A method for stereoselective C-H bond monofluoroalkenylation of C7 position of indoline compounds catalyzed by ruthenium

Abstract

The present application relates to the technical field of stereoselective monofluoroolefination of indolines at C7 position, in particular to a method for stereoselective C-H bond monofluoroolefination of indolines at C7 position catalyzed by ruthenium, comprising the following steps: under the action of a ruthenium catalyst and a base, carrying out C-H bond monofluoroolefination reaction of indolines represented by formula (I) with gem-difluoroalkenes represented by formula (II) or 3-(2,2-difluorovinyl)thiophene or 4-(2,2-difluorovinyl)benzo[d][1,3]dioxole to prepare compounds represented by formula (III). The present application uses inexpensive ruthenium catalyst, and through C-H bond activation / C-F bond cleavage, a series of Z-type alpha-monofluoroolefination pyridine indolines are obtained, and the method has strong site and stereoselectivity, is efficient and low in cost. In addition, the target compounds obtained by synthesis have certain antibacterial activity, and can provide a basis for the development of such lead compounds.

Description

Technical Field

[0001] This invention relates to the field of C7 selective monofluoroolefination technology for indoline compounds, and specifically to a ruthenium-catalyzed method for C7 stereoselective monofluoroolefination of indoline compounds. Background Technology

[0002] In recent years, chemists have been dedicated to introducing fluorine atoms or fluorine-containing groups (CF3, OCF3, monofluoroolefins, etc.) into small molecules, mainly because 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 due to their stereo and dipolar properties similar to amide bonds.

[0003] Currently, the construction of monofluoroolefins mainly employs transition metal-catalyzed CH bond activation. In 2015, Loh's group first reported a rhodium(III)-catalyzed pyrimidine-directed indole monofluoroolefination reaction. Nat. Commun (2015, 6, 7472). Since then, monofluoroolefination reactions catalyzed by cobalt(III), manganese(I), and ruthenium(II) have been reported. However, the activation site of this type of reaction is mainly at the C2 position of indole, and monofluoroolefination at the inert C7 position has not yet been studied.

[0004] Given the application value of indole compounds and monofluoroolefins in the fields of organic chemistry and medicinal chemistry, it is extremely necessary to develop an economical, efficient, site- and configuration-selective method for the monofluoroolefination of indole compounds. Summary of the Invention

[0005] To address the aforementioned technical problems, the present invention aims to provide a ruthenium-catalyzed method for the stereoselective monofluoroalkenylation of the C7-position of indoline compounds. This method uses inexpensive ruthenium as a catalyst, and through CH bond activation / CF bond cleavage, yields a series of Z-type monofluoroalkenylated indoline compounds. This method achieves, for the first time, the monofluoroalkenylation reaction at the C7 position of indoline compounds, with highly specific product configurations, providing an efficient, economical method for the monofluoroalkenylation of indoline compounds with good site and configuration selectivity. Furthermore, the synthesized target compounds exhibit certain antibacterial activity, with compounds 4p and 4q showing the best inhibitory effect against Staphylococcus aureus, providing a foundation for the development of such lead compounds.

[0006] To achieve the above objectives, embodiments of the present invention provide a ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position indoline compounds, comprising the following steps: Under the action of ruthenium catalyst and base, indoline of formula (I) and gem-difluoroolefin of formula (II) or 3-(2,2-difluorovinyl)thiophene or 4-(2,2-difluorovinyl)benzo[d][1,3]dioxane are subjected to CH bond monofluoroolefination reaction to obtain compound of formula (III).

[0007] Among them, R1, R2, and R3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, thiophene, and C6-C6, respectively. 14 Any of the aryl groups.

[0008] As some embodiments of the present invention, the ruthenium catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium(II).

[0009] As some embodiments of the present invention, the alkali is any one of cesium acetate, cesium carbonate, and sodium hydroxide.

[0010] As some embodiments of the present invention, the monofluoroolefination reaction is carried out in an organic solvent.

[0011] As some embodiments of the present invention, the organic solvent is any one of trifluoroethanol, hexafluoroisopropanol, and methanol.

[0012] As some embodiments of the present invention, the reaction conditions for the monofluoroolefination reaction are: a reaction temperature of 40°C to 100°C and a reaction time of 4 hours.

[0013] As some embodiments of the present invention, the molar ratio of indoline: geminofluoroolefin or 3-(2,2-difluorovinyl)thiophene or 4-(2,2-difluorovinyl)benzo[d][1,3]dioxane: dichlorobis(4-methylisopropylphenyl)ruthenium(II): base is 1:2:0.15:2.

[0014] As some embodiments of the present invention, the indoline class represented by formula (I) is selected from one of the following compounds:

[0015] As some embodiments of the present invention, the geminofluoroolefins or 3-(2,2-difluorovinyl)thiophene or 4-(2,2-difluorovinyl)benzo[d][1,3]dioxacyclopentene represented by formula (II) are selected from one of the following compounds:

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention uses relatively inexpensive ruthenium as a catalyst to obtain a series of Z-type monofluoroalkenylated indoline compounds through CH bond activation / CF bond cleavage. This method is the first to achieve C7-position monofluoroalkenylation of indoline compounds, and the product configuration exhibits high specificity, providing an efficient, economical method for C7-position monofluoroalkenylation of indoline compounds with good site and configuration selectivity.

[0017] 2. The method of the present invention has the advantages of being economical, easy to operate, high yield, wide substrate applicability, easy product separation and high product configuration specificity. Moreover, the synthesized compound exhibits certain antibacterial activity, which can provide a basis for the development of such lead compounds. Attached Figure Description

[0018] 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.

[0019] Figure 1 This is a schematic diagram of the synthesis route in an embodiment of the present invention; Figure 2 This is the hydrogen NMR spectrum of product 3a from Example 1 of the present invention.

[0020] Figure 3 This is the carbon NMR spectrum of product 3a from Example 1 of the present invention.

[0021] Figure 4 This is the NMR fluorine spectrum of product 3a from Example 1 of the present invention.

[0022] Figure 5 This is a high-resolution mass spectrum of product 3a from Example 1 of the present invention.

[0023] Figure 6 This is the 1H NMR spectrum of product 4b from Example 12 of the present invention.

[0024] Figure 7 This is the carbon NMR spectrum of product 4b from Example 12 of the present invention.

[0025] Figure 8 The NMR fluorine spectrum of product 4b from Example 12 of this invention is shown.

[0026] Figure 9 This is a high-resolution mass spectrum of product 4b from Example 12 of the present invention.

[0027] Figure 10 This is the 1H NMR spectrum of product 4e from Example 15 of the present invention.

[0028] Figure 11 This is the carbon NMR spectrum of product 4e from Example 15 of the present invention.

[0029] Figure 12 This is the NMR fluorine spectrum of product 4e from Example 15 of the present invention.

[0030] Figure 13 This is a high-resolution mass spectrum of product 4e from Example 15 of the present invention.

[0031] Figure 14 This is a schematic diagram of the X-ray single crystal of product 4e in Example 15 of the present invention. Detailed Implementation

[0032] 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.

[0033] 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.

[0034] 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.

[0035] The following embodiments of the present invention provide a method for the stereoselective monofluoroolefination of the C7-position of indoline compounds catalyzed by ruthenium, 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 indoline of formula (Ⅰ), gemini of formula (Ⅱ), 3-(2,2-difluorovinyl)thiophene or 4-(2,2-difluorovinyl)benzo[d][1,3]dioxane, ruthenium catalyst, base and organic solvent are added to the reaction vessel respectively. The reaction is carried out at 60 °C for 4 h. After the reaction is completed, the mixture is cooled to room temperature and the reaction solution is poured into a container containing water. The mixture is extracted with dichloromethane, the organic layer is collected and dried with anhydrous sodium sulfate, concentrated under vacuum, and purified and separated by silica gel column chromatography to prepare the corresponding Z-type monofluoroolefin pyridine indoline compound (the compound shown in formula (Ⅲ)).

[0036] Among them, R1, R2, and R3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, thiophene, and C6-C6, respectively. 14 Any of the aryl groups.

[0037] To better understand the above technical solution, the following detailed description of the specific implementation method is provided.

[0038] Example 1: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific method includes the following steps: 1-(2-pyridyl)indoline (Ⅰ-1a) (0.2 mmol), 4-bromostyrene geminitrofluorine (Ⅱ-2a) (0.4 mmol), dichlorobis(4-methylisopropylphenyl)ruthenium(II) (0.03 mmol), cesium acetate (0.4 mmol), and trifluoroethanol (2.0 mL) were added to a 10 mL thick-walled pressure-resistant tube. The tube was sealed and placed in an oil bath. The reaction was carried out at 60 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature and poured into a separatory funnel containing water. The mixture was extracted with dichloromethane (15 mL × 3). 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 = 40:1) to obtain a yellow solid with a yield of 90%.

[0039] The NMR spectra, NMR spectra, NMR spectra, and high-resolution mass spectra of the product obtained in Example 1 are as follows: Figure 2-5 As shown. The characterization data is as follows: 1 ¹H NMR (400 MHz, CDCl₃, ppm): δ 8.19 (dd, J 1 = 5.2 Hz, J 2 = 1.2 Hz,1H), 7.43−7.35 (m, 4H), 7.26 (d, J = 6.8 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.74−6.71 (m, 1H), 6.01(d, J = 39.2 Hz, 1H), 4.37 (t, J = 8.4 Hz, 2H), 3.18 (t, J = 8.4 Hz, 2H); 13 CNMR (100 MHz, CDCl3, ppm): δ 158.1 (d, 1J CF = 259.0 Hz), 156.2, 147.7, 142.0(d, 4 J CF = 2.2 Hz), 136.8, 135.3, 133.0 (d, 4 J CF = 3.1 Hz), 131.5 (2C), 130.2,130.1, 126.7 (d, 3 J CF = 6.2 Hz), 125.9, 121.9, 120.6 (d, 4 J CF = 3.5 Hz), 119.7(d, 2 J CF = 27.5 Hz), 116.3, 111.4, 107.3 (d, 3 J CF = 10.1 Hz), 53.6, 28.9; 19 FNMR (376 MHz, CDCl3, ppm): δ -104.33; HRMS (ESI): m / z [M+H] + calcd. forC 21 H 17 BrFN2: 395.0559; found: 395.0573 Based on the above data, the structure of the product can be inferred as follows: .

[0040] Example 2: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific methods and process parameters are the same as those in Example 1.

[0041] Example 3: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific methods and process parameters are the same as those in Example 1.

[0042] Example 4: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific methods and process parameters are the same as those in Example 1.

[0043] Example 5: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific methods and process parameters are the same as those in Example 1.

[0044] Example 6: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific methods and process parameters are the same as those in Example 1.

[0045] Example 7: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific methods and process parameters are the same as those in Example 1.

[0046] Example 8: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific methods and process parameters are the same as those in Example 1.

[0047] Example 9: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific methods and process parameters are the same as those in Example 1.

[0048] Example 10: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific methods and process parameters are the same as those in Example 1.

[0049] Example 11: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific methods and process parameters are the same as those in Example 1.

[0050] Example 12: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The specific method includes the following steps: 1-(2-pyridyl)indoline (Ⅰ-1a) (0.2 mmol), 4-methylstyrene-difluoro(Ⅱ-2a) (0.4 mmol), dichlorobis(4-methylisopropylphenyl)ruthenium(II) (0.03 mmol), cesium acetate (0.4 mmol), and trifluoroethanol (2.0 mL) were added to a 10 mL thick-walled pressure-resistant tube. The tube was sealed and placed in an oil bath. The reaction was carried out at 60 °C for 4 h. After the reaction was completed, the tube was cooled to room temperature. The reaction solution was poured into a separatory funnel containing saturated saline solution and extracted with dichloromethane (15 mL × 3). The organic layer was collected and dried over anhydrous sodium sulfate. The solution was concentrated under vacuum and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1) to obtain a black solid with a yield of 91%.

[0051] The NMR spectra, NMR spectra, NMR spectra, and high-resolution mass spectra of the product obtained in Example 12 are as follows: Figure 6-9 As shown. The characterization data is as follows: 1 ¹H NMR (400 MHz, CDCl₃, ppm): δ 8.23 (dd, J 1 = 4.8 Hz, J 2 = 1.2 Hz,1H), 7.43−7.40 (m, 2H), 7.26 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.01 (t, J = 7.6 Hz, 1H), 6.80 (d,J = 8.4 Hz, 1H),6.74−6.71 (m, 1H), 6.08 (d, J = 40.0 Hz, 1H), 4.41 (t, J =8.4 Hz, 2H), 3.17(t, J = 8.4 Hz, 2H), 2.31 (s, 3H); 13 C NMR (100 MHz, CDCl3, ppm): δ 156.9 (d, 1 J CF = 256.6 Hz), 156.1, 147.7, 141.8, 136.8, 136.7 (d, 4 J CF = 2.2 Hz), 135.4, 131.2 (d, 4 J CF = 3.0 Hz), 129.1 (2C), 128.6, 128.5, 126.7 (d, 3 J CF = 6.4 Hz),125.5, 122.0, 120.2 (d, 2 J CF = 27.9 Hz), 116.1, 111.4, 108.4 (d, 3 J CF = 10.2Hz), 53.6, 28.9, 21.3; 19 F NMR (376 MHz, CDCl3, ppm): δ -107.02; HRMS (ESI): m / z [M+H] + calcd. for C 22 H 19 FN2: 331.1611; found: 331.1617 Based on the above data, the structure of the product can be inferred as follows: .

[0052] Example 13: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0053] Example 14: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0054] Example 15: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific method and process parameters are the same as those in Example 12; the structure of the product 4e obtained in this example is... Its 1H NMR spectrum, 1C NMR spectrum, 1N NMR spectrum, high-resolution mass spectrum, and X-ray single crystal schematic diagram are as follows: Figure 10-14 As shown.

[0055] Example 16: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0056] Example 17: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0057] Example 18: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0058] Example 19: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0059] Example 20: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0060] Example 21: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0061] Example 22: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0062] Example 23: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0063] Example 24: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0064] Example 25: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12.

[0065] Example 26: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12, except for the type and equivalent of the alkali used (0.2 mmol cesium acetate and 0.2 mmol calcium hydroxide).

[0066] Example 27: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of geminofluoroolefins is as follows: The specific methods and process parameters are the same as those in Example 12, except for the type and equivalent of the alkali used (0.2 mmol cesium acetate and 0.2 mmol calcium hydroxide).

[0067] Example 28: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of 3-(2,2-difluorovinyl)thiophene is: The specific methods and process parameters are the same as those in Example 12, except for the type and equivalent of the alkali used (0.2 mmol cesium acetate and 0.2 mmol calcium hydroxide).

[0068] Example 29: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of 4-(2,2-difluorovinyl)benzo[d][1,3]dioxane is: The specific methods and process parameters are the same as those in Example 12.

[0069] Example 30: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The alkali used is cesium carbonate; the specific method and process parameters are the same as those in Example 1.

[0070] Example 31: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The alkali used is sodium hydroxide; the specific method and process parameters are the same as those in Example 1.

[0071] Example 32: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The organic solvent is hexafluoroisopropanol; the specific method and process parameters are the same as those in Example 1.

[0072] Example 33: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The organic solvent is methanol; the specific method and process parameters are the same as those in Example 1.

[0073] Example 34: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The reaction temperature was 40 °C; the specific method and process parameters were the same as those in Example 1.

[0074] Example 35: A ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position of indoline compounds, wherein the indoline structure is as follows: The structure of gemino-difluoroolefins is The reaction temperature was 100 °C; the specific method and process parameters were the same as those in Example 1.

[0075] Example 36: The antibacterial activity of target compounds (3a)–(3k) and (4b)–(4s) against Staphylococcus aureus was evaluated using the micro-broth dilution method; the specific steps are as follows: Dissolve each target compound in sterile DMSO, and add bacterial solution (5 × 10⁻⁶) to the well with the highest concentration. 5 Add 100 μL of the analyte compound at a concentration of 160.0 μM (CFU / mL) to each of the two wells, and add 100 μL of bacterial culture (5 × 10⁻⁶ CFU / mL) to the remaining wells. 5The experiment involved serial dilutions of the compound (CFU / mL), with 100 μL added from each well to create gradients of 160.0 μM, 80.0 μM, 40.0 μM, 20.0 μM, 10.0 μM, and 5.0 μM. Three replicates were performed for each concentration. A positive control (amoxicillin) and a blank control (MHB broth only) were also included. The 96-well plate was incubated at 37 °C for 24 h, and the experiment was repeated three times. The minimum drug concentration that completely inhibited bacterial growth, as observed visually, was defined as the MIC value of the compound.

[0076] The above embodiments of the present invention mainly focus on the optimization of the conditions for monofluoroolefination reactions using indoline (1a) to (1k) as substrates and geminidinenes, 3-(2,2-difluorovinyl)thiophene, or 4-(2,2-difluorovinyl)benzo[d][1,3]dioxane (2a) to (2s) as coupling pairs via CH bond activation / CF bond cleavage, and the evaluation of the antibacterial activity of the synthesized target compounds against Staphylococcus aureus. The optimization of the above reaction conditions is shown in Tables 1-4, and the antibacterial activity is shown in Table 5.

[0077] Table 1. Optimization of Alkali

[0078] As shown in Table 1, after screening alkalis including cesium acetate, cesium carbonate, and sodium hydroxide, cesium acetate showed the best reaction yield (90%).

[0079] Table 2 Organic solvent optimization

[0080] As shown in Table 2, after screening organic solvents including trifluoroethanol, hexafluoroisopropanol, and methanol, the reaction yield was best when trifluoroethanol was used as the organic solvent (yield 90%).

[0081] Table 3 Optimization of Reaction Temperature

[0082] As shown in Table 3, after screening the reaction temperatures (40 ℃, 60 ℃, and 100 ℃), the reaction yield was best at a reaction temperature of 60 ℃ (yield of 90%).

[0083] The applicability of the ruthenium-catalyzed stereoselective CH bond monofluoroolefination method at the C7 position of indoline compounds to the substrates and coupling pairs is investigated, and the optimized conditions described above are verified. See Table 4 for details.

[0084] Table 4. Results of substrate suitability assessment

[0085] As can be seen from the results in Table 4, Examples 1 to 29 of the present invention, using indoline (1a) to (1k) as substrates and geminidin (2a) to (2s) as coupling pairs, can obtain a series of C7-position Z-type monofluoroolefin indoline compounds (yields of 75% to 95%) with excellent configuration specificity and yield through CH bond activation / CF bond cleavage.

[0086] Table 5 Evaluation of the antibacterial activity of the target compound against Staphylococcus aureus

[0087] As shown in Table 5, compounds 4p and 4q exhibited the best inhibitory effects against Staphylococcus aureus, providing a basis for the development of such lead compounds.

[0088] The above results demonstrate that the method of this invention has advantages such as being economical, easy to operate, having high yield, wide substrate applicability, easy product separation, and high product configuration specificity. In addition, the synthesized target compounds have certain antibacterial activity, among which compounds 4p and 4q have the best inhibitory effect on Staphylococcus aureus, which can provide a basis for the development of such lead compounds.

[0089] 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 ruthenium-catalyzed method for stereoselective monofluoroolefination of the C7-position indoline compounds, characterized in that, Includes the following steps: Under the action of ruthenium catalyst and base, pyridine indoline of formula (I) is reacted with gemdifluoroolefin of formula (II) or 3-(2,2-difluorovinyl)thiophene or 4-(2,2-difluorovinyl)benzo[d][1,3]dioxane to undergo CH bond monofluoroolefination reaction to obtain compound of formula (III). ； Among them, R1, R2, and R3 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, thiophene, and C6-C6, respectively. 14 Any of the aryl groups.

2. The method for stereoselective monofluoroolefination of C7-position indoline compounds catalyzed by ruthenium according to claim 1, characterized in that, The ruthenium catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium(II).

3. The method for stereoselective monofluoroolefination of C7-position indoline compounds catalyzed according to claim 1, characterized in that, The alkali is any one of cesium acetate, cesium carbonate, and sodium hydroxide.

4. The method for stereoselective monofluoroolefination of C7-CH bonds in ruthenium-catalyzed indoline compounds according to claim 1, characterized in that, The monofluoroolefination reaction is carried out in an organic solvent.

5. The method for stereoselective monofluoroolefination of C7-CH bonds in ruthenium-catalyzed indoline compounds according to claim 4, characterized in that, The organic solvent is any one of trifluoroethanol, hexafluoroisopropanol, and methanol.

6. The method for stereoselective monofluoroolefination of C7-position indoline compounds catalyzed according to claim 1, characterized in that, The reaction conditions for the monofluoroolefination reaction are: a reaction temperature of 40 ℃ to 100 ℃ and a reaction time of 4 h.

7. The method for stereoselective monofluoroolefination of C7-position indoline compounds catalyzed according to claim 2, characterized in that, The molar ratio of pyridine indoline (I) to gemdifluoroolefin (II) or 3-(2,2-difluorovinyl)thiophene or 4-(2,2-difluorovinyl)benzo[d][1,3]dioxane: dichlorobis(4-methylisopropylphenyl)ruthenium (II): base is 1:2:0.15:

2.

8. The method for stereoselective monofluoroolefination of C7-position indoline compounds catalyzed according to claim 1, characterized in that, The pyridine indoline class represented by formula (Ⅰ) is selected from one of the following compounds: 。 9. The method for stereospecific monofluoroolefination of C7-position indoline compounds catalyzed according to claim 1, characterized in that, The gemini or 3-(2,2-difluorovinyl)thiophene or 4-(2,2-difluorovinyl)benzo[d][1,3]dioxane represented by formula (II) is selected from one of the following compounds: 。 10. The method for stereoselective monofluoroolefination of C7-position indoline compounds catalyzed according to claim 2, characterized in that, After the monofluoroolefin reaction is completed, the mixture is cooled to room temperature and poured into a separatory funnel containing water or saturated saline solution. The mixture is then extracted with dichloromethane, the organic layer is collected and dried with anhydrous sodium sulfate, concentrated under vacuum, and then separated by silica gel column chromatography in a petroleum ether:ethyl acetate ratio of 20:1.

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