Z-selective C-H bond monofluoroalkenylation method for ruthenium-catalyzed benzophenone oxime ether compound

Abstract

The invention relates to the technical field of Z-selective monofluoroalkenylation of oxime ether compounds, in particular to a Z-selective C-H bond monofluoroalkenylation method of a ruthenium-catalyzed benzophenone oxime ether compound, which comprises the following steps: under the action of a ruthenium catalyst and alkali, carrying out a one-pot reaction to obtain the Z-selective C-H bond monofluoroalkenylation of the benzophenone oxime ether compound. A benzophenone oxime ether compound as shown in a formula (I) and a gem-difluoroolefin compound as shown in a formula (II) are subjected to C-H bond monofluoroalkenylation reaction, and a compound as shown in a formula (III) is prepared; wherein R is independently selected from any one of C1-C6 alkyl groups; r1, R2 and R3 are respectively and independently selected from any one of hydrogen, alkyl of C1-C6, alkoxy of C1-C6, halogen, thiophene and aryl of C6-C14. Cheap metal ruthenium is used for catalysis, oxime ether is used as a positioning group, gem-difluoroolefin is used as a coupling paron, C-H bond activation / C-F bond cracking is carried out, a series of Z-type alpha-monofluoroalkenylation benzophenone oxime ether compounds are obtained, and the method is high in configuration selectivity, efficient and low in cost.

Description

Technical Field

[0001] The present invention relates to the technical field of Z-selective monofluoroalkenylation of oxime ether compounds, and specifically relates to a ruthenium-catalyzed Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds. Background Art

[0002] Fluorine is one of the most popular elements. In recent years, chemists have been committed to introducing fluorine atoms or fluorine-containing groups (CF 3 , OCF 3 , SCF 3 , monofluoroalkenes, etc.) into small molecules. The main reason is that the introduction of fluorine can significantly improve the drug activity and pharmacokinetics / pharmacodynamics properties. Among them, monofluoroalkenes are widely used as bio-peptide chain bioisosteres due to their similar steric and dipole properties to amide bonds.

[0003] Currently, the construction of monofluoroalkenes mainly adopts the transition metal-catalyzed C-H bond activation method. In 2015, the Loh group first reported the monofluoroalkenylation reaction of rhodium(III)-catalyzed pyrimidine / pyridine-directed indole compounds (Nat. Commun. 2015, 6, 7472). Since then, cobalt(III), manganese(I), and ruthenium(II)-catalyzed monofluoroalkenylation reactions have been successively reported. However, when using manganese(I) (Chem. Commun. 2017, 53, 8731) or ruthenium(II) (Org. Chem. Front. 2018, 5, 1978) as catalysts, the product configurational selectivity is poor. At the same time, chemists have developed other nitrogen-containing directing groups such as amide and quinoline-directed monofluoroalkenylation reactions. Although these reactions show good functional group tolerance and configurational selectivity, these reactions must use expensive rhodium(III) as a catalyst (Org. Chem. Front. 2018, 5, 3406). Therefore, it is of great significance to develop an economical and efficient monofluoroalkenylation reaction.

[0004] In recent years, due to the advantages of simple structure, convenient synthesis, strong coordination ability, etc., oxime ethers are often used as directing groups for C-H bond activation / functionalization reactions, such as amidation, arylation, alkenylation, selenylation, fluorination, hydroxylation, etc. However, the directed C-H bond monofluoroalkenylation reaction of benzophenone compounds has not been reported. In view of the application value of benzophenone compounds and monofluoroalkenes in the fields of organic chemistry and medicinal chemistry, it is extremely necessary to develop an economical and efficient monofluoroalkenylation method for benzophenone oxime ether compounds with high product configurational specificity. Summary of the Invention

[0005] To solve the above technical problems, the object of the present invention is to provide a method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds. This method uses inexpensive ruthenium as a catalyst, an oxime ether as a directing group, and gem-difluoroalkenes as coupling partners, and obtains a series of Z-type α-mono-fluoroalkenylated benzophenone oxime ether compounds through C-H bond activation / C-F bond cleavage. This method realizes the mono-fluoroalkenylation reaction of benzophenone oxime ether compounds for the first time, and the product configuration has high specificity, providing a method for mono-fluoroalkenylation of benzophenone oxime ether compounds with high efficiency, low cost, and good configurational selectivity.

[0006] To achieve the above object, an embodiment of the present invention provides a method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, including the following steps:

[0007] Under the action of a ruthenium catalyst and a base, the benzophenone oxime ether compound shown in formula (I) is subjected to a C-H bond mono-fluoroalkenylation reaction with the gem-difluoroalkene compound shown in formula (II) to obtain the compound shown in formula (III);

[0008]

[0009] The mono-fluoroalkenylation reaction is to subject the benzophenone oxime ether compound shown in formula (I) to a C-H bond mono-fluoroalkenylation reaction with the gem-difluoroalkene compound shown in formula (II);

[0010] Wherein, R is independently selected from any one of C 1 -C 6 alkyls; R 1 , R 2 , R 3 are independently selected from hydrogen, C 1 -C 6 alkyls, C 1 -C 6 alkoxyls, halogens, thiophenes, C 6 -C 14 aryl groups, respectively.

[0011] As some embodiments of the present invention, the ruthenium catalyst is dichloro-bis(4-methylisopropylphenyl)ruthenium(II).

[0012] As some embodiments of the present invention, the base is any one of calcium hydroxide, cesium acetate, and cesium carbonate.

[0013] As some embodiments of the present invention, the mono-fluoroalkenylation reaction is carried out in an organic solvent.

[0014] As some embodiments of the present invention, the organic solvent is any one of hexafluoroisopropanol, trifluoroethanol, and tetrahydrofuran.

[0015] As some embodiments of the present invention, the reaction conditions for the monofluoroalkenylation reaction are: the reaction temperature is 25°C to 100°C, and the time is 2 h to 12 h.

[0016] As some embodiments of the present invention, the molar ratio of benzophenone oxime ether compound: gem-difluoroalkene compound: dichloro-bis(4-methylcumyl)palladium(II): base is 0.2:0.4:0.02:0.2.

[0017] As some embodiments of the present invention, the benzophenone oxime ether compound represented by formula (I) is selected from one of the following compounds:

[0018]

[0019] As some embodiments of the present invention, the gem-difluoroalkene compound represented by formula (II) is selected from one of the following compounds:

[0020]

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] 1. The present invention uses inexpensive metal ruthenium as a catalyst, an oxime ether as a directing group, and a gem-difluoroalkene as a coupling partner, and obtains a series of Z-type α-monofluoroalkenylated benzophenone oxime ether compounds through C-H bond activation / C-F bond cleavage. This method realizes the monofluoroalkenylation reaction of benzophenone oxime ether compounds for the first time, and the product configuration has high specificity, providing a highly efficient, low-cost, and configuration-selective method for the monofluoroalkenylation of benzophenone oxime ether compounds.

[0023] 2. The method of the present invention has the advantages of low cost, simple operation, high yield, wide substrate applicability, easy separation of products, and high product configuration specificity, and is not only applicable to gram-scale reactions but also suitable for industrial-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for describing the specific embodiments or the prior art. Obviously, the following drawings are only one embodiment of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0025] Figure 1 It is a schematic diagram of the synthesis route of the embodiment of the present invention.

[0026] Figure 2 This is the X-single crystal schematic diagram of the product of Example 24 of the present invention for 4 h. Detailed implementation manners

[0027] In order to make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0028] All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.

[0029] Unless otherwise specified, the experimental methods described in the following embodiments of the present invention are all conventional methods; the reagents and materials, unless otherwise specified, can all be obtained commercially.

[0030] In the following embodiments of the present invention, a method for Z-selective C-H bond monofluoroalkenylation of benzophenone oxime ether compounds is provided, and its synthetic route is as Figure 1 shown. The general idea of this method is: add a certain amount of benzophenone oxime ether compound shown in formula (I), gem-difluoroalkene compound shown in formula (II), ruthenium catalyst, base and organic solvent to the reaction vessel respectively, and react fully at 25 °C to 100 °C for 2 h to 12 h. After the reaction is completed, cool to room temperature, pour the reaction solution into a container filled with saturated brine, extract with dichloromethane, collect the organic layer and dry it with anhydrous sodium sulfate, concentrate under vacuum, and then purify and separate by silica gel column chromatography to prepare the corresponding Z-type α-monofluoroalkenylated benzophenone oxime ether compound (the compound shown in formula (III)).

[0031] Among them, R is independently selected from any one of alkyl groups of C 1 -C 6 ; R 1 , R 2 , R 3 are independently selected from hydrogen, alkyl groups of C 1 -C 6 , alkoxy groups of C 1 -C 6 , halogen, thiophene, aryl groups of C 6 -C 14 respectively.

[0032] In order to better understand the above technical solutions, the above technical solutions will be described in detail below in specific implementation manners.

[0033] Example 1:

[0034] A Z-selective C-H bond mono-fluoroalkenylation method of ruthenium-catalyzed benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The structure of the gem-difluoroalkene compounds is The specific method comprises the following steps:

[0035] Add benzophenone-O-isopropyl oxime (Ⅰ-1a) (0.2 mmol), 4-bromostyrene gem-difluoride (Ⅱ-2a) (2.0 eq, 0.4 mmol), dichloro-bis(4-methylcumyl)ruthenium(II) (0.1 eq, 0.02 mmol), cesium carbonate (1.0 eq, 0.2 mmol), and hexafluoroisopropanol (1.5 mL) into a 10 mL thick-walled pressure-resistant tube respectively, seal it and place it in an oil bath at 90 °C for a full reaction of 6 h. After the reaction is completed, cool it to room temperature, pour the reaction solution into a separatory funnel filled with saturated brine, extract it with dichloromethane (15 mL × 3), collect the organic layer and dry it with anhydrous sodium sulfate, concentrate it under vacuum, and separate it by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to obtain a yellow solid with a yield of 90%.

[0036] The structure characterization data of the product obtained in Example 1 are as follows:

[0037] 1 H NMR (400 MHz, CDCl 3 , ppm): δ 7.56 - 7.54 (m, 1H), 7.52 - 7.50 (m, 2H), 7.44 - 7.38 (m, 5H), 7.28 - 7.25 (m, 5H), 5.96 (d, J = 37.6 Hz, 1H), 4.52 - 4.42 (m, 1H), 1.27 (s, 3H), 1.26 (s, 3H); 13 C NMR (100 MHz, CDCl 3 , ppm): δ 159.2 (d, 1 J CF = 261.7 Hz), 155.0, 136.7, 133.5 (d, 2 J CF = 25.0 Hz), 133.2, 132.8, 132.7, 131.6 (2C), 131.3, 130.4 (2C), 130.3, 130.2, 129.5, 129.3, 128.8 (d, 4 J CF = 2.5 Hz), 127.7 (2C), 121.0 (d, 4 J CF = 3.5 Hz), 109.3 (d, 3 J CF= 9.9 Hz), 76.5, 21.8 (2C); 19 F NMR (376 MHz, CDCl 3 , ppm): δ -97.54; HRMS (ESI): m / z [M + H] + calcd. for C 24 H 22 BrFNO: 438.0869; found: 438.0863

[0038] Based on the above data, the structure of the obtained product is:

[0039] Example 2:

[0040] A ruthenium-catalyzed Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0041] Example 3:

[0042] A ruthenium-catalyzed Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0043] Example 4:

[0044] A ruthenium-catalyzed Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0045] Example 5:

[0046] A ruthenium-catalyzed Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0047] Example 6:

[0048] A ruthenium-catalyzed Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0049] Example 7:

[0050] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0051] Example 8:

[0052] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0053] Example 9:

[0054] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0055] Example 10:

[0056] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0057] Example 11:

[0058] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0059] Example 12:

[0060] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0061] Example 13:

[0062] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0063] Example 14:

[0064] A method for Z-selective C-H bond monofluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0065] Example 15:

[0066] A method for Z-selective C-H bond monofluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0067] Example 16:

[0068] A method for Z-selective C-H bond monofluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0069] Example 17:

[0070] A method for Z-selective C-H bond monofluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the benzophenone oxime ether compounds is: The specific method is the same as that of Example 1.

[0071] Example 18:

[0072] A method for Z-selective C-H bond monofluoroalkenylation of benzophenone oxime ether compounds, wherein the structural formula of the benzophenone oxime ether compounds is The structure of the gem-difluoroalkene compounds is The specific method comprises the following steps:

[0073] Add benzophenone-O-isopropyl oxime (Ⅰ-1a) (0.2 mmol), 4-methylstyrene gem-difluoride (Ⅱ-2a) (2.0 eq, 0.4 mmol), dichloro-bis(4-methylisopropylphenyl)ruthenium(II) (0.1 eq, 0.02 mmol), cesium carbonate (1.0 eq, 0.2 mmol), and hexafluoroisopropanol (1.5 mL) into a 10 mL thick-walled pressure-resistant tube respectively, seal it and place it in an oil bath, react fully at 90 °C for 6 h. After the reaction is completed, cool it to room temperature, pour the reaction solution into a separatory funnel filled with saturated brine, extract with dichloromethane (15 mL × 3), collect the organic layer and dry it with anhydrous sodium sulfate, concentrate it under vacuum, and separate it by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to obtain a yellow oily liquid with a yield of 87%.

[0074] The structural characterization data of the product obtained in Example 18 are as follows:

[0075] 1 H NMR (400 MHz, CDCl 3 , ppm): δ 7.56 - 7.54 (m, 1H), 7.52 - 7.50 (m, 2H), 7.44 - 7.38 (m, 5H), 7.28 - 7.25 (m, 5H), 5.96 (d, J=37.6 Hz, 1H), 4.52 - 4.42 (m, 1H), 1.27 (s, 3H), 1.26 (s, 3H); 13 C NMR (100 MHz, CDCl 3 , ppm): δ 159.2 (d, 1 J CF =261.7 Hz), 155.0, 136.7, 133.5 (d, 2 J CF =25.0 Hz), 133.2, 132.8, 132.7, 131.6 (2C), 131.3, 130.4 (2C), 130.3, 130.2, 129.5, 129.3, 128.8 (d, 4 J CF =2.5 Hz), 127.7 (2C), 121.0 (d, 4 J CF =3.5 Hz), 109.3 (d, 3 J CF =9.9 Hz), 76.5, 21.8 (2C); 19 F NMR (376 MHz, CDCl 3 , ppm): δ -97.54; HRMS (ESI): m / z [M + H] + calcd. for C 24 H 22 BrFNO: 438.0869; found: 438.0863

[0076] Based on the above data, the structure of the obtained product is:

[0077] Example 19:

[0078] A Z-selective C-H bond mono-fluoroalkenylation method of ruthenium-catalyzed benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0079] Example 20:

[0080] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0081] Example 21:

[0082] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0083] Example 22:

[0084] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0085] Example 23:

[0086] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0087] Example 24:

[0088] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18. The X-ray single crystal schematic diagram of the compound 4h prepared in this example is as Figure 2 shown.

[0089] Example 25:

[0090] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0091] Example 26:

[0092] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0093] Example 27:

[0094] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0095] Example 28:

[0096] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0097] Example 29:

[0098] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0099] Example 30:

[0100] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0101] Example 31:

[0102] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0103] Example 32:

[0104] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0105] Example 33:

[0106] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0107] Example 34:

[0108] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0109] Example 35:

[0110] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0111] Example 36:

[0112] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the structure of the gem-difluoroalkene compound is: The specific method is the same as that of Example 18.

[0113] Example 37:

[0114] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the base used is cesium acetate; the specific method is the same as that of Example 1.

[0115] Example 38:

[0116] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the base used is calcium hydroxide; the specific method is the same as that of Example 1.

[0117] Comparative Example 39:

[0118] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the base used is 1,8-diazabicyclo[5.4.0]undec-7-ene; the specific method is the same as that of Example 1.

[0119] Comparative Example 40:

[0120] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the base used is pyridine; the specific method is the same as that of Example 1.

[0121] Example 41:

[0122] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the organic solvent is trifluoroethanol; the specific method is the same as that of Example 1.

[0123] Comparative Example 42:

[0124] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the organic solvent is methanol; the specific method is the same as that of Example 1.

[0125] Comparative Example 43:

[0126] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the organic solvent is tetrahydrofuran; the specific method is the same as that of Example 1.

[0127] Example 44:

[0128] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the reaction temperature is 25 °C; the specific method is the same as that of Example 1.

[0129] Example 45:

[0130] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the reaction temperature is 60 °C; the specific method is the same as that of Example 1.

[0131] Example 46:

[0132] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the reaction temperature is 100 °C; the specific method is the same as that of Example 1.

[0133] Example 47:

[0134] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the reaction time is 2 h; the specific method is the same as that of Example 1.

[0135] Example 48:

[0136] A method for Z-selective C-H bond mono-fluoroalkenylation of benzophenone oxime ether compounds, wherein the reaction time is 12 h; the specific method is the same as that of Example 1.

[0137] The above embodiments of the present invention mainly optimize the conditions for the mono-fluoroalkenylation reaction by C-H bond activation / C-F bond cleavage, using benzophenone oxime ether compounds (1a) to (1q) as substrates and gem-difluoroalkene compounds (2a) to (2t) as coupling partners. The optimization of the above reaction conditions is shown in Table 1-4.

[0138] Table 1 Optimization of bases

[0139]

[0140] As can be seen from the results in Table 1, by screening bases including cesium carbonate, cesium acetate, calcium hydroxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, and pyridine, we found that the reaction yield was the best when cesium carbonate was used as the base (yield 90%).

[0141] Table 2 Optimization of organic solvents

[0142]

[0143]

[0144] As can be seen from the results in Table 2, by screening organic solvents including hexafluoroisopropanol, trifluoroethanol, methanol, and tetrahydrofuran, we found that the reaction yield was the best when hexafluoroisopropanol was used as the organic solvent (yield 90%).

[0145] Table 3 Optimization of reaction temperature

[0146]

[0147]

[0148] As can be seen from the results in Table 3, by screening reaction temperatures including 25°C, 60°C, 90°C, and 100°C, we found that the reaction yield was the best when the reaction temperature was 90°C (yield 90%).

[0149] Table 4 Optimization of reaction time

[0150]

[0151] As can be seen from the results in Table 4, by screening reaction times including 2 h, 6 h, and 12 h, we found that the reaction yield was the best when the reaction time was 6 h (yield 90%).

[0152] Next, the applicability of the ruthenium-catalyzed Z-selective C-H bond mono-fluoroalkenylation method of benzophenone oxime ether compounds was investigated for substrates and coupling partners, and a verification exploration of the above optimized conditions was carried out. See Table 5 for details.

[0153] Table 5 Investigation of the applicability of reaction substrates

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161] As can be seen from the results in Table 6, in Examples 1 to 36 of the present invention, benzophenone oxime ether compounds (1a) to (1q) were used as substrates, and gem-difluoroalkene compounds (2a) to (2t) were used as coupling pairs. Through C-H bond activation / C-F bond cleavage, a series of Z-type α-monofluoroalkenylated benzophenone oxime ether compounds could be obtained with excellent configurational specificity and high yields (yields 68% - 91%).

[0162] The above results show that the method of the examples of the present invention has the advantages of low cost, simple operation, high yield, wide substrate applicability, easy separation of products, and high product configurational specificity. Moreover, it is not only applicable to gram-scale reactions but also suitable for industrial-scale production.

[0163] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for Z-selective CH bond monofluoroolefination of benzophenone oxime ether compounds catalyzed by ruthenium, characterized in that: The following steps are involved: Under the action of a ruthenium catalyst and a base, the benzophenone oxime ether compound represented by formula (I) and the geminal difluoroolefin compound represented by formula (II) are subjected to a CH bond monofluoroolefination reaction to obtain a compound represented by formula (III); Wherein, R is independently selected from any one of C1-C6 alkyl groups; R1, R2, and R3 are independently selected from hydrogen, C1-C6 alkyl groups, C1-C6 alkoxy groups, halogen, thiophene, C6-C 14 Any one of the aromatic groups.

2. The method for Z-selective CH bond monofluoroolefination of benzophenone oxime ether compounds catalyzed by ruthenium according to claim 1, characterized in that: The ruthenium catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium(II).

3. The method for Z-selective CH bond monofluoroolefination of benzophenone oxime ether compounds catalyzed by ruthenium according to claim 1, characterized in that: The base is any one of calcium hydroxide, cesium acetate and cesium carbonate.

4. The method for Z-selective CH bond monofluoroolefination of benzophenone oxime ether compounds catalyzed by ruthenium according to claim 1, characterized in that: The monofluoroolefination reaction is carried out in an organic solvent.

5. The method for Z-selective CH bond monofluoroolefination of benzophenone oxime ether compounds catalyzed by ruthenium according to claim 4, characterized in that: The organic solvent is any one of hexafluoroisopropanol, trifluoroethanol and tetrahydrofuran.

6. The method for Z-selective CH bond monofluoroolefination of benzophenone oxime ether compounds catalyzed by ruthenium according to claim 1, characterized in that: The reaction conditions of the monofluoroolefination reaction are: reaction temperature is 25° C. to 100° C., and time is 2 h to 12 h.

7. The method for Z-selective CH bond monofluoroolefination of benzophenone oxime ether compounds catalyzed by ruthenium according to claim 2, characterized in that: The molar ratio of the benzophenone oxime compound represented by formula (I): the geminal difluoroolefin compound represented by formula (II): dichlorobis(4-methylisopropylphenyl)ruthenium(II): the base is 0.2:0.4:0.02:0.

2.

8. The method for Z-selective CH bond monofluoroolefination of benzophenone oxime ether compounds catalyzed by ruthenium according to claim 1, characterized in that: The benzophenone oxime ether compound represented by formula (I) is selected from one of the following compounds:

9. The method for Z-selective CH bond monofluoroolefination of benzophenone oxime ether compounds catalyzed by ruthenium according to claim 1, characterized in that: The geminal difluoroolefin compound represented by formula (II) is selected from one of the following compounds:

10. The method for Z-selective CH bond monofluoroolefination of benzophenone oxime ether compounds catalyzed by ruthenium according to claim 2, characterized in that: The reaction conditions of the monofluoroolefination reaction are: reaction temperature is 90°C and time is 6h; The molar ratio of the benzophenone oxime compound represented by formula (I): the geminal difluoroolefin compound represented by formula (II): dichlorobis(4-methylisopropylphenyl)ruthenium(II): the base is 0.2:0.4:0.02:0.2.

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