example 2: 1-(3-(1,1-difluoro-5-(4-phenylpiperazin-1-yl)pentyl)-5-(trifluoromethyl)phenyl)-1H-indole

[0087]

[0088] Using S6 and S28 as raw materials, a colorless liquid was obtained by following the general procedure B and C. The product was 1-(3-(1,1-difluoro-5-(4-phenylpiperazin-1-yl)pentyl)-5-(trifluoromethyl)phenyl)-1H-indole (34 mg, 54% , 65%). 1 H NMR (400MHz, CDCl3) δ7.76 (s, 1H), 7.74 (s, 1H), 7.63–7.61 (m, 2H), 7.45 (dd, J = 8. 0,1.2Hz,1H),7.26(d,J=3.4Hz,1H),7.21–7.11(m,4H),6.84–6.81(m,2H),6.76( tt,J=7.3,1.2Hz,1H),6.66(dd,J=3.4,0.9Hz,1H),3.09(dd,J=6.1,4.0Hz,4H),2 .49(t,J=5.0Hz,4H),2.31(t,J=7.0Hz,2H),2.20–2.08(m,2H),1.54–1.44(m,4H). 13C NMR (101MHz, CDCl3) δ150.22, 139.73, 139.42 (t, J = 28.0Hz), 134.41, 131.70 (q, J = 33. 3Hz),128.64,128.05,126.26,124.94(q,J=273.3Hz),123.31(t,J=239.2Hz),122.80 (t,J=6.1Hz),122.18,120.89,120.55,120.19,118.68,118.45–118.41(m),115.00,1 08.85,104.29,57.06,52.21,48.04,37.77(t,J=26.9Hz),25.30,19.38(d,J=4.0Hz). 19 F NMR(376MHz, CDCl3)δ-62.66(d,J=3.7Hz),-95.95(td,J=16.5,3.9Hz).HRMS(ESI-TOF)m / z calcd.for C 30 H 31 F5N3([M+H) + ):528.2433,found:528.2403.

[0089] Example 3: 1-(5,5-difluoro-5-(3-((1,2,2,6,6-pentamethylpiperazin-4-yl)oxo)-5-(trifluoromethyl)phenyl)pentyl)-4-phenylpiperazine

[0090]

[0091] Using S9 and S28 as raw materials, a colorless liquid was obtained by following the general procedure A and C. The product was 1-(5,5-difluoro-5-(3-((1,2,2,6,6-pentamethylpiperazin-4-yl)oxo)-5-(trifluoromethyl)phenyl)pentyl)-4-phenylpiperazine (57 mg, 89%, 98%). 1H NMR (400MHz, CDCl3) δ7.22–7.13(m,3H),7.08(s,2H),6.84(d,J=8.2Hz,2H),6. 77(t,J=7.3Hz,1H),4.51(tt,J=11.2,3.9Hz,1H),3.10(t,J=4.9Hz,4H),2.49( t,J=5.0Hz,4H),2.29(t,J=7.3Hz,2H),2.20(s,3H),2.07(tt,J=15.9,8.2Hz,2 H),1.91(dd,J=11.8,3.3Hz,2H),1.64–1.37(m,6H),1.12(s,6H),1.06(s,6H). 13 C NMR (101MHz, CDCl3) δ157.04, 150.26, 138.92 (t, J = 27.4Hz), 131.26 (q, J = 32.7 Hz),128.07,122.56(q,J=272.6Hz),119.90(t,J=244.4Hz),118.69,115.02,1 14.93(t,J=7.1Hz),112.84,112.24,69.77,57.15,54.28,52.22,48.06,44.84 ,37.71(t,J=27.1Hz),31.89,28.68,27.04,25.33,20.06,19.45(t,J=4.0Hz). 19 F NMR(376MHz, CDCl3)δ-62.81,-95.88(t,J=16.3Hz).HRMS(ESI-TOF)m / z calcd.for C 32 H 45 F5N3O([M+H)) + ):582.3477,found:582.3444.

[0092] Example 4: 1-(5,5-difluoro-5-(2-methoxypyridin-3-yl)pentyl)-4-phenylpiperazine

[0093]

[0094] Using S13 and S28 as raw materials, a white solid was obtained by following the general procedure B and C. The product was 1-(5,5-difluoro-5-(2-methoxypyridin-3-yl)pentyl)-4-phenylpiperazine (37 mg, 81%, 98%). 1H NMR (400MHz, CDCl3) δ8.13(dd,J=5.1,1.9Hz,1H),7.69(dd,J=7.5,1.9Hz,1H),7.20–7.16(m,2H),6.86–6.83(m,3H),6.77( t,J=7.3Hz,1H),3.92(s,3H),3.10(t,4H),2.49(t,J=5.0Hz,4H),2.33–2.21(m,4H),1.51–1.44(m,2H),1.37–1.29(m,2H). 13 C NMR (101MHz, CDCl3) δ160.50 (t, J = 4.4Hz), 151.33, 148.30 (t, J = 1.7Hz), 135.82 (t, J = 8.3Hz), 129.11, 121.83 (t, J = 243.4Hz) ,119.70,119.42(t,J=28.3Hz),116.37,116.05,58.29,53.68,53.26,49.11,36.20(t,J=26.0Hz),26.45,20.65(t,J=4.2Hz). 19 F NMR(376MHz, CDCl3)δ-96.14(t,J=17.0Hz).HRMS(ESI-TOF)m / z calcd.for C 21 H 28 F2N3O([M+H)) + ):376.2195,found:376.2173.

[0095] Example 5: (4-((5-(1,1-difluoro-5-(4-phenylpiperazin-1-yl)pentyl)pyridin-2-yl)oxo)phenyl)methanol

[0096]

[0097] Using S22 and S28 as raw materials, a white solid was obtained by following the general procedure B and C. The product was (4-((5-(1,1-difluoro-5-(4-phenylpiperazin-1-yl)pentyl)pyridin-2-yl)oxo)phenyl)methanol (36 mg, 42% , 77%). 1H NMR (400MHz, CDCl3) δ8.19 (dd, J=2.4, 1.0Hz, 1H), 7.68 (dd, J=8.6, 2.5Hz, 1H ),7.31(d,J=8.4Hz,2H),7.20–7.15(m,3H),7.05–7.02(m,2H),6.87–6.82(m ,3H),6.77(tt,J=7.2,1.1Hz,1H),4.59(s,2H),3.10(t,J=5.2Hz,3H),2.49( t,J=5.2Hz,3H),2.28(t,J=6.8Hz,2H),2.13–2.01(m,2H),1.53–1.36(m,4H). 13 C NMR (101MHz, CDCl3) δ163.58,151.93,150.26,143.93(t,J=6.9Hz),136.97,135.63(t,J=5.6Hz),128.08,127.40,126.94(t,J=27.7Hz) ,121.17(t,J=242.4Hz),120.43,118.73,115.06,109.99,63.59,57.10,52.20,48.06,37.68(t,J=27.3Hz),25.27,19.48(t,J=4.1Hz). 19 F NMR(376MHz, CDCl3)δ-94.25(t,J=16.2Hz).HRMS(ESI-TOF)m / z calcd.for C 27 H 32 F2N3O2([M+H) + ):468.2457,found:468.2434.

[0098] Example 6: (13S)-2-(3-(1,1-difluoro-5-(4-phenylpiperazin-1-yl)pentyl)-5-trifluoromethyl)phenoxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopentan[a]phenanthroline-17-one

[0099]

[0100] Using S24 and S28 as raw materials, a pink solid was obtained by following the general procedure A and C. The product was (13S)-2-(3-(1,1-difluoro-5-(4-phenylpiperazin-1-yl)pentyl)-5-trifluoromethyl)phenoxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopentan[a]phenanthrene-17-one (42 mg, 60%, 87%).1 H NMR(400MHz, CDCl3)δ7.32(s,1H),7.21–7.14(m,5H),6.83(d,J=7.8Hz,2H),6.77–6.69(m,3H),3.11–3.08(m,4H) ),2.83–2.79(m,2H),2.50–2.39(m,5H),2.35–2.18(m,4H),2.12–1.87(m,6H),1.60–1.34(m,10H),0.85(s,3H). 13 C NMR (101MHz, CDCl3) δ158.58,153.32,151.31,140.31(t,J=27.7Hz),138.91,136.39,132.50(q,J= 33.0Hz),129.12,127.14,123.39(q,J=274.7Hz),122.04(t,J=244.4Hz),119.74,119.71,118.02( t,J=6.1Hz),116.94,116.04,115.90–115.77(m),58.14,53.28,50.44,49.10,47.97,44.14,38.71 (t,J=27.0Hz),38.08,35.86,31.60,29.50,26.37,26.35,25.84,21.61,20.43(t,J=3.9Hz),13.89. 19 F NMR(376MHz, CDCl3)δ-62.62(d,J=4.1Hz),-95.79(td,J=16.6,5.4Hz).HRMS(ESI-TOF)m / z calcd.forC 40 H 46 F5N2O2([M+H) + ):681.3474,found:681.3442.

[0101] Example 7: 1-(5,5-difluoro-5-(3-(((3aR,5R,5aR,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxapentenone)[4,5-b:4',5'-d]pyran-5-yl)methoxy)-5-(trifluoromethyl)phenyl)pentyl)-4-phenylpiperazine

[0102]

[0103] Using S25 and S28 as raw materials, a white solid was obtained by following the general procedure A and C. The product was 1-(5,5-difluoro-5-(3-(((3aR,5R,5aR,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxapentenone)[4,5-b:4',5'-d]pyran-5-yl)methoxy)-5-(trifluoromethyl)phenyl)pentyl)-4-phenylpiperazine (65 mg, 82%, 97%). 1 HNMR (400MHz, CDCl3) δ7.22 (s, 1H), 7.19–7.15 (m, 4H), 6.84 (d, J = 7.7Hz, 2H), 6.7 7(t,J=7.3Hz,1H),5.50(d,J=4.9Hz,1H),4.59(dd,J=7.9,2.4Hz,1H),4.30–4.26( m,2H),4.15–4.08(m,3H),3.11(t,J=5.2Hz,4H),2.50(t,J=5.2Hz,4H),2.30(t,J =7.2Hz,2H),2.07(tt,J=16.1,7.8Hz,2H),1.53–1.35(m,10H),1.29–1.27(m,6H). 13 C NMR (101MHz, CDCl3) δ157.98, 150.29, 138.86 (t, J = 27.5Hz), 131.16 (q, J = 32.9Hz), 128. 06,122.53(q,J=272.5Hz),121.12(t,J=244.4Hz),118.65,115.01,114.23(t,J=6.5Hz) ,113.30,111.72,108.63,107.83,95.34,69.91,69.64,69.50,66.35,65.22,57.14,52. 22, 48.06, 37.74 (t, J = 27.1Hz), 25.34, 25.03, 24.97, 23.88, 23.40, 19.42 (t, J = 4.0Hz). 19 FNMR(376MHz, CDCl3)δ-62.72,-87.33–-106.50(m).HRMS(ESI-TOF)m / z calcd.for C 34 H 44 F5N2O6([M+H) + ):671.3114,found:671.3084.

[0104] Example 8: 1-(5-(3-((1-diphenylmethylazacyclobutyl-3-yl)oxa)-5-(trifluoromethyl)phenyl)-5,5-difluoropentyl)-4-phenylpiperazine

[0105]

[0106] Using S26 and S28 as raw materials, a white solid was obtained by following the general procedure A and C. The product was 1-(5-(3-((1-diphenylmethylazacyclobutyl-3-yl)oxa)-5-(trifluoromethyl)phenyl)-5,5-difluoropentyl)-4-phenylpiperazine (36 mg, 71%, 55%). 1 H NMR(400MHz, CDCl3)δ7.34(dt,J=8.2,1.9Hz,4H),7.22–7.10(m,9H),6.94( d,J=10.6Hz,2H),6.84(d,J=7.9Hz,2H),6.77(td,J=7.3,1.1Hz,1H),4.76( p,J=5.7Hz,1H),4.35(s,1H),3.66–3.62(m,2H),3.12–3.04(m,6H),2.49(t ,J=5.0Hz,4H),2.28(t,J=7.4Hz,2H),2.09–1.97(m,2H),1.52–1.33(m,4H). 13 C NMR (101MHz, CDCl3) δ156.46,150.22,140.66,139.08(t,J=27.4Hz),131.36(q,J=32.8Hz),128.08,127.54,126.34,122.38(q,J=273.7Hz),1 20.96(t,J=243.3Hz),118.71,115.02,113.99,113.49,111.47,77.27, 65.67,59.09,57.06,52.17,48.01,37.67(t,J=27.0Hz),25.23,19.35. 19 F NMR(376MHz, CDCl3)δ-62.75,-96.01(t,J=16.4Hz).HRMS(ESI-TOF)m / z calcd.for C 38 H 41 F5N3O([M+H)) + ):650.3164,found:650.3138.

[0107] Example 9: 2-(3-(1,1-difluoro-5-(methyl(2-(pyridin-2-yl)ethyl)amino)pentyl)-5-(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propionamide

[0108]

[0109] Using S27 and S67 as raw materials, a yellow solid was obtained by following the general procedure A and C. The product was 2-(3-(1,1-difluoro-5-(methyl(2-(pyridin-2-yl)ethyl)amino)pentyl)-5-(trifluoromethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridin-3-yl)propionamide (45 mg, 98%, 60%). 1 H NMR(400MHz, CDCl3)δ8.42(d,J=5.0Hz,1H),7.93(s,1H),7.53–7.42(m,5H ),7.24–7.05(m,5H),7.02(dd,J=7.5,5.0Hz,1H),6.43(s,1H),3.49(t,J=5 .0Hz,4H),2.84(dd,J=9.3,6.1Hz,2H),2.67(dd,J=9.5,6.0Hz,2H),2.43( t,J=5.1Hz,5H),2.34–2.16(m,8H),2.11–1.87(m,3H),1.55–1.19(m,13H). 13 C NMR(101MHz, CDCl3)δ160.53,158.20,149.29,148.16,147.35,139.60(t,J=27.5Hz),136.8 4,136.40,131.91(q,J=32.9Hz),130.29,129.11,128.32,125.52,125.05,124.62,123.31,1 22.82,122.29,122.21,121.23,120.29,119.79,108.25,57.53,57.16,54.89,47.38,46.26 ,45.40,42.15,38.95(t,J=27.1Hz),35.95,31.92,26.88,23.40,20.36(t,J=4.0Hz),20.02. 19 F NMR(376MHz, CDCl3)δ-62.53,-95.08–-96.84(m).HRMS(ESI-TOF)m / z calcd.for C 38 H41 F5N3O([M+H)) + ):650.3164,found:650.3138.

[0110] Example 10: N-(3-((5,5-difluoro-5-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pentyl)amino)phenyl)acetamide

[0111]

[0112] Using S1 and S59 as raw materials, following general procedures B and C, a yellow-green solid was obtained. The product was N-(3-((5,5-difluoro-5-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pentyl)amino)phenyl)acetamide (24 mg, 94%, 62%). 1 HNMR(400MHz, CDCl3)δ7.90(s,1H),7.86(s,1H),7.70(s,1H),7.63–7.60(m,2H),7.52–7.47(m,2H),7.46–7.41(m,1H),7.32(s,1H),7. 08–7.04(m,2H),6.61(dd,J=7.9,2.0Hz,1H),6.32(dd,J=8.1,2.3Hz,1H),3.10(t,J=6.7Hz,2H),2.27–2.13(m,5H),1.68–1.57(m,4H). 13 CNMR(101MHz, CDCl3)δ168.51,148.99,142.85,139.03,139.10(t,J=28.3Hz),131.73(q,J=33.3Hz),129.72,129.27,128.64,127.39,127.1 4,125.41,123.88(q,J=273.7Hz),122.37(t,J=244.4Hz),120.72,108 .73,108.69,104.44,43.66,38.96(t,J=27.1Hz),29.10,24.82,20.16. 19 F NMR(376MHz, CDCl3)δ-62.54,-96.08(t,J=16.4Hz).HRMS(ESI-TOF)m / z calcd.for C 26 H 26 F5N2O([M+H)) + ):477.1960,found:477.1940.

[0113] Example 11: N-(1-(5,5-difluoro-5-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pentyl)piperidin-3-yl)-3,4,5-trimethoxybenzamide

[0114]

[0115] Using S1 and S64 as raw materials, a pale yellow solid was obtained by following the general procedure A and C. The product was N-(1-(5,5-difluoro-5-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pentyl)piperidin-3-yl)-3,4,5-trimethoxybenzamide (49 mg, 82%, 79%). 1 H NMR (400MHz, CDCl3) δ7.88(s,1H),7.83(s,1H),7.67(s,1H),7.59(d,J=7.6Hz,2H),7.49–7.39(m,3H),7.04(s,2H), 6.90(s,1H),4.27(s,1H),3.89–3.86(m,9H),2.61–2.49(m,4H),2.34(s,2H),2.21–2.12(m,2H),1.73–1.53(m,8H). 13 C NMR(101MHz,CDCl3)δ166.29,153.20,142.80,140.85,139.13(t,J=27.4Hz),1 38.94,132.10,131.67(q,J=32.6Hz),130.31,129.24,128.63,127.31,127.04, 125.33,123.82(q,J=273.7Hz),122.32(t,J=243.4Hz),120.61,104.51,60.96 ,58.24,56.38,53.95,45.52,39.01(t,J=27.1Hz),29.06,26.41,21.99,20.28. 19 F NMR(376MHz, CDCl3)δ-62.58,-96.36–-96.49(m).HRMS(ESI-TOF)m / z calcd.for C 33 H 38 F5N2O4([M+H) + ):621.2746,found:621.2722.

[0116] Example 12: N-(3-(9,10-ethylanthracene-9(10H)-yl)propyl)-5,5-difluoro-N-methyl-5-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pentane-1-amine

[0117]

[0118] Using S1 and S65 as raw materials, a white solid was obtained by following the general procedure A and C. The product was N-(3-(9,10-ethylanthracene-9(10H)-yl)propyl)-5,5-difluoro-N-methyl-5-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pentane-1-amine (42 mg, 82%, 79%). 1 H NMR (400MHz, CDCl3) δ7.79(d,J=9.2Hz,2H),7.63(s,1H),7.50(d,J=7.5Hz,2H),7.37(t,J=7.4Hz,2H),7.31(t,J=7.1Hz,1H),7.17–7.13(m,4H),7.02 –6.94(m,4H),4.17(s,1H),2.53(t,J=7.5Hz,2H),2.34(t,J=7.2Hz,4H),2 .21–2.09(m,5H),1.87–1.80(m,2H),1.74–1.69(m,2H),1.54–1.45(m,6H). 13 C NMR (101MHz, CDCl3) δ145.59, 145.13, 142.79, 139.26 (t, J = 27.3Hz), 139.08, 131.72(q,J=32.5Hz),129.25,128.61,127.38,127.19,125.36,125.32,123.4 5,122.50(t,J=243.4Hz),121.40,120.80,59.09,57.62,44.94,44.66,42.48 ,39.16(t,J=27.0Hz),29.81,29.01,27.79,27.18,22.81,20.61(t,J=4.0Hz). 19 F NMR(376MHz, CDCl3)δ-62.50,-95.82(t,J=16.5Hz).HRMS(ESI-TOF)m / z calcd.for C 38 H 39 F5N([M+H) + ):604.2997,found:604.2979.

[0119] Example 13: (1R,3r,5S)-8-(5,5-difluoro-5-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pentyl)-8-azacyclo[3.2.1]octane-3-ol

[0120]

[0121] Using S1 and S70 as raw materials, a white solid was obtained by following the general procedure A and C. The product was (1R,3r,5S)-8-(5,5-difluoro-5-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pentyl)-8-azacyclo[3.2.1]octane-3-ol (35 mg, 70%, 77%). 1 H NMR(400MHz, CDCl3)δ7.89(s,1H),7.85(s,1H),7.69(s,1H),7.62–7.59(m,2H),7 .49(td,J=7.3,1.1Hz,2H),7.45–7.41(m,1H),4.01–3.98(m,1H),3.12(t,J=3.7H z,2H),2.95–2.88(m,1H),2.31(t,J=7.0Hz,2H),2.19(tt,J=16.0,7.7Hz,2H),2. 06–2.00(m,4H),1.89–1.85(m,2H),1.63(s,1H),1.60(s,1H),1.51–1.49(m,4H). 13 C NMR (101MHz, CDCl3) δ142.76, 139.22 (t, J = 27.5Hz), 139.10, 131.70 (q, J = 32.6Hz), 129.26, 128.63, 127.37, 127.20 (t, J = 6.1Hz), 125.28, 123.91 (q,J=273.7Hz),122.54(t,J=244.4Hz),120.79–120.78(m),65.09,58.1 4,51.92,39.26,39.04(t,J=26.8Hz),28.49,26.31,20.62(t,J=4.0Hz). 19 F NMR(376MHz, CDCl3)δ-62.60,-95.79(t,J=16.3Hz).HRMS(ESI-TOF)m / zcalcd.for C 25 H 29 F5NO([M+H] + ):454.2164,found:454.2145.

[0122] Example 14: N-(3-(10,11-dihydro-5H-diphenyl[a,d][7]roton-5-methylene)propyl)-5,5-difluoro-N-methyl-5-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pentane-1-amine

[0123]

[0124] Using S1 and S68 as raw materials, a yellow solid was obtained by following the general procedure A and C. The product was N-(3-(10,11-dihydro-5H-diphenyl[a,d][7]roton-5-methylene)propyl)-5,5-difluoro-N-methyl-5-(5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)pentane-1-amine (32 mg, 85%, 54%). 1 H NMR (400MHz, CDCl3) δ7.91(s,1H),7.86(s,1H),7.71(s,1H),7.62(dd,J=7.5,1.9 Hz,2H),7.50(t,J=7.4Hz,2H),7.44(t,J=7.4Hz,1H),7.29–7.27(m,1H),7.20–7. 11(m,6H),7.05–7.02(m,1H),5.86(t,J=7.3Hz,1H),3.34(d,J=41.0Hz,2H),2.97 (s,1H),2.77(s,1H),2.44(t,J=7.5Hz,2H),2.30–2.14(m,9H),1.48–1.44(m,4H). 13 C NMR (101MHz, CDCl3) δ143.68,142.81,141.42,140.22,139.46,139.28(t,J=27.4Hz),139.13,13 7.18,131.74(q,J=32.7Hz),130.09,129.49,129.28,128.71,128.64,128.33,128.08,127.50,12 7.40,127.20,127.13,126.11,125.83,125.30,123.94(q,J=273.7Hz),122.47(t,J=244.4Hz),12 0.81,57.43,57.02,42.18,39.07(t,J=27.0Hz),33.91,32.17,27.30,26.93,20.50(t,J=4.0Hz). 19F NMR(376MHz, CDCl3)δ-62.55,-95.80(t,J=16.5Hz).HRMS(ESI-TOF)m / z calcd.for C 37 H 37 F5N([M+H) + ):590.2841,found:590.2813.

[0125] Example 15: Methyl (E)-1-(5,5-difluoro-5-(3-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)pent-2-en-1-yl)-2-oxocycloheptane-1-carboxylate

[0126]

[0127] Using S8 and S76 as raw materials, a colorless liquid was obtained by following the general procedure A. The product was methyl (E)-1-(5,5-difluoro-5-(3-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)pent-2-en-1-yl)-2-oxocycloheptane-1-carboxylate (111 mg, 73%). 1 H NMR (400MHz, CDCl3) δ8.82(d,J=2.4Hz,1H),8.62(dd,J=4.8,1.6Hz,1H),7.89(dt,J=7.9,2.1Hz,1H),7. 84(s,1H),7.79(s,1H),7.69(s,1H),7.39(dd,J=7.9,4.8Hz,1H),5.53–5.46(m,1H),5.37(dt,J=14.8,6 .9Hz,1H),3.60(s,3H),2.86(td,J=15.9,6.9Hz,2H),2.63(dd,J=14.0,6.4Hz,1H),2.58–2.52(m,1H),2 .38–2.32(m,1H),2.24(dd,J=14.1,7.9Hz,1H),1.98–1.91(m,1H),1.66–1.44(m,6H),1.31–1.23(m,1H). 13C NMR (101MHz, CDCl3) δ208.96,172.29,149.66,148.22,139.41,139.13 (t,J=27.1Hz) ,134.67,134.59,132.50,131.98(q,J=33.3Hz),127.28(t,J=5.9Hz),125.30,123.8 2,123.68(t,J=4.9Hz),123.57(q,J=273.7Hz),121.69–121.61(m),121.05(t,J=245 .4Hz),62.81,52.19,42.42(t,J=27.8Hz),42.10,38.43,32.19,29.84,25.52,24.54. 19 F NMR(376MHz, CDCl3)δ-62.71,-94.63(t,J=15.9Hz),-94.98–-95.09(m),-95.28 (t,J=15.9Hz),-95.44(t,J=16.0Hz),-96.10(t,J=16.0Hz).HRMS(ESI-TOF)m / z calcd.for C 26 H 26 F5NO3([M+H) + ):496.1906,found:496.1883.

[0128] The embodiments described above provide a detailed explanation of the technical solutions and beneficial effects of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, additions, and equivalent substitutions made within the scope of the principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A three-component coupling method for a class of aromatic trifluoroalkyl compounds, conjugated olefins, and nucleophiles, characterized in that, include: (1) Aromatic trifluoroalkyl compounds produce aromatic difluoroalkyl-palladium complexes under the conditions of palladium catalyst, phosphine ligand, organic solvent, alkali and light under an inert atmosphere at room temperature; (2) The aromatic difluoroalkyl-palladium complex is added to the conjugated olefin, and then added to the amine or 1,3-dicarbonyl compound to obtain the difluoroalkyl functionalized product; The aromatic trifluoroalkyl compounds are as shown in formula (I) or formula (II), the amines are as shown in formula (III) or formula (IV), and the 1,3-dicarbonyl compounds are as shown in formula (V) or formula (VI); the difluoroalkyl functionalized products are selected from the compounds shown in formulas (VII)-(XIV). ； Where X is CH or N; Y is CH2 or O; n = 1, 2 or 3; R 1 The radical group is selected from hydrogen, phenyl, alkoxy, amino, cyano, or any substituted alkyl group. N -Indoleyl, N -Carbazole group, N -pyrazolyl, 3-pyridyl, aryloxy; R 2 The group is selected from hydrogen, any substituted alkyl, cyano, methoxycarbonyl, any substituted phenyl, any substituted phenoxy, 2-naphthoxy; R 3 The radical group is selected from hydrogen, methoxy, fluorine, and amino. R 2 Group and R 3 The groups are not both hydrogen; R 4 R 5 The group is independently selected from hydrogen, C1-C10 alkyl or cycloalkyl, benzyl, or R. 4 R 5 It can form 4-8 membered nitrogen heterocycles with N in any substitutional form; R 6 The group is selected from hydrogen, formamido, or any substituted C3-C7 alkyl group; R 7 R 8 The groups are independently selected from any substituted alkyl or any substituted alkoxy groups; R 9 The group can be hydrogen or any substituted alkyl group; R 10 The group is selected from any substituted alkyl or any substituted alkoxy group.

2. The three-component coupling method according to claim 1, characterized in that, X is CH; R 3 The radical is hydrogen; R 2 The group is selected from trifluoromethyl, cyano, methoxycarbonyl, p-trifluoromethylphenyl, and p-hydroxymethylphenyl; Or X is nitrogen; R 3 The radical is hydrogen; R 2 The group is selected from hydrogen, cyano, phenoxy, 3-methyl-4-fluorophenoxy, p-cyclohexylphenoxy, 2-naphthoxy, p-hydroxymethylphenoxy, and 2,4-difluorophenyl; Or X is nitrogen; R 2 The radical is hydrogen; R 3 The radical group is selected from methoxy, fluorine, and amino.

3. The three-component coupling method according to claim 1, characterized in that, The aromatic trifluoroalkyl compounds are selected from the following compounds: 。 4. The three-component coupling method according to claim 1, characterized in that, The amine is selected from the following compounds: 。 5. The three-component coupling method according to claim 1, characterized in that, The 1,3-dicarbonyl compound is selected from the following compounds: 。 6. The three-component coupling method according to claim 1, characterized in that, Based on the molar amount of amine or 1,3-dicarbonyl compound, the amount of palladium catalyst is 1.0~1.5%; The molar amount of phosphine ligands is 4-8%; the molar amount of aromatic trifluoroalkyl compounds is 100-300%; and the molar amount of conjugated olefins is 100-200%.

7. The three-component coupling method according to claim 1, characterized in that, Based on the molar amount of amine or 1,3-dicarbonyl compound, the molar amount of base is 100-300%; the molar amount of organic solvent is 10000-30000%.

8. The three-component coupling method according to claim 1, characterized in that, The palladium catalyst is at least one of tetra(triphenylphosphine)palladium, bis(triphenylphosphine)chlorine (II), bis(acetylacetone)palladium (II), dichlorobis(di-tert-butylphenylphosphine)palladium (II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium (II), and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II); the phosphine ligand is at least one of 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene and bis(2-methoxyphenyl)(phenyl)phosphine.

9. The three-component coupling method according to claim 1, characterized in that, In step (1), an additive is also added; the additive is at least one of magnesium trifluoromethanesulfonate and zinc trifluoromethanesulfonate.

10. The three-component coupling method according to claim 1, characterized in that, The light wavelength is 370~467 nm, the reaction temperature is room temperature, and the reaction time is 6~24 h.

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