A method for ruthenium-catalyzed z-selective c-h bond monofluoroalkenylation of benzophenone oxime ethers

Abstract

The present application relates to oxime ether compound Z-selective monofluoroalkenylation technical field, specifically relates to a kind of ruthenium catalysis benzophenone oxime ether compound Z-selective C-H bond monofluoroalkenylation method, comprising the following steps: under the action of ruthenium catalyst, base, formula (I) shown benzophenone oxime ether compound and formula (II) shown geminal difluoroalkene class compound are carried out C-H bond monofluoroalkenylation reaction, and the compound shown in formula (III) is prepared;Wherein, R is independently selected from any one of C1-C6 alkyl;R1, R2, R3 are respectively independently selected from any one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, thiophene, C6-C 14 The present application uses inexpensive metal ruthenium catalysis, with oxime ether as positioning base, with geminal difluoroalkene as coupling pair, to obtain a series of Z-type α-monofluoroalkenylation benzophenone oxime ether compound by C-H bond activation / C-F bond cleavage, and the method has strong configuration selectivity, high efficiency and low cost.

Description

Technical Field

[0001] This invention relates to the field of Z-selective monofluoroalkenylation technology for oxime ether compounds, and specifically to a ruthenium-catalyzed Z-selective CH bond monofluoroalkenylation method for benzophenone oxime ether compounds. Background Technology

[0002] Fluorine is one of the most popular elements. In recent years, chemists have been dedicated to introducing fluorine atoms or fluorine-containing groups (CF3, OCF3, SCF3, monofluoroolefins, etc.) into small molecules. The main reason is that the introduction of fluorine can significantly improve drug activity and enhance pharmacokinetic properties. Among them, monofluoroolefins are widely used as isosteres of biological peptide chains because they have stereo and dipolar properties similar to amide bonds.

[0003] Currently, the main method for constructing monofluoroolefins is transition metal-catalyzed CH bond activation. In 2015, Loh's group first reported the monofluoroalkenylation reaction of rhodium(III)-catalyzed pyrimidine / pyridine-oriented indole compounds. Nat.Commun. 2015 ,6 Since then, monofluoroalkenylation reactions catalyzed by cobalt(III), manganese(I), and ruthenium(II) have been reported, but the use of manganese(I) (7472) Chem.Commun. 2017, 53 ,8731) or Ruthenium(II) ( Org.Chem.Front. 2018, 5 When catalyzed by (1978), the product configuration selectivity is poor. Meanwhile, chemists have developed other nitrogen-directing group-oriented monofluoroalkenylation reactions such as amides and quinolines. Although these reactions exhibit good functional group tolerance and configuration selectivity, they require expensive rhodium(III) as a catalyst. Org.Chem.Front. 2018, 5 (3406). Therefore, developing economical and efficient monofluoroolefination reactions is of great significance.

[0004] In recent years, oxime ethers have been frequently used for directing CH bond activation / functionalization reactions due to their simple structure, convenient synthesis, and strong coordination ability, such as amidation, arylation, alkenylation, selenization, fluorination, and hydroxylation. However, the directing of CH bond monofluoroalkenylation of benzophenone compounds using oxime ethers has not been reported. Given the application value of benzophenone compounds and monofluoroalkenes in organic chemistry and medicinal chemistry, it is extremely necessary to develop an economical, efficient, and configurationally specific method for the monofluoroalkenylation of benzophenone oxime ethers. Summary of the Invention

[0005] To address the aforementioned technical problems, the present invention aims to provide a ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers. This method uses inexpensive ruthenium as a catalyst, oxime ethers as directing groups, and gem-difluoroolefins as coupling pairs. Through CH-bond activation / CF-bond cleavage, a series of Z-type α-monofluoroalkenylated benzophenone oxime ether compounds are obtained. This method achieves the monofluoroalkenylation reaction of benzophenone oxime ethers for the first time, and the product configuration exhibits high specificity, providing an efficient, low-cost, and configuration-selective method for the monofluoroalkenylation of benzophenone oxime ethers.

[0006] To achieve the above objectives, embodiments of the present invention provide a ruthenium-catalyzed Z-selective CH bond monofluoroalkenylation method for benzophenone oxime ether compounds, comprising the following steps:

[0007] In the presence of a ruthenium catalyst and a base, the benzophenone oxime ether compound shown in formula (I) and the gemdifluoroolefin compound shown in formula (II) undergo a CH bond monofluoroalkenylation reaction to obtain the compound shown in formula (III).

[0008]

[0009] The monofluoroalkenylation reaction is a CH bond monofluoroalkenylation reaction between the benzophenone oxime ether compound shown in formula (I) and the gemini difluoroalkene compound shown in formula (II);

[0010] 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, halogens, thiophenes, and C6-C6 alkyl groups, respectively. 14 Any of the aryl groups.

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

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

[0013] As some embodiments of the present invention, the monofluoroolefination 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 monofluoroolefination reaction are: a reaction temperature of 25°C to 100°C and a reaction time of 2h to 12h.

[0016] As some embodiments of the present invention, the molar ratio of benzophenone oxime ether compound: geminofluoroolefin compound: dichlorobis(4-methylisopropylphenyl)ruthenium(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 gemini difluoroolefin 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. This invention uses inexpensive ruthenium as a catalyst, oxime ethers as directing groups, and gem-difluoroolefins as coupling pairs to obtain a series of Z-type α-monofluoroalkenylated benzophenone oxime ether compounds through CH bond activation / CF bond cleavage. This method is the first to achieve the monofluoroalkenylation reaction of benzophenone oxime ether compounds, and the product configuration exhibits high specificity. It provides an 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 product separation and high product configuration specificity. It is not only suitable for gram-scale reactions, but also for industrial-scale production. Attached Figure Description

[0024] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only one embodiment of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

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

[0026] Figure 2 This is a schematic diagram of the X-ray single crystal of product 4h in Example 24 of the present invention. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0028] Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are 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 conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0030] The following embodiments of the present invention provide a ruthenium-catalyzed Z-selective CH bond monofluoroalkenylation method for benzophenone oxime ether compounds, the synthetic route of which is as follows: Figure 1 As shown, the general idea of ​​this method is as follows: a certain amount of benzophenone oxime ether compound represented by formula (Ⅰ), gemini difluoroolefin compound represented by formula (Ⅱ), ruthenium catalyst, base and organic solvent are added to the reaction vessel, and the reaction is carried out at 25℃~100℃ for 2h~12h. After the reaction is completed, the mixture is cooled to room temperature, and the reaction solution is poured into a container containing saturated brine. The mixture is extracted with dichloromethane, the organic layer is collected and dried with anhydrous sodium sulfate, concentrated under vacuum, and then purified and separated by silica gel column chromatography to prepare the corresponding Z-type α-monofluoroalkenylated benzophenone oxime ether compound (the compound represented by formula (Ⅲ)).

[0031] 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, halogens, thiophenes, and C6-C6 alkyl groups, respectively. 14 Any of the aryl groups.

[0032] To better understand the above technical solution, the following detailed description of the specific implementation method is provided.

[0033] Example 1:

[0034] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The structure of geminofluoroolefins is as follows: The specific method includes the following steps:

[0035] Add benzophenone to each 10 mL thick-walled pressure-resistant tube. O- Isopropyl oxime (Ⅰ-1a) (0.2 mmol), 4-bromostyrene geminitrofluorine (Ⅱ-2a) (2.0 eq, 0.4 mmol), dichlorobis(4-methylisopropylphenyl)ruthenium(II) (0.1 eq, 0.02 mmol), cesium carbonate (1.0 eq, 0.2 mmol), and hexafluoroisopropanol (1.5 mL) were sealed in an oil bath and reacted at 90 °C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and poured into a separatory funnel containing saturated brine. The mixture was extracted with dichloromethane (15 mL × 3), and the organic layer was collected and dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give a yellow solid in 90% yield.

[0036] The structural characterization data of the product obtained in Example 1 are shown below:

[0037] 1 ¹H NMR (400 MHz, CDCl₃, ppm): d 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, CDCl3, ppm): d 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, CDCl3, ppm): d -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 product can be inferred as follows: .

[0039] Example 2:

[0040] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0041] Example 3:

[0042] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0043] Example 4:

[0044] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0045] Example 5:

[0046] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0047] Example 6:

[0048] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0049] Example 7:

[0050] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0051] Example 8:

[0052] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0053] Example 9:

[0054] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0055] Example 10:

[0056] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0057] Example 11:

[0058] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0059] Example 12:

[0060] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0061] Example 13:

[0062] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0063] Example 14:

[0064] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0065] Example 15:

[0066] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0067] Example 16:

[0068] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0069] Example 17:

[0070] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the benzophenone oxime ether is as follows: The specific method is the same as that in Example 1.

[0071] Example 18:

[0072] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the structural formula of the benzophenone oxime ether compound is as follows: The structure of geminofluoroolefins is as follows: The specific method includes the following steps:

[0073] Add benzophenone to each 10 mL thick-walled pressure-resistant tube. O - Isopropyl oxime (Ⅰ-1a) (0.2 mmol), 4-methylstyrene-difluoro(Ⅱ-2a) (2.0 eq, 0.4 mmol), dichlorobis(4-methylisopropylphenyl)ruthenium(II) (0.1 eq, 0.02 mmol), cesium carbonate (1.0 eq, 0.2 mmol), and hexafluoroisopropanol (1.5 mL) were sealed in an oil bath and reacted at 90 °C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and poured into a separatory funnel containing saturated brine. The mixture was extracted with dichloromethane (15 mL × 3), and the organic layer was collected and dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum and separated 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 shown below:

[0075] 1 ¹H NMR (400 MHz, CDCl₃, ppm): d 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, CDCl3, ppm): d 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, CDCl3, ppm): d -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 product can be inferred as follows: .

[0077] Example 19:

[0078] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0079] Example 20:

[0080] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0081] Example 21:

[0082] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0083] Example 22:

[0084] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0085] Example 23:

[0086] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0087] Example 24:

[0088] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18. A schematic diagram of the X-ray single crystal of the compound prepared in this example after 4 hours is shown below. Figure 2 As shown.

[0089] Example 25:

[0090] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0091] Example 26:

[0092] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0093] Example 27:

[0094] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0095] Example 28:

[0096] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0097] Example 29:

[0098] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0099] Example 30:

[0100] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0101] Example 31:

[0102] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0103] Example 32:

[0104] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0105] Example 33:

[0106] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0107] Example 34:

[0108] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0109] Example 35:

[0110] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0111] Example 36:

[0112] A ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers, wherein the structure of the geminofluoroalkenes is as follows: The specific method is the same as that in Example 18.

[0113] Example 37:

[0114] A ruthenium-catalyzed Z-selective monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the base used is cesium acetate; the specific method is the same as that in Example 1.

[0115] Example 38:

[0116] A ruthenium-catalyzed Z-selective CH bond monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the base used is calcium hydroxide; the specific method is the same as that in Example 1.

[0117] Comparative Example 39:

[0118] A ruthenium-catalyzed Z-selective monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the base used is 1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene; the specific method is the same as that in Example 1.

[0119] Comparative Example 40:

[0120] A ruthenium-catalyzed Z-selective monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the base used is pyridine; the specific method is the same as that in Example 1.

[0121] Example 41:

[0122] A ruthenium-catalyzed Z-selective monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the organic solvent is trifluoroethanol; the specific method is the same as that in Example 1.

[0123] Comparative Example 42:

[0124] A ruthenium-catalyzed Z-selective CH bond monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the organic solvent is methanol; the specific method is the same as that in Example 1.

[0125] Comparative Example 43:

[0126] A ruthenium-catalyzed Z-selective monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the organic solvent is tetrahydrofuran; the specific method is the same as that in Example 1.

[0127] Example 44:

[0128] A ruthenium-catalyzed Z-selective monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the reaction temperature is 25 °C; the specific method is the same as that in Example 1.

[0129] Example 45:

[0130] A ruthenium-catalyzed Z-selective monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the reaction temperature is 60 °C; the specific method is the same as that in Example 1.

[0131] Example 46:

[0132] A ruthenium-catalyzed Z-selective monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the reaction temperature is 100 °C; the specific method is the same as that in Example 1.

[0133] Example 47:

[0134] A ruthenium-catalyzed Z-selective CH bond monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the reaction time is 2 h; the specific method is the same as that in Example 1.

[0135] Example 48:

[0136] A ruthenium-catalyzed Z-selective CH bond monofluoroalkenylation method for benzophenone oxime ether compounds, wherein the reaction temperature is 12 h; the specific method is the same as that in Example 1.

[0137] The above embodiments of the present invention mainly focus on optimizing the conditions for the monofluoroalkenylation reaction, which uses benzophenone oxime ether compounds (1a) to (1q) as substrates and gem-difluoroolefin compounds (2a) to (2t) as coupling pairs, through CH bond activation / CF bond cleavage. The optimization of the above reaction conditions is shown in Tables 1-4.

[0138] Table 1. Optimization of Alkali

[0139]

[0140] As shown in Table 1, through screening of bases including cesium carbonate, cesium acetate, calcium hydroxide, 1,8-diazobisspirocyclic[5.4.0]undec-7-ene, and pyridine, we found that cesium carbonate had the best reaction yield (90%) when used as a base.

[0141] Table 2 Organic solvent optimization

[0142]

[0143] As shown in Table 2, through screening organic solvents including hexafluoroisopropanol, trifluoroethanol, methanol, and tetrahydrofuran, we found that hexafluoroisopropanol had the best reaction yield (90%) when used as an organic solvent.

[0144] Table 3 Optimization of Reaction Temperature

[0145]

[0146] As shown in Table 3, by screening the reaction temperature (25 ℃, 60 ℃, 90 ℃, 100 ℃), we found that the reaction yield was the best at a reaction temperature of 90 ℃ (yield of 90%).

[0147] Table 4 Optimization of Reaction Time

[0148]

[0149] As shown in Table 4, by screening the reaction time to 2 h, 6 h and 12 h, we found that the reaction yield was the best (90%) when the reaction temperature was 6 h.

[0150] The suitability of the ruthenium-catalyzed Z-selective CH-bond monofluoroalkenylation method for benzophenone oxime ethers is investigated in terms of substrates and coupling pairs, and the optimized conditions described above are verified. See Table 5 for details.

[0151] Table 5. Results of substrate suitability assessment

[0152]

[0153] As shown in Table 5, Examples 1-36 of this invention, using benzophenone oxime ether compounds (1a)-(1q) as substrates and gem-difluoroolefin compounds (2a)-(2t) as coupling pairs, can obtain a series of Z-type α-monofluoroalkenylated benzophenone oxime ether compounds (yields of 68%-91%) with excellent configuration specificity and high yield through CH bond activation / CF bond cleavage.

[0154] The above results demonstrate that the method of the present invention has the advantages of low cost, simple operation, high yield, wide substrate applicability, easy product separation and high product configuration specificity. Furthermore, it is suitable not only for gram-scale reactions but also for industrial-scale production.

[0155] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for Z-selective C-H bond monofluoroalkenylation of benzophenone oxime ether compounds catalyzed by ruthenium, characterized in that, The method comprises the following steps: The C-H bond monofluoroalkenylation reaction of a benzophenone oxime ether compound or a (2-thiophene) ketone oxime ether compound shown in formula (I) and a gem-difluoroalkene compound or 4-(2,2-difluorovinyl) benzo[d][1,3]dioxole shown in formula (II) is carried out under the action of a ruthenium catalyst and a base to prepare a compound shown in formula (III). ； wherein R is independently selected from any one of C1-C6 alkyl; R1, R2, R3are each independently selected from any one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, thiophene, C6-C10 aryl. 14 wherein R is independently selected from any one of C1-C6 alkyl; R1, R2, R3are each independently selected from any one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, thiophene, C6-C10 aryl.

2. The Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds with ruthenium catalysis according to claim 1, characterized in that, The ruthenium catalyst is dichlorobis(4-methylisopropylphenyl) ruthenium (II).

3. The Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds with ruthenium catalysis according to claim 1, characterized in that, The base is any one of calcium hydroxide, cesium acetate and cesium carbonate.

4. The Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds with ruthenium catalysis according to claim 1, characterized in that, The monofluoroalkenylation reaction is carried out in an organic solvent.

5. The Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds with ruthenium catalysis according to claim 4, characterized in that, The organic solvent is any one of hexafluoroisopropanol, trifluoroethanol and tetrahydrofuran.

6. The Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds with ruthenium catalysis according to claim 1, characterized in that, The reaction condition of the monofluoroalkenylation reaction is that the reaction temperature is 25-100 DEG C and the reaction time is 2-12 hours.

7. The Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds with ruthenium catalysis according to claim 2, characterized in that, The molar ratio of the benzophenone oxime compound or the (2-thiophene) ketone oxime ether compound shown in formula (I), the gem-difluoroalkene compound or 4-(2,2-difluorovinyl) benzo[d][1,3]dioxole shown in formula (II), dichlorobis(4-methylisopropylphenyl) ruthenium (II) and the base is 0.2:0.4:0.02:0.

2.

8. The Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds with ruthenium catalysis according to claim 1, characterized in that, The benzophenone oxime ether compound or the (2-thiophene) ketone oxime ether compound shown in formula (I) is selected from one of the following compounds: 。 9. The Z-selective C-H bond monofluoroalkenylation of benzophenone oxime ether ruthenium catalyzed process according to claim 1, characterized in that, The gem-difluoroalkene compound or 4-(2,2-difluorovinyl) benzo[d][1,3]dioxole shown in formula (II) is selected from one of the following compounds: 。 10. The Z-selective C-H bond monofluoroalkenylation method of benzophenone oxime ether compounds with ruthenium catalysis according to claim 2, characterized in that, The reaction condition of the monofluoroalkenylation reaction is that the reaction temperature is 90 DEG C and the reaction time is 6 hours. The molar ratio of the benzophenone oxime compound or the (2-thiophene) ketone oxime ether compound shown in formula (I), the gem-difluoroalkene compound or 4-(2,2-difluorovinyl) benzo[d][1,3]dioxole shown in formula (II), dichlorobis(4-methylisopropylphenyl) ruthenium (II) and the base is 0.2:0.4:0.02:0.2.

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