A method for synthesizing monofluoroolefin compounds

Abstract

The application discloses a synthesis method of monofluoro olefin compound and belongs to the technical field of organic synthesis. 3 )‑F bond and C(sp 2 )‑F bond are broken to obtain a trisubstituted (E) monofluoro olefin compound 3; when the olefin substrate is gem-di-fluoro olefin 4, a di / trisubstituted (E) monofluoro olefin compound 5 is also obtained at a high yield and excellent stereoselectivity. The synthesis method has the advantages of cheap catalyst, simple and easily-obtained raw materials and good substrate applicability, and the synthesized product is a very valuable fluorinated component, and a new method is provided for modification of fluorine-containing molecules.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing di / tri-substituted (E)-monofluoro olefin compounds, and belongs to the technical field of organic synthesis. BACKGROUND

[0002] Fluorine-containing organic molecules have unique biological and chemical properties, and have wide applications in the development of new materials, drugs and agrochemicals. Although many organofluorine compounds have been synthesized, the stability of C-F bond brings challenges to its degradation. Efficient defluorination and functionalization of existing fluorine chemicals is an attractive way to recycle organofluorine compounds. However, due to the high dissociation energy of C-F bond, exploring methods to activate these bonds, especially achieving high stereoselective C-F bond cleavage in one-step reaction, is still an active research field.

[0003] Fluorine-substituted olefins not only play a key role in the synthesis of high-value organofluorine compounds, but also play an important role in various applications related to drug research and development. Scientists have made significant progress in activating the C-F bond in fluorinated olefins to form C-C, C-O or C-N bonds. However, due to the small size of hydrogen atoms, it is very challenging to achieve precise stereoselectivity in the hydrogenation defluorination (HDF) reaction of fluorinated olefins. The stereoselective hydrogenation defluorination (HDF) of fluorinated olefins has attracted considerable attention, especially in the generation of monofluoro olefins.

[0004] Monofluoro olefins are an important class of fluorinated olefins, similar to amide groups, which are often found in active compounds. Their Z and E isomers exhibit different biological activities and have potential application prospects in medicinal chemistry and materials science. In addition, monofluoro olefins are also very valuable fluorinated building blocks in the synthesis of organofluorine compounds. Therefore, it is necessary to explore a simpler, more practical and economically feasible hydrogenation defluorination (HDF) reaction with high stereoselectivity. SUMMARY

[0005] In order to overcome the above technical defects, hydrogenation defluorination (HDF) reaction using silanes is a promising method to replace C-F bond with C-H bond. The present application provides a method for synthesizing monofluoro olefin compounds by high stereoselective hydrogenation defluorination of fluorinated olefins and polyfluorinated arenes catalyzed by zinc. The reaction is achieved by the addition of hydride ion in silane. Trifluoromethyl-substituted olefin 1 and silane 2 are heated in dimethyl sulfoxide solvent with zinc acetate as catalyst in the presence of different ligands to achieve C(sp 3 )-F bond and C(sp 2) F bond cleavage to give tri-substituted (E)-monofluoro olefin compound 3; when the olefin substrate is gem-difluoro olefin 4, di- / tri-substituted (E)-monofluoro olefin compound 5 is also obtained in high yield and excellent stereoselectivity. The synthetic method has a cheap catalyst, simple and readily available raw materials, good substrate applicability, and the synthesized product is a very valuable fluorinated component, providing a new method for the modification of fluorine-containing molecules.

[0006] The method for synthesizing monofluoro olefin compounds described in the present application comprises the following steps:

[0007] Method A, tri-fluoromethyl substituted olefin 1 and silane 2 are heated in an organic solvent in the presence of a ligand and zinc acetate as a catalyst to give tri-substituted (E)-monofluoro olefin compound 3; the reaction equation is represented as:

[0008]

[0009] wherein: R is selected from H or cyclopropane; Ar is selected from substituted or unsubstituted phenyl, naphthyl, heteroaryl, substituted or unsubstituted biaryl; silane 2 is selected from diphenyl silane or phenyl silane;

[0010] Method B, gem-difluoro olefin 4 and diphenyl silane 2a are heated in an organic solvent in the presence of a ligand and zinc acetate as a catalyst to give di- / tri-substituted (E)-monofluoro olefin compound 5; the reaction equation is represented as:

[0011]

[0012] wherein: R 1 is selected from hydrogen, methyl, propyl, phenyl, ethyl formate; Ar 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted heteroaryl, substituted or unsubstituted biaryl.

[0013] Further, in the above technical solution, the substituent in the substituted or unsubstituted phenyl group refers to one or more, same or different substituents at any position of the phenyl group, which are halogen, methyl, trifluoromethoxy, tert-butyl formate, diphenylamine, methoxy, tert-butyl, phenyl, phenoxy, methyl formate, neopentyl; the substituent in the substituted or unsubstituted naphthyl group refers to one or more, same or different substituents at any position of the naphthyl group, which are methoxy, benzyloxy, allyloxy; the heteroaryl group is selected from quinolinyl, indolyl, benzofuranyl, benzothiophenyl; the substituted heteroaryl group is selected from phenyl-substituted thiophenyl, chlorobenzene-substituted thiophenyl, fluorobenzene-substituted furanyl; the substituent in the substituted or unsubstituted biaryl group refers to one or more, same or different substituents at any position of the phenyl group, which are methyl, methoxy, methyl formate, halogen, trifluoromethyl.

[0014] Further, in the above technical solution, the organic solvent is selected from DMSO, DMF, DCE, THF, dimethylacetamide, ethylene glycol dimethyl ether, toluene, methanol, tert-butyl methyl ether or 1,4-dioxane.

[0015] Further, in the above technical solution, the ligand is a compound shown in the following structure:

[0016]

[0017] Further, in the above technical solution, in method A, the ligand is selected from Xanphos; in method B, the ligand is selected from PPh3.

[0018] Further, in the above technical solution, the molar ratio of the compound 1 to the compound 2 is 1:3; the molar ratio of the compound 4 to the compound 2a is 1:1-2; the molar ratio of the compound 1 or 4, zinc acetate to the ligand is 1:0.1-0.2:0.1-0.2.

[0019] Further, in the above technical solution, the heating reaction temperature is 50-130°C.

[0020] Further, in the above technical solution, the reaction is carried out under inert gas protection.

[0021] The application also provides a method for synthesizing a tetrafluoro aryl compound 7, which comprises the following steps: polyfluoro aromatic hydrocarbon 6 and diphenylsilane 2a are reacted in DMSO solvent, zinc acetate is used as a catalyst, triphenylphosphine is used as a ligand, and a hydrogenation defluorination compound 7 is obtained by heating reaction; the reaction equation is represented as:

[0022]

[0023] wherein: R2 selected from trifluoromethyl or pentafluorophenyl.

[0024] Further, in the above technical solution, the molar ratio of compound 6 to compound 2a is 1:1; the molar ratio of compound 6, zinc acetate and triphenylphosphine is 1:0.1:0.1; the heating reaction temperature is 50-60℃; and the reaction is carried out under inert gas protection.

[0025] Advantages of the application:

[0026] A. The catalyst of the application is cheap and easy to obtain, has good functional group compatibility, and can be used in a wide range of substrates to synthesize a variety of disubstituted or trisubstituted (E)-monofluoroalkenes with high application value with high yield and excellent stereoselectivity.

[0027] B. The method of the application can also be applied to the hydrogenation defluorination reaction of polyfluoroarenes. The method provides an attractive approach for C-F bond degradation and recovery of organic fluorides, and also provides a new method for modification of fluorine-containing molecules. DETAILED DESCRIPTION

[0028] The application will be further described below in conjunction with specific examples, but the examples do not limit the application in any form.

[0029] General synthetic method A for hydrogenation defluorination (HDF) reaction of trifluoromethyl-substituted olefins

[0030] Under an argon atmosphere, Zn(OAc)2(3.7 mg, 0.02 mmol), Xantphos (11.6 mg, 0.02 mmol) and DMSO (2.0 mL) were added to a 25 mL pressure tube, and the reaction solution was stirred at room temperature for 30 minutes. Then Ph2SiH2(110.6 mg, 0.6 mmol) and trifluoromethyl olefin 1 (0.2 mmol) were sequentially added to the above reaction solution. After the addition was completed, the reaction tube was sealed and placed in an oil bath at a temperature of 120℃ and stirred for 24 hours. After the reaction was completed, the reaction solution was quenched with water (2.0 mL) and extracted with dichloromethane. The obtained organic layer was dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain a crude product. Finally, monofluoroalkene product 3a-3p was obtained by column chromatography purification.

[0031] Example 1 condition optimization experiment

[0032]

[0033] In an argon atmosphere, a 25 mL pressure tube was charged with catalyst cat. (10 mmol%), ligand L (10 mmol%) and solvent (2.0 mL), the reaction solution was stirred at room temperature for 30 minutes, then silane 2 (0.6 mmol) and trifluoromethyl olefin 1a (0.2 mmol) were added successively to the above reaction solution, after addition, the reaction tube was sealed and placed in a T ℃ oil bath and stirred for 24 hours. After the reaction was completed, the reaction solution was quenched with water (2.0 mL) and extracted with dichloromethane, the obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain the crude product, which was finally purified by silica gel column chromatography to obtain compounds 3a and 3a'. The results are shown in the following table:

[0034]

[0035] a Reaction conditions: 1a (0.20 mmol), 2 (0.60 mmol), catalyst cat. (10 mmol%), ligand L (10 mmol%), solvent (2.0 mL), reaction under argon protection for 24 hours, yield and E / Z ratio were determined by GC-MS with trifluoromethylbenzene (0.1 mmol) as internal standard. 19 F NMR determination. b 2a (0.40 mmol). c 2a (0.80 mmol). d 2a (0.20 mmol). e CsOAc (0.02 mmol) was added.

[0036] Through the investigation of reaction temperature (entries 1-5), it was determined that the optimal reaction temperature was 120 ℃; the selection of ligand had a significant effect on the efficiency of target product generation (entries 6-10), and through screening it was determined that the optimal ligand was Xanphos; through the investigation of catalyst, it was found that Zn(OAc)2 had the highest catalytic efficiency (entries 11-19); through the investigation of solvent, it was determined that the optimal reaction solvent was DMSO (entries 20-23); compared with Ph2SiH2, other silane substrates such as (MeO)2MeSiH and PhSiH3 all showed lower reactivity (entries 24-26).

[0037] Example 2

[0038]

[0039] Except for the reaction conditions specially marked or explained, the following product preparation methods refer to the general synthesis method A.

[0040]

[0041] a Reaction conditions: 1 (0.20 mmol), Ph2SiH2(0.60 mmol), Zn(OAc)2(0.02 mmol), Xantphos (0.02 mmol), DMSO (2.0 mL), 120 °C, under argon for 24 h, isolated yield and E / Z ratio by1H NMR determination. 19 F NMR determination. b NMR yield. c Reaction conditions: PhSiH3(0.60 mmol), Zn(OAc)2(0.04 mmol), Xantphos (0.04 mmol), NaOAc (1.0 eq.), NMR yield, 130 °C. d Reaction conditions: PhSiH3(0.60 mmol), NaOAc (1.0 eq.), NMR yield, 120 °C,1pE / Z ratio is 74 / 26.

[0042] Lower reactivity efficiency was observed when the aryl para-position was an electron-donating group (3f and 3g), which indicates a unique reaction pathway involving hydride addition in the reaction process.

[0043] Example 3

[0044]

[0045] General synthetic method A, purified by silica gel column chromatography (PE). Colorless oil; 32.4 mg (yield 87%, E / Z = 85 / 15); 1 H NMR (400 MHz, CDC13) δ (E isomer) 7.85-7.79 (m, 3H), 7.74 (s, 1H), 7.49-7.44 (m, 3H), 7.06 (dq, J = 84.8, 1.6 Hz, 1H), 2.16 (dd, J = 3.8, 1.6 Hz, 3H). HRMS (ESI, m / z): calcd for C 13 H 12 F + [M+H] + : 187.0918, found 187.0946.

[0046] Example 4

[0047]

[0048] In an argon atmosphere, a 25 mL pressure tube was charged with Zn(OAc)2(7.3 mg, 0.04 mmol), Xantphos (23.1 mg, 0.04 mmol), NaOAc (16.4 mg, 0.2 mmol) and DMSO (2.0 mL), the reaction was stirred at room temperature for 30 min, then the above reaction was charged with PhSiH3(64.9 mg, 0.6 mmol) and trifluoromethyl olefin 1f (0.2 mmol) successively, the reaction tube was sealed and placed in a 130 °C oil bath and stirred for 24 h. After the reaction was completed, the reaction was quenched with water (2.0 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE:DCM = 8:1) to obtain compound 3f. Colorless oil; yield 56% by NMR, E / Z = 83 / 17; 1 HNMR (400 MHz, CDC13) δ (E isomer) 7.25-7.21 (m, 2H), 6.89-6.85 (m, 2H), 6.85 (dq, J = 86.0, 1.6 Hz, 1H), 3.81 (s, 3H), 2.01 (dd, J = 3.8, 1.6 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ (E isomer) 159.2, 145.3 (d, J = 256.4 Hz), 130.1 (d, J = 8.7 Hz), 127.1 (d, J = 3.0 Hz), 119.6 (d, J = 9.6 Hz), 114.1, 55.4, 12.5 (d, J = 5.8 Hz). 19 F NMR (376 MHz, CDC13) (mixture of isomers) δ (Z isomer) -130.31 (dq, J = 84.6, 4.8 Hz); (E isomer) -133.01 (dq, J = 86.0, 3.8 Hz). HRMS (ESI, m / z): calcd for C 10 H 12 FO + [M+H] + : 167.0867, found 167.0876.

[0049] Example 5

[0050]

[0051] General synthetic method A, purified by silica gel column chromatography (PE:EA = 10:1). Colorless oil; 17.2 mg (yield 46%, E / Z = 75 / 25); 1H NMR (400 MHz, CDC13) δ (E isomer) 8.90 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.57 - 7.53 (m, 1H), 7.09 (dq, J = 83.6, 1.6 Hz, 1H), 2.16 (dd, J = 3.8, 1.6 Hz, 3H). 13 CNMR (101 MHz, CDC13) δ (E isomer) 148.5 (d, J = 2.2 Hz), 147.5, 147.1 (d, J = 261.0 Hz), 132.3 (d, J = 4.5 Hz), 130.6 (d, J = 9.0 Hz), 129.5, 129.3, 128.0, 127.9, 127.2, 117.7 (d, J = 11.0 Hz), 12.2 (d, J = 5.8 Hz). 19 F NMR (376 MHz, CDC13) δ (E isomer) -127.07 (dq, J = 83.6, 3.8 Hz). HRMS (ESI, m / z): calcd for C 12 H 11 NF + [M+H] + : 188.0870, found 188.0871.

[0052] Example 6

[0053]

[0054] General synthesis method A, purified by column chromatography on silica gel (PE). White solid (m.p. 71-72 °C); 20.8 mg (yield 54%, E / Z = 66 / 34); 1 H NMR (400 MHz, CDC13) δ (E isomer) 7.76 - 7.68 (m, 2H), 7.35 - 7.08 (m, 3H), 7.20 (s, 1H), 2.14 (dd, J = 3.6, 1.6 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ (E isomer) 147.1 (d, J = 262.9 Hz), 140.3 (d, J = 8.6 Hz), 139.9, 138.3, 124.7, 124.6, 123.3, 122.2, 120.8 (d, J = 8.0 Hz), 115.9 (d, J = 13.8 Hz), 12.1 (d, J = 5.4 Hz). 19F NMR (376 MHz, CDCb) d (E isomer) -129.18 (dq, J = 83.6, 3.6 Hz). HRMS (ESI, m / z): calcd for C 11 H 10 FS + [M+H] + :193.0482, found 193.0483.

[0055] Example 7

[0056]

[0057] Into a 25 mL pressure tube was added Zn(OAc)2(3.7 mg, 0.02 mmol), Xantphos (11.6 mg, 0.02 mmol), NaOAc (16.4 mg, 0.2 mmol) and DMSO (2.0 mL) under argon atmosphere. The reaction was stirred at room temperature for 30 min, then PhSiH3(64.9 mg, 0.6 mmol) and trifluoromethyl olefin 1p (0.2 mmol) were added successively to the above reaction. After the addition, the reaction tube was sealed and placed in a 120 °C oil bath with stirring for 24 h. After the reaction was completed, the reaction was quenched with water (2.0 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE) to give compound 3p. Colorless oil; yield 33%, E / Z = 77 / 23; 1 H NMR (400 MHz, CDCb) d (Z isomer) 7.43-7.41 (m, 2H), 7.38-7.34 (m, 2H), 7.29-7.27 (m, 1H), 6.70 (dt, J = 84.8, 1.6 Hz, 1H), 2.21-2.18 (m, 2H), 0.82-0.73 (m, 1H), 0.47-0.43 (m, 2H), 0.08 (dt, J = 6.0, 4.5 Hz, 2H). 13 C NMR (151 MHz, CDCb) d (Z isomer) 144.3 (d, J = 259.7 Hz), 135.5, 128.1, 128.1, 127.2, 122., 35.5 (d, J = 6.3 Hz), 9.4, 4.5. 19 F NMR (376 MHz, CDCb) d (Z isomer) -133.26 (dt, J = 84.8, 4.2 Hz). HRMS (ESI, m / z): calcd for C 12 H 17 NF +[M + NH4] + : 194.1340, found 194.1348.

[0058] General synthetic procedure B for hydrodefluorination (HDF) reaction of gem-difluoro olefins

[0059] Into a 25 mL pressure tube was added Zn(OAc)2(3.7 mg, 0.02 mmol), PPh3(5.3 mg, 0.02 mmol) and DMSO (2.0 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 30 min, then the gem-difluoro olefin 4 (0.2 mmol) was added. After the addition was completed, the reaction tube was sealed and placed in an oil bath at 50 °C and stirred for 24 h. After the reaction was completed, the reaction mixture was quenched with water (2.0 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography to give the monofluoro olefin 3a, 3m and 5a-5z.

[0060] Example 8

[0061] Condition optimization experiment

[0062]

[0063] Into a 25 mL pressure tube was added catalyst cat. (10 mmol%), ligand L (10 mmol%) and solvent (2.0 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 30 min, then the silane 2 (0.4 mmol) and the gem-difluoro olefin 4a (0.2 mmol) were added. After the addition was completed, the reaction tube was sealed and placed in an oil bath at T °C and stirred for 24 h. After the reaction was completed, the reaction mixture was quenched with water (2.0 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography to give compound 5a.

[0064] The results are shown in the following table:

[0065]

[0066] a Reaction condition: 4a (0.20 mmol), 2 (0.40 mmol), catalyst cat. (10 mmol%), ligand L (10 mmol%), solvent (2.0 mL), under argon atmosphere for 24 h, the yield was determined by1H NMR with trifluoromethylbenzene (0.1 mmol) as internal standard. 1 The E / Z ratio was determined by1H NMR. b 2a (0.20 mmol).c 2a (0.20 mmol), Zn(OAc)2(5 mmol %). d under air.

[0067] Through a series of condition screening, the monofluoro olefin compound 5a (entry 17) was successfully synthesized in 84% yield and 95 / 5 E / Z ratio under Zn(OAc)2 / PPh3 catalytic system.

[0068] Example 9

[0069]

[0070] The following product preparation methods refer to General Synthetic Method B, unless otherwise noted or specified reaction conditions.

[0071]

[0072] a Reaction conditions: 1 (0.20 mmol), Ph2SiH2(0.20 mmol), Zn(OAc)2(0.02 mmol), PPh3(0.02 mmol), DMSO (2.0 mL), 50 °C, under argon protection for 24 h, isolation yield and E / Z ratio were determined by GC. 1 determined by1H NMR. b Ph2SiH2(0.40 mmol), 100 °C.

[0073] Example 10

[0074]

[0075] General Synthetic Method B, purified by silica gel column chromatography (PE). White solid (m.p. 67-68 °C); 28.9 mg (84% yield, E / Z = 95 / 5); 1 H NMR (400 MHz, CDC13) (mixture of isomers) δ (E isomer) 7.82-7.77 (m, 3H), 7.65 (s, 1H), 7.49-7.20 (m, 4H), 6.56 (dd, J = 19.6, 11.2 Hz, 1H); (Z isomer) 6.74 (dd, J = 82.8, 5.6 Hz, 1H), 5.78 (dd, J = 44.8, 5.6 Hz, 1H). 13C NMR (101 MHz, CDC13) (mixture of isomers) δ 150.6 (d, J = 259.3 Hz), 133.7, 132.9, 130.3 (d, J = 11.8 Hz), 128.6, 127.9, 126.6, 126.1, 125.9 (d, J = 5.0 Hz), 123.5, 114.3 (d, J = 16.3 Hz). 19 F NMR (376 MHz, CDC13) (mixture of isomers) δ (Z isomer) -121.74 (dd, J = 82.8, 44.8 Hz); (E isomer) -129.39 (dd, J = 83.2, 19.6 Hz). HRMS (ESI, m / z): calcd for C 12 H 10 F + [M+H] + : 173.0761, found 173.0756.

[0076] Example 11

[0077]

[0078] General synthesis method B, purified by column chromatography on silica gel (PE). White solid (m.p. 100-101 °C); 33.7 mg (yield 85%, E / Z = 95 / 5); 1 H NMR (600 MHz, CDC13) (mixture of isomers) δ (E isomer) 7.61-7.56 (m, 4H), 7.47-7.45 (m, 2H), 7.38-7.16 (m, 4H), 6.45 (dd, J = 19.2, 11.4 Hz, 1H); (Z isomer) 6.70 (dd, J = 82.8, 5.4 Hz, 1H), 5.68 (dd, J = 45.0, 5.4 Hz, 1H). 13 C NMR (151 MHz, CDC13) (mixture of isomers) δ 150.3 (d, J = 259.5 Hz), 140.7, 140.4 (d, J = 2.2 Hz), 131.8 (d, J = 12.0 Hz), 129.0, 127.6, 127.5, 127.0, 126.7 (d, J = 3.2 Hz), 113.7 (d, J = 16.1 Hz). 19F NMR (376 MHz, CDCb) (mixture of isomers) δ (Z isomer) -120.58 (dd, J = 82.6, 43.8 Hz); (E isomer) -127.48 (dd, J = 82.8, 18.9 Hz). HRMS (ESI, m / z): calcd for C 14 H 15 FN + [M+NH4] + :216.1183,found 216.1178.

[0079] Example 12

[0080]

[0081] General synthesis method B, purified by column chromatography on silica gel (PE:EA = 5: 1). White solid (m.p. 72-73 °C); 32.9 mg (yield 95%, E / Z = 95 / 5); 1 H NMR (600 MHz, CDCb) δ (E isomer) 8.86 (s, 1H), 8.09-8.02 (m, 2H), 7.63-7.23 (m, 4H), 6.55 (dd, J = 19.2, 11.4 Hz, 1H). 13 C NMR (151 MHz, CDCb) δ (E isomer) 151.2 (d, J = 252.0 Hz), 150.3, 147.9, 135.9, 131.2 (d, J = 12.1 Hz), 130.1, 128.6, 127.2, 125.4 (d, J = 4.5 Hz), 121.8, 113.7 (d, J = 16.5 Hz). 19 F NMR (376 MHz, CDCb) (mixture of isomers) δ (Z isomer) -120.58 (dd, J = 82.6, 43.8 Hz); (E isomer) -127.48 (dd, J = 82.8, 18.9 Hz). HRMS (ESI, m / z): calcd for C 11 H9FN + [M+H] + :174.0714,found174.0711.

[0082] Example 13

[0083]

[0084] General synthetic method B, purified by column chromatography on silica gel (PE). White solid (m.p. 65-66 °C); 40.1 mg (yield 98%, E / Z = 89 / 11); 1 H NMR (400 MHz, CDC13) (mixture of isomers) δ (E isomer) 7.55-7.53 (m, 2H), 7.37-7.33 (m, 2H), 7.28-6.86 (m, 4H), 6.50 (dd, J = 17.6, 11.2 Hz, 1H); (Z isomer) 5.93 (dd, J = 43.2, 5.2 Hz, 1H). 13 C NMR (101 MHz, CDC13) (mixture of isomers) δ 149.8 (d, J = 262.0 Hz), 142.8 (d, J = 3.4 Hz), 134.4 (d, J = 11.6 Hz), 134.1, 129.1 (d, J = 1.8 Hz), 127.8, 127.2 (d, J = 6.6 Hz), 125.8, 123.4, 108.5 (d, J = 20.3 Hz). 19 F NMR (376 MHz, CDC13) (mixture of isomers) δ (Z isomer) -120.38 (dd, J = 81.8, 43.2 Hz); (E isomer) -129.04 (dd, J = 82.2, 17.6 Hz). HRMS (ESI, m / z): calcd for C 12 H 10 FS + [M+H] + : 205.0482, found 205.0479.

[0085] Example 14

[0086]

[0087] General synthetic method B, purified by column chromatography on silica gel (PE). Colorless oil; 15.9 mg (yield 41%, E / Z = 73 / 27); 1 H NMR (400 MHz, CDC13) (mixture of isomers) δ (E isomer) 7.74 (d, J = 80.8 Hz, 1H), 7.41-7.33 (m, 5H), 4.27 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); (Z isomer) 6.99 (d, J = 79.6 Hz, 1H). 13C NMR (101MHz, CDCl3) (mixture of isomers) δ166.1 (d, J = 16.4Hz), 158.0 (d, J = 282.0Hz), 130.0 (d, J = 2.8Hz), 128.4, 128.2, 119.8 (d, J = 7.3Hz), 61.3, 14.3. 19 F NMR(376MHz, CDCl3)(mixture of isomers)δ(Zisomer)-110.62(d,J=79.6Hz); (E isomer)-114.70(d,J=80.8Hz).HRMS(ESI,m / z):calcd for C 11 H 12 FO2 + [M+H] + :195.0816,found 195.0817.

[0088] General Synthetic Method C for Dehydrofluorination (HDF) of Polyfluoroaromatics

[0089] Under an argon atmosphere, Zn(OAc)₂ (3.7 mg, 0.02 mmol), PPh₃ (5.3 mg, 0.02 mmol), and DMSO (2.0 mL) were added to a 25 mL pressure-resistant tube. The reaction solution was stirred at room temperature for 30 minutes. Then, Ph₂SiH₂ (36.8 mg, 0.2 mmol) and polyfluoroalkyl substances (PAS) 6 (0.2 mmol) were added sequentially to the above reaction solution. After the addition was complete, the reaction tube was sealed and placed in an oil bath at 50 °C with stirring for 24 hours. After the reaction was completed, the reaction solution was quenched with water (2.0 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain the crude product. Finally, the crude product was purified by silica gel column chromatography to obtain compounds 7a and 7b.

[0090] Example 15

[0091]

[0092] General synthetic method C. After the reaction is complete, 0.1 mmol of trifluoromethylbenzene is added as an internal standard to a sealed tube to obtain crude... 19 F NMR yield 76%. 19 F NMR(376MHz, DMSO-d6)δ-55.05--55.19(m,3F),-136.29-136.43(m,2F),-141.15--141.32(m,2F).HRMS(ESI,m / z):calcd for C7HF7Na + [M+Na] +:240.9859, found 240.9870.

[0093] Example 16

[0094]

[0095] General synthesis method C, purified by silica gel column chromatography (PE). White solid (m.p. 75-76 °C); 41.7 mg (yield 66%); 1 H NMR (400 MHz, CDC13) δ 7.35 - 7.27 (m, 1H). 19 F NMR (376 MHz, CDC13) δ -137.38 - -137.49 (m, 4F), -138.16 - -138.28 (m, 2F), -149.92 - -150.34 (m, 1F), -160.47 - -160.60 (m, 2F). HRMS (ESI, m / z): calcd for C 12 HF9K + [M+K] + :354.9566, found 354.9571.

[0096] Example 17 - scale up

[0097]

[0098] Under argon atmosphere, a 100 mL pressure tube was charged with Zn(OAc)2(36.7 mg, 0.2 mmol), Xantphos (115.7 mg, 0.2 mmol) and DMSO (20.0 mL), the reaction was stirred at room temperature for 30 min, then Ph2SiH2(1105.9 mg, 6 mmol) and trifluoromethyl olefin 1m (496.2 mg, 2 mmol) were added successively into the above reaction, after addition, the reaction tube was sealed and placed in a 120 °C oil bath and stirred for 24 h. After the reaction was completed, the reaction was quenched by water (20 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain the crude product, which was finally purified by silica gel column chromatography (PE) to obtain monofluoro olefin product 3m (313.8 mg, yield 74%, E / Z = 87 / 13). 1H NMR (400 MHz, CDC13) (mixture of isomers) δ 7.63 - 7.53 (m, 4H), 7.46-7.44 (m, 2H), 7.41-7.30 (m, 3H), 6.98 (dq, J = 84.9, 1.5 Hz, 1H), 2.09 (dd, J = 3.8, 1.5 Hz, 3H); (Z isomer) 6.71 (dq, J = 84.5, 1.8 Hz, 1H), 1.96 (dd, J = 4.9, 1.6 Hz, 3H). 13 C NMR (101 MHz, CDC13) (mixture of isomers) δ 146.2 (d, J = 258.6 Hz), 140.8, 140.4, 136.7 (d, J = 8.8 Hz), 129.0, 127.5, 127.4, 127.1, 126.4 (d, J = 3.0 Hz), 119.8 (d, J = 10.1 Hz), 12.3 (d, J = 5.9 Hz). 19 F NMR (376 MHz, CDC13) (mixture of isomers) δ (Z isomer) -128.05 - -128.32 (m); (E isomer) -130.75 - -131.01 (m).

[0099] Example 18 - Derivatization reaction

[0100]

[0101] Under argon atmosphere, monofluoro olefin compound 5a (34.4 mg, 0.2 mmol), NiCl2(dppe) (4.2 mg, 0.008 mmol) and 0.4 mL dry THF were added into 25 mL pressure tube and mixed well. Then Grignard reagent THF solution (0.8 mmol) was added dropwise into above reaction solution, after addition, the reaction solution was stirred at room temperature for 2 hours. After reaction was completed, saturated aqueous ammonium chloride solution (2.0 mL) was added for quenching, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain the crude product, which was finally purified by silica gel column chromatography (PE) to obtain compound 8 (40.1 mg, yield 87%). 1 H NMR (400 MHz, CDC13) δ 7.85-7.80 (m, 4H), 7.75-7.73 (m, 1H), 7.57-7.55 (m, 2H), 7.49-7.42 (m, 2H), 7.39-7.37 (m, 2H), 7.30-7.20 (m, 3H). 13C NMR (101 MHz, CDC13) δ 137.5, 135.0, 133.9, 133.2, 129.2, 128.9, 128.9, 128.5, 128.2, 127.8, 127.8, 126.8, 126.7, 126.5, 126.0, 123.7. HRMS (ESI, m / z): calcd for C 18 H 15 + [M+H] + : 231.1168, found 231.1169.

[0102] Example 19 - Derivatization reaction

[0103]

[0104] Pd(OAc)2(2.3 mg, 0.01 mmol), Neocuproine (3.1 mg, 0.015 mmol), N- fluorobenzensulfonamide (158 mg, 0.5 mmol) and 1,4-dioxane (1.0 mL) were added into a 25 mL pressure tube under argon atmosphere and mixed well, then the monofluoroalkene compound 5a (34.4 mg, 0.2 mmol) was added, after addition, the reaction tube was sealed and placed in a 50 °C oil bath for stirring for 20 hours. After the reaction was completed, the diatomite was filtered and washed with ethyl acetate, the obtained filtrate was purified by silica gel column chromatography (PE:EA = 5:1) after removing the organic solvent under reduced pressure to obtain compound 9 (60.4 mg, yield 62%). 1 H NMR (400 MHz, CDC13) δ 7.89-6.87 (m, 18H), 5.93 (dt, J = 10.4, 8.0 Hz, 1H). 13 C NMR (101 MHz, CDC13) δ 139.6, 133.9, 133.2, 132.8, 128.9, 128.8, 128.6, 128.5, 127.6, 127.3, 126.8, 126.4, 114.5 (dd, J = 246.8, 241.8 Hz), 64.0 (dd, J = 35.9, 23.4 Hz). 19 F NMR (376 MHz, CDC13) δ -116.40 (ddd, J = 293.0, 57.1, 10.2 Hz, 1F), -124.87 (ddd, J = 293.0, 56.4, 8.3 Hz, 1F). HRMS (ESI, m / z): calcd for C 24 H 20 F2NO4S2 + [M+H] +:488.0796, found 488.0773.

[0105] Example 20 - Derivatization reaction

[0106]

[0107] To a 25 mL pressure tube was added Zn(OAc)2(3.7 mg, 0.02 mmol), PPh3(5.3 mg, 0.02 mmol) and DMSO (2.0 mL) under argon atmosphere. The reaction was stirred at room temperature for 30 min, then Ph2SiH2(73.6 mg, 0.4 mmol) and the gem-difluoro olefin 10 (135.7 mg, 0.2 mmol) were added successively to the above reaction. After the addition, the reaction tube was sealed and placed in an oil bath at 100 °C and stirred for 24 h. After the reaction was completed, the reaction was quenched with water (2.0 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and the organic solvent was removed under reduced pressure to give the crude product. Finally, the monofluoro olefin product 11 (46.2 mg, 35% yield, E / Z = 90 / 10) was purified by silica gel column chromatography (PE:EA = 10:1).

[0108] Gem-difluoro olefin 10, 1 H NMR (400 MHz, CDC13) δ 7.38 - 7.20 (m, 22H), 7.06 - 7.04 (m, 2H), 5.51 (d, J = 7.9 Hz, 1H), 5.20 (dd, J = 26.4, 3.8 Hz, 1H), 4.95 - 4.29 (m, 8H), 4.22 (m, 1H), 4.17 (t, J = 2.6 Hz, 1H), 3.85 - 3.63 (m, 2H), 3.54 (m, 2H). 13 C NMR (101 MHz, CDC13) δ 156.6 (t, J = 2.3 Hz), 156.0 (dd, J = 297.1, 286.9 Hz), 139.0, 138.6, 138.4, 137.9, 128.8 (dd, J = 6.2, 3.4 Hz), 128.5, 128.5, 128.4, 128.3, 128.1, 127.9, 127.9, 127.8, 127.8, 127.8, 127.6, 127.6, 124.4 (t, J = 6.3 Hz), 117.2, 99.3, 81.7 (dd, J = 29.3, 14.2 Hz), 78.8, 75.6, 74.8, 74.7, 73.6, 73.2, 72.9, 71.7, 69.2. 19F NMR (376 MHz, CDC13) δ -84.07 (dd, J = 35.4, 26.2 Hz, IF), -85.86 (dd, J = 36.0, 4.1 Hz, IF). HRMS (ESI, m / z): calcd for C 42 H 41 F2O6 + [M+H] + :679.2866, found 679.2857.

[0109] monofluoro product 11, 1 H NMR (400 MHz, CDC13) (mixture of isomers) δ (E isomer) 7.38 - 7.20 (m, 20H), 7.19 - 6.96 (m, 5H), 6.35 (dd, J = 19.2, 11.2 Hz, IH), 5.49 (d, J = 7.9 Hz, IH), 4.94 - 4.36 (m, 8H), 4.22 (m, IH), 4.18 (t, J = 2.6 Hz, IH), 3.89 - 3.63 (m, 2H), 3.61 - 3.49 (m, 2H); (Z isomer) 6.60 (dd, J = 82.8, 5.2 Hz, IH). 13 C NMR (151 MHz, CDC13) (mixture of isomers) δ 157.2, 149.4 (d, J = 256.8 Hz), 139.0, 138.6, 138.5, 137.9, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.9, 127.8, 127.8, 127.6, 127.6, 127.3 (d, J = 3.1 Hz), 126.8 (d, J = 12.1 Hz), 117.3, 113.5 (d, J = 15.6 Hz), 99.3, 78.8, 75.6, 74.9, 74.7, 73.6, 73.2, 72.9, 71.8, 69.3. 19 F NMR (376 MHz, CDC13) (mixture of isomers) δ (Z isomer) -124.68 (dd, J = 82.8, 45.7 Hz); (E isomer) -132.03 (dd, J = 84.0, 19.2 Hz). HRMS (ESI, m / z): calcd for C 42 H 42 F06 + [M+H] + :661.2960, found679.2955.

[0110] The above merely describes the preferred embodiments of the present application, and cannot be deemed to limit the specific implementation of the present application to these descriptions. For those skilled in the art to which the present application pertains, without departing from the concept of the present application, a number of simple deductions and replacements can be made, and any modification, equivalent replacement, improvement, etc. made shall be included in the protection scope of the present application.

Claims

1. A method for synthesizing monofluoroolefin compounds, characterized in that, The process includes the following steps: Method A, trifluoromethyl substituted olefin 1 and silane 2 are reacted in DMSO with zinc acetate as a catalyst in the presence of a ligand by heating to obtain trisubstituted (E)-monofluoroolefin compound 3. The reaction equation is expressed as follows: Wherein: R is selected from H or cyclopropane; Ar is selected from substituted or unsubstituted phenyl, naphthyl, heteroaryl, substituted or unsubstituted biaryl; silane 2 is selected from diphenylsilane or phenylsilane; the ligand is Method B: Gem-difluoroolefin 4 and diphenylsilane 2a were reacted in DMSO with zinc acetate as a catalyst in the presence of ligands by heating to give di / trisubstituted (E)-monofluoroolefin compound 5. The reaction equation is expressed as follows: Where: R 1 Selected from hydrogen, methyl, propyl, phenyl, and ethyl formate; Ar 1 Selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted heteroaryl, substituted or unsubstituted biaryl; the ligand is: The substitution in the substituted or unsubstituted phenyl group refers to substitution at any site of the phenyl group by one or more of the following substituents, either identical or different: halogen, methyl, trifluoromethoxy, tert-butyl formate, diphenylamino, methoxy, tert-butyl, phenyl, phenoxy, methyl formate, neopentyl; the substitution in the substituted or unsubstituted naphthyl group refers to substitution at any site of the naphthyl group by one or more of the following substituents, either identical or different: methoxy, benzyloxy, allyloxy; the heteroaryl group is selected from quinolinyl, indolyl, benzofuranyl, benzothiophene; the substituted heteroaryl group is selected from phenyl-substituted thiophene, chlorobenzene-substituted thiophene, fluorobenzene-substituted furanyl; the substitution in the substituted or unsubstituted biaryl group refers to substitution at any site of the phenyl group by one or more of the following substituents, either identical or different: methyl, methoxy, methyl formate, halogen, trifluoromethyl.

2. The method for synthesizing monofluoroolefin compounds according to claim 1, characterized in that: In Method A, the ligand is selected from Xanphos; in Method B, the ligand is selected from PPh3.

3. The method for synthesizing monofluoroolefin compounds according to claim 1, characterized in that: The molar ratio of compound 1 to compound 2 is 1:3; the molar ratio of compound 4 to compound 2a is 1:1-2; and the molar ratio of compound 1 or 4, zinc acetate, and ligand is 1:0.1-0.2:0.1-0.

2.

4. The method for synthesizing monofluoroolefin compounds according to claim 1, characterized in that: The heating reaction temperature is 50-130℃.

5. The method for synthesizing monofluoroolefin compounds according to claim 1, characterized in that: The reaction is carried out under the protection of an inert gas.

6. A method for synthesizing tetrafluoroaryl compound 7, characterized in that, The reaction includes the following steps: polyfluoroaromatic hydrocarbon 6 and diphenylsilane 2a are reacted in DMSO solvent with zinc acetate as a catalyst and triphenylphosphine as a ligand by heating to obtain hydrodefluorinated compound 7; the reaction equation is as follows: Where R 2 Selected from trifluoromethyl or pentafluorophenyl.

7. The method for synthesizing tetrafluoroaryl compound 7 according to claim 6, characterized in that: The molar ratio of compound 6 to compound 2a is 1:1; the molar ratio of compound 6, zinc acetate, and triphenylphosphine is 1:0.1:0.1; the reaction temperature is 50-60℃; and the reaction is carried out under an inert gas atmosphere.

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