Method for sec-nitro alkane to participate in selective fluoroallyl alkylation of difluorocyclopropane

Abstract

The invention discloses a method for selective fluoroallyl alkylation of difluorocyclopropane by using sec-nitro alkane, which comprises the following steps: by using sec-nitro alkane and gem-difluorocyclopropane as raw materials, carrying out ring-opening selective ring-opening reaction on the sec-nitro alkane and gem-difluorocyclopropane through transition metal catalysis to generate a branched chain type fluorine-containing allyl tertiary nitro compound. The method has obvious advantages in the aspects of synthesis conditions and practicability, has the advantages of simple synthesis steps, simplicity and convenience in operation, cheap and easily available raw materials, good compatibility to functional groups, regioselectivity, high reaction efficiency and the like, and also provides reference and reliable technical support for a branched chain type regioselective allylation method.

Description

Technical Field

[0001] This invention relates to the fields of regioselective chemistry and synthetic chemistry, specifically to a method for the selective fluoroallyl alkylation of secondary nitroalkanes and difluorocyclopropane through ring-opening. Background Technology

[0002] Transition metal-catalyzed cross-coupling reactions are widely recognized as important tools for constructing carbon-carbon and carbon-heteroatom bonds. Among these, the Tsuji-Trost type allylic substitution reaction, through its key π-allylic metal intermediate, provides a flexible and efficient platform for the precise construction of C-C and C-heteroatom bonds. The core advantage of this reaction lies in its in-depth study of chemo, regio, and stereoselectivity control, giving it a crucial role in modern synthetic organic chemistry and leading to its widespread use in the assembly of complex molecules, such as natural products and bioactive molecules. With the increasing demand for fluorine-containing drug candidates, developing synthetic methods that achieve regioselectivity in the presence of fluorine atoms is particularly important. Notably, introducing a fluorine substituent at the allylic position enhances the electrophilicity of the metal-allylic intermediate, making regioselectivity control in Tsuji-Trost type reactions more challenging.

[0003] The allylation of nitroalkanes has long been a hot topic and frontier in organic synthesis research. As a class of functional groups that have been extensively studied, nitroalkanes can be transformed into various functional structures through multiple pathways and are widely used in organic synthesis and drug molecule modification. Among them, the allylation of secondary nitroalkanes has seen limited progress in regioselectivity control due to significant steric hindrance and low reactivity. Researchers have been exploring more direct and efficient methods to achieve the direct allylation of secondary nitroalkanes. However, the use of fluorinated organic compounds in the allylation of secondary nitroalkanes has not yet been reported. Therefore, conducting research in this direction is of clear significance and necessity. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for selectively synthesizing branched fluoroallyl alkylation by ring-opening of secondary nitroalkanes and gem-difluorocyclopropanes.

[0005] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: a method for selectively synthesizing branched fluoroallyl alkylates from secondary nitroalkanes and gem-difluorocyclopropane through ring-opening, using gem-difluoropropane and secondary nitroalkanes as raw materials, generating fluoroallyl-metal complexes through transition metal catalysis of ring-opening of gem-difluorocyclopropane, and then reacting with secondary nitroalkanes to obtain branched fluoroallyl alkylated compounds. Attached Figure Description

[0006] This method conforms to the following reaction equation:

[0007]

[0008] Figure 1 The reaction equation is: gem-difluorocyclopropane with secondary nitroalkanes.

[0009]

[0010] Figure 2 It is a gemdifluorocyclopropane derivative.

[0011]

[0012] Figure 3 Secondary nitroalkanes

[0013] Among them, R 1 Indicates the presence of one or more substituted alkyl, alkoxy, phenyl, halogen, etc.; R 2 Represents a hydrogen atom or an alkyl or phenyl group containing one or more substitutions; R 3 It represents a hydrogen atom or an alkyl group. Detailed Implementation

[0014] The above-mentioned method for selective fluoroallyl alkylation of difluorocyclopropane involving secondary nitroalkanes is carried out according to the following steps: In a reaction tube, gem-difluorocyclopropane derivatives, secondary nitroalkanes, transition metal catalysts, ligands, bases and solvents are added, and the reaction is carried out at 50 °C under a nitrogen atmosphere for 24 hours. After cooling to room temperature, the mixture is filtered, and the solvent is removed under reduced pressure to obtain a crude product. The crude product is purified by column chromatography to obtain branched fluoroallyl alkylated compounds.

[0015] The metal catalyst is one or a mixture of two or more of Ni(acac)2, NiCl2·DME, CuCl, Cu(OTf)2, Pd(dba)2, Pd(TFA)2, Pd(acac)2, Pd(dppf)Cl2, Pd2(dba)3, and PdCl2.

[0016] The ligands are 5-di-tert-butylphosphine-1',3',5'-triphenyl-1'H-1,4'-dipyrazole (BippyPhos), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (XantPhos), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), and 5-diisopropylphosphine-1',3',5'-triphenyl-1,4'-di-1H-pyrazole (…). iPr-BippyPhos), 5-dicyclohexylphosphine-1',3',5'-triphenyl-1,4'-di-1H-pyrazole (Cy-BippyPhos), 5-(di(adamantane-1-yl)phosphine)-1',3',5'-triphenyl-1'H-1,4'-dipyrazole (Ad-BippyPhos), 1-[2-[bis(tert-butyl)phosphine]phenyl]-3,5-diphenyl-1H-pyrazole (TrippyPhos), (4R)-4-tert-butyl-2-[2-(diphenylphosphine)phenyl]-4,5-dihydrooxazole ( t One or more of the following (Bu-Phox) mixtures.

[0017] The base is one or a mixture of two or more of cesium hydroxide monohydrate, cesium hydroxide, sodium hydroxide, sodium bicarbonate, potassium phosphate, cesium fluoride, potassium tert-butoxide, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0018] The solvent is one or a mixture of two or more of the following: 1,4-dioxane, 2-methyltetrahydrofuran, methyl tert-butyl ether, diethylene glycol dimethyl ether, trifluorotoluene, n-heptane, N,N-dimethylformamide, and dimethyl sulfoxide.

[0019] The molar ratio of geminitrocyclopropane derivatives to secondary nitroalkanes is 2:3.

[0020] The reaction tubes are Schlenk tubes.

[0021] The eluent in column chromatography is a mixture of petroleum ether, petroleum ether and ethyl acetate in a volume ratio of (2-100):1, or a mixture of dichloromethane and methanol in a volume ratio of (2-100):1.

[0022] To address the problems existing in current branched fluoroallyl tertiary nitroalkanes, the inventors have established a highly efficient method for the synthesis of branched fluoroallyl alkylation. Using secondary nitroalkanes and gem-difluorocyclopropane as raw materials, a ring-opening selective reaction between secondary nitroalkanes and gem-difluorocyclopropane is achieved through transition metal catalysis to generate branched allyl alkylation, yielding complementary branched fluoroallyl tertiary nitro compounds. This invention has significant advantages in terms of synthetic conditions and practicality. It features simple synthetic steps, convenient operation, inexpensive and readily available raw materials, good compatibility with functional groups, regioselectivity, and high reaction efficiency. It also provides a reference and reliable technical support for branched regioselective allylation methods.

[0023] Example 1

[0024] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 50:1 mixture of petroleum ether and ethyl acetate.

[0025] The structural characterization data of the obtained product are as follows:

[0026] 1 H NMR (600 MHz, CDCl3) δ 7.87-7.82 (m, 4H), 7.54-7.50 (m, 2H), 7.47(dt, J = 8.6, 1.5 Hz, 1H), 4.85-4.80 (m, 1H), 4.65-4.54 (m, 2H), 1.84 (s,3H), 1.58 (s, 3H).

[0027] 13 C NMR (151 MHz, CDCl3) δ 163.0 (d, J = 263.2 Hz), 133.1, 132.9,132.3, 128.9 (d, J = 2.8 Hz), 128.3, 128.1, 127.5, 126.8 (d, J = 3.4 Hz), 126.5, 126.4, 95.8 (d, J = 20.0 Hz), 91.1 (d, J = 2.8 Hz), 56.8 (d, J = 22.6Hz), 24.8 (d, J = 2.9 Hz), 24.4 (d, J = 2.3 Hz).

[0028] 19 F NMR (565 MHz, CDCl3) δ -98.66.

[0029] HRMS (APCI) m / z: [M+H + calcd for C 16 H 17 FNO2 + 274.1238; found: 274.1266.

[0030] Based on the above data, the structure of the product is inferred as follows:

[0031]

[0032] Example 2

[0033] (2,2-Difluorocyclopropyl)benzene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 100:1 volume ratio of petroleum ether to ethyl acetate mixture.

[0034] The structural characterization data of the obtained product are as follows:

[0035] 1 H NMR (600 MHz, CDCl3) δ 7.34 (s, 5H), 4.77 (ddd, J = 17.8, 3.3, 0.8Hz, 1H), 4.54 (dd, J = 49.2, 3.2 Hz, 1H), 4.36 (d, J = 27.5 Hz, 1H), 1.77 (s,3H), 1.52 (s,3H).

[0036] 13 C NMR (151 MHz, CDCl3) δ 162.9 (d, J = 263.5 Hz), 134.8, 129.4 (d, J= 3.2 Hz), 128.7, 128.3, 95.7 (d, J = 20.4 Hz), 91.0 (d, J = 3.2 Hz), 56.8 (d, J = 22.6 Hz), 24.5 (d, J = 3.1 Hz), 24.3 (d, J = 2.3 Hz).

[0037] 19 F NMR (565 MHz, CDCl3) δ -98.94.

[0038] HRMS (APCI) m / z: [M+H + calcd for C 12 H 15 FNO2 +224.1081; found: 224.1070.

[0039] Based on the above data, the structure of the product is inferred as follows:

[0040]

[0041] Example 3

[0042] 1-(2,2-difluorocyclopropyl)-4-methylbenzene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 100:1 volume ratio of petroleum ether:ethyl acetate mixed solvent.

[0043] The structural characterization data of the obtained product are as follows:

[0044] 1 H NMR (600 MHz, CDCl3) δ 7.22 (dd, J = 8.2, 1.2 Hz, 2H), 7.15 (d, J =7.9 Hz, 2H), 4.75 (ddd, J = 17.9, 3.2, 0.9 Hz, 1H), 4.52 (dd, J = 49.2, 3.2Hz, 1H), 4.32 (d, J = 27.4 Hz, 1H), 2.34 (s, 3H), 1.76 (s, 3H), 1.52 (s, 3H).

[0045] 13 C NMR (151 MHz, CDCl3) δ 163.2 (d, J = 263.2 Hz), 138.1, 131.8,129.4, 129.3 (d, J = 3.1 Hz), 95.4 (d, J = 20.3 Hz), 91.1 (d, J = 2.9 Hz), 56.4 (d, J = 22.6 Hz), 24.6 (d, J = 3.0 Hz), 24.3 (d, J = 2.2 Hz), 21.0.

[0046] 19F NMR (565 MHz, CDCl3) δ -98.91.

[0047] HRMS (APCI) m / z: [M+H + calcd for C 13 H 17 FNO2 + 238.1238; found: 238.1223.

[0048] Based on the above data, the structure of the product is inferred as follows:

[0049]

[0050] Example 4

[0051] 1-(2,2-difluorocyclopropyl)-4-methoxybenzene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 100:1 (v / v) mixture of petroleum ether and ethyl acetate.

[0052] The structural characterization data of the obtained product are as follows:

[0053] 1 H NMR (600 MHz, CDCl3) δ 7.26-7.23 (m, 2H), 6.88-6.84 (m, 2H), 4.74 (ddd, J = 17.9, 3.2, 0.8 Hz, 1H), 4.52 (dd, J = 49.3, 3.2 Hz, 1H), 4.30 (d, J= 27.5 Hz, 1H), 3.80 (s, 3H), 1.75 (s, 3H), 1.51 (s, 3H).

[0054] 13C NMR (151 MHz, CDCl3) δ 163.2 (d, J = 263.0 Hz), 159.4, 130.5 (d, J= 3.3 Hz), 126.7, 114.0, 95.3 (d, J = 20.4 Hz), 91.1 (d, J = 3.2 Hz), 56.0 (d, J = 22.6 Hz), 55.2, 24.4 (d, J = 2.9 Hz), 24.2 (d, J = 2.2 Hz).

[0055] 19 F NMR (565 MHz, CDCl3) δ -99.16.

[0056] HRMS (APCI) m / z: [M+H + calcd for C 13 H 17 FNO3 + 254.1187; found: 254.1208.

[0057] Based on the above data, the structure of the product is inferred as follows:

[0058]

[0059] Example 5

[0060] 1-tert-butyl-4-(2,2-difluorocyclopropyl)benzene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 50:1 mixture of petroleum ether and ethyl acetate.

[0061] The structural characterization data of the obtained product are as follows:

[0062] 1 H NMR (600 MHz, CDCl3) δ 7.36-7.33 (m, 2H), 7.27-7.25 (m, 2H), 4.74(ddd, J = 17.8, 3.2, 0.9 Hz, 1H), 4.53 (dd, J = 49.2, 3.2 Hz, 1H), 4.34 (d, J= 27.8 Hz, 1H), 1.77 (s, 3H), 1.52 (s, 3H), 1.31 (s, 9H).

[0063] 13 C NMR (151 MHz, CDCl3) δ 163.1 (d, J = 263.4 Hz), 151.2, 131.7 (d, J= 1.7 Hz), 129.1 (d, J = 2.9 Hz), 125.6, 95.4 (d, J = 20.1 Hz), 91.1 (d, J =3.2 Hz), 56.4 (d, J = 22.3 Hz), 34.5, 31.2, 24.7 (d, J = 2.9 Hz), 24.2 (d, J= 2.2 Hz).

[0064] 19 F NMR (565 MHz, CDCl3) δ -98.92.

[0065] HRMS (APCI) m / z: [M+H + calcd for C 16 H 23 FNO2 + 280.1707; found: 280.1690.

[0066] Based on the above data, the structure of the product is inferred as follows:

[0067]

[0068] Example 6

[0069] 4-(2,2-difluorocyclopropyl)-N,N-dimethylaniline (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 20:1 volume ratio of petroleum ether to ethyl acetate mixture.

[0070] The structural characterization data of the obtained product are as follows:

[0071] 1 H NMR (600 MHz, CDCl3) δ 7.22-7.17 (m, 2H), 6.70-6.64 (m, 2H), 4.71(dd, J = 18.0, 2.9 Hz, 1H), 4.49 (dd, J = 49.4, 3.1 Hz, 1H), 4.26 (d, J =27.1 Hz, 1H), 2.95 (s, 6H), 1.75 (s, 3H), 1.51 (s, 3H).

[0072] 13 C NMR (151 MHz, CDCl3) δ 163.7 (d, J = 263.1 Hz), 150.2, 130.2 (d, J= 3.0 Hz), 121.9, 112.2, 94.8 (d, J = 20.4 Hz), 91.3 (d, J = 2.9 Hz), 56.1 (d, J = 22.7 Hz), 40.3, 24.8 (d, J = 2.8 Hz), 23.9 (d, J = 2.2 Hz).

[0073] 19 F NMR (565 MHz, CDCl3) δ -98.76.

[0074] HRMS (APCI) m / z: [M+H + calcd for C 14 H 20 FN2O2 + 267.1503; found: 267.1498.

[0075] Based on the above data, the structure of the product is inferred as follows:

[0076]

[0077] Example 7

[0078] (4-(2,2-difluorocyclopropyl)phenyl)methyl sulfide (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a petroleum ether:ethyl acetate mixture with a volume ratio of 30:1.

[0079] The structural characterization data of the obtained product are as follows:

[0080] 1 H NMR (600 MHz, CDCl3) δ 7.24 (d, J = 8.0 Hz, 2H), 7.22-7.18 (m, 2H), 4.76 (dd, J = 17.8, 3.1 Hz, 1H), 4.53 (dd, J = 49.2, 3.2 Hz, 1H), 4.31 (d, J= 27.6 Hz, 1H), 2.47 (s, 3H), 1.75 (s, 3H), 1.51 (s, 3H).

[0081] 13 C NMR (151 MHz, CDCl3) δ 162.8 (d, J = 263.2 Hz), 139.0, 131.2 (d, J= 1.9 Hz), 129.8 (d, J = 3.1 Hz), 126.3, 95.6 (d, J = 20.1 Hz), 90.9 (d, J =3.0 Hz), 56.2 (d, J = 22.5 Hz), 24.4 (d, J = 3.0 Hz), 24.3 (d, J = 2.1 Hz), 15.4.

[0082] 19 F NMR (565 MHz, CDCl3) δ -99.13.

[0083] HRMS (APCI) m / z: [M+H + calcd for C 13 H 17 FNO2S + 270.0959; found: 270.0929.

[0084] Based on the above data, the structure of the product is inferred as follows:

[0085]

[0086] Example 8

[0087] 4'-(2,2-difluorocyclopropyl)-1,1'-biphenyl (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 50:1 mixture of petroleum ether and ethyl acetate.

[0088] The structural characterization data of the obtained product are as follows:

[0089] 1 H NMR (600 MHz, CDCl3) δ 7.59 (td, J = 7.8, 7.1, 1.7 Hz, 4H), 7.46 (dd, J = 8.4, 7.0 Hz, 2H), 7.43-7.41 (m, 2H), 7.39-7.35 (m, 1H), 4.81 (ddd, J = 17.9, 3.2, 0.9 Hz, 1H), 4.59 (dd, J = 49.2, 3.3 Hz, 1H), 4.43 (d, J = 27.7Hz, 1H), 1.82 (s, 3H), 1.59 (s, 3H).

[0090] 13C NMR (151 MHz, CDCl3) δ 162.9 (d, J = 263.2 Hz), 141.1, 140.2,133.7 (d, J = 2.0 Hz), 129.8, 129.8, 128.8, 127.5, 127.3, 127.0, 95.7 (d, J =20.0 Hz), 91.0 (d, J = 3.1 Hz), 56.4 (d, J = 22.6 Hz), 24.5 (d, J = 3.0 Hz), 24.4 (d, J = 2.2 Hz).

[0091] 19 F NMR (565 MHz, CDCl3) δ -98.94.

[0092] HRMS (APCI) m / z: [M+H + calcd for C 18 H 19 FNO2 + 300.1394; found: 300.1375.

[0093] Based on the above data, the structure of the product is inferred as follows:

[0094]

[0095] Example 9

[0096] 1-(2,2-difluorocyclopropyl)-4-(trifluoromethyl)benzene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 100:1 volume ratio of petroleum ether:ethyl acetate mixed solvent.

[0097] The structural characterization data of the obtained product are as follows:

[0098] 1 H NMR (600 MHz, CDCl3) δ 7.60 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.1Hz, 2H), 4.82 (ddd, J = 17.7, 3.4, 1.0 Hz, 1H), 4.60 (dd, J = 49.0, 3.4 Hz,1H), 4.43 (d, J = 28.2 Hz, 1H), 1.78 (s, 3H), 1.54 (s, 3H).

[0099] 13 C NMR (151 MHz, CDCl3) δ 162.0 (d, J = 263.2 Hz), 138.8, 130.6 (q, J= 32.8 Hz), 129.8 (d, J = 3.6 Hz), 125.6 (q, J = 3.7 Hz), 123.8 (q, J = 272.2Hz), 96.5 (d, J = 20.0 Hz), 90.7 (d, J = 3.3 Hz), 56.4 (d, J = 22.5 Hz), 24.8 (d, J = 2.0 Hz), 24.0 (d, J = 3.4 Hz).

[0100] 19 F NMR (565 MHz, CDCl3) δ -62.81, -99.60.

[0101] HRMS (APCI) m / z: [M+H + calcd for C 13 H 14 F4NO2 + 292.0955; found: 292.0944.

[0102] Based on the above data, the structure of the product is inferred as follows:

[0103]

[0104] Example 10

[0105] Methyl 4-(2,2-difluorocyclopropyl)benzoate (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a petroleum ether:ethyl acetate mixture with a volume ratio of 20:1.

[0106] The structural characterization data of the obtained product are as follows:

[0107] 1 H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.1Hz, 2H), 4.80 (dd, J = 17.8, 3.3 Hz, 1H), 4.57 (dd, J = 49.0, 3.4 Hz, 1H), 4.41 (d, J = 27.8 Hz, 1H), 3.90 (s, 3H), 1.76 (s, 3H), 1.51 (s, 3H).

[0108] 13 C NMR (151 MHz, CDCl3) δ 166.5, 162.1 (d, J = 263.5 Hz), 139.7 (d, J= 2.3 Hz), 130.1, 129.8, 129.4 (d, J = 3.3 Hz), 96.3 (d, J = 20.0 Hz), 90.7(d, J = 3.0 Hz), 56.5 (d, J = 22.6 Hz), 52.2, 24.6 (d, J = 2.1 Hz), 24.2 (d,J = 3.3 Hz).

[0109] 19 F NMR (565 MHz, CDCl3) δ -99.31.

[0110] HRMS (APCI) m / z: [M+H + calcd for C 14 H 17 FNO4 + 282.1136; found: 282.1125.

[0111] Based on the above data, the structure of the product is inferred as follows:

[0112]

[0113] Example 11

[0114] 1-(2,2-difluorocyclopropyl)-4-nitrobenzene (0.20 mmol), 2-nitrobanane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a petroleum ether:dichloromethane mixture with a volume ratio of 3:1.

[0115] The structural characterization data of the obtained product are as follows:

[0116] 1 H NMR (600 MHz, CDCl3) δ 8.31-8.10 (m, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.86 (ddd, J = 17.6, 3.5, 1.0 Hz, 1H), 4.64 (dd, J = 48.9, 3.5 Hz, 1H), 4.47(d, J = 28.6 Hz, 1H), 1.79 (s, 3H), 1.56 (s, 3H).

[0117] 13 C NMR (151 MHz, CDCl3) δ 161.3 (d, J = 263.5 Hz), 147.8, 142.0 (d, J= 2.9 Hz), 130.3 (d, J = 3.8 Hz), 123.8, 97.0 (d, J = 19.8 Hz), 90.6 (d, J =3.4 Hz), 56.3 (d, J = 22.7 Hz), 25.2 (d, J = 1.9 Hz), 23.5 (d, J = 3.5 Hz).

[0118] 19 F NMR (565 MHz, CDCl3) δ -100.02.

[0119] HRMS (APCI) m / z: [M+Na + calcd for C 12 H 13 FN2NaO4 + 291.0752.

[0120] Based on the above data, the structure of the product is inferred as follows:

[0121]

[0122] Example 12

[0123] 4-(2,2-difluorocyclopropyl)phenol acetate (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 2:1 volume ratio of petroleum ether to dichloromethane.

[0124] The structural characterization data of the obtained product are as follows:

[0125] 1 H NMR (600 MHz, CDCl3) δ 7.34 (d, J = 8.5 Hz, 2H), 7.10-7.04 (m, 2H), 4.76 (ddd, J = 17.8, 3.3, 0.9 Hz, 1H), 4.54 (dd, J = 49.2, 3.3 Hz, 1H), 4.36(d, J = 27.9 Hz, 1H), 2.29 (s, 3H), 1.75 (s, 3H), 1.52 (s, 3H).

[0126] 13C NMR (151 MHz, CDCl3) δ 169.2, 162.6 (d, J = 263.2 Hz), 150.6,132.2 (d, J = 2.0 Hz), 130.5 (d, J = 3.4 Hz), 121.8, 95.9 (d, J = 20.2 Hz), 91.0 (d, J = 3.3 Hz), 56.1 (d, J = 22.6 Hz), 24.4 (d, J = 3.2 Hz), 24.3 (d, J= 2.2 Hz), 21.1.

[0127] 19 F NMR (565 MHz, CDCl3) δ -99.56.

[0128] HRMS (APCI) m / z: [M+Na + calcd for C 14 H 16 FNNaO4 + 304.0956; found: 304.0950.

[0129] Based on the above data, the structure of the product is inferred as follows:

[0130]

[0131] Example 13

[0132] 1-(2,2-difluorocyclopropyl)-4-fluorobenzene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a petroleum ether:ethyl acetate mixture with a volume ratio of 100:1.

[0133] The structural characterization data of the obtained product are as follows:

[0134] 1 H NMR (600 MHz, CDCl3) δ 7.32-7.28 (m, 2H), 7.05-7.00 (m, 2H), 4.78(ddd, J = 17.8, 3.3, 0.9 Hz, 1H), 4.55 (dd, J = 49.1, 3.3 Hz, 1H), 4.34 (d, J= 28.0 Hz, 1H), 1.76 (s, 3H), 1.52 (s, 3H).

[0135] 13 C NMR (151 MHz, CDCl3) δ 162.6 (dd, J = 255.5, 7.5 Hz), 131.1 (dd, J = 8.1, 3.6 Hz), 130.6 (dd, J =3.3, 2.3 Hz), 115.7, 115.6, 95.9 (d, J = 20.3Hz), 90.9 (d, J = 3.2 Hz), 56.0 (d, J = 22.6 Hz), 24.6 (d, J = 2.1 Hz), 24.1(d, J = 3.3 Hz).

[0136] 19 F NMR (565 MHz, CDCl3) δ -99.67, -113.57.

[0137] HRMS (APCI) m / z: [M+Na + calcd for C 12 H 13 F2NNaO2 + 264.0807; found: 264.0802.

[0138] Based on the above data, the structure of the product is inferred as follows:

[0139]

[0140] Example 14

[0141] 1-(2,2-difluorocyclopropyl)-4-(phenylethynyl)benzene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 100:1 mixture of petroleum ether and ethyl acetate.

[0142] The structural characterization data of the obtained product are as follows:

[0143] 1 H NMR (600 MHz, CDCl3) δ 7.56-7.51 (m, 3H), 7.51 (d, J = 8.1 Hz, 3H), 7.35 (dd, J = 5.1, 2.0 Hz, 3H), 7.32 (d, J = 8.1 Hz, 2H), 4.80 (dd, J = 17.8, 3.1 Hz, 1H), 4.57 (dd, J = 49.2, 3.3 Hz, 1H), 4.37 (d, J = 27.5 Hz, 1H), 1.77 (s, 3H), 1.53 (s, 3H).

[0144] 13 C NMR (151 MHz, CDCl3) δ 162.5 (d, J = 263.4 Hz), 134.8, 131.8,131.6, 129.4 (d, J = 3.3 Hz), 128.4, 128.4, 123.5, 123.0, 96.0 (d, J = 20.0Hz), 90.9 (d, J = 2.9 Hz), 90.3, 88.5, 56.5 (d, J = 22.6 Hz), 24.4 (d, J =3.2 Hz).

[0145] 19 F NMR (565 MHz, CDCl3) δ -99.17.

[0146] HRMS (APCI) m / z: [M+H + calcd for C 20 H 19 FNO2 +324.1394; found: 324.1387.

[0147] Based on the above data, the structure of the product is inferred as follows:

[0148]

[0149] Example 15

[0150] 1-(2,2-difluorocyclopropyl)-2-methylbenzene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 50:1 mixture of petroleum ether and ethyl acetate.

[0151] The structural characterization data of the obtained product are as follows:

[0152] 1 H NMR (600 MHz, CDCl3) δ 7.45 (dt, J = 6.4, 1.9 Hz, 1H), 7.24-7.19(m, 3H), 4.82 (d, J = 21.6 Hz, 1H), 4.71 (dd, J = 17.9, 3.2 Hz, 1H), 4.40(dd, J = 49.3, 3.2 Hz, 1H), 2.45 (s, 3H), 1.84 (s, 3H), 1.50 (s, 3H).

[0153] 13 C NMR (151 MHz, CDCl3) δ 163.1 (d, J = 263.2 Hz), 137.4, 133.1,131.2, 128.6 (d, J = 4.2 Hz), 128.1, 126.2, 95.2 (d, J = 20.5 Hz), 91.4 (d, J= 2.7 Hz), 50.7 (d, J = 23.2 Hz), 25.7 (d, J = 1.7 Hz), 23.7 (d, J = 2.6 Hz), 20.4.

[0154] 19F NMR (565 MHz, CDCl3) δ -98.54.

[0155] HRMS (APCI) m / z: [M+H + calcd for C 13 H 17 FNO2 + 238.1238; found: 238.1224.

[0156] Based on the above data, the structure of the product is inferred as follows:

[0157]

[0158] Example 16

[0159] 1-(2,2-difluorocyclopropyl)-3-methylbenzene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 50:1 mixture of petroleum ether and ethyl acetate.

[0160] The structural characterization data of the obtained product are as follows:

[0161] 1 H NMR (600 MHz, CDCl3) δ 7.23 (td, J = 7.4, 1.2 Hz, 1H), 7.18-7.10(m, 3H), 4.76 (ddd, J = 17.8, 3.2, 0.9 Hz, 1H), 4.53 (dd, J = 49.2, 3.2 Hz, 1H), 4.32 (d, J = 27.5 Hz, 1H), 2.35 (s, 3H), 1.77 (s, 3H), 1.52 (s, 3H).

[0162] 13C NMR (151 MHz, CDCl3) δ 163.1 (d, J = 263.6 Hz), 138.3, 134.8,130.1 (d, J = 3.1 Hz), 129.0, 128.5, 126.4 (d, J = 3.3 Hz), 95.5 (d, J = 20.0Hz), 91.0 (d, J = 3.2 Hz), 56.7 (d, J = 22.3 Hz), 24.6 (d, J = 3.2 Hz), 24.3(d, J = 2.2 Hz), 21.4.

[0163] 19 F NMR (565 MHz, CDCl3) δ -98.76.

[0164] HRMS (APCI) m / z: [M+H + calcd for C 13 H 17 FNO2 + 238.1238; found: 238.1226.

[0165] Based on the above data, the structure of the product is inferred as follows:

[0166]

[0167] Example 17

[0168] 4-(2,2-difluorocyclopropyl)-1,2-dimethoxybenzene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a petroleum ether:ethyl acetate mixture with a volume ratio of 20:1.

[0169] The structural characterization data of the obtained product are as follows:

[0170] 1 H NMR (600 MHz, CDCl3) δ 6.86 (ddd, J = 8.3, 2.2, 1.0 Hz, 1H), 6.83-6.79 (m, 2H), 4.75 (ddd, J = 17.9, 3.2, 0.8 Hz, 1H), 4.53 (dd, J = 49.3, 3.2Hz, 1H), 4.28 (d, J = 27.8 Hz, 1H), 3.86 (s, 6H), 1.75 (s, 3H), 1.52 (s, 3H).

[0171] 13 C NMR (151 MHz, CDCl3) δ 163.1 (d, J = 263.1 Hz), 149.0, 148.4,127.1, 121.9 (d, J = 3.2 Hz), 112.5 (d, J = 3.6 Hz), 111.0, 95.5 (d, J = 20.2Hz), 91.1 (d, J = 3.0 Hz), 56.3 (d, J = 22.6 Hz), 55.9, 55.8, 24.4 (d, J =2.1 Hz), 24.3 (d, J = 3.1 Hz).

[0172] 19 F NMR (565 MHz, CDCl3) δ -99.37.

[0173] HRMS (APCI) m / z: [M+Na + calcd for C 14 H 19 FNNaO4 + 306.1112; found: 306.1106.

[0174] Based on the above data, the structure of the product is inferred as follows:

[0175]

[0176] Example 18

[0177] 2-(2,2-difluorocyclopropyl)benzofuran (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 50:1 mixture of petroleum ether and ethyl acetate.

[0178] The structural characterization data of the obtained product are as follows:

[0179] 1 H NMR (600 MHz, CDCl3 ) δ 7.58-7.54 (m, 1H), 7.47 (dd, J = 8.2, 1.2Hz, 1H), 7.30 (ddd, J = 8.3, 7.2, 1.4 Hz, 1H), 7.25 (td, J = 7.5, 1.0 Hz, 1H), 6.76 (s, 1H), 4.88 (dd, J = 17.3, 3.4 Hz, 1H), 4.77 (d, J = 23.1 Hz, 1H), 4.63 (dd, J = 48.6, 3.4 Hz, 1H), 1.83 (s, 3H), 1.62 (s, 3H).

[0180] 13 C NMR (151 MHz, CDCl3) δ 160.4 (d, J = 262.9 Hz), 154.8, 150.9,127.8, 124.7, 123.2, 121.1, 111.3, 107.1 (d, J = 2.8 Hz), 96.5 (d, J = 18.7Hz), 90.0 (d, J = 3.8 Hz), 51.0 (d, J = 25.4 Hz), 24.9 (d, J = 2.5 Hz), 24.0(d, J = 2.3 Hz).

[0181] 19 F NMR (565 MHz, CDCl3) δ -98.98.

[0182] HRMS (APCI) m / z: [M+H + calcd for C14 H 15 FNO3 + 264.1030; found: 264.1023.

[0183] Based on the above data, the structure of the product is inferred as follows:

[0184]

[0185] Example 19

[0186] 2-(2,2-difluorocyclopropyl)benzo[b]thiophene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 50:1 mixture of petroleum ether and ethyl acetate.

[0187] The structural characterization data of the obtained product are as follows:

[0188] 1 H NMR (600 MHz, CDCl3) δ 7.82-7.78 (m, 1H), 7.77-7.74 (m, 1H), 7.38-7.33 (m, 2H), 7.29 (d, J = 1.2 Hz, 1H), 4.86-4.79 (m, 2H), 4.66 (dd, J =48.4, 3.4 Hz, 1H), 1.83 (s, 3H), 1.65 (s, 3H).

[0189] 13 C NMR (151 MHz, CDCl3) δ 161.3 (d, J = 263.5 Hz), 139.6, 139.0,135.9, 125.2 (d, J = 2.2 Hz), 124.8, 124.5, 123.6, 122.0, 96.2 (d, J = 19.2Hz), 91.0 (d, J = 3.9 Hz), 52.7 (d, J = 23.8 Hz), 24.5 (d, J = 3.2 Hz), 24.3(d, J = 2.3 Hz).

[0190] 19 F NMR (565 MHz, CDCl3) δ -99.87.

[0191] HRMS (APCI) m / z: [M+H + calcd for C 14 H 15 FNO2S + 280.0802; found: 280.0794.

[0192] Based on the above data, the structure of the product is inferred as follows:

[0193]

[0194] Example 20

[0195] 1-(2,2-difluorocyclopropyl)ferrocene (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 50:1 mixture of petroleum ether and ethyl acetate.

[0196] The structural characterization data of the obtained product are as follows:

[0197] 1 H NMR (600 MHz, CDCl3) δ 4.82 (ddd, J = 17.2, 3.0, 1.3 Hz, 1H), 4.61 (dd, J = 48.6, 3.0 Hz, 1H), 4.33 (td, J = 2.5, 1.3 Hz, 1H), 4.23-3.96 (m,9H), 1.60 (s, 3H), 1.39 (s, 3H).

[0198] 13C NMR (151 MHz, CDCl3) δ 163.0 (d, J = 264.5 Hz), 94.7 (d, J = 20.3Hz), 91.8 (d, J = 4.2 Hz), 80.5 (d, J = 2.3 Hz), 69.9, 69.2, 68.80 68.7 (d, J= 7.2 Hz), 67.6, 52.5 (d, J = 22.7 Hz), δ 24.2 (d, J = 2.1 Hz), 23.8 (d, J =3.3 Hz).

[0199] 19 F NMR (565 MHz, CDCl3) δ -98.50.

[0200] HRMS (APCI) m / z: [M+Na + calcd for C 16 H 18 FFeNNaO2 + 354.0563; found: 354.05558.

[0201] Based on the above data, the structure of the product is inferred as follows:

[0202]

[0203] Example 21

[0204] Isopropyl 2-(4-(4-(2,2-difluorocyclopropyl)benzoyl)phenoxy)-2-methylpropionic acid (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a petroleum ether:ethyl acetate mixture with a volume ratio of 10:1.

[0205] The structural characterization data of the obtained product are as follows:

[0206] 1H NMR (600 MHz, CDCl3) δ 7.76-7.70 (m, 4H), 7.43 (d, J = 8.0 Hz, 2H), 6.88-6.83 (m, 2H), 5.08 (hept, J = 6.3 Hz, 1H), 4.82 (ddd, J = 17.8, 3.3, 0.9Hz, 1H), 4.59 (dd, J = 49.0, 3.3 Hz, 1H), 4.43 (d, J = 28.0 Hz, 1H), 1.79 (s,3H), 1.65 (s, 6H), 1.56 (s, 3H), 1.19 (d, J = 6.3 Hz, 6H).

[0207] 13 C NMR (151 MHz, CDCl3) δ 194.7, 173.1, 162.2 (d, J = 263.4 Hz), 159.7, 138.7 (d, J = 2.2 Hz), 138.0, 132.0, 130.2, 130.0, 129.3 (d, J = 3.3Hz), 117.2, 96.3 (d, J = 20.0 Hz), 90.8 (d, J = 3.0 Hz), 79.4, 69.3, 56.6 (d,J = 22.6 Hz), 25.3, 24.7 (d, J = 2.0 Hz), 24.2 (d, J = 3.2 Hz), 21.5.

[0208] 19 F NMR (565 MHz, CDCl3) δ -99.25.

[0209] HRMS (APCI) m / z: [M+H + calcd for C 26 H 31 FNO6 + 472.2130; found: 472.2124.

[0210] Based on the above data, the structure of the product is inferred as follows:

[0211]

[0212] Example 22

[0213] In a reaction tube, (8S,9R,13R,14R)-3-(2,2-difluorocyclopropyl)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopentane[a]phenanthrene-17-one (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 2:1 volume ratio of petroleum ether:dichloromethane mixed solvent.

[0214] The structural characterization data of the obtained product are as follows:

[0215] 1 H NMR (600 MHz, CDCl3) δ 7.24 (dt, J = 8.2, 1.8 Hz, 1H), 7.10 (dd, J= 11.3, 8.6 Hz, 1H), 7.06-6.97 (m, 1H), 4.74 (dd, J = 17.8, 3.2 Hz, 1H), 4.52(ddd, J = 49.2, 3.2, 1.0 Hz, 1H), 4.28 (dd, J = 28.1, 1.6 Hz, 1H), 2.89 (dd,J = 9.5, 4.4 Hz, 2H), 2.50 (dd, J = 19.0, 8.8 Hz, 1H), 2.42-2.37 (m, 1H),2.28 (td, J = 11.0, 4.1 Hz, 1H), 2.14 (dt, J = 19.0, 8.9 Hz, 1H), 2.09-1.99(m, 2H), 1.98-1.93 (m, 1H), 1.76 (s, 3H), 1.65-1.57 (m, 2H), 1.56-1.37 (m,7H), 0.91 (d, J = 1.8 Hz, 3H).

[0216] 13C NMR (151 MHz, CDCl3) δ 220.8, 163.1 (d, J = 263.3 Hz), 139.8 (d, J= 3.2 Hz), 136.8, 132.2, 130.0 (dd, J = 14.4, 2.9 Hz), 126.6 (dd, J = 12.4,3.1 Hz), 125.6, 95.5 (d, J = 20.3 Hz), 91.0 (d, J = 3.0 Hz), 56.4 (d, J =22.5 Hz), 50.5, 47.9, 44.2, 37.9, 35.8, 31.5, 29.4 (d,J = 6.2 Hz), 26.4 (d,J = 3.1 Hz), 25.5 (d, J = 3.5 Hz), 24.5 (q, J = 2.9, 2.4 Hz), 21.5, 13.8.

[0217] 19 F NMR (565 MHz, CDCl3) δδ -98.84.

[0218] HRMS (APCI) m / z: [M+H + calcd for C 24 H 31 FNO3 + 400.2282; found: 400.2290.

[0219] Based on the above data, the structure of the product is inferred as follows:

[0220]

[0221] Example 23

[0222] In a reaction tube, (3aR,5R,6S,6aR)-6-((4-(2,2-difluorocyclopropyl)benzyl)oxy)-5-((S)-2,2-dimethyl-1,3-dioxolane-4-yl)-2,2-dimethyltetrahydrofurano[2,3-d][1,3]dioxolane (0.20 mmol), 2-nitropropane (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 2:1 volume ratio of petroleum ether to dichloromethane.

[0223] The structural characterization data of the obtained product are as follows:

[0224] 1 H NMR (600 MHz, CDCl3) δ 7.33-7.28 (m, 4H), 5.89 (d, J = 3.7 Hz, 1H), 4.76 (dt, J = 17.9, 2.1 Hz, 1H), 4.65 (qd, J = 12.0, 3.1 Hz, 2H), 4.58-4.49(m, 2H), 4.37-4.31 (m, 2H), 4.14-4.09 (m, 2H), 4.00 (ddd, J = 8.6, 4.8, 1.6Hz, 2H), 1.76 (s, 3H), 1.52 (s, 3H), 1.49 (s, 3H), 1.42 (d, J = 3.1 Hz, 3H),1.37 (s, 3H), 1.31 (s, 3H).

[0225] 13C NMR (151 MHz, CDCl3) δ 162.8 (d, J = 263.4 Hz), 137.9 (d, J = 2.7Hz), 134.4, 129.4 (d, J = 3.3 Hz), 127.8 (d, J = 3.7 Hz), 111.8, 109.0,105.3, 95.7 (d, J = 20.2 Hz), 90.9 (d, J = 3.0 Hz), 82.6, 81.9 (d, J = 3.8Hz), 81.3, 72.4 (d, J = 2.4 Hz), 71.8 (d, J = 3.3 Hz), 67.5, 56.5 (d, J =22.5 Hz), 26.8, 26.8, 26.2, 25.4 (d, J = 2.0 Hz), 24.5 (d, J = 2.0 Hz), 24.3 (d, J = 3.1 Hz).

[0226] 19 F NMR (565 MHz, CDCl3) δ -99.11.

[0227] HRMS (APCI) m / z: [M+H + calcd for C 25 H 35 FNO8 + 496.2341; found: 496.2327

[0228] Based on the above data, the structure of the product is inferred as follows:

[0229]

[0230] Example 24

[0231] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), nitrocyclopentane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 50:1 mixture of petroleum ether and ethyl acetate.

[0232] The structural characterization data of the obtained product are as follows:

[0233] 1 H NMR (600 MHz, CDCl3) δ 7.84 (dt, J = 8.5, 3.9 Hz, 4H), 7.54-7.49(m, 2H), 7.48 (dd, J = 8.8, 1.6 Hz, 1H), 4.80 (dd, J = 17.8, 3.3 Hz, 1H), 4.67 (dd, J = 25.7, 1.5 Hz, 1H), 4.57 (ddd, J = 49.1, 3.3, 1.1 Hz, 1H), 2.81-2.75 (m, 1H), 2.61-2.55 (m, 1H), 2.25 (dt, J = 14.9, 9.0 Hz, 1H), 2.06 (dt, J= 14.4, 9.2 Hz, 1H), 1.76-1.57 (m, 4H).

[0234] 13 C NMR (151 MHz, CDCl3) δ 163.3 (d, J = 263.1 Hz), 133.2, 132.8,132.7, 128.8 (d, J = 2.6 Hz), 128.3, 128.1, 127.52, 126.9 (d, J = 2.8 Hz), 126.5, 126.4, 103.2 (d, J = 2.1 Hz), 95.3 (d, J = 20.3 Hz), 54.7 (d, J = 23.6Hz), 35.6 (d, J = 2.5 Hz), 34.1, 23.3, 23.1.

[0235] 19 F NMR (565 MHz, CDCl3) δ -97.71.

[0236] HRMS (APCI) m / z: [M+H + calcd for C 18 H 19 FNO2 + 300.1394; found: 300.1365.

[0237] Based on the above data, the structure of the product is inferred as follows:

[0238]

[0239] Example 25

[0240] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), nitrocyclohexane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 50:1 mixture of petroleum ether and ethyl acetate.

[0241] The structural characterization data of the obtained product are as follows:

[0242] 1 H NMR (600 MHz, CDCl3) δ 7.86-7.79 (m, 4H), 7.53-7.49 (m, 2H), 7.45(dt, J = 8.5, 1.6 Hz, 1H), 4.77 (ddd, J = 17.4, 3.2, 1.2 Hz, 1H), 4.58 (dd, J= 48.6, 3.2 Hz, 1H), 4.10 (dd, J = 31.1, 1.1 Hz, 1H), 2.79-2.74 (m, 1H), 2.55-2.50 (m, 1H), 1.87 (ddd, J = 14.5, 13.1, 4.3 Hz, 1H), 1.76-1.72 (m, 1H),1.68-1.60 (m, 3H), 1.39-1.33 (m, 1H), 1.31-1.26 (m, 1H), 1.13-1.06 (m, 1H).

[0243] 13C NMR (151 MHz, CDCl3) δ 162.8 (d, J = 264.4 Hz), 133.1, 132.9,132.0 (d, J = 2.9 Hz), 128.9 (d, J = 3.6 Hz), 128.1, 128.1, 127.5, 127.0 (d,J = 4.0 Hz), 126.4, 126.4, 95.8 (d, J = 20.2 Hz), 95.2 (d, J = 3.5 Hz), 58.9(d, J = 22.1 Hz), 32.2 (d, J = 2.8 Hz), 32.0 (d, J = 2.2 Hz), 24.2, 22.3,22.2.

[0244] 19 F NMR (565 MHz, CDCl3) δ -97.73.

[0245] HRMS (APCI) m / z: [M+Na + calcd for C 19 H 20 FNNaO2 + 336.1370; found: 336.1360.

[0246] Based on the above data, the structure of the product is inferred as follows:

[0247]

[0248] Example 26

[0249] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 4-nitrotetrahydro-2H-pyran (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 5:1 mixture of petroleum ether and ethyl acetate.

[0250] The structural characterization data of the obtained product are as follows:

[0251] 1 H NMR (600 MHz, CDCl3) δ 7.86-7.82 (m, 3H), 7.79 (d, J = 1.9 Hz, 1H), 7.54-7.50 (m, 2H), 7.43 (dt, J = 8.7, 1.6 Hz, 1H), 4.81 (dd, J = 17.4, 3.4Hz, 1H), 4.60 (dd, J = 48.6, 3.3 Hz, 1H), 4.13 (d, J = 30.4 Hz, 1H), 3.90 (ddd, J = 43.7, 12.4, 5.1 Hz, 2H), 3.38 (dtd, J = 40.3, 12.3, 2.1 Hz, 2H),2.66-2.61 (m, 1H), 2.43-2.39 (m, 1H), 2.29 (ddd, J = 14.7, 12.2, 5.2 Hz, 1H), 2.08 (ddd, J = 14.7, 12.2, 5.2 Hz, 1H.

[0252] 13 C NMR (151 MHz, CDCl3) δ 162.2 (d, J = 264.3 Hz), 133.1, 133.0,131.2 (d, J = 2.8 Hz), 128.9 (d, J = 3.3 Hz), 128.5, 128.1, 127.6, 126.8 (d,J = 3.9 Hz), 126.7, 126.6, 96.3 (d, J = 20.1 Hz), 92.8 (d, J = 3.4 Hz), 64.1,64.0, 58.4 (d, J = 22.1 Hz), 32.1 (d, J = 2.7 Hz), 31.9 (d, J = 2.0 Hz).

[0253] 19 F NMR (565 MHz, CDCl3) δ -98.02.

[0254] HRMS (APCI) m / z: [M+Na + calcd for C 18 H 18 FNNaO3 + 338.1163; found: 338.1159.

[0255] Based on the above data, the structure of the product is inferred as follows:

[0256]

[0257] Example 27

[0258] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), methyl 4-nitropiperidine-1-carboxylate (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a petroleum ether:ethyl acetate mixture with a volume ratio of 10:1.

[0259] The structural characterization data of the obtained product are as follows:

[0260] 1 H NMR (600 MHz, CDCl3) δ 7.87-7.82 (m, 3H), 7.77 (s, 1H), 7.53 (dt, J= 6.2, 3.4 Hz, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.36-7.26 (m, 5H), 5.08 (s,2H), 4.81 (dd, J = 17.4, 3.4 Hz, 1H), 4.60 (dd, J = 48.6, 3.4 Hz, 1H), 4.15(d, J = 30.5 Hz, 3H), 2.87-2.67 (m, 3H), 2.49 (s, 1H), 2.10 (s, 1H), 1.91 (d, J = 14.8 Hz, 1H).

[0261] 13C NMR (151 MHz, CDCl3) δ 162.04 (d, J = 264.4 Hz), 154.9, 136.4,133.1, 133.0, 131.1 (d, J = 2.8 Hz), 128.9 (d, J = 3.3 Hz), 128.5, 128.5,128.1 (d, J = 5.1 Hz), 127.9, 127.5, 126.6 (d, J = 3.8 Hz), 126.6 (d, J =17.7 Hz), 96.4 (d, J = 20.1 Hz), 93.4 (d, J = 3.4 Hz), 67.3, 58.2 (d, J =22.1 Hz), 40.2, 31.4, 31.2.

[0262] 19 F NMR (565 MHz, CDCl3) δ -98.22.

[0263] HRMS (APCI) m / z: [M+H + calcd for C 26 H 26 FN2O4 + 449.1871; found: 449.1857.

[0264] Based on the above data, the structure of the product is inferred as follows:

[0265]

[0266] Example 28

[0267] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 3-nitropentane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 50:1 mixture of petroleum ether and ethyl acetate.

[0268] The structural characterization data of the obtained product are as follows:

[0269] 1 H NMR (600 MHz, CDCl3) δ 7.85-7.81 (m, 3H), 7.77-7.75 (m, 1H), 7.52-7.49 (m, 2H), 7.42 (dt, J = 8.6, 1.6 Hz, 1H), 4.82 (ddd, J = 17.7, 3.2, 0.8Hz, 1H), 4.58 (dd, J = 48.8, 3.3 Hz, 1H), 4.22 (d, J = 26.8 Hz, 1H), 2.31 (dt, J = 14.9, 7.5 Hz, 1H), 2.16 (dtd, J = 14.9, 7.4, 2.4 Hz, 2H), 2.02 (dd,J = 14.9, 7.4 Hz, 1H), 0.95 (td, J = 7.4, 6.2 Hz, 6H.

[0270] 13 C NMR (151 MHz, CDCl3) δ 163.1 (d, J = 263.8 Hz), 133.1, 132.9,132.4, 129.0 (d, J = 2.7 Hz), 128.1, 128.1, 127.5, 127.0 (d, J = 3.3 Hz), 126.4, 126.3, 96.3 (d, J = 2.7 Hz), 95.7 (d, J = 20.7 Hz), 55.8 (d, J = 23.7Hz), 26.8, 26.5, 8.6, 8.5.

[0271] 19 F NMR (565 MHz, CDCl3) δ -95.58.

[0272] HRMS (APCI) m / z: [M+H + calcd for C 18 H 21 FNO2 + 302.1551; found: 302.1522.

[0273] Based on the above data, the structure of the product is inferred as follows:

[0274]

[0275] Example 29

[0276] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 2-nitrononane (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 50:1 mixture of petroleum ether and ethyl acetate.

[0277] The structural characterization data of the obtained product are as follows:

[0278] 1 H NMR (600 MHz, CDCl3) δ 7.89-7.83 (m, 4H), 7.55-7.49 (m, 3H), 4.76 (dd, J = 18.3, 3.3 Hz, 1H), 4.54-4.43 (m, 2H), 2.05 (ddd, J = 14.8, 12.2, 3.9Hz, 1H), 1.80 (s, 3H), 1.39-1.34 (m, 1H), 1.21 (dt, J = 12.6, 5.8 Hz, 3H), 1.17-1.12 (m, 5H), 1.11-1.06 (m, 1H), 1.00 (qd, J = 8.1, 4.5 Hz, 1H), 0.82(t, J = 7.2 Hz, 3H).

[0279] 13 C NMR (151 MHz, CDCl3) 163.1 (d, J = 263.2 Hz), 133.2, 132.9, 132.1,129.5 (d, J = 2.6 Hz), 128.3, 128.1, 127.6, 127.3 (d, J = 2.9 Hz), 126.6,126.5, 95.4 (d, J = 20.1 Hz), 94.7 (d, J = 2.3 Hz), 57.8 (d, J = 22.7 Hz), 39.5, 31.5, 29.2, 28.9, 23.5, 22.5, 18.3 (d, J = 3.3 Hz), 13.9.

[0280] 19 F NMR (565 MHz, CDCl3) δ -97.75.

[0281] HRMS (APCI) m / z: [M+Na + calcd for C 22 H 28 FNNaO2 + 380.1996; found: 380.1992.

[0282] Based on the above data, the structure of the product is inferred as follows:

[0283]

[0284] Example 30

[0285] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 4-nitropentanonitrile (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 5:1 mixture of petroleum ether and ethyl acetate.

[0286] The structural characterization data of the obtained product are as follows:

[0287] 1 H NMR (600 MHz, CDCl3) δ 7.95-7.72 (m, 4H), 7.62-7.46 (m, 2H), 7.41 (ddt, J = 30.7, 8.6, 1.5 Hz, 1H), 4.93-4.81 (m, 1H), 4.63 (ddd, J = 77.7, 49.1, 3.5 Hz, 1H), 4.50-4.43 (m, 1H), 2.88-2.49 (m, 1H), 2.42-1.93 (m, 3H), 1.75 (s, 3H).

[0288] 13C NMR (151 MHz, CDCl3) δ 162.1 (d, J = 263.1 Hz), 133.1 (d, J = 14.1Hz), 131.3 (d, J = 3.0 Hz), 130.8, 129.2 (d, J = 2.8 Hz), 128.9, 128.7,128.1, 127.6, 126.9 (d, J = 19.1 Hz), 126.5 (d, J = 3.3 Hz), 118.1, 96.6 (d,J = 19.8 Hz), 92.9 (d, J = 2.9 Hz), 57.7 (d, J = 22.6 Hz), 33.4 (d, J = 2.7Hz), 19.2 (d, J = 2.9 Hz), 12.4.

[0289] 19 F NMR (565 MHz, CDCl3) δ -98.73.

[0290] HRMS (APCI) m / z: [M+H + calcd for C 18 H 18 FN2O2 + 313.1347; found: 313.1327.

[0291] Based on the above data, the structure of the product is inferred as follows:

[0292]

[0293] Example 31

[0294] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), N,N-dimethyl-4-nitropentanamide (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 5:1 mixture of petroleum ether and ethyl acetate.

[0295] The structural characterization data of the obtained product are as follows:

[0296] 1 H NMR (600 MHz, CDCl3) δ 7.89-7.73 (m, 4H), 7.52-7.39 (m, 3H), 4.88-4.75 (m, 1H), 4.75-4.45 (m, 2H), 2.94 (s, 3H), 2.85 (d, J = 12.0 Hz, 3H),2.72-1.89 (m, 4H), 1.72 (d, J = 109.7 Hz, 3H).

[0297] 13 C NMR (151 MHz, CDCl3) δ 170.8, 163.1 (d, J = 263.2 Hz), 133.4,133.2, 132.5 (d, J = 3.3 Hz), 131.8, 129.7 (d, J = 2.7 Hz), 128.7, 127.7,127.7, 127.3 (d, J = 2.8 Hz), 126.7 (d, J = 19.5 Hz), 95.9 (d, J = 19.9 Hz), 94.3 (d, J = 2.7 Hz), 58.1 (d, J = 22.8 Hz), 37.2, 35.6, 34.5, 27.8, 18.8 (d,J = 3.2 Hz).

[0298] 19 F NMR (565 MHz, CDCl3) δ-97.87.

[0299] HRMS (APCI) m / z: [M+H + calcd for C 20 H 24 FN2O3 + 359.1765; found: 359.1757.

[0300] Based on the above data, the structure of the product is inferred as follows:

[0301]

[0302] Example 32

[0303] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 1-(4-nitropentyl)benzene (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 50:1 mixture of petroleum ether and ethyl acetate.

[0304] The structural characterization data of the obtained product are as follows:

[0305] 1 H NMR (600 MHz, CDCl3) δ 7.90-7.84 (m, 4H), 7.57-7.53 (m, 2H), 7.49 (dt, J = 8.6, 1.3 Hz, 1H), 7.21 (dd, J = 8.2, 6.8 Hz, 2H), 7.17-7.13 (m, 1H),7.04-7.00 (m, 2H), 4.77 (dd, J = 18.2, 3.3 Hz, 1H), 4.54-4.45 (m, 2H), 2.50-2.41 (m, 2H), 2.13 (ddd, J = 13.8, 12.0, 3.7 Hz, 1H), 1.80 (s, 3H), 1.56-1.53(m, 1H), 1.49-1.44 (m, 1H), 1.41-1.36 (m, 1H).

[0306] 13 C NMR (151 MHz, CDCl3) δ 162.9 (d, J = 263.4 Hz), 141.1, 133.2,132.9, 131.9, 129.5 (d, J = 2.6 Hz), 128.4, 128.3, 128.2, 128.1, 127.6, 127.2(d, J = 3.1 Hz), 126.6, 126.5, 125.9, 95.5 (d, J = 20.1 Hz), 94.4 (d, J = 2.4Hz), 57.7 (d, J = 22.7 Hz), 39.0, 35.4, 25.5, 18.5 (d, J = 3.4 Hz).

[0307] 19 F NMR (565 MHz, CDCl3) δ -97.81.

[0308] HRMS (APCI) m / z: [M+H + calcd for C 24 H 25 FNO2 + 378.1864; found: 378.1844.

[0309] Based on the above data, the structure of the product is inferred as follows:

[0310]

[0311] Example 33

[0312] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 1-methoxy-4-(2-nitropropyl)benzene (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 100:1 mixture of petroleum ether and ethyl acetate.

[0313] The structural characterization data of the obtained product are as follows:

[0314] 1 H NMR (600 MHz, CDCl3) δ 7.99-7.96 (m, 1H), 7.93-7.88 (m, 3H), 7.60(dt, J = 8.5, 1.5 Hz, 1H), 7.58-7.54 (m, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.75(d, J = 8.7 Hz, 2H), 4.79 (dd, J = 18.2, 3.3 Hz, 1H), 4.70 (d, J = 23.4 Hz,1H), 4.55 (dd, J = 49.5, 3.3 Hz, 1H), 3.75 (s, 3H), 3.44 (d, J = 14.2 Hz,1H), 2.50 (d, J = 14.2 Hz, 1H), 1.69 (s, 3H).

[0315] 13 C NMR (151 MHz, CDCl3) δ 162.84 (d, J = 263.0 Hz), 159.01, 133.22,132.99, 131.95, 131.02, 129.82 (d, J = 2.6 Hz), 128.54, 128.08, 127.60,127.39 (d, J = 2.9 Hz), 126.71, 126.62, 125.53, 113.86, 95.61 (d, J = 20.0Hz), 95.11 (d, J = 2.4 Hz), 57.77 (d, J = 22.7 Hz), 55.10, 44.48, 17.72 (d, J = 3.4 Hz).

[0316] 19 F NMR (565 MHz, CDCl3) δ -97.85.

[0317] HRMS (APCI) m / z: [M+H + calcd for C 23 H 23 FNO3 + 380.1656; found: 380.1628.

[0318] Based on the above data, the structure of the product is inferred as follows:

[0319]

[0320] Example 34

[0321] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 1-nitro-4-(2-nitropropyl)benzene (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 3:1 mixture of petroleum ether and dichloromethane.

[0322] The structural characterization data of the obtained product are as follows:

[0323] 1 H NMR (600 MHz, CDCl3) δ 8.17-8.05 (m, 2H), 7.99-7.76 (m, 4H), 7.61-7.40 (m, 3H), 7.31-7.08 (m, 2H), 5.01-4.51 (m, 3H), 3.71 (dd, J = 156.7, 14.0Hz, 1H), 3.01 (dd, J = 389.6, 14.0 Hz, 1H), 1.62 (d, J = 101.5 Hz, 4H).

[0324] 13 C NMR (151 MHz, CDCl3) δ 162.3 (d, J = 263.1 Hz), 147.5, 141.3,133.2, 133.1, 131.4, 131.0, 129.8 (d, J = 2.7 Hz), 128.8, 128.1, 127.6, 126.9(d, J = 17.9 Hz), 126.6 (d, J = 20.2 Hz), 123.6, 96.2 (d, J = 19.7 Hz), 94.6(d, J = 2.8 Hz), 57.9 (d, J = 22.7 Hz), 44.4, 18.1 (d, J = 3.5 Hz).

[0325] 19 F NMR (565 MHz, CDCl3) δ -98.39.

[0326] HRMS (APCI) m / z: [M+H + calcd for C 22 H 20 FN2O4 + 395.1402; found: 395.1359.

[0327] Based on the above data, the structure of the product is inferred as follows:

[0328]

[0329] Example 35

[0330] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 2-(2-nitropropyl)benzo[b]thiophene (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a petroleum ether:dichloromethane mixture with a volume ratio of 3:1.

[0331] The structural characterization data of the obtained product are as follows:

[0332] 1 H NMR (600 MHz, CDCl3) δ 8.01-7.84 (m, 4H), 7.79-7.66 (m, 2H), 7.62-7.48 (m, 3H), 7.36-7.27 (m, 2H), 7.03 (d, J = 76.2 Hz, 1H), 4.98-4.57 (m,3H), 4.00 (dd, J = 151.6, 15.2 Hz, 1H), 3.25 (dd, J = 332.7, 15.2 Hz, 1H), 1.79 (d, J = 91.4 Hz, 3H).

[0333] 13 C NMR (151 MHz, CDCl3) δ 162.4 (d, J = 263.5 Hz), 139.9, 139.5,135.9, 133.2, 133.1, 131.5, 129.6 (d, J = 2.8 Hz), 128.7, 128.1, 127.6, 127.1(d, J = 3.0 Hz), 126.8, 126.7, 124.9, 124.3, 124.2, 123.3, 121.9, 96.1 (d, J= 19.9 Hz), 94.6 (d, J = 3.1 Hz), 58.0 (d, J = 22.7 Hz), 39.6, 18.9 (d, J = 3.2 Hz).

[0334] 19 F NMR (565 MHz, CDCl3) δ -98.35.

[0335] HRMS (APCI) m / z: [M+H + calcd for C 24 H 21 FNO2S + 406.1272; found: 406.1272.

[0336] Based on the above data, the structure of the product is inferred as follows:

[0337]

[0338] Example 36

[0339] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 1-methyl-3-(2-nitropropyl)-2-phenyl-1H-indole (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The eluent used for column chromatography was a 50:1 mixture of petroleum ether and ethyl acetate.

[0340] The structural characterization data of the obtained product are as follows:

[0341] 1 H NMR (600 MHz, CDCl3) δ 7.93-7.89 (m, 1H), 7.83 (td, J = 8.6, 8.1,6.1 Hz, 3H), 7.59 (qd, J = 7.2, 3.5 Hz, 2H), 7.47-7.42 (m, 1H), 7.34 (d, J =8.0 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.22 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.20-7.11 (m, 2H), 7.12-7.07 (m, 2H), 7.03 (s, 2H), 4.71-4.63 (m, 2H), 4.43(dd, J = 49.6, 3.2 Hz, 1H), 3.77 (d, J = 15.3 Hz, 1H), 3.49 (s, 3H), 3.02 (d,J = 15.3 Hz, 1H), 1.43 (s, 3H).

[0342] 13 C NMR (151 MHz, CDCl3) δ 162.8 (d, J = 263.0 Hz), 140.4, 136.6,133.1, 132.9, 132.2, 131.0, 130.3, 129.7 (d, J = 2.6 Hz), 128.3, 128.2,128.1, 128.0, 127.7, 127.5, 126.5, 126.4, 121.9, 119.9, 118.8, 109.3, 105.3,95.1 (d, J = 19.9 Hz), 94.9 (d, J = 2.3 Hz), 57.3 (d, J = 23.0 Hz), 34.8,30.7, 17.7 (d, J = 3.4 Hz).

[0343] 19 F NMR (565 MHz, CDCl3) δ δ -97.84.

[0344] HRMS (APCI) m / z: [M+H + calcd for C 31 H 28 FN2O2 + 479.2129; found:479.2129.

[0345] Based on the above data, the structure of the product is inferred as follows:

[0346]

[0347] Example 37

[0348] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), 1-(2-nitropropyl)ferrocene (0.30 mmol), Pd(dba)₂ (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 50:1 mixture of petroleum ether and ethyl acetate.

[0349] The structural characterization data of the obtained product are as follows:

[0350] 1H NMR (600 MHz, CDCl3) δ 7.96-7.90 (m, 4H), 7.60-7.55 (m, 3H), 4.75(dd, J = 18.1, 3.3 Hz, 1H), 4.56-4.46 (m, 2H), 4.07-4.05 (m, 1H), 4.04-4.02(m, 1H), 4.01 (s, 6H), 3.86-3.84 (m, 1H), 3.34 (d, J = 14.4 Hz, 1H), 2.36 (d,J = 14.4 Hz, 1H), 1.62 (s, 3H).

[0351] 13 C NMR (151 MHz, CDCl3) δ 162.8 (d, J = 263.3 Hz), 133.3, 132.9,132.0, 129.5 (d, J = 3.1 Hz), 128.5, 128.2, 127.6, 127.5 (d, J = 2.8 Hz),126.7, 126.6, 95.5 (d, J = 20.1 Hz), 95.2 (d, J = 2.4 Hz), 79.8, 70.3, 69.1,68.7, 68.0, 57.7 (d, J = 22.8 Hz), 40.6, 18.1 (d, J = 3.4 Hz).

[0352] 19 F NMR (565 MHz, CDCl3) δ -97.98.

[0353] HRMS (APCI) m / z: [M+H + calcd for C 26 H 24 FFeNNaO2 + 480.1033; found: 480.1030.

[0354] Based on the above data, the structure of the product is inferred as follows:

[0355]

[0356] Example 38

[0357] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-(2-nitropropyl)phenoxy)phenyl)propionate (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to a reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 5:1 mixture of petroleum ether and ethyl acetate.

[0358] The structural characterization data of the obtained product are as follows:

[0359] 1 H NMR (600 MHz, CDCl3) δ 8.02-7.75 (m, 4H), 7.62-7.42 (m, 3H), 7.13-6.80 (m, 8H), 5.05 (d, J = 6.0 Hz, 1H), 4.95-4.47 (m, 3H), 3.72 (d, J = 4.6Hz, 3H), 3.46 (d, J = 14.1 Hz, 1H), 3.13-2.96 (m, 2H), 2.53 (d, J = 14.1 Hz,1H), 1.92 (d, J = 152.9 Hz, 1H), 1.63 (d, J = 90.2 Hz, 3H), 1.43 (d, J = 3.7Hz, 9H).

[0360] 13C NMR (151 MHz, CDCl3) δ 172.2, 162.7 (d, J = 263.1 Hz), 156.7,155.8, 154.9, 133.2, 132.9, 131.8, 131.4, 131.3, 130.5, 129.8 (d, J = 2.6Hz), 128.5, 128.0, 127.6, 127.3 (d, J = 2.9 Hz), 126.7, 126.6, 119.0, 118.5,95.7 (d, J = 20.0 Hz), 94.9 (d, J = 2.4 Hz), 79.9, 60.3, 57.8 (d, J = 22.8Hz), 54.4, 52.1, 44.4, 37.6, 17.8 (d, J = 3.3 Hz).

[0361] 19 F NMR (565 MHz, CDCl3) δ -98.00.

[0362] HRMS (APCI) m / z: [M+H + calcd for C 37 H 40 FN2O7 + 643.2814; found: 643.2805.

[0363] Based on the above data, the structure of the product is inferred as follows:

[0364]

[0365] Example 39

[0366] 2-(2,2-difluorocyclopropyl)naphthalene (0.20 mmol), (2R)-2,5,7,8-tetramethyl-6-(4-(2-nitropropyl)phenoxy)-2-((4S,8S)-4,8,12-trimethyltetrazyl)chromium (0.30 mmol), Pd(dba)2 (5.0 mol%), BippyPhos (10 mol%), cesium hydroxide monohydrate (0.20 mmol), and 1,4-dioxane (1.5 mL) were added to the reaction tube. The reaction was carried out at 50 °C under nitrogen protection for 16 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product. The column chromatography eluent was a 100:1 mixture of petroleum ether and ethyl acetate.

[0367] The structural characterization data of the obtained product are as follows:

[0368] 1 H NMR (600 MHz, CDCl3) δ 7.97 (s, 1H), 7.93-7.88 (m, 3H), 7.60 (dt, J= 8.7, 1.3 Hz, 1H), 7.58-7.54 (m, 2H), 6.79 (d, J = 8.7 Hz, 2H), 6.60 (d, J =8.7 Hz, 2H), 4.79 (dd, J = 18.1, 3.3 Hz, 1H), 4.67 (d, J = 23.8 Hz, 1H), 4.55(dd, J = 49.5, 3.3 Hz, 1H), 3.44 (d, J = 14.2 Hz, 1H), 2.60 (t, J = 6.9 Hz,2H), 2.51 (d, J = 14.3 Hz, 1H), 2.12 (s, 3H), 1.97 (s, 3H), 1.94 (s, 3H),1.87-1.78 (m, 2H), 1.70 (s, 3H), 1.60-1.52 (m, 3H), 1.45 – 1.38 (m, 3H),1.34-1.25 (m, 12H), 1.19-1.14 (m, 3H), 1.10 (dtd, J = 12.8, 7.4, 2.8 Hz, 3H),0.89 (dd, J = 12.6, 6.5 Hz, 12H).

[0369] 13C NMR (151 MHz, CDCl3) δ 162.9 (d, J = 263.3 Hz), 158.3, 148.7,143.3, 133.2, 133.0, 132.0, 131.1, 129.8 (d, J = 2.6 Hz), 128.5, 128.1,128.0, 127.6, 127.4 (d, J = 2.8 Hz), 126.86-126.66 (m), 126.6, 126.2, 125.7,123.2, 117.8, 114.7, 95.6 (d, J = 19.9 Hz), 95.1 (d, J = 2.3 Hz), 74.9, 57.8(d, J = 22.7 Hz), 44.4, 39.3, 37.4, 37.3, 37.2, 32.7 (d, J = 3.2 Hz), 32.6(d, J = 3.0 Hz), 31.2 (d, J = 6.8 Hz), 27.9, 24.7 (d, J = 2.3 Hz), 24.4, 23.8 (d, J = 4.9 Hz), 22.7, 22.6, 21.0, 20.6, 19.7, 19.7, 19.6, 17.8 (d, J = 3.4Hz), 12.8, 11.9, 11.7.

[0370] 19 F NMR (565 MHz, CDCl3) δ -97.87.

[0371] HRMS (APCI) m / z: [M+H + calcd for C 51 H 69 FNO4 + 778.5205; found: 778.5198.

[0372] Based on the above data, the structure of the product is inferred as follows:

[0373]

Claims

1. A method for the selective fluoroallyl alkylation of difluorocyclopropane involving secondary nitroalkanes, characterized in that: Using gem-difluoropropane and secondary nitroalkanes as raw materials, a fluoroallyl-metal complex is generated by ring-opening of gem-difluorocyclopropane via transition metal catalysis. This complex then reacts with secondary nitroalkanes to yield branched fluoroallyl alkylated compounds.

2. The method for selective fluoroallyl alkylation of difluorocyclopropane with secondary nitroalkanes according to claim 1, characterized in that... This method conforms to the following reaction equation: The gem-difluorocyclopropane derivative is Secondary nitroalkanes are , where R 1 Represents a hydrogen atom or an alkyl, alkoxy, phenyl, nitrile, trifluoromethyl, ester, halogen, etc., containing one or more substituted groups; R 2 Represents a hydrogen atom or an alkyl or phenyl group containing one or more substituted atoms; R 3 It represents a hydrogen atom or an alkyl group.

3. The method for selective fluoroallyl alkylation of difluorocyclopropane with secondary nitroalkanes according to claim 2, characterized in that... The following steps were performed: In a reaction tube, geminal difluorocyclopropane derivatives, secondary nitroalkanes, transition metal catalysts, ligands, bases, and solvents were added. The reaction was carried out at 50 °C under a nitrogen atmosphere for 24 hours. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain branched fluoroallyl alkylated compounds.

4. The method for selective fluoroallyl alkylation of difluorocyclopropane with secondary nitroalkanes according to claim 3, characterized in that: The metal catalyst is one or a mixture of two or more of Ni(acac)2, NiCl2·DME, CuCl, Cu(OTf)2, Pd(dba)2, Pd(TFA)2, Pd(acac)2, Pd(dppf)Cl2, Pd2(dba)3, and PdCl2.

5. The method for selective fluoroallyl alkylation of difluorocyclopropane with secondary nitroalkanes according to claim 3, characterized in that: The ligands are 5-di-tert-butylphosphine-1',3',5'-triphenyl-1'H-1,4'-dipyrazole (BippyPhos), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (XantPhos), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), and 5-diisopropylphosphine-1',3',5'-triphenyl-1,4'-di-1H-pyrazole (…). i Pr-BippyPhos), 5-dicyclohexylphosphine-1',3',5'-triphenyl-1,4'-di-1H-pyrazole (Cy-BippyPhos), 5-(di(adamantane-1-yl)phosphine)-1',3',5'-triphenyl-1'H-1,4'-dipyrazole (Ad-BippyPhos), 1-[2-[bis(tert-butyl)phosphine]phenyl]-3,5-diphenyl-1H-pyrazole (TrippyPhos), (4R)-4-tert-butyl-2-[2-(diphenylphosphine)phenyl]-4,5-dihydrooxazole ( t One or more of the following (Bu-Phox) mixtures.

6. The method for selective fluoroallyl alkylation of difluorocyclopropane with secondary nitroalkanes according to claim 3, characterized in that: The alkali is one or a mixture of two or more of the following: cesium hydroxide monohydrate, cesium hydroxide, sodium hydroxide, sodium bicarbonate, potassium phosphate, cesium fluoride, potassium tert-butoxide, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

7. The method for selective fluoroallyl alkylation of difluorocyclopropane with secondary nitroalkanes according to claim 3, characterized in that: The solvent is one or a mixture of two or more of the following: 1,4-dioxane, 2-methyltetrahydrofuran, methyl tert-butyl ether, diethylene glycol dimethyl ether, trifluorotoluene, n-heptane, N,N-dimethylformamide, and dimethyl sulfoxide.

8. The method for selective fluoroallyl alkylation of difluorocyclopropane with secondary nitroalkanes according to claim 3, characterized in that: The molar ratio of the geminitrocyclopropane derivative to the secondary nitroalkane is 2:

3.

9. The method for selective fluoroallyl alkylation of difluorocyclopropane with secondary nitroalkanes according to claim 3, characterized in that: The reaction tube is a Schlenk tube.

10. The method for selective fluoroallyl alkylation of difluorocyclopropane with secondary nitroalkanes according to claim 3, characterized in that: The eluent in the column chromatography is a mixture of petroleum ether, petroleum ether and ethyl acetate in a volume ratio of (2-100):1, or a mixture of dichloromethane and methanol in a volume ratio of (2-100):1.

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