Synthetic method of 3-spirobutyl oxoindole compound containing trifluoromethyl

Abstract

The invention discloses a synthetic method of a 3-spirobutyl oxoindole compound containing trifluoromethyl, and belongs to the technical field of organic synthesis. According to the invention, under the action of visible light induction, a photocatalyst and alkali, CF3Br and N-aryl bicyclo [1.1. 0] butane-1-formamide are subjected to a free radical tandem cyclization reaction in an organic solvent, so that the 3-spirobutyl oxoindole compound containing trifluoromethyl is prepared. According to the invention, free radical series cyclization reaction of CF3Br and saturated carbon atoms, namely sp3 hybrid carbon atoms, is realized for the first time, and the variety of organic matters reacting with CF3Br is enriched. The preparation method provided by the invention provides a new path for synthesis of 3-spirobutyl oxindole containing trifluoromethyl, has the advantages of cheap and easily available raw materials, mild reaction conditions, simple operation, high product yield and the like, and accords with the concept of green synthesis.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and particularly relates to a method for synthesizing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups. Background Technology

[0002] Spirocycloindole is a common core skeleton in many natural alkaloids and drug molecules. Its derivatives not only exhibit anticancer, anti-inflammatory, and antibacterial biological activities, but are also frequently used as inhibitors, antimalarial drugs, and antagonists. To further improve the pharmacokinetic properties of these compounds, researchers have developed methods to introduce cyclobutane structural units into spirocycloindole molecules to precisely control their three-dimensional configuration and improve their metabolic stability, lipophilicity, permeability, and acid-base properties (reference: ChemMedChem. 2022, 17, e202200020.), thereby increasing the biological activity and efficacy of these compounds. For example, 3-spirocyclobutylindole compounds with the following A~C chemical structures:

[0003]

[0004] Studies have shown that compound A possesses antifungal activity (Reference: J. Am. Chem. Soc. 2006, 128, 1448-1449.); compound B can be used as a phosphodiesterase inhibitor for the treatment of Parkinson's disease (Reference: Biorg. Med. Chem. 2015, 23, 7138-7149.); and compound C is a bromine domain inhibitor that shows great potential in the treatment of tumors, inflammation, autoimmune diseases, and cardiovascular diseases (Reference: CN 107709298 A.). Therefore, exploring synthetic methods for these compounds is of great significance.

[0005] Regarding the synthesis of 3-spirocyclobutyl indole compounds, besides metal-catalyzed CH activation / coupling and [2+2] cycloaddition reactions (reference: Org. Chem. Front., 2021, 8, 1026-1084.), recently reported methods mainly use N-arylbicyclo[1.1.0]butane-1-carboxamide derivatives as starting materials, reacting these compounds with various free radical precursors to prepare various functionalized 3-spirocyclobutyl indole compounds (a total of 6 papers). The specific methods are as follows:

[0006] (I) Oxidant oxidation strategy: This involves generating free radicals under the action of an oxidant, which then undergo a free radical tandem cyclization reaction with an N-arylbicyclo[1.1.0]butane-1-carboxamide derivative to yield 3-spirocyclobutyl-oxidized indole compounds (2 references: Org. Chem. Front., 2024, 26, 6486-6490 and Org. Lett. 2024, 26, 6486-6490). The drawbacks of this synthetic method are the requirement for stoichiometric oxidants, which are primarily unstable and explosive peroxide compounds, and the demanding reaction conditions: the reaction must be carried out at high temperatures.

[0007] (II) Visible light irradiation strategy: Free radicals are generated under visible light induction, and then these free radicals undergo a radical tandem cyclization reaction with an N-arylbicyclo[1.1.0]butane-1-carboxamide derivative to obtain 3-spirocyclobutylindole oxide compounds (two references: Org. Lett. 2024, 26, 2073-2078 and Org. Lett. 2025, 27, 11027-11032). The advantages of this synthetic method are mild reaction conditions, simple operation, avoidance of unstable peroxide compounds, and relative safety, classifying it as a green synthesis. For example:

[0008] In 2024, Li Jinheng's research group reported a photoredox-catalyzed radical tandem cyclization reaction of N-arylbicyclo[1.1.0]butane-1-carboxamide derivatives with α-carbonylalkyl bromides, yielding functionalized 3-spirocyclobutylindole with up to three all-carbon quaternary carbon centers with moderate to excellent diastereoselectivity (dr = 1:1 to >20:1) (Org. Lett. 2024, 26, 2073-2078). This study confirmed that various primary, secondary, and tertiary α-bromoalkyl esters, ketones, nitriles, and nitro compounds can participate in the reaction as radical precursors, with the highest reaction yield reaching 93%. The drawbacks of this method are the use of the high-boiling-point solvent N,N-dimethylformamide (DMF), the need for an inert gas atmosphere, and the requirement to heat the reaction to 70 °C (note: reactions under visible light irradiation are generally carried out at room temperature). The reaction route is as follows:

[0009] .

[0010] Trifluoromethyl is a common fluorine-containing group. Introducing trifluoromethyl groups into organic compounds can significantly alter the chemical, physical, and biological properties of the parent compound, such as acidity / basicity, bioavailability, lipid solubility, and protein binding ability. Therefore, trifluoromethyl compounds have been widely used in the fields of medicine, pesticides, and materials science. In new drug design, introducing trifluoromethyl groups into drug molecules can significantly alter the drug's acidity / basicity, increase its metabolic stability and pharmacokinetic properties, and improve its absorption by the body, thus enhancing efficacy. Therefore, chemists have also attempted to introduce trifluoromethyl groups into 3-spirocyclobutylindole compounds, and two papers have been published on this topic, as follows:

[0011] In 2024, Hari's group developed a visible light irradiation strategy, using Togni reagent as a trifluoromethyl radical source, to synthesize trifluoromethylated spirocyclobutyl indole compounds under mild conditions via ring strain-driven radical spirocyclization (Org. Lett. 2024, 26, 6396-6401), with yields ranging from 48% to 78% and diastereomer ratios (dr values) between 1.6:1 and 2:1. The drawbacks of this synthetic method are that only four target products were synthesized, and the trifluoromethyl reagent (Togni reagent) used is expensive and has low atom utilization. The reaction route is as follows:

[0012] .

[0013] In 2025, Maji's research group developed a photoelectrochemical co-catalysis strategy, using sodium trifluoromethanesulfinate as the trifluoromethyl radical source, to synthesize trifluoromethylated spirocyclobutylindole via a tandem cyclization reaction of an N-arylbicyclo[1.1.0]butane-1-carboxamide derivative and a trifluoromethyl radical, achieving yields of 45%–73% and moderate diastereoselectivity (dr = 1:1–1:3) (Org. Lett. 2025, 27, 11788-11793). This method is characterized by requiring both visible light irradiation and electrochemical conditions, and features a short reaction time. The reaction route is as follows:

[0014] .

[0015] In summary, two strategies—oxidation with oxidizing agents and visible light irradiation—have been developed to successfully synthesize 3-spirocyclobutylindole oxides. For the synthesis of 3-spirocyclobutylindole oxides containing trifluoromethyl groups, the visible light irradiation strategy is primarily used, the difference lying in the trifluoromethyl reagent employed. These are described below:

[0016] 1) Togni reagent, namely 1-(trifluoromethyl)-1,2-benzyl-3(1H)-one reagent (structural formula is...) )

[0017] The biggest drawback of this trifluoromethyl reagent is its extremely high price: approximately 2965.9 yuan / 100g (manufacturer: Shanghai Aladdin Biochemical Technology Co., Ltd.). This reagent requires a multi-step reaction synthesis and is not easily obtained directly. (Note: This reagent is obtained by reacting trifluorobromomethane (CF3Br) with trimethylchlorosilane (Me3SiCl) and o-iodobenzoic acid; references: Org. Process. Res. Dev. 2020, 24, 470-480; Chem. Rev. 2015, 115, 650-682. Its synthetic route is as follows:) Another drawback of this reagent is its low atom utilization rate, which does not conform to the principle of atom economy. During the reaction, in addition to generating the useful trifluoromethyl radical, the Togni reagent molecule also produces a large organic byproduct (i.e., o-iodobenzoic acid), leading to insufficient atom utilization. Furthermore, using this reagent also causes problems such as complex post-reaction processing and difficulties in product separation, thus hindering its industrial-scale synthetic application.

[0018] 2) Sodium trifluoromethanesulfonate (CF3SO2Na)

[0019] The commercial price of CF3SO2Na is approximately 1765 RMB / kg (manufacturer: Shanghai Haohong Biomedical Technology Co., Ltd.). Although its price is significantly lower than that of Togni reagent, it is still at a relatively high level. Furthermore, this reagent still requires a multi-step reaction for synthesis, and its source is relatively limited, making it difficult to obtain directly. (Note: This reagent is obtained by reacting trifluorobromomethane (CF3Br) with Na2S2O4; see Inorg. Chem. 1993, 32, 5007–5010. The synthetic route is as follows:) ).

[0020] Therefore, developing a new method for preparing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups using inexpensive raw materials remains of great significance.

[0021] On the other hand, trifluorobromomethane is a non-toxic, odorless gas with stable chemical properties and is inexpensive and readily available. In modern industry, trifluorobromomethane is mainly used as a refrigerant, fire extinguishing agent (Halon-1301), and etching material. In organic synthesis, besides being used as a reagent for synthesizing trifluoromethyl compounds, trifluorobromomethane is also an upstream raw material for preparing many common trifluoromethyl reagents, especially expensive ones such as Togni reagent, Umemoto reagent, and Langlois (sodium trifluoromethanesulfonate) reagent. Furthermore, compared to the aforementioned trifluoromethyl reagents, the greatest advantages of using trifluorobromomethane as a trifluoromethyl reagent are its low cost, ease of acquisition, high atom economy, and greater potential for industrial-scale production. Using trifluorobromomethane as a trifluoromethylating agent, although various methods have been developed to introduce trifluoromethyl groups into organic molecules (reference: review article Chin. J. Org. Chem. 2022, 42, 353-362), current research mainly focuses on the interaction of trifluorobromomethane with unsaturated carbon atoms (i.e., sp...). 2 Reactions of trifluorobromomethane with sp-hybridized carbon atoms (such as alkenes, aromatics, and alkynes) and sp-hybridized carbon atoms (i.e., sp-hybridized carbon atoms) 3 Reactions of hybrid carbon atoms, such as those in bicyclic compounds, have not yet been reported. Summary of the Invention

[0022] To address the aforementioned technical problems, this invention proposes a method for synthesizing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups.

[0023] To achieve the above objectives, the present invention provides the following technical solution:

[0024] This invention provides a method for synthesizing a 3-spirocyclobutyl indole compound containing trifluoromethyl, comprising the following steps: under visible light induction, photocatalysis and base action, CF3Br and N-arylbicyclo[1.1.0]butane-1-carboxamide undergo a free radical tandem cyclization reaction in an organic solvent, and after the reaction is completed, the 3-spirocyclobutyl indole compound containing trifluoromethyl is obtained;

[0025] The base is selected from inorganic weak acid strong base salts or organic weak acid strong base salts.

[0026] The organic solvent is a non-polar solvent;

[0027] The molar ratio of the N-arylbicyclo[1.1.0]butane-1-carboxamide to the base is 1.0:(1.5~2.0). The amount of base has a significant effect on the reaction yield. When the molar ratio of N-arylbicyclo[1.1.0]butane-1-carboxamide to the base is 1.0:1.0, the yield is not high (Comparative Example 3, yield is only 31%); when the amount of base is increased to a molar ratio of 1.0:1.5, the reaction yield is significantly improved (Example 1, yield is 78%). This shows that the molar ratio of N-arylbicyclo[1.1.0]butane-1-carboxamide to the base is crucial for this reaction, and its amount is appropriate.

[0028] The amount of photocatalyst used is 1.5 mol% to 2.5 mol% of the amount of N-arylbicyclo[1.1.0]butane-1-carboxamide. The amount of photocatalyst also significantly affects the reaction yield. When the amount of photocatalyst is 1.0 mol% of the amount of the raw material (i.e., the N-arylbicyclo[1.1.0]butane-1-carboxamide), the reaction yield is low (Comparative Example 4, yield is only 32%), which may be because the amount of photocatalyst is too small to maintain the catalytic cycle of the reaction. When the amount of photocatalyst is increased to 1.5 mol% of the amount of the raw material, the reaction yield is significantly improved (Example 1, yield is 78%). When the amount of photocatalyst is further increased to 2.5 mol% of the amount of the raw material, the reaction yield decreases (Example 10, yield is 55%). This may be due to excessive catalyst usage. While maintaining the catalytic cycle of the reaction, it may also cause some side reactions such as the self-coupling reaction of free radicals, leading to a decrease in yield. These results indicate that photocatalysts are indispensable for this reaction, but their usage must still be controlled within a certain range.

[0029] The visible light power was 5W. The intensity of visible light irradiation also affected the reaction. When the reaction was carried out under blue light irradiation with a power of 5W, the reaction yield was the highest (Example 1, yield 78%). When the intensity of visible light was increased, i.e., the reaction was carried out under blue light irradiation with a power of 10W, the reaction yield decreased significantly (Comparative Example 5, yield only 34%). This may be because increasing the intensity of visible light irradiation accelerates the excitation-catalysis cycle of the photocatalyst. However, it also causes the breaking of chemical bonds at multiple sites in the reactant molecules, making the reaction very complex and seriously affecting the formation of the target product.

[0030] This invention utilizes CF3Br as a trifluoromethyl reagent. Under visible light induction, photocatalysis, and the presence of a base, CF3Br undergoes a radical tandem cyclization reaction with N-arylbicyclo[1.1.0]butane-1-carboxamide. This not only provides a novel trifluoromethyl radical source for the synthesis of 3-spirocyclobutylindole containing trifluoromethyl groups, but also develops a new method for the construction of this type of compound. Compared with other commonly used trifluoromethyl reagents in the prior art, CF3Br has the following significant advantages: low price, easy availability (commercial price approximately 80 RMB / kg, manufacturer: Shanghai Zhongfu Chemical Technology Co., Ltd.), high atom utilization, and convenient storage and transportation, providing good feasibility for subsequent industrial synthesis. Simultaneously, this invention achieves for the first time the reaction of CF3Br with sp... 3 The free radical tandem cyclization reaction of hybrid carbon atoms has enriched the variety of organic compounds that react with CF3Br.

[0031] Furthermore, the general structural formula of the N-arylbicyclo[1.1.0]butane-1-carboxamide is as follows:

[0032]

[0033] Among them, R 1 Selected from methyl or benzyl, R 2 Selected from hydrogen, methyl, or halogen.

[0034] Furthermore, R 1 Selected from -CH3 or -Bn, R 2 Selected from H, 4-CH3, or 4-F, i.e., N-arylbicyclo[1.1.0]butane-1-carboxamide is selected from N-methyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide, N-methyl-N-(4-methylphenyl)bicyclo[1.1.0]butane-1-carboxamide, N-methyl-N-(4-fluorophenyl)bicyclo[1.1.0]butane-1-carboxamide, or N-benzyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide.

[0035] Furthermore, the pressure during the free radical tandem cyclization reaction is 1.0 atm, meaning that CF3Br is a gas, and the pressure of the system after introducing CF3Br gas is 1.0 atm.

[0036] Furthermore, the base is selected from one of K2CO3, Na2CO3, and CH3COONa, preferably K2CO3. The type of base has a significant impact on the reaction yield. When a non-salt organic weak base (such as 1,4-diazabicyclo[2.2.2]octane (DABCO)) is used, the reaction is difficult to occur, and the product yield is very low (Comparative Example 1, yield is only 28%). When an organic weak acid strong base salt (such as CH3COONa) is used, the reaction can occur, and the product yield is also improved (Example 6, yield is 40%). When an inorganic weak acid strong base salt (such as Na2CO3) is used, the reaction yield is also improved (Example 5, yield is 41%). When an inorganic weak acid strong base salt (such as K2CO3) is used, the reaction yield is the highest (Example 1, yield is 78%). Therefore, K2CO3 can be used as the optimal base for the reaction of this invention.

[0037] Furthermore, the organic solvent is selected from tetrahydrofuran (THF), 1,4-dioxane, and acetonitrile (CH3CN). THF has a dielectric constant of approximately 7.6 (25°C), which is higher than that of nonpolar solvents (such as hexane, dielectric constant ≈2) but lower than that of strongly polar solvents (such as DMSO, dielectric constant 47.2), classifying it as a moderately polar solvent. 1,4-dioxane is a weakly polar solvent with a relatively low dielectric constant (approximately 2.3, 25°C), approaching the range of nonpolar solvents. CH3CN has a high dielectric constant of 37.5 (25°C), classifying it as a polar solvent. The polarity of the solvent also affects the reaction. When the reaction is carried out in a strongly polar solvent such as DMSO, the reaction is extremely unfavorable, resulting in very low product yields (Comparative Example 2, yield only 19%). However, when the reaction is carried out in a relatively strongly polar solvent such as acetonitrile, the reaction proceeds smoothly, and the product yield is improved (Example 9, yield 51%), indicating that reducing the polarity of the solvent is beneficial to the reaction. Further reducing the solvent polarity to a moderately polar solvent such as tetrahydrofuran also improves the product yield (Example 8, yield 55%). The highest yield is achieved when the reaction is carried out in a less polar 1,4-dioxane solvent (Example 1, yield 78%). All these experimental results indicate that weakly polar solvents are more favorable for the reaction, while strongly polar solvents are very unsuitable. Therefore, the weakly polar 1,4-dioxane can be considered the optimal solvent for the reaction of this invention.

[0038] Furthermore, the photocatalyst is tris(2-phenylpyridine)iridium(fac-Ir) III (ppy)3).

[0039] Furthermore, the visible light is blue light with a wavelength of 390 nm to 460 nm.

[0040] Furthermore, the temperature of the free radical tandem cyclization reaction is room temperature (25±2℃), and the time of the free radical tandem cyclization reaction is 12~24h, preferably 24h.

[0041] Furthermore, after the free radical tandem cyclization reaction is completed, a column chromatography separation process is also included.

[0042] Furthermore, the eluent used in column chromatography is a mixed solution of petroleum ether (PE) and ethyl acetate (EA) in a volume ratio of (20~6):1.

[0043] Furthermore, the structural formula of the 3-spirocyclobutyl indole compound containing trifluoromethyl groups is as follows:

[0044]

[0045] Among them, R 1 Selected from methyl (-CH3) or benzyl (-Bn), R 2 It is selected from hydrogen (H), methyl or halogen.

[0046] Furthermore, R 1 Selected from -CH3 or -Bn, R 2 The compounds are selected from H, 4-CH3, or 4-F, meaning that the 3-spirocyclobutyl oxide indole compounds containing trifluoromethyl groups are selected from the following compounds: 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one, 1',5'-dimethyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one, 1'-methyl-5'-fluoro-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one, or 1'-benzyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one.

[0047] Compared with the prior art, the present invention has the following advantages and technical effects:

[0048] (1) This invention is the first to apply trifluorobromomethane (CF3Br) to the construction of 3-spirocyclobutylindole compounds containing trifluoromethyl groups. Compared with other trifluoromethyl reagents used in the prior art, the greatest advantage of using CF3Br as a trifluoromethyl reagent in this invention is its stable chemical properties, low price, easy availability, high atom utilization, and ease of transportation and storage, making it more suitable for industrial-scale synthetic applications.

[0049] (2) This invention is the first to realize the reaction of CF3Br with saturated carbon atoms (i.e., sp... 3 The free radical tandem cyclization reaction of hybrid carbon atoms has enriched the variety of organic compounds that react with CF3Br.

[0050] (3) The synthesis method developed in this invention has simple reaction steps, high atom economy, simple operation, mild reaction conditions and high yield. The reaction is carried out under visible light induction and does not require the use of traditional high-risk reagents, which is in line with the development trend of green synthesis.

[0051] (4) The 3-spirocyclobutyl indole compounds containing trifluoromethyl groups synthesized in this invention were analyzed by nuclear magnetic resonance (NMR) 1 HNMR, 13 C NMR, 19 The product obtained by detection and analysis by ¹H NMR and high-resolution mass spectrometry is a pure target compound with high purity, which meets the requirements of subsequent applications.

[0052] (5) The 3-spirocyclobutylindoxo compound containing trifluoromethyl synthesized in this invention can be used to prepare candidate drugs for antifungal, antitumor, anti-inflammatory and treatment of Parkinson's disease, autoimmune diseases and cardiovascular diseases, and exert excellent effects. Attached Figure Description

[0053] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

[0054] Figure 1 The 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) synthesized in Example 1 1 H NMR spectrum;

[0055] Figure 2 The 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) synthesized in Example 1 13 C NMR spectrum;

[0056] Figure 3 The 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) synthesized in Example 1 19 F NMR spectrum;

[0057] Figure 4 This is a high-resolution mass spectrometry monitoring image of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) synthesized in Example 1;

[0058] Figure 5 The 1',5'-dimethyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3b) synthesized in Example 2 1 H NMR spectrum;

[0059] Figure 6 The 1',5'-dimethyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3b) synthesized in Example 2 13 C NMR spectrum;

[0060] Figure 7 The 1',5'-dimethyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3b) synthesized in Example 2 19 F NMR spectrum;

[0061] Figure 8 This is a high-resolution mass spectrometry monitoring image of 1',5'-dimethyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3b) synthesized in Example 2;

[0062] Figure 9 The 1'-methyl-5'-fluoro-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3c) synthesized in Example 3 1 H NMR spectrum;

[0063] Figure 10 The 1'-methyl-5'-fluoro-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3c) synthesized in Example 3 13 C NMR spectrum;

[0064] Figure 11 The 1'-methyl-5'-fluoro-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3c) synthesized in Example 3 19 F NMR spectrum;

[0065] Figure 12 This is a high-resolution mass spectrometry (HMS) image of 1'-methyl-5'-fluoro-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3c) synthesized in Example 3;

[0066] Figure 13 The 1'-benzyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3d) synthesized in Example 4 1 H NMR spectrum;

[0067] Figure 14 The 1'-benzyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3d) synthesized in Example 4 13 C NMR spectrum;

[0068] Figure 15 The 1'-benzyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3d) synthesized in Example 4 19 F NMR spectrum;

[0069] Figure 16 This is a high-resolution mass spectrometry (HMS) image of 1'-benzyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3d) synthesized in Example 4. Detailed Implementation

[0070] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0071] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0072] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0073] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0074] Embodiments of the present invention provide a method for synthesizing 3-spirocyclobutyl oxidized indole compounds containing trifluoromethyl groups, the synthetic route of which is as follows:

[0075]

[0076] Among them, R 1 Selected from -CH3 or -Bn, R 2 Selected from H, 4-CH3, or 4-F;

[0077] Specifically, the steps include: adding N-arylbicyclo[1.1.0]butane-1-carboxamide 1 (1 equiv), and the photocatalyst fac-Ir... III(ppy)3 (1.5 mol%~2.5 mol%, representing the molar percentage of photocatalyst in N-arylbicyclo[1.1.0]butane-1-carboxamide), base (one of K2CO3, Na2CO3 and CH3COONa, 1.5~2.0 equiv), and organic solvent (one of tetrahydrofuran, 1,4-dioxane and acetonitrile, 3 mL) were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF3Br gas, repeated three to six times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from a barometer). The reaction mixture was placed under blue light with a wavelength of 390 nm to 460 nm and a power of 5 W, and stirred at room temperature for 12 to 24 h. After the reaction was completed, the solvent was evaporated, and the mixture was purified by column chromatography using silica gel as the stationary phase and petroleum ether and ethyl acetate as eluents (PE:EA = (20~6):1, volume ratio) to obtain 3-spirocyclobutyl indole compounds containing trifluoromethyl groups.

[0078] The reaction principle of the method of the present invention is as follows (taking the synthesis of compound 3a in a specific embodiment as an example):

[0079]

[0080] First, under visible light irradiation, the ground-state photocatalyst fac-Ir... III (ppy)3 absorbs energy and transitions to the excited state fac-Ir. III (ppy)3*, through single-electron transfer (SET), reduces CF3Br to generate a trifluoromethyl radical and a bromide anion, while simultaneously, the excited-state fac-Ir III (ppy)3* is oxidized to a tetravalent iridium complex fac-Ir. IV (ppy)3; Next, the trifluoromethyl radical undergoes radical addition to N-methyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide (compound 1a) to generate a cyclic carbon radical intermediate A; the carbon atom with a single electron in this radical intermediate A can attack the benzene ring in either a cis or anti-articulation manner (i.e., syn- or anti-attack), i.e., an intramolecular radical cyclization reaction occurs to generate carbon radical intermediate B, which is then subjected to fac-Ir IV (ppy)3 is oxidized to the carbocation intermediate C, while the tetravalent iridium complex fac-Ir is formed. IV (ppy)3 was reduced to the trivalent iridium catalyst fac-Ir. III(ppy)3 proceeds to the next catalytic cycle reaction; finally, in the presence of a base, the carbocation intermediate C undergoes deprotonation to form the target product 3a.

[0081] 3-Spirocycloindole is a class of compounds with broad biological activities. Its structural skeleton is the core skeleton of many natural products and drug molecules, playing a crucial role in drug discovery and the pharmaceutical industry. To further improve the pharmacokinetic properties of these compounds, researchers have developed a method of introducing cyclobutane, including oxygen or aziridine structural units, into indole molecules to construct novel 3-spirocycloindole derivatives, namely four-membered ring 3-spirocycloindole. The aim is to improve the physicochemical properties of indole and increase the biological activity and efficacy of these compounds by precisely controlling their three-dimensional configuration. Four-membered ring spirocycloindole, such as 3-spirocyclobutylindole and 3-spirooxa- or aziridine-butylindole, have been shown to possess antifungal, antitumor, antiviral, and anti-inflammatory activities, and have been used as phosphodiesterase inhibitors, RSV inhibitors, and bromine domain inhibitors (Reference: Org. Chem. Front., 2021, 8, 1026-1084.). Based on the properties of trifluoromethyl compounds, introducing a trifluoromethyl group into a four-membered ring 3-spirocyclobutyl indole molecule can alter the acidity, basicity, lipophilicity, and bioavailability of these compounds, making them more readily absorbed by the body and improving efficacy (J. Chem. Inf. Model. 2020, 60, 6242-6250). Therefore, the 3-spirocyclobutyl indole containing trifluoromethyl groups prepared in this invention can be used as a candidate drug for the preparation of antifungal, antitumor, anti-inflammatory, and therapeutic applications in Parkinson's disease, autoimmune diseases, and cardiovascular diseases, exhibiting excellent effects.

[0082] For example, studies have shown that 3-spirocyclobutylindole has a certain antagonistic effect on progesterone receptors (Bioorg. Med. Chem. Lett. 2002, 12, 3487-3490). Introducing a trifluoromethyl group into this type of compound, by adjusting its acidity, alkalinity, lipid solubility, membrane permeability, and bioavailability, could potentially increase the antagonistic effect of 3-spirocyclobutylindole on progesterone receptors and enhance therapeutic efficacy. Therefore, the 3-spirocyclobutylindole containing a trifluoromethyl group prepared in this invention can be used as a progesterone receptor antagonist.

[0083] Unless otherwise specified, the room temperature in this invention is 25±2℃.

[0084] In the following examples and comparative examples of the present invention, the diastereomeric ratio (dr) of the compounds is based on the ratio of the diastereomeric compounds obtained by column chromatography. 19Determined by F NMR spectral analysis.

[0085] The raw materials used in the embodiments and comparative examples of this invention were synthesized according to known literature. As an example, the main raw materials N-methyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide, N-methyl-N-(4-methylphenyl)bicyclo[1.1.0]butane-1-carboxamide, N-methyl-N-(4-fluorophenyl)bicyclo[1.1.0]butane-1-carboxamide and N-benzyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide were all synthesized according to the method in the literature (Org. Lett. 2024, 26, 2073-2078.).

[0086] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention.

[0087] The technical solution of the present invention will be further illustrated by the following embodiments.

[0088] Example 1 Synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a)

[0089] The synthesis route is as follows:

[0090]

[0091] The specific synthesis process is as follows:

[0092] N-methyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide (37 mg, 0.2 mmol, 1.0 equiv), fac-Ir III (ppy)3 (1.96 mg, 1.5 mol%), K2CO3 (41.5 mg, 0.3 mmol, 1.5 equiv), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF3Br gas, repeated three times. Finally, the gas pressure in the Schlenk flask was maintained at 1.0 atm (observed from a barometer). The reaction mixture was placed under 5W (390 nm~460 nm) blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography. 1'-Methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) was obtained as a white solid, 40.0 mg, yield 78%, dr value 1.6:1.

[0093] The synthesized 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) was subjected to... 1 HNMR, 13 CNMR, 19 FNMR and high-resolution mass spectrometry detection (such as FNMR and high-resolution mass spectrometry detection) Figure 1-4 As shown in the figure, it can be concluded that the product is a pure target compound. The corresponding characterization data of the product are as follows:

[0094] 1 H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 19.6, 6.8 Hz, 1H), 7.33 – 7.26(m, 1H), 7.13 (t, J = 6.4 Hz, 1H), 6.85 – 6.80 (m, 1H), 3.58 – 3.31 (m, 1H), 3.2 (s, 3H), 7.13 (t, J = 10.8 Hz, 1H), 2.67 – 2.57 (m, 2H), 2.34 (t, J = 9.6Hz, 1H).

[0095] 13 C { 1 H} NMR (150 MHz, CDCl3) 180.0, 177.4, 143.3, 143.2, 133.1,131.7, 128.6, 128.4, 126.9 (q, J C-F = 274.1 Hz), 126.3 (q, J C-F = 274.7 Hz),122.9, 122.9, 122.8, 121.6, 108.1, 107.8, 44.2, 43.9, 43.3, 43.1, 32.6 (q,J C-F = 32.0 Hz), 31.2 (q, J C-F = 31.5 Hz), 30.8 (q, J C-F = 3.2 Hz), 30.7 (q, J C-F = 3.6 Hz), 26.3, 26.1.

[0096] 19 F NMR (376 MHz, CDCl3) δ -73.80 (d, J = 7.90 Hz), -74.23 (d, J =8.65 Hz);

[0097] HRMS (ESI): m / z calcd for C 13 H 13 ONF3 [M + H] + 256.0944, found 256.0943.

[0098] Example 2 Synthesis of 1',5'-dimethyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3b)

[0099] The synthesis route is as follows:

[0100]

[0101] The specific synthesis process is as follows:

[0102] N-methyl-N-(4-methylphenyl)bicyclo[1.1.0]butane-1-carboxamide (40.3 mg, 0.2 mmol, 1.0 equiv), fac-Ir III (ppy)3 (1.96 mg, 1.5 mol%), K2CO3 (41.5 mg, 0.3 mmol, 1.5 equiv), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then purged with CF3Br gas, repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from a barometer). The reaction mixture was placed under 5 W (390 nm~460 nm) blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=7:1) to give 1',5'-dimethyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3b): white solid, 29.8 mg, yield 74%, dr value 1.2:1.

[0103] The synthesized 1',5'-dimethyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3b) was subjected to... 1 H NMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry detection (such as F NMR and high-resolution mass spectrometry detection) Figure 5-8 As shown in the figure, the results indicate that the product is a pure target compound. The corresponding characterization data of the product are as follows:

[0104] 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 27.6 Hz, 1H), 7.09 (t, J = 13.6Hz, 1H), 6.73 – 6.67 (m, 1H), 3.56 – 3.31 (m, 1H), 3.17 (s, 3H), 2.92 (t, J =10.0 Hz, 1H), 2.64 – 2.54 (m, 2H), 2.38 (s, 3H), 3.35 – 3.28 (m, 1H);

[0105] 13 C { 1 H} NMR (150 MHz, CDCl3) δ 179.9, 177.2, 140.8, 140.6, 133.0,132.4, 132.2, 131.7, 128.7, 128.5, 126.8 (q, J C-F = 274.0 Hz), 126.2 (q, J C-F =274.5 Hz), 123.7, 122.4, 107.7, 107.4, 43.2, 43.1, 32.5 (q, J C-F = 31.8 Hz), 31.1 (q, J C-F = 31.3 Hz), 30.7 (q, J C-F = 3.3 Hz), 30.6 (q, J C-F = 3.6 Hz),26.2, 26.0, 20.9, 20.9, 0.9, 0.8;

[0106] 19 F NMR (376 MHz, CDCl3) δ -73.79 (d, J = 8.27 Hz), -74.18 (d, J =9.02 Hz);

[0107] HRMS (ESI): m / z calcd for C 14 H 15 ONF3 [M + H] + 270.1100, found 270.1099.

[0108] Example 3 Synthesis of 1'-methyl-5'-fluoro-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3c)

[0109] The synthesis route is as follows:

[0110]

[0111] The specific synthesis process is as follows:

[0112] N-methyl-N-(4-fluorophenyl)bicyclo[1.1.0]butane-1-carboxamide (41.1 mg, 0.2 mmol, 1.0 equiv), fac-Ir III (ppy)3 (1.96 mg, 1.5 mol%), K2CO3 (41.5 mg, 0.3 mmol, 1.5 equiv), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF3Br gas, repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from a barometer). The reaction mixture was placed under 5 W (390 nm~460 nm) blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=8:1) to give 1'-methyl-5'-fluoro-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3c): white solid, 31.7 mg, yield 58%, dr value 1.5:1.

[0113] The synthesized 1'-methyl-5'-fluoro-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3c) was subjected to... 1 H NMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry detection (such as F NMR and high-resolution mass spectrometry detection) Figure 9-12 As shown in the figure, the results indicate that the product is a pure target compound. The corresponding characterization data of the product are as follows:

[0114] 1 H NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 22.0 Hz, 7.6 Hz, 1H), 7.03 –6.96 (m, 1H), 6.76 – 6.70 (m, 1H), 3.56 – 3.2 (m, 1H), 3.19 (s, 3H), 2.95 (t,J = 10.8 Hz, 1H), 2.69 – 2.53 (m, 2H), 2.34 (t,J = 10.0 Hz, 1H);

[0115] 13 C {1 H} NMR (150 MHz, CDCl3) δ 179.7, 177.1, 160.3 (d, J C-F = 26.0Hz), 158.7 (d, J C-F = 25.7 Hz), 139.2 (d, J C-F = 2.0 Hz), 139.1 (d, J C-F = 2.0Hz), 134.5 (d, J C-F = 7.8 Hz), 133.3 (d, J C-F = 8.0 Hz), 126.8 (q, J C-F = 274.1Hz), 126.2 (q, J C-F = 274.7 Hz), 114.8 (d, J C-F = 23.4 Hz), 114.5 (d, J C-F =23.1 Hz), 111.2 (d, J C-F = 24.6 Hz), 110.0 (d, J C-F = 24.8 Hz), 108.5 (d, J C-F =8.1 Hz), 108.3 (d, J C-F = 8.0 Hz), 44.1, 43.7, 43.6, 43.5, 32.5 (d, J C-F = 32.1Hz), 31.2 (d, J C-F = 31.5 Hz), 30.7 (d, J C-F = 3.5 Hz), 30.6 (d, J C-F = 3.6 Hz),26.4, 26.3;

[0116] 19 F NMR (376 MHz, CDCl3) δ -73.87 (d, J = 8.27 Hz), -74.32 (d, J =9.02 Hz), -119.98 (m), -120.27 (m);

[0117] HRMS (ESI): m / z calcd for C 13 H 12 ONF4 [M + H] +274.0850, found 274.0846.

[0118] Example 4 Synthesis of 1'-benzyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3d)

[0119] The synthesis route is as follows:

[0120]

[0121] The specific synthesis process is as follows:

[0122] N-benzyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide (52.7 mg, 0.2 mmol, 1.0 equiv), fac-Ir III (ppy)3 (1.96 mg, 1.5 mol%), K2CO3 (41.5 mg, 0.3 mmol, 1.5 equiv), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF3Br gas, repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from a barometer). The reaction mixture was placed under 5 W (390 nm~460 nm) blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=12:1) to give 1'-benzyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3d): white solid, 45.7 mg, yield 69%, dr value 1:1.

[0123] The synthesized 1'-benzyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3d) was subjected to... 1 HNMR, 13 C NMR, 19 F NMR and high-resolution mass spectrometry monitoring (such as F NMR and high-resolution mass spectrometry monitoring) Figure 13-16 As shown in the figure, the results indicate that the product is a pure target compound. The corresponding characterization data of the product are as follows:

[0124] 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 18.8, 7.6 Hz, 1H), 7.34 – 7.24(m, 5H), 7.22 – 7.16 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.73 (dd, J = 16.0,7.6 Hz, 1H), 4.90 (d, J = 3.6 Hz, 2H), 3.63 – 3.43 (m, 1H), 3.05 – 3.00 (m,1H), 2.74 – 2.62 (m, 2H), 2.43 – 2.37 (m, 1H);

[0125] 13 C { 1 H} NMR (150 MHz, CDCl3) δ 180.2, 177.6, 142.4, 142.3, 135.7,135.7, 133.1, 131.7, 128.8, 128.7, 128.5, 128.3, 127.6, 127.6, 127.4, 127.2,126.9 (q, J C-F = 274.1 Hz), 126.5 (q, J C-F = 274.4 Hz), 123.0, 122.9, 122.8,121.8, 109.1, 108.8, 44.4, 44.1, 44.0, 43.7, 43.3, 43.1, 32.5 (d, J C-F = 32.0Hz), 31.3 (d, J C-F = 31.4 Hz), 31.0 (d, J C-F = 3.9 Hz), 30.9 (d, J C-F = 3.6 Hz);

[0126] 19 F NMR (376 MHz, CDCl3) δ -73.79 (d, J = 7.90 Hz), -74.20 (d, J =8.65 Hz);

[0127] HRMS (ESI): m / z calcd for C 19 H 17 ONF3 [M + H] + 332.1257, found 332.1257.

[0128] Example 5

[0129] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from that in Example 1 in that the base K2CO3 (41.5 mg, 0.3 mmol, 1.5 equiv) was replaced with Na2CO3 (31.8 mg, 0.3 mmol, 1.5 equiv). All other process steps and parameters were the same as in Example 1, yielding 20.9 mg of white solid 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) with a yield of 41% and a dr value of 1.6:1.

[0130] Example 6

[0131] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from that in Example 1 in that the base K2CO3 (41.5 mg, 0.3 mmol, 1.5 equiv) was replaced with CH3COONa (24.6 mg, 0.3 mmol, 1.5 equiv). All other process steps and parameters were the same as in Example 1, yielding 20.4 mg of white solid 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) in yield of 40% and dr value of 1.6:1.

[0132] Example 7

[0133] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from that in Example 1 in that the molar ratio of N-methyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide and base was replaced with 1.0:2.0 instead of 1.0:1.5. All other process steps and parameters were the same as in Example 1, yielding 20.9 mg of white solid 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) with a yield of 41% and a dr value of 1.6:1.

[0134] Example 8

[0135] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from that in Example 1 in that the solvent 1,4-dioxane was replaced with tetrahydrofuran (THF). All other process steps and parameters were the same as in Example 1, yielding 28.1 mg of white solid 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) with a yield of 55% and a dr value of 1.6:1.

[0136] Example 9

[0137] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from that in Example 1 in that the solvent 1,4-dioxane was replaced with acetonitrile (CH3CN). All other process steps and parameters were the same as in Example 1, yielding 26.0 mg of white solid 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) with a yield of 51% and a dr value of 1.6:1.

[0138] Example 10

[0139] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from that in Example 1 in that the amount of photocatalyst was replaced from 1.5 mol% to 2.5 mol%. All other process steps and parameters were the same as in Example 1. 28.1 mg of white solid 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) was obtained, with a yield of 55% and a dr value of 1.6:1.

[0140] Example 11

[0141] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from that in Example 1 in that the reaction time was adjusted from 24 h to 12 h, while other process steps and parameters were the same as in Example 1. 33.2 mg of white solid 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) was obtained, with a yield of 65% and a dr value of 1.6:1.

[0142] Comparative Example 1

[0143] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from that in Example 1 in that the base K2CO3 (41.5 mg, 0.3 mmol, 1.5 equiv) was replaced with a non-salt organic weak base 1,4-diazabicyclo[2.2.2]octane (DABCO) (33.7 mg, 0.3 mmol, 1.5 equiv). All other process steps and parameters were the same as in Example 1, yielding 14.3 mg of a white solid 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a), with a yield of 28% and a dr value of 1.6:1. It can be seen that compared to Example 1, the yield was significantly reduced by simply changing the base to a non-salt organic weak base 1,4-diazabicyclo[2.2.2]octane.

[0144] Comparative Example 2

[0145] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from that in Example 1 in that the solvent 1,4-dioxane was replaced with dimethyl sulfoxide (DMSO). All other process steps and parameters were the same as in Example 1, yielding 10.0 mg of a white solid, 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a), with a yield of 19% and a dr value of 1.6:1. It can be seen that compared to Example 1, the yield was significantly reduced by simply changing the solvent to the highly polar solvent DMSO.

[0146] Comparative Example 3

[0147] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from Example 1 in that the molar ratio of N-methyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide to the base was replaced from 1.0:1.5 to 1.0:1.0. All other process steps and parameters were the same as in Example 1, yielding 15.8 mg of a white solid, 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a), with a yield of 31% and a dr value of 1.6:1. It can be seen that compared to Example 1, the yield was significantly reduced by simply changing the molar ratio of N-arylbicyclo[1.1.0]butaneamide to the base to 1.0:1.0.

[0148] Comparative Example 4

[0149] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from Example 1 in that the amount of photocatalyst was replaced from 1.5 mol% to 1.0 mol%. All other process steps and parameters were the same as in Example 1, yielding 16.3 mg of a white solid, 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a), with a yield of 32% and a dr value of 1.6:1. It can be seen that compared to Example 1, the yield was significantly reduced by simply changing the amount of photocatalyst to 1.0 mol%.

[0150] Comparative Example 5

[0151] The synthesis of 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a) differed from Example 1 in that the light source was replaced with 10 W blue light instead of 5 W. All other process steps and parameters remained the same as in Example 1, yielding 17.3 mg of a white solid, 1'-methyl-3-(trifluoromethyl)spiro[cyclobutane-1,3'-indoline]-2'-one (3a), with a yield of 34% and a dr value of 1.6:1. It can be seen that compared to Example 1, the yield was significantly reduced by simply changing the light source to 10 W blue light.

[0152] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing a 3-spirocyclobutyl indole compound containing trifluoromethyl groups, characterized in that, The process includes the following steps: under visible light induction, photocatalysis and alkaline action, CF3Br and N-arylbicyclo[1.1.0]butane-1-carboxamide undergo a free radical tandem cyclization reaction in an organic solvent, and after the reaction is completed, the 3-spirocyclobutyl oxide indole compound containing trifluoromethyl is obtained; The base is selected from inorganic weak acid strong base salts or organic weak acid strong base salts. The organic solvent is a non-polar solvent; The molar ratio of the N-arylbicyclo[1.1.0]butane-1-carboxamide to the base is 1:(1.5~2.0); The amount of the photocatalyst used is 1.5 mol% to 2.5 mol% of the amount of N-arylbicyclo[1.1.0]butane-1-carboxamide used. The power of the visible light is 5W.

2. The method for synthesizing 3-spirocyclobutylindole compounds containing trifluoromethyl groups according to claim 1, characterized in that, The general structural formula of the N-arylbicyclo[1.1.0]butane-1-carboxamide is as follows: Among them, R 1 Selected from methyl or benzyl, R 2 Selected from hydrogen, methyl, or halogen.

3. The method for synthesizing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups according to claim 2, characterized in that, The N-arylbicyclo[1.1.0]butane-1-carboxamide is selected from N-methyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide, N-methyl-N-(4-methylphenyl)bicyclo[1.1.0]butane-1-carboxamide, N-methyl-N-(4-fluorophenyl)bicyclo[1.1.0]butane-1-carboxamide or N-benzyl-N-phenylbicyclo[1.1.0]butane-1-carboxamide.

4. The method for synthesizing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups according to claim 1, characterized in that, The pressure for the free radical tandem cyclization reaction is 1.0 atm.

5. The method for synthesizing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups according to claim 1, characterized in that, The alkali is selected from one of K2CO3, Na2CO3 and CH3COONa.

6. The method for synthesizing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups according to claim 1, characterized in that, The organic solvent is selected from one of tetrahydrofuran, 1,4-dioxane, and acetonitrile.

7. The method for synthesizing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups according to claim 1, characterized in that, The photocatalyst is tris(2-phenylpyridine)iridium.

8. The method for synthesizing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups according to claim 1, characterized in that, The visible light is blue light with a wavelength of 390 nm to 460 nm.

9. The method for synthesizing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups according to claim 1, characterized in that, The free radical tandem cyclization reaction was carried out at room temperature for 12-24 hours.

10. The method for synthesizing 3-spirocyclobutyl indole compounds containing trifluoromethyl groups according to claim 1, characterized in that, The structural formula of the 3-spirocyclobutyl indole compound containing trifluoromethyl groups is as follows: Among them, R 1 Selected from methyl or benzyl, R 2 Selected from hydrogen, methyl, or halogen.

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